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Office of Neuroscience Research > Resources and Facilities > WUSTL Neuroscience Publications for the week > Weekly Neuroscience Publications - Archives > WUSTL Neuroscience Publications Archive - October 2012

WUSTL Neuroscience Publications Archive - October 2012

Scopus Weekly Report:

October 31, 2012

October 24, 2012

October 17, 2012

October 10, 2012

October 3, 2012

 

October 31, 2012

Cheung, T.H.C.a b , Nolan, B.C.a b e , Hammerslag, L.R.a b f , Weber, S.M.a b , Durbin, J.P.c , Peartree, N.A.a b , MacH, R.H.c , Luedtke, R.R.d , Neisewander, J.L.a b
Phenylpiperazine derivatives with selectivity for dopamine D3 receptors modulate cocaine self-administration in rats
(2012) Neuropharmacology, 63 (8), pp. 1346-1359. 

a School of Life Sciences, Arizona State University, P.O. Box 874501, Tempe, AZ 85287-4501, United States
b Psychology, Arizona State University, P.O. Box 871104, Tempe, AZ 85287-1104, United States
c Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, United States
d Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, United States
e Quincy University, Division of Behavioral and Social Sciences, 1800 College Ave., Quincy, IL 62301, United States
f Neuroscience Program, University of Illinois Urbana-Champaign, 603 E. Daniel St., Champaign, IL 61820, United States

Abstract
This study examined cocaine self-administration after pretreatments with three structurally related compounds that bind selectively to dopamine D3 receptors (D3Rs) relative to the D2 receptor subtype (D2Rs) and exhibit varying intrinsic activities in the forskolin-stimulated adenylyl cyclase assay. The compounds are: a) WC10, a D3R weak partial agonist/antagonist with 42-fold D3R:D2R selectivity, b) WC26, a 51-fold selective D3R partial agonist, c) WC44, a 23-fold selective D3R agonist. Rats were stabilized on a multiple variable-interval 60-s (VI60) schedule with alternating components of sucrose (45 mg pellets) or cocaine reinforcement (0.375 mg/kg, IV) and then tested for effects of the WC compounds (0.0, 1.0, 3.0, 5.6, or 10.0 mg/kg, IP). Another cohort was trained to self-administer cocaine (0.75 mg/kg, IV) on a VI60 schedule then tested with various doses of cocaine available (0.0-1.5 mg/kg, IV) following pretreatment with WC10 (5.6 or 10.0 mg/kg) or WC44 (10.0 mg/kg). WC10 and WC26 decreased both cocaine and sucrose reinforcement rates at the 10.0 mg/kg dose, whereas WC44 decreased only cocaine reinforcement rate at this dose. Furthermore, WC26 and WC44 increased response latency for cocaine but not sucrose. In the cocaine dose-response experiment, WC10 and WC44 flattened the dose-effect function of cocaine reinforcement rate. All compounds decreased spontaneous locomotion. WC10 and WC26 also reduced cocaine-induced locomotion. These results support the targeting of D3Rs for treatments for cocaine dependence. WC26 and WC44, in particular, show promise as they increased the latency to respond for cocaine but not sucrose, suggesting selective reduction of the motivation for cocaine. © 2012 Elsevier Ltd. All rights reserved.

Author Keywords
Cocaine addiction;  D3 dopamine receptors;  D3 selective compound;  Self-administration

Document Type: Article
Source: Scopus

 

Chen, H.-J.a , Balan, S.b , Price, R.K.b
Association of Contextual Factors with Drug Use and Binge Drinking among White, Native American, and Mixed-Race Adolescents in the General Population
(2012) Journal of Youth and Adolescence, 41 (11), pp. 1426-1441. 

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

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

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

Document Type: Article
Source: Scopus

 

Piasecki, T.M.a b , Alley, K.J.a , Slutske, W.S.a b , Wood, P.K.a b , Sher, K.J.a b , Shiffman, S.c , Heath, A.C.b d
Low sensitivity to alcohol: Relations with hangover occurrence and susceptibility in an ecological momentary assessment investigation
(2012) Journal of Studies on Alcohol and Drugs, 73 (6), pp. 925-932. 

a Department of Psychological Sciences, University of Missouri, Columbia, MO, United States
b Midwest Alcoholism Research Center, St. Louis and Columbia, MO, United States
c Smoking Research Group, University of Pittsburgh, Pittsburgh, PA, United States
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective: The current investigation tested whether low sensitivity to alcohol, as measured by the Self-Rating of the Effects of Alcohol (SRE) form, is associated with hangover occurrence or resis- tance, two potentially important predictors of later problematic drinking outcomes. Method: Drinkers who reported using alcohol at least four times in the past month (N = 402) completed the SRE at baseline and used ecological momentary assessment methods with an electronic di- ary to record drinking behaviors and related experiences over 21 days. Each morning, the diary assessed prior-night drinking behaviors and the presence of current hangover. Results: After adjustments for sex, body weight, age, and smoking status, higher SRE scores (indicating lower alcohol sensitivity) predicted hangover occurrence on postdrink- ing mornings (odds ratio [OR] = 1.24 per interquartile range [IQR], p =.003). However, when the number of drinks consumed in the drink- ing episode was covaried, SRE scores were negatively associated with hangover (OR = 0.67 per IQR, p <.001). An interaction between SRE scores and the number of drinks consumed indicated that low-sensitivity drinkers tend to be differentially resistant to hangover at a given number of drinks. Higher SRE scores were associated with consuming more drinks on average (generalized estimating equations coefficient = 2.20 per IQR, p <.001). Conclusions: Individuals lower in alcohol sensitivity appear to be more resistant to hangovers per unit of alcohol. However, they are also more likely to engage in excessive drinking, and this may account for their increased odds of experiencing hangover during an arbitrary monitoring period. Heavy consumption, hangover resistance, and hangover frequency may each be manifestations of low sensitivity to alcohol, an established risk factor for alcohol use disorder.

Document Type: Article
Source: Scopus

 

Fernandez, K.C., Levinson, C.A., Rodebaugh, T.L.
Profiling: Predicting social anxiety from facebook profiles
(2012) Social Psychological and Personality Science, 3 (6), pp. 706-713. 

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

Abstract
Research on Facebook has suggested that individuals' profiles are an accurate portrayal of the self and that it may be possible to identify traits such as narcissism and extraversion by viewing a Facebook profile. It has been suggested, however, that largely internal experiences, such as anxiety, should be less detectable in such contexts. In the current study, the authors tested if objective criteria (e.g., number of interests) on users' profiles (N = 62) could discriminate between individuals who were higher and lower in social anxiety. The authors asked six coders to view each participant's Facebook profile and rate the participant's level of social anxiety and then tested whether these ratings correlated with the participant's own self-reported social anxiety level. Our results suggest that social anxiety is recognizable both in objective criteria on the Facebook profile page and from raters' impressions of the Facebook profile. Clinical and research implications are discussed. © The Author(s) 2012.

Author Keywords
anxiety;  assessment;  internet/cyberpsychology;  psychopathology;  social anxiety;  social identity

Document Type: Article
Source: Scopus

 

Rosenberger, E.M.a , Dew, M.A.b c d e , DiMartini, A.F.b f g , DeVito Dabbs, A.J.h , Yusen, R.D.i
Psychosocial Issues Facing Lung Transplant Candidates, Recipients and Family Caregivers
(2012) Thoracic Surgery Clinics, 22 (4), pp. 517-529. 

a Department of Clinical and Translational Science, School of Medicine, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA 15213, United States
b Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811O'Hara Street, Pittsburgh, PA 15213, United States
c Department of Psychology, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA 15213, United States
d Department of Epidemiology, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA 15213, United States
e Department of Biostatistics, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA 15213, United States
f Department Surgery, School of Medicine, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA 15213, United States
g Starzl Transplant Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
h Department of Acute and Tertiary Care, School of Nursing, University of Pittsburgh, 3500 Victoria Street, Pittsburgh, PA 15261, United States
i Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8052, St Louis, MO 63110, United States

Abstract
Although lung transplantation is an accepted treatment for many individuals with severe lung disease, transplant candidates and recipients experience a range of psychosocial stressors that begin at the initiation of the transplant evaluation and continue throughout patients' wait for donor lungs, their perioperative recovery, and their long-term adjustment to posttransplant life. Transplant programs should strive to incorporate evidence-based interventions that aim to improve physical functioning, psychological distress, global quality of life, and medical adherence as well as to integrate symptom management and palliative care strategies throughout the pre- and posttransplantation course. © 2012 Elsevier Inc.

Author Keywords
Lung transplantation;  Psychological stressors;  Psychosocial factors;  Quality of life

Document Type: Review
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, 73 (5), pp. 391-397. 

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, United States
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.

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

Document Type: Article
Source: Scopus

 

Foster, E.R.a c d , Golden, L.a , Duncan, R.P.b , Earhart, G.M.b c e
Community-Based Argentine Tango Dance Program Is Associated With Increased Activity Participation Among Individuals With Parkinson's Disease

 

(2012) Archives of Physical Medicine and Rehabilitation, . Article in Press. 

a Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO
b Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO
c Department of Neurology, Washington University School of Medicine, St. Louis, MO
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO
e Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO

Abstract
Foster ER, Golden L, Duncan RP, Earhart GM. Community-based Argentine tango dance program is associated with increased activity participation among individuals with Parkinson's disease. Objective: To determine the effects of a 12-month community-based tango dance program on activity participation among individuals with Parkinson's disease (PD). Design: Randomized controlled trial with assessment at baseline, 3, 6, and 12 months. Setting: Intervention was administered in the community; assessments were completed in a university laboratory. Participants: Volunteers with PD (n=62) enrolled in the study and were randomized to a treatment group; 10 participants did not receive the allocated intervention, and therefore the final analyzed sample included 52 participants. Interventions: Participants were randomly assigned to the tango group, which involved 12 months of twice-weekly Argentine tango dance classes, or to the no intervention control group (n=26 per group). Main Outcome Measure: Current, new, and retained participation in instrumental, leisure, and social activities, as measured by the Activity Card Sort (with the dance activity removed). Results: Total current participation in the tango group was higher at 3, 6, and 12 months compared with baseline (Ps≤.008), while the control group did not change (Ps≥.11). Total activity retention (since onset of PD) in the tango group increased from 77% to 90% (P=.006) over the course of the study, whereas the control group remained around 80% (P=.60). These patterns were similar in the separate activity domains. The tango group gained a significant number of new social activities (P=.003), but the control group did not (P=.71). Conclusions: Individuals with PD who participated in a community-based Argentine tango class reported increased participation in complex daily activities, recovery of activities lost since the onset of PD, and engagement in new activities. Incorporating dance into the clinical management of PD may benefit participation and subsequently quality of life for this population. © 2012 the American Congress of Rehabilitation Medicine.

Author Keywords
Exercise;  Parkinson disease;  Quality of life;  Rehabilitation;  Social participation

Document Type: Article in Press
Source: Scopus

 

Ceyhan, E.a , Beg, M.F.b , Ceritoglu, C.c , Wang, L.d , Morris, J.C.e f , Csernansky, J.G.d g , Miller, M.I.c g , Ratnanather, J.T.c g
Metric distances between hippocampal shapes indicate different rates of change over time in nondemented and demented subjects
(2012) Current Alzheimer Research, 9 (8), pp. 972-981. 

a Dept. of Mathematics, Koç University, Rumelifeneri Yolu, 34450 Sariyer, Istanbul, Turkey
b School of Engineering Science, Simon Fraser University, Burnaby, V5A 1S6, Canada
c Center for Imaging Science, The Johns Hopkins University, Baltimore, MD 21218, United States
d Dept. of Psychiatry and Behavioral Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, United States
e Dept. of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
f Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
g Institute for Computational Medicine, The Johns Hopkins University, Baltimore, MD 21218, United States

Abstract
In this article, we use longitudinal morphometry (shape and size) measures of hippocampus in subjects with mild dementia of Alzheimer type (DAT) and nondemented controls in logistic discrimination. The morphometric measures we use are volume and metric distance measures at baseline and follow-up (two years apart from baseline). Morphometric differences with respect to a template hippocampus were measured by the metric distance obtained from the large deformation diffeomorphic metric mapping (LDDMM) algorithm. LDDMM assigns metric distances on the space of anatomical images, thereby allowing for the direct comparison and quantization of morphometric changes. We also apply principal component analysis (PCA) on volume and metric distance measures to obtain principal components that capture some salient aspect of morphometry. We construct classifiers based on logistic regression to distinguish diseased and healthy hippocampi (hence potentially diagnose the mild form of DAT). We consider logistic classifiers based on volume and metric distance change over time (from baseline to follow-up), on the raw volumes and metric distances, and on principal components from various types of PCA analysis. We provide a detailed comparison of the performance of these classifiers and guidelines for their practical use. Moreover, combining the information conveyed by volume and metric distance measures by PCA can provide a better biomarker for detection of dementia compared to volume, metric distance, or both. © 2012 Bentham Science Publishers.

Author Keywords
Computational anatomy;  Dementia of Alzheimer Type;  Hippocampus;  Large deformation diffeomorphic metric mapping (LDDMM);  Logistic discrimination;  Morphometry;  Principal component analysis

Document Type: Article
Source: Scopus

 

Wang, J.-C.a , Foroud, T.b , Hinrichs, A.L.a , Le, N.X.H.a , Bertelsen, S.a , Budde, J.P.a , Harari, O.a , Koller, D.L.b , Wetherill, L.b , Agrawal, A.a , Almasy, L.c , Brooks, A.I.d , Bucholz, K.a , Dick, D.e , Hesselbrock, V.f , Johnson, E.O.g , Kang, S.h , Kapoor, M.a , Kramer, J.i , Kuperman, S.j , Madden, P.A.F.a , Manz, N.h , Martin, N.G.k , McClintick, J.N.j , Montgomery, G.W.k , Nurnberger Jr, J.I.k , Rangaswamy, M.h , Rice, J.a , Schuckit, M.l , Tischfield, J.A.c , Whitfield, J.B.k , Xuei, X.j , Porjesz, B.h , Heath, A.C.a , Edenberg, H.J.j m , Bierut, L.J.a , Goate, A.M.a
A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53
(2012) Molecular Psychiatry, . Article in Press. 

a Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA
b Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
c Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
d Department of Genetics, Rutgers University, Piscataway, NJ, USA
e Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA
f Department of Psychiatry, University of Connecticut Health Center, Farmington, CT, USA
g Division of Health, Social and Economic Research, Research Triangle Institute International, Research Triangle Park, NC, USA
h Henri Begleiter Neurodynamics Laboratory, Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY, USA
i Department of Psychiatry, University of Iowa College of Medicine, Iowa City, IA, USA
j Division of Child Psychiatry, University of Iowa Hospitals, Iowa City, IA, USA
k Queensland Institute of Medical Research, Queensland, Australia
l Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
m 1] Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

Abstract
Several studies have identified genes associated with alcohol-use disorders (AUDs), but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism to identify novel genes affecting risk for alcohol dependence (AD). To maximize the power of the extended family design, we used a quantitative endophenotype, measured in all individuals: number of alcohol-dependence symptoms endorsed (symptom count (SC)). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with SC were also associated with the dichotomous phenotype, DSM-IV AD. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol-dependence symptom counts (P=4.5 × 10 -8, inflation-corrected P=9.4 × 10 -7). Results with DSM-IV AD in the regions of interest support our findings with SC, although the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: nonoverlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian Twin Family Study of AUDs (OZALC). Nominal association of C15orf53 with SC was observed in SAGE. The variant that showed strongest association with SC, rs12912251 and its highly correlated variants (D′=1, r 2≥ 0.95), have previously been associated with risk for bipolar disorder.Molecular Psychiatry advance online publication, 23 October 2012; doi:10.1038/mp.2012.143.

Document Type: Article in Press
Source: Scopus

 

Galli, M.
Diplopia following cosmetic surgery
(2012) American Orthoptic Journal, 62 (1), pp. 19-21. 

Department 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
Cosmetic blepharoplasty is the most often performed procedure in plastic surgery and ophthalmic plastic surgery. Many complications have been reported including ectropion, exposure keratitis, hemorrhage, epiphora, infection, vision loss, and, very rarely, diplopia. Although uncommon, there have been several case reports and case series published evaluating possible causes of this problem, including aggressive excision of fat, wound- related infl ammation, conjunctival edema, and temporary muscle disturbances. Although the inferior oblique muscle is most susceptible to injury, the inferior rectus and superior oblique muscles are also subject to trauma. When performing cosmetic blepharoplasties, surgeons should be cautious when dissecting fat pads and should do so under direct visualization. Meticulous cautery is also important to avoiding injury to the extraocular muscles. Fresnel prisms and Bangerter fi lters can be used to help alleviate diplopia in patients with small- angle strabismus. Surgical exploration and extraocular muscle surgery may be indicated in patients with diplopia that cannot be resolved with nonsurgical treatment. © 2012 Board of Regents of the University of Wisconsin System, American Orthoptic Journal, Volume 62, 2012, ISSN 0065- 955X, E-ISSN 1553- 4448.

Author Keywords
Cosmetic blepharoplasty;  Diplopia;  Strabismus

Document Type: Conference Paper
Source: Scopus

 

Peng, G.H., Chen, S.
Revealing looping organization of mammalian photoreceptor genes using chromosome conformation capture (3C) assays.
(2012) Methods in molecular biology (Clifton, N.J.), 884, pp. 305-318. 

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

Abstract
Chromosome conformation capture (3C) is a biochemical assay to reveal higher order chromosomal organizations mediated by physical contact between discrete DNA segments in vivo. Chromosomal organizations are involved in transcriptional regulation of a number of genes in various cell types. We have adapted 3C for analyzing the intrachromosomal looping organization of rod and cone photoreceptor genes in the mammalian retina. Here, we describe a detailed protocol for 3C assays on whole mouse retinas. Using the M-cone opsin gene as an example, we demonstrate how to genetically distinguish 3C signals from cones versus rods in retinal 3C assays. We also describe the challenges and key points of 3C design and performance as well as appropriate controls and result interpretations.

Document Type: Article
Source: Scopus

 

Rao, R.C.a , Dlouhy, B.J.b
Exposure to fireworks and eye injuries
(2012) JAMA - Journal of the American Medical Association, 308 (15), pp. 1523-1524. 

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

Document Type: Letter
Source: Scopus

 

Liu, Q.a b d , Sikand, P.c , Ma, C.c , Tang, Z.a b , Han, L.a , Li, Z.a , Sun, S.a , LaMotte, R.H.c , Dong, X.a b
Mechanisms of itch evoked by β-alanine

 

(2012) Journal of Neuroscience, 32 (42), pp. 14532-14537. 

a The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
b Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
c Department of Anesthesiology, Yale University School of Medicine, New Haven, CT 06520, United States
d The Center for the Study of Itch, Departments of Anesthesiology, Washington University, St. Louis, MO 63130, United States

Abstract
β-alanine, a popular supplement for muscle building, induces itch and tingling after consumption, but the underlying molecular and neural mechanisms are obscure. Here we show that, in mice, β-alanine elicited itch-associated behavior that requires MrgprD, a G-protein-coupled receptor expressed by a subpopulation of primary sensory neurons. These neurons exclusively innervate the skin, respond to β-alanine, heat, and mechanical noxious stimuli but do not respond to histamine. In humans, intradermally injected β-alanine induced itch but neither wheal nor flare, suggesting that the itch was not mediated by histamine. Thus, the primary sensory neurons responsive toβ-alanine are likely part of a histamine-independent itch neural circuit and a target for treating clinical itch that is unrelieved by anti-histamines. © 2012 the authors.

Document Type: Article
Source: Scopus

 

Sanchez, P.E.a b , Zhu, L.a b , Verret, L.a b , Vossel, K.A.a b , Orr, A.G.a b , Cirrito, J.R.c , Devidze, N.a , Ho, K.a , Yu, G.-Q.a , Palop, J.J.a b , Mucke, L.a b
Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model
(2012) Proceedings of the National Academy of Sciences of the United States of America, 109 (42), pp. E2895-E2903. 

a Gladstone Institute of Neurological Disease, San Francisco, CA 94158, United States
b Department of Neurology, University of California, San Francisco, CA 94158, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
In light of the rising prevalence of Alzheimer's disease (AD), new strategies to prevent, halt, and reverse this condition are needed urgently. Perturbations of brain network activity are observed in AD patients and in conditions that increase the risk of developing AD, suggesting that aberrant network activity might contribute to AD-related cognitive decline. Human amyloid precursor protein (hAPP) transgenic mice simulate key aspects of AD, including pathologically elevated levels of amyloid-β peptides in brain, aberrant neural network activity, remodeling of hippocampal circuits, synaptic deficits, and behavioral abnormalities. Whether these alterations are linked in a causal chain remains unknown. To explore whether hAPP/amyloid-β-induced aberrant network activity contributes to synaptic and cognitive deficits, we treated hAPP mice with different antiepileptic drugs. Among the drugs tested, only levetiracetam (LEV) effectively reduced abnormal spike activity detected by electroencephalography. Chronic treatment with LEV also reversed hippocampal remodeling, behavioral abnormalities, synaptic dysfunction, and deficits in learning and memory in hAPP mice. Our findings support the hypothesis that aberrant network activity contributes causally to synaptic and cognitive deficits in hAPP mice. LEV might also help ameliorate related abnormalities in people who have or are at risk for AD.

Author Keywords
Dementia;  Epilepsy;  Hyperexcitability;  Plasticity;  Therapy

Document Type: Article
Source: Scopus

 

Tielbeek, J.J.a , Medland, S.E.a , Benyamin, B.a , Byrne, E.M.a , Heath, A.C.b , Madden, P.A.F.b , Martin, N.G.a , Wray, N.R.a , Verweij, K.J.H.a c
Unraveling the Genetic Etiology of Adult Antisocial Behavior: A Genome-Wide Association Study
(2012) PLoS ONE, 7 (10), art. no. e45086, . 

a Genetic Epidemiology, Molecular Epidemiology, and Queensland Statistical Genetics Laboratories, Queensland Institute of Medical Research, Brisbane, QLD, Australia
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c School of Psychology, University of Queensland, Brisbane, QLD, Australia

Abstract
Crime poses a major burden for society. The heterogeneous nature of criminal behavior makes it difficult to unravel its causes. Relatively little research has been conducted on the genetic influences of criminal behavior. The few twin and adoption studies that have been undertaken suggest that about half of the variance in antisocial behavior can be explained by genetic factors. In order to identify the specific common genetic variants underlying this behavior, we conduct the first genome-wide association study (GWAS) on adult antisocial behavior. Our sample comprised a community sample of 4816 individuals who had completed a self-report questionnaire. No genetic polymorphisms reached genome-wide significance for association with adult antisocial behavior. In addition, none of the traditional candidate genes can be confirmed in our study. While not genome-wide significant, the gene with the strongest association (p-value = 8.7×10 -5) was DYRK1A, a gene previously related to abnormal brain development and mental retardation. Future studies should use larger, more homogeneous samples to disentangle the etiology of antisocial behavior. Biosocial criminological research allows a more empirically grounded understanding of criminal behavior, which could ultimately inform and improve current treatment strategies. © 2012 Tielbeek et al.

Document Type: Article
Source: Scopus

 

Fox, I.K.a b , Brenner, M.J.c d , Johnson, P.J.a b , Hunter, D.A.a b , MacKinnon, S.E.a b
Axonal regeneration and motor neuron survival after microsurgical nerve reconstruction
(2012) Microsurgery, 32 (7), pp. 552-562. 

a Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, Box 8328, 660 South Euclid Avenue, Saint Louis, MO 63110, United States
b Department of Surgery, Washington University School of Medicine, Saint Louis, MO, United States
c Division of Otolaryngology-Head and Neck Surgery, Southern Illinois University School of Medicine, Springfield, IL, United States
d Department of Surgery, Southern Illinois University School of Medicine, Springfield, IL, United States

Abstract
Rodent models are used extensively for studying nerve regeneration, but little is known about how sprouting and pruning influence peripheral nerve fiber counts and motor neuron pools. The purpose of this study was to identify fluctuations in nerve regeneration and neuronal survival over time. One hundred and forty-four Lewis rats were randomized to end-to-end repair or nerve grafting (1.5 cm graft) after sciatic nerve transection. Quantitative histomorphometry and retrograde labeling of motor neurons were performed at 1, 3, 6, 9, 12, and 24 months and supplemented by electron microscopy. Fiber counts and motor neuron counts increased between 1 and 3 months, followed by plateau. End-to-end repair resulted in persistently higher fiber counts compared to the grafting for all time points (P < 0.05). Percent neural tissue and myelin width increased with time while fibrin debris dissipated. In conclusion, these data detail the natural history of regeneration and demonstrate that overall fiber counts may remain stable despite pruning. © 2012 Wiley Periodicals, Inc.

Document Type: Article
Source: Scopus

 

Kopan, R.a b
Notch signaling
(2012) Cold Spring Harbor Perspectives in Biology, 4 (10), . 

a Department of Developmental Biology, Washington University, St. Louis, MI 63110, United States
b Department of Medicine (Division of Dermatology), Washington University, St. Louis, MI 63110, United States

Document Type: Article
Source: Scopus

 

Helwani, M.A.a , Saied, N.N.b , Asaad, B.c , Rasmussen, S.b , Fingerman, M.E.a
The Current Role of Ultrasound Use in Teaching Regional Anesthesia: A Survey of Residency Programs in the United States
(2012) Pain Medicine (United States), 13 (10), pp. 1342-1346. 

a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Anesthesiology and Critical Care, Vanderbilt University School of Medicine, Nashville, TN, United States
c Department of Anesthesiology, State University of New York, Stony Brook, NY, United States

Abstract
Background and Objectives. The purpose of this survey was to determine the current teaching practices of regional anesthesia and the prevalence of ultrasound use in guiding peripheral nerve blocks in the academic institutions across the United States. Methods. A survey was distributed to all American Board of Anesthesiology-accredited residency programs via email and/or the U.S. postal service. The survey was designed to determine the number of peripheral nerve blocks (PNBs) performed, the role of the ultrasound guidance, the barriers to its use, and the methods by which teaching physicians acquired their ultrasound skills. Results. We received 82 responses (62%) of the 132 programs surveyed. Eighty-eight percent of the responding programs performed more than 20PNBs/week and 46% performed more than 40PNBs/week. Three-fourths of the respondents relied on ultrasound to guide the majority of single injection and continuous PNBs. When using ultrasound, most programs (79%) used real-time ultrasound without nerve stimulator. Most teaching physicians supervising ultrasound-guided PNBs received their training via workshops and/or from other colleagues. The three main reasons for using ultrasound were to 1) achieve a higher success rate; 2) improve safety; and 3) teach anesthesia trainees. However, the three main barriers to using ultrasound were 1) lack of training; 2) perceived decreased efficiency; and 3) the lack of immediate availability of equipment. Overall, ultrasound was less utilized to guide lower extremity vs upper extremity PNBs. Conclusions. Ultrasound-guided PNBs are universally taught across residency programs in the United States. Most teaching physicians believe that ultrasound increases PNB's success and improves safety of regional anesthesia. Barriers to ultrasound use are lack of faculty training and unavailability of ultrasound equipment. © 2012 Wiley Periodicals, Inc.

Author Keywords
Continuing;  Education;  Nerve block;  Ultrasound

Document Type: Article
Source: Scopus

 

Meyers, P.M.a , Schumacher, H.C.b , Alexander, M.J.c , Derdeyn, C.P.d , Furlan, A.J.e , Higashida, R.T.f , Moran, C.J.g , Tarr, R.W.s , Heck, D.V.h , Hirsch, J.A.i , Jensen, M.E.j , Linfante, I.k , McDougall, C.G.l , Nesbit, G.M.m , Rasmussen, P.A.n , Tomsick, T.A.o , Wechsler, L.R.p , Wilson, J.R.q , Zaidat, O.O.r
Performance and training standards for Endovascular acute ischemic Stroke treatment
(2012) Neurology, 79 (13 SUPPL. 1), pp. S234-S238. 

a New York Presbyterian Hospital, Columbia University, Neurological Institute, United States
b Albert Einstein College of Medicine, New York, NY, United States
c Cedars-Sinai Medical Center, Los Angeles, CA, United States
d Washington University, St Louis, MO, United States
e Case Western Reserve University, Cleveland, OH, United States
f University of California San Francisco, San Francisco, United States
g University Hospitals Case Medical Center, Cleveland, OH, United States
h Forsyth Medical Center, Winston-Salem, NC, United States
i Harvard University, Boston, MA, United States
j University of Virginia, Health Sciences Center, Charlottesville, United States
k Miami Vascular Institute, Miami, FL, United States
l Barrow Neurological Institute, Phoenix, AZ, United States
m Oregon Health Sciences, Portland, United States
n Cleveland Clinic, Cleveland, United States
o University of Cincinnati, Cincinnati, OH, United States
p University of Pittsburgh, Pittsburgh, PA, United States
q Wake Forest University, School of Medicine, Winston-Salem, NC, United States
r Medical College of Wisconsin, Milwaukee, United States

Abstract
Stroke is the third leading cause of death in the United States, Canada, Europe, and Japan. According to the American Heart Association and the American Stroke Association, there are now 750,000 new strokes that occur each year, resulting in 200,000 deaths, or 1 of every 16 deaths, per year in the United States alone. Endovascular therapy for patients with acute ischemic stroke is an area of intense investigation. The American Stroke Association has given a qualified endorsement of intra-arterial thrombolysis in selected patients. Intra-arterial thrombolysis has been studied in 2 randomized trials and numerous case series. Although 2 devices have been granted FDA phase 3 approval with an indication for mechanical stroke thrombectomy, none of these thrombectomy devices has demonstrated efficacy for the improvement of patient outcomes. The purpose of the present document is to define what constitutes adequate training to perform neuroendovascular procedures in patients with acute ischemic stroke and what performance standards should be adopted to assess outcomes. These guidelines have been written and approved by multiple neuroscience societies that historically have been directly involved in the medical, surgical and endovascular care of patients with acute stroke. These organizations include the Neurovascular Coalition and its participating societies, including the Society of NeuroInterventional Surgery (SNIS), American Academy of Neurology (AAN), American Association of Neurological Surgeons/Cerebrovascular Section (AANS/CNS), and Society of Vascular & Interventional Neurology (SVIN). © 2012 American Academy of Neurology.

Document Type: Review
Source: Scopus

 

Mancuso, S.G.a b , Knoesen, N.P.a , Chamberlain, J.A.c , Cloninger, C.R.d , Castle, D.J.a e
The temperament and character profile of a body dysmorphic disorder outpatient sample

(2009) Personality and Mental Health, 3 (4), pp. 284-294. 

a St Vincent's Mental Health, Melbourne, Australia
b Swin-PsyCHE Research Unit, Swinburne University of Technology, Melbourne, Australia
c Frameworks for Health, Integrated Care, St Vincent's Health, Melbourne, Australia
d Department of Psychiatry, School of Medicine, Washington University, St. Louis, MO, United States
e Department of Psychiatry, St Vincent's Hospital, Melbourne, Australia

Abstract
Background Given the paucity in research investigating personality in body dysmorphic disorder (BDD), this study examined the temperament and character profile of BDD outpatients, and explored the relationship between BDD symptom severity and the temperament and character dimensions. Method Thirty-three consecutive BDD outpatients completed the Temperament and Character Inventory (TCI), Dysmorphic Concern Questionnaire (DCQ), Self-Rating Depression Scale (SDS) and the Social Interactional Anxiety Scale (SAIS). Thirty non-clinical controls completed the TCI, DCQ and Body Dysmorphic Disorder Questionnaire. Results Compared with non-clinical controls, BDD patients reported significantly higher Harm Avoidance (HA) scores (p < 0.001) and significantly lower Self-Directedness (SD; p <001) and Cooperativeness (C) scores (p = 0.04). The finding for C, however, may be confounded by age. For the BDD sample, DCQ scores were positively related to HA scores and negatively related to SD scores. Discussion Results suggest a temperament and character profile for BDD comprising high HA, low SD and possibly low C. High HA and low SD may represent non-specific risk factors in the development of BDD. Further research with siblings of cases and controls is required to demonstrate the causal role of antecedent personality traits. Additional research with larger samples is also required to investigate the possible confounding effects of delusionality, depression and social anxiety in the relationship between BDD and temperament and character. © 2009 John Wiley & Sons, Ltd.

Document Type: Article
Source: Scopus

 

October 24, 2012

Liang, C.L.a , Ances, B.M.b , Perthen, J.E.a , Moradi, F.a , Liau, J.c , Buracas, G.T.a , Hopkins, S.R.a d , Buxton, R.B.a
Luminance contrast of a visual stimulus modulates the BOLD response more than the cerebral blood flow response in the human brain
(2012) NeuroImage, 64, pp. 104-111. Article in Press. 

a Department of Radiology, University of California, San Diego, CA, USA
b Department of Neurology, Washington University in St. Louis, MO, USA
c Department of Bioengineering, University of California, San Diego, CA, USA
d Department of Medicine, University of California, San Diego, CA, USA

Abstract
The blood oxygenation level dependent (BOLD) response measured with functional magnetic resonance imaging (fMRI) depends on the evoked changes in cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO 2) in response to changes in neural activity. This response is strongly modulated by the CBF/CMRO 2 coupling relationship with activation, defined as n, the ratio of the fractional changes. The reliability of the BOLD signal as a quantitative reflection of underlying physiological changes depends on the stability of n in response to different stimuli. The effect of visual stimulus contrast on this coupling ratio was tested in 9 healthy human subjects, measuring CBF and BOLD responses to a flickering checkerboard at four visual contrast levels. The theory of the BOLD effect makes a robust prediction-independent of details of the model-that if the CBF/CMRO 2 coupling ratio n remains constant, then the response ratio between the lowest and highest contrast levels should be higher for the BOLD response than the CBF response because of the ceiling effect on the BOLD response. Instead, this response ratio was significantly lower for the BOLD response (BOLD response: 0.23±0.13, mean±SD; CBF response: 0.42±0.18; p=0.0054). This data is consistent with a reduced dynamic range (strongest/weakest response ratio) of the CMRO 2 response (~1.7-fold) compared to that of the CBF response (~2.4-fold) as luminance contrast increases, corresponding to an increase of n from 1.7 at the lowest contrast level to 2.3 at the highest contrast level. The implication of these results for fMRI studies is that the magnitude of the BOLD response does not accurately reflect the magnitude of underlying physiological processes. © 2012 Elsevier Inc.

Author Keywords
Arterial spin labeling (ASL);  Blood oxygen level dependent (BOLD) effect;  Cerebral blood flow (CBF);  Cerebral metabolic rate of oxygen consumption (CMRO 2);  Functional magnetic resonance imaging (fMRI);  Visual contrast;  Visual cortex

Document Type: Article in Press
Source: Scopus

 

Yao, J.a , Xia, J.a , Maslov, K.I.a , Nasiriavanaki, M.a , Tsytsarev, V.b , Demchenko, A.V.c , Wang, L.V.a
Noninvasive photoacoustic computed tomography of mouse brain metabolism in vivo
(2012) NeuroImage, 64, pp. 257-266. Article in Press. 

a Optical Imaging Laboratory, Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA
b Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
c Department of Chemistry and Biochemistry, University of Missouri-St. Louis, St. Louis, MO 63121, USA

Abstract
We have demonstrated the feasibility of imaging mouse brain metabolism using photoacoustic computed tomography (PACT), a fast, noninvasive and functional imaging modality with optical contrast and acoustic resolution. Brain responses to forepaw stimulations were imaged transdermally and transcranially. 2-NBDG, which diffuses well across the blood-brain-barrier, provided exogenous contrast for photoacoustic imaging of glucose response. Concurrently, hemoglobin provided endogenous contrast for photoacoustic imaging of hemodynamic response. Glucose and hemodynamic responses were quantitatively decoupled by using two-wavelength measurements. We found that glucose uptake and blood perfusion around the somatosensory region of the contralateral hemisphere were both increased by stimulations, indicating elevated neuron activity. While the glucose response area was more homogenous and confined within the somatosensory region, the hemodynamic response area had a clear vascular pattern and spread wider than the somatosensory region. Our results demonstrate that 2-NBDG-enhanced PACT is a promising tool for noninvasive studies of brain metabolism. © 2012 Elsevier Inc.

Author Keywords
2-NBDG;  Brain imaging;  Forepaw stimulation;  Glucose metabolism;  Hemodynamic response;  Photoacoustic computed tomography

Document Type: Article in Press
Source: Scopus

 

Zhu, X.-H.a , Chen, J.M.b , Tu, T.-W.b , Chen, W.a , Song, S.-K.b
Simultaneous and noninvasive imaging of cerebral oxygen metabolic rate, blood flow and oxygen extraction fraction in stroke mice
(2012) NeuroImage, 64, pp. 437-447. Article in Press. 

a Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
b Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA

Abstract
Many brain diseases have been linked to abnormal oxygen metabolism and blood perfusion; nevertheless, there is still a lack of robust diagnostic tools for directly imaging cerebral metabolic rate of oxygen (CMRO 2) and cerebral blood flow (CBF), as well as the oxygen extraction fraction (OEF) that reflects the balance between CMRO 2 and CBF. This study employed the recently developed in vivo 17O MR spectroscopic imaging to simultaneously assess CMRO 2, CBF and OEF in the brain using a preclinical middle cerebral arterial occlusion mouse model with a brief inhalation of 17O-labeled oxygen gas. The results demonstrated high sensitivity and reliability of the noninvasive 17O-MR approach for rapidly imaging CMRO 2, CBF and OEF abnormalities in the ischemic cortex of the MCAO mouse brain. It was found that in the ischemic brain regions both CMRO 2 and CBF were substantially lower than that of intact brain regions, even for the mildly damaged brain regions that were unable to be clearly identified by the conventional MRI. In contrast, OEF was higher in the MCAO affected brain regions. This study demonstrates a promising 17O MRI technique for imaging abnormal oxygen metabolism and perfusion in the diseased brain regions. This 17O MRI technique is advantageous because of its robustness, simplicity, noninvasiveness and reliability: features that are essential to potentially translate it to human patients for early diagnosis and monitoring of treatment efficacy. © 2012 Elsevier Inc.

Author Keywords
CBF;  CMRO 2 ;  In vivo 17O MRS imaging;  OEF;  Stroke

Document Type: Article in Press
Source: Scopus

 

Thangarajh, M.a , Yang, G.b , Fuchs, D.c , Ponisio, M.R.c , Mckinstry, R.C.c , Jaju, A.c , Noetzel, M.J.a , Casella, J.F.d , Barron-Casella, E.d , Hooper, W.C.b , Boulet, S.L.b , Bean, C.J.b , Pyle, M.E.b , Payne, A.B.b , Driggers, J.b , Trau, H.A.b , Vendt, B.A.e , Rodeghier, M.f , Debaun, M.R.g
Magnetic resonance angiography-defined intracranial vasculopathy is associated with silent cerebral infarcts and glucose-6-phosphate dehydrogenase mutation in children with sickle cell anaemia
(2012) British Journal of Haematology, 159 (3), pp. 352-359. 

a Department of Neurology and Pediatrics, Washington University School of Medicine, Saint Louis, MO, United States
b Clinical and Molecular Hemostasis Laboratory Branch, Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, United States
c Pediatric Radiology and Neuroradiology Sections, Washington University School of Medicine, Saint Louis, MO, United States
d Division of Hematology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
e Electronic Radiology Laboratory, Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, United States
f Statistical Collaborator, Chicago, IL, United States
g Department of Pediatrics, Vanderbilt Meharry Sickle Cell Disease Center of Excellence, Vanderbilt University, Nashville, TN, United States

Abstract
Silent cerebral infarct (SCI) is the most commonly recognized cause of neurological injury in sickle cell anaemia (SCA). We tested the hypothesis that magnetic resonance angiography (MRA)-defined vasculopathy is associated with SCI. Furthermore, we examined genetic variations in glucose-6-phosphate dehydrogenase (G6PD) and HBA (α-globin) genes to determine their association with intracranial vasculopathy in children with SCA. Magnetic resonance imaging (MRI) of the brain and MRA of the cerebral vasculature were available in 516 paediatric patients with SCA, enrolled in the Silent Infarct Transfusion (SIT) Trial. All patients were screened for G6PD mutations and HBA deletions. SCI were present in 41·5% (214 of 516) of SIT Trial children. The frequency of intracranial vasculopathy with and without SCI was 15·9% and 6·3%, respectively (P < 0·001). Using a multivariable logistic regression model, only the presence of a SCI was associated with increased odds of vasculopathy (P = 0·0007, odds ratio (OR) 2·84; 95% Confidence Interval (CI) = 1·55-5·21). Among male children with SCA, G6PD status was associated with vasculopathy (P = 0·04, OR 2·78; 95% CI = 1·04-7·42), while no significant association was noted for HBA deletions. Intracranial vasculopathy was observed in a minority of children with SCA, and when present, was associated with G6PD status in males and SCI. © 2012 Blackwell Publishing Ltd.

Author Keywords
α-thalassaemia;  Glucose-6-phosphate dehydrogenase;  Sickle cell anaemia;  Silent cerebral infarcts;  Vasculopathy

Document Type: Article
Source: Scopus

 

Dew, I.T.Z.a , Buchler, N.b , Dobbins, I.G.c , Cabeza, R.a
Where is ELSA? the early to late shift in aging
(2012) Cerebral Cortex, 22 (11), pp. 2542-2553. 

a Center for Cognitive Neuroscience, Duke University, LSRC B254 Box 90999, Durham, NC 27708, United States
b Cognitive Sciences Branch, US Army Research Laboratory, MD 21005, United States
c Department of Psychology, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Studies of cognitive and neural aging have recently provided evidence of a shift from an early-to late-onset cognitive control strategy, linked with temporally extended activity in the prefrontal cortex (PFC). It has been uncertain, however, whether this age-related shift is unique to PFC and executive control tasks or whether the functional location might vary depending on the particular cognitive processes that are altered. The present study tested whether an early-to-late shift in aging (ELSA) might emerge in the medial temporal lobes (MTL) during a protracted context memory task comprising both anticipatory cue (retrieval preparation) and retrieval probe (retrieval completion) phases. First, we found reduced MTL activity in older adults during the early retrieval preparation phase coupled with increased MTL activity during the late retrieval completion phase. Second, we found that functional connectivity between MTL and PFC regions was higher during retrieval preparation in young adults but higher during retrieval completion in older adults, suggesting an important interactive relationship between the ELSA pattern in MTL and PFC. Taken together, these results critically suggest that aging results in temporally lagged activity even in regions not typically associated with cognitive control, such as the MTL. © 2012 The Author.

Author Keywords
episodic memory;  fMRI;  medial temporal lobe;  older adults;  retrieval preparation

Document Type: Article
Source: Scopus

 

Willis, A.W.a , Schootman, M.b , Kung, N.a , Racette, B.A.a
Epidemiology and neuropsychiatric manifestations of Young Onset Parkinson's Disease in the United States
(2012) Parkinsonism and Related Disorders, . Article in Press. 

a Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
b Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA

Abstract
Background: To determine the demographic distribution of Young Onset Parkinson's Disease (YOPD) in the United States and to quantify the burden of neuropsychiatric disease manifestations. Methods: Cross sectional study of 3,459,986 disabled Americans, aged 30-54, who were receiving Medicare benefits in the year 2005. We calculated race and sex distributions of YOPD and used logistic regression to compare the likelihood of common and uncommon psychiatric disorders between beneficiaries with YOPD and the general disability beneficiary population, adjusting for race, age, and sex. Results: We identified 14,354 Medicare beneficiaries with YOPD (prevalence = 414.9 per 100,000 disabled Americans). White men comprised the majority of cases (48.9%), followed by White women (34.7%), Black men (6.8%), Black women (5.0%), Hispanic men (2.4%), and Hispanic women (1.2%). Asian men (0.6%) and Asian women (0.4%) were the least common race-sex pairs with a YOPD diagnosis in this population (chi square, p < 0.001). Compared to the general population of medically disabled Americans, those with YOPD were more likely to receive medical care for depression (OR: 1.89, 1.83-1.95), dementia (OR: 7.73, 7.38-8.09), substance abuse/dependence (OR: 3.00, 2.99-3.01), and were more likely to be hospitalized for psychosis (OR: 3.36, 3.19-3.53), personality/impulse control disorders (OR: 4.56, 3.28-6.34), and psychosocial dysfunction (OR: 3.85, 2.89-5.14). Conclusions: Young Onset Parkinson's Disease is most common among white males in our study population. Psychiatric illness, addiction, and cognitive impairment are more common in YOPD than in the general population of disabled Medicare beneficiaries. These may be key disabling factors in YOPD. © 2012 Elsevier Ltd. All rights reserved.

Author Keywords
Addiction;  Dementia;  Medicare;  Psychiatry;  Young Onset Parkinson's Disease

Document Type: Article in Press
Source: Scopus

 

Su, Y.a , Arbelaez, A.M.b , Benzinger, T.L.S.a , Snyder, A.Z.a , Vlassenko, A.G.a , Mintun, M.A.c , Raichle, M.E.a
Noninvasive estimation of the arterial input function in positron emission tomography imaging of cerebral blood flow

(2012) Journal of Cerebral Blood Flow and Metabolism, . Article in Press. 

a Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Missouri, USA
b Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA
c Avid Radiopharmaceuticals, Philadelphia, PA, USA

Abstract
Positron emission tomography (PET) with 15O-labeled water can provide reliable measurement of cerebral blood flow (CBF). Quantification of CBF requires knowledge of the arterial input function (AIF), which is usually provided by arterial blood sampling. However, arterial sampling is invasive. Moreover, the blood generally is sampled at the wrist, which does not perfectly represent the AIF of the brain, because of the effects of delay and dispersion. We developed and validated a new noninvasive method to obtain the AIF directly by PET imaging of the internal carotid artery in a region of interest (ROI) defined by coregistered high-resolution magnetic resonance angiography. An ROI centered at the petrous portion of the internal carotid artery was defined, and the AIF was estimated simultaneously with whole brain blood flow. The image-derived AIF (IDAIF) method was validated against conventional arterial sampling. The IDAIF generated highly reproducible CBF estimations, generally in good agreement with the conventional technique.Journal of Cerebral Blood Flow &amp; Metabolism advance online publication, 17 October 2012; doi:10.1038/jcbfm.2012.143.

Document Type: Article in Press
Source: Scopus

 

Mamah, D.a , Owoso, A.a , Mbwayo, A.W.d , Mutiso, V.N.d , Muriungi, S.K.e , Khasakhala, L.I.d , Barch, D.M.a b c , Ndetei, D.M.d f
Classes of Psychotic Experiences in Kenyan Children and Adolescents
(2012) Child Psychiatry and Human Development, pp. 1-8. Article in Press. 

a Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid, St. Louis, 63110, United States
b Department of Psychology, Washington University, St. Louis, United States
c Department of Anatomy and Neurobiology, Washington University, St. Louis, United States
d Africa Mental Health Foundation, Nairobi, Kenya
e Kenya Medical Training College, Nairobi, Kenya
f Department of Psychiatry, University of Nairobi, Nairobi, Kenya

Abstract
Psychotic-like experiences (PLEs) have been observed worldwide in both adults and children outside the context of a clinical disorder. In the current study, we investigate the prevalence and patterns of PLEs among children and adolescents in Kenya. Among 1,971 students from primary and secondary schools around Nairobi (aged 8-19), 22.1 % reported a lifetime history of a psychotic experience, and 16.3 % reported this unrelated to sleep or drugs. Psychotic experiences were more common in males compared to females. LCA resulted in a three-class model comprised of a normative class (83.3 %), a predominately hallucinatory class (Type 1 psychosis: 9.6 %), and a pan-psychotic class (Type 2 psychosis: 7.2 %). These results indicate that PLEs are prevalent in children and adolescents, and the distributions of symptom clusters are similar to that found in adulthood. The relationship of specific PLEs to the future development of psychotic disorder, functional impairment or distress will require further study. © 2012 Springer Science+Business Media New York.

Author Keywords
Adolescents;  Africa;  Children;  Kenya;  LCA;  Psychosis

Document Type: Article in Press
Source: Scopus

 

Levinson, C.A.a c , Rodebaugh, T.L.a , Menatti, A.R.b , Weeks, J.W.b
Development and Validation of the Social Exercise and Anxiety Measure (SEAM): Assessing Fears, Avoidance, and Importance of Social Exercise
(2012) Journal of Psychopathology and Behavioral Assessment, pp. 1-10. Article in Press. 

a Washington University in St. Louis, St. Louis, United States
b Ohio University, Athens, United States
c Department of Psychology, Washington University in St. Louis, St. Louis, 63130, United States

Abstract
In two studies (N = 416; N = 118) examining responses from undergraduates, we developed the Social Exercise and Anxiety Measure (SEAM) and tested its factorial, convergent, and divergent validity. Our results demonstrate that the SEAM exhibits an excellent three factor structure consisting of the following subscales: Social Exercise Self-efficacy, Gym Avoidance, and Exercise Importance. In both studies, Social Exercise Self-efficacy correlated negatively, and Gym Avoidance correlated positively with social interaction anxiety, fear of scrutiny, and fear of negative evaluation. Exercise Importance correlated positively with frequency of exercise and frequency of public exercise. Implications for the mental and physical health of individuals with high levels of social anxiety are discussed. © 2012 Springer Science+Business Media New York.

Author Keywords
Anxiety;  Assessment;  Exercise;  Self-efficacy;  Social anxiety

Document Type: Article in Press
Source: Scopus

 

Knapp, W.H.a , Abrams, R.A.b
Fundamental differences in visual search with verbal and pictorial cues
(2012) Vision Research, 71, pp. 28-36. 

a Department of Psychology, Istanbul Sehir University, Altunizade Mahallesi Kus bakis iCaddesi, No. 27, 34662 üsküdar-Istanbul, Turkey
b Department of Psychology, Washington University in Saint Louis, United States

Abstract
Three experiments examined the effects of using informative verbal and pictorial cues on participants' abilities to perform visual search. By providing participants with more time to encode the cues than had been used previously, all three experiments revealed long-lasting pictorially cued search advantages that stabilized over time. Experiments 1 and 3 demonstrated that searching for changing targets with pictorial cues was equivalent to searching for the same target over multiple trials in which target-switching costs would have been minimized. Experiment 3 additionally revealed that earlier evidence of pictorially cued search advantages was not due to inadequately equating the amount of information contained in the cues or uncertainty about when the search display would appear. Together, the data suggest that there are fundamental differences in the ability of participants to engage in visual search when the targets are identified with verbal, as opposed to pictorial, cues even when participants have sufficient time to fully encode the cues. © 2012.

Author Keywords
Attention;  Cues;  Visual attention;  Visual search

Document Type: Article
Source: Scopus

 

Ebejer, J.L.a b , Medland, S.E.b , van der Werf, J.a , Gondro, C.a , Henders, A.K.b , Lynskey, M.c , Martin, N.G.b , Duffy, D.L.b
Attention Deficit Hyperactivity Disorder in Australian Adults: Prevalence, Persistence, Conduct Problems and Disadvantage
(2012) PLoS ONE, 7 (10), art. no. e47404, . 

a School Of Rural Science and Agriculture, University of New England, Armidale, NSW, Australia
b Genetic Epidemiology, Queensland Institute of Medical Research, Brisbane, QLD, Australia
c Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States

Abstract
Background: The Prevalence and persistence of ADHD have not been described in young Australian adults and few studies have examined how conduct problems (CP) are associated with ADHD for this age group. We estimate lifetime and adult prevalence and persistence rates for three categories of ADHD for 3795 Australian adults, and indicate how career, health and childhood risk factors differ for people with ADHD symptoms and ADHD symptoms plus CP. Methodology: Trained interviewers collected participant experience of ADHD, CP, education, employment, childhood experience, relationship and health variables. Three diagnostic definitions of ADHD used were (i) full DSM-IV criteria; (ii) excluding the age 7 onset criterion (no age criterion); (iii) participant experienced difficulties due to ADHD symptoms (problem symptoms). Results: Prevalence rates in adulthood were 1.1%, 2.3% and 2.7% for each categorization respectively. Persistence of ADHD from childhood averaged across gender was 55.3% for full criteria, 50.3% with no age criterion and 40.2% for problem symptoms. ADHD symptoms were associated with parental conflict, poor health, being sexually assaulted during childhood, lower education, income loss and higher unemployment. The lifetime prevalence of conduct problems for adults with ADHD was 57.8% and 6.9% for adults without ADHD. The greatest disadvantage was experienced by participants with ADHD plus CP. Conclusion: The persistence of ADHD into adulthood was greatest for participants meeting full diagnostic criteria and inattention was associated with the greatest loss of income and disadvantage. The disadvantage associated with conduct problems differed in severity and was relevant for a high proportion of adults with ADHD. Women but not men with ADHD reported more childhood adversity, possibly indicating varied etiology and treatment needs. The impact and treatment needs of adults with ADHD and CP and the report of sexual assault during childhood by women and men with ADHD also deserve further study. © 2012 Ebejer et al.

Document Type: Article
Source: Scopus

 

Crock, L.W.a b c d , Kolber, B.J.b d e f , Morgan, C.D.b d , Sadler, K.E.e f , Vogt, S.K.b d , Bruchas, M.R.a b d , Gereau, R.W.a b d
Central amygdala metabotropic glutamate receptor 5 in the modulation of visceral pain
(2012) Journal of Neuroscience, 32 (41), pp. 14217-14226. 

a Program in Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO 63110, United States
d Washington University Pain Center, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Biological Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States
f Chronic Pain Research Consortium, Duquesne University, Pittsburgh, PA 15282, United States

Abstract
Painful bladder syndrome is a debilitating condition that affects 3-6% of women in the United States. Multiple lines of evidence suggest that changes inCNSprocessing are key to the development of chronic bladder pain conditions but little isknownregarding the underlying cellular, molecular, and neuronal mechanisms. Using a mouse model of distention-induced bladder pain, we found that the central nucleus of the amygdala (CeA) is a critical site of neuromodulation for processing of bladder nociception. Furthermore, we demonstrate that metabotropic glutamate receptor 5 (mGluR5) activation in the CeA induces bladder pain sensitization by increasing CeA output. Thus, pharmacological activation of mGluR5 in the CeA is sufficient to increase the response to bladder distention. Additionally, pharmacological blockade or virally mediated conditional deletion of mGluR5 in the CeA reduced responses to bladder distention suggesting that mGluR5 in the CeA is also necessary for these responses. Finally, we used optogenetic activation of the CeA and demonstrated that this caused a robust increase in the visceral pain response. The CeA-localized effects on responses to bladder distention are associated with changes in extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation in the spinal cord. Overall, these data demonstrate that mGluR5 activation leads to increased CeA output that drives bladder pain sensitization. © 2012 the authors.

Document Type: Article
Source: Scopus

 

Klug, A.a , Borst, J.G.G.b , Carlson, B.A.c , Kopp-Scheinpflug, C.d , Klyachko, V.A.e , Xu-Friedman, M.A.f
How do short-term changes at synapses fine-tune information processing?

(2012) Journal of Neuroscience, 32 (41), pp. 14058-14063. 

a Department of Physiology and Biophysics, University of Colorado School of Medicine, Aurora CO 80045, United States
b Department of Neuroscience, Erasmus MC, University Medical Center Rotterdam, 3015 GE Rotterdam, Netherlands
c Department of Biology, Washington University in St. Louis, St. Louis, MO 63130, United States
d MRC Toxicology Unit, Leicester LE1 9HN, United Kingdom
e Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, United States
f Department of Biological Sciences, University at Buffalo, SUNY, Buffalo, NY 14260, United States

Abstract
Synaptic transmission is highly dependent on recent activity and can lead to depression or facilitation of synaptic strength. This phenomenon is called "short-term synaptic plasticity" and is shown at all synapses. While much work has been done to understand the mechanisms of shortterm changes in the state of synapses, short-term plasticity is often thought of as a mechanistic consequence of the design of a synapse. This review will attempt to go beyond this view and discuss how, on one hand, complex neuronal activity affects the short-term state of synapses, but also how these dynamic changes in synaptic strength affect information processing in return. ©2012 the authors.

Document Type: Article
Source: Scopus

 

Gutmann, D.H.a , Parada, L.F.b , Silva, A.J.c , Ratner, N.d
Neurofibromatosis type 1: Modeling CNS dysfunction
(2012) Journal of Neuroscience, 32 (41), pp. 14087-14093. 

a Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110, United States
b University of Texas Southwestern Medical Center, Dallas, TX 75390, United States
c University of California-Los Angeles, Los Angeles, CA 90095, United States
d Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States

Abstract
Neurofibromatosis type 1 (NF1) is the most common monogenic disorder in which individuals manifest CNS abnormalities. Affected individuals develop glial neoplasms (optic gliomas, malignant astrocytomas) and neuronal dysfunction (learning disabilities, attention deficits). Nf1 genetically engineered mouse models have revealed the molecular and cellular underpinnings of gliomagenesis, attention deficit, and learning problems with relevance to basic neurobiology. Using NF1 as a model system, these studies have revealed critical roles for the NF1 gene in non-neoplastic cells in the tumor microenvironment, the importance of brain region heterogeneity, novel mechanisms of glial growth regulation, the neurochemical bases for attention deficit and learning abnormalities, and new insights into neural stem cell function. Here we review recent studies, presented at a symposium at the 2012 Society for Neuroscience annual meeting, that highlight unexpected cell biology insights intoRAS and cAMP pathway effects on neural progenitor signaling, neuronal function, and oligodendrocyte lineage differentiation. © 2012 the authors.

Document Type: Article
Source: Scopus

 

Yang, J.-M.a , Chen, R.b , Favazza, C.a , Yao, J.a , Li, C.a , Hu, Z.a , Zhou, Q.b , Shung, K.K.b , Wang, L.V.a
A 2.5-mm diameter probe for photoacoustic and ultrasonic endoscopy
(2012) Optics Express, 20 (21), pp. 23944-23953. 

a Optical Imaging Laboratory, Department of Biomedical Engineering, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130, United States
b NIH Ultrasonic Transducer Resource Center, Department of Biomedical Engineering, University of Southern California, 1042 Downey Way, Los Angeles, CA 90089, United States

Abstract
We have created a 2.5-mm outer diameter integrated photoacoustic and ultrasonic mini-probe which can be inserted into a standard video endoscope's instrument channel. A small-diameter focused ultrasonic transducer made of PMN-PT provides adequate signal sensitivity, and enables miniaturization of the probe. Additionally, this new endoscopic probe utilizes the same scanning mirror and micromotor-based built-in actuator described in our previous reports; however, the length of the rigid distal section of the new probe has been further reduced to
35 mm. This paper describes the technical details of the mini-probe and presents experimental results that both quantify the imaging performance and demonstrate its in vivo imaging capability, which suggests that it could work as a mini-probe for certain clinical applications. © 2012 Optical Society of America.

Document Type: Article
Source: Scopus

 

Evans, S.R.a , Lee, A.J.b , Ellis, R.J.c , Chen, H.d , Wu, K.d , Bosch, R.J.d , Clifford, D.B.e
HIV peripheral neuropathy progression: Protection with glucose-lowering drugs?
(2012) Journal of NeuroVirology, 18 (5), pp. 428-433. 

a Center for Biostatistics in AIDS Research, Department of Biostatistics, FXB-513 Harvard School of Public Health, 651 Huntington Avenue, Boston, MA 02115, United States
b Center for Biostatistics in AIDS Research, Department of Biostatistics, FXB-543 Harvard School of Public Health, 651 Huntington Avenue, Boston, MA 02115, United States
c Department of Neurosciences, University of California at San Diego, San Diego, CA, United States
d Center for Biostatistics in AIDS Research, Department of Biostatistics, Harvard School of Public Health, 651 Huntington Avenue, Boston, MA 02115, United States
e Department of Neurology, Washington University, Saint Louis, MO, United States

Abstract
The purpose of this study is to evaluate risk factors for progression from asymptomatic peripheral neuropathy (APN) to symptomatic peripheral neuropathy (SPN). Antiretroviral therapy (ART)-naïve patients initiating combination ART were followed longitudinally and screened for signs/symptoms of PN. Having APN was associated with higher odds of future SPN (odds ratio (OR)=1.58, 95 % confidence interval (CI)=(1.08, 2.29), p=0.027). Neurotoxic ART use was associated with increased odds of progression to SPN (OR= 2.16, 95 % CI=(1.21, 3.85), p=0.009) while use of glucoselowering drugs (non-insulin) was protective (OR=0.12, 95 % CI=(0.02, 0.83), p=0.031). Use of glucose-lowering drugs (non-insulin) may prevent progression from APN to SPN. © Journal of NeuroVirology, Inc. 2012.

Author Keywords
Glucose-lowering drugs;  HIV;  Peripheral neuropathy;  Risk factors;  Symptomatic peripheral neuropathy

Document Type: Article
Source: Scopus

 

Hayano, J.a , Carney, R.M.b , Watanabe, E.d , Kawai, K.e , Kodama, I.f , Stein, P.K.c , Watkins, L.L.g , Freedland, K.E.b , Blumenthal, J.A.g
Interactive associations of depression and sleep apnea with adverse clinical outcomes after acute myocardial infarction
(2012) Psychosomatic Medicine, 74 (8), pp. 832-839. 

a Center for Medical Education Research and Development, Nagoya City University, Graduate School of Medical Sciences, 1 Kawasumi Mizuho-cho, Mizuhoku, Nagoya 467-8601, Japan
b Departments of Psychiatry, Japan
c Departments of Medicine, Washington University School of Medicine, St. Louis, MI, United States
d Division of Cardiology, Department of Internal Medicine, Fujita Health University School of Medicine, Toyoake, Japan
e Suzuken Company Limited, Nagoya, Japan
f Nagoya University, Nagoya, Japan
g Department of Psychiatry, Duke University Medical Center, Durham, NC, United States

Abstract
OBJECTIVE: Depression and sleep apnea (SA) are common among patients with a recent acute myocardial infarction (AMI), and both are associated with increased risk for adverse outcomes. We tested the hypothesis that there is an interaction between them in relation to post-AMI prognosis. METHODS: Participants were patients with a recent AMI, 337 of them were depressed and 379 were nondepressed, who participated in a substudy of the Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial. SA was identified from Holter electrocardiogram by an algorithm that detects cyclic variation of heart rate. RESULTS: During a median follow-up of 25 months, 83 (11.6%) patients either died or experienced a recurrent AMI and 43 (6.0%) patients died. Among 94 patients with both depression and SA, these end points occurred in 25 (26.6%) and 20 (21.3%) at 3.9-and 6.9-times higher prevalence than predicted probabilities by ENRICHD clinical risk scores (p <.001 for both). In the patients with depression alone, SA alone, or neither, the prevalence was similar to the predicted probability. Depression and SA showed significant interactions in prediction of these end points (p = .02 and p = .03). SA independently predicted these end points in patients with depression (p = .001 and p <.001) but not in those without depression (p = .84 and p = .73). Similarly, depression independently predicted these end points in patients with SA (p <.001 for both) but not in those without SA (p = .12 and p = .61). CONCLUSIONS: Depression and SA are interactively associated with adverse clinical outcomes after AMI. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00313573. Copyright © 2012 by the American Psychosomatic Society.

Author Keywords
depression;  mortality;  myocardial infarction;  sleep apnea

Document Type: Article
Source: Scopus

 

Kotzbauer, P.T.a d e , Cairns, N.J.a b d f , Campbell, M.C.d g , Willis, A.W.d , Racette, B.A.d , Tabbal, S.D.d , Perlmutter, J.S.a c d g h
Pathologic accumulation of α-synuclein and Aβ in Parkinson disease patients with dementia
(2012) Archives of Neurology, 69 (10), pp. 1326-1331. 

a Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, United States
b Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, MO, United States
c Programs in Occupational Therapy and Physical Therapy, Washington University School of Medicine, St Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 S Euclid Ave, St Louis, MO 63110, United States
e Department of Developmental Biology, Washington University School of Medicine, St Louis, MO, United States
f Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, United States
g Department of Radiology, Washington University School of Medicine, St Louis, MO, United States
h Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO, United States

Abstract
Objective: To determine the relative contributions of individual pathologic protein deposits associated with dementia in patients with Parkinson disease (PD). Design: Autopsied patients were analyzed from February 24, 2005, through July 25, 2010, to determine the distribution and severity of individual pathologic protein deposits (α-synuclein, Aβ, and tau) using routine protocols for histologic and immunohistochemical analysis and established neuropathologic staging criteria. Clinical data were extracted from an electronic medical record system used for all patients with PD. Patients: Thirty-two consecutive autopsied patients treated at the Washington University Movement Disorders Center who had neuropathologic confirmation of PD and a history of dementia, regardless of the timing of the onset of dementia with respect to motor symptoms. Results: Three pathologic subgroups of dementia associated with PD were identified: (1) predominant synucleinopathy (Braak Lewy body stages 5-6) (12 [38%]), (2) predominant synucleinopathy with Aβ deposition (Braak amyloid stages B-C) but minimal or no cortical tau deposition (19 [59%]), and (3) synucleinopathy and Aβ deposition with at least moderate neocortical tauopathy (Braak tau stages 5-6; 1 [3%]). Kaplan-Meier and Cox regression analyses revealed that patients with synucleinopathy plus Aβ deposition had significantly shorter survival (years from PD onset until death and years from dementia onset until death) than patients with synucleinopathy only. Conclusions: Dementia associated with PD has 2 major pathologic subgroups: neocortical synucleinopathy and neocortical synucleinopathy with Aβ deposition. Alzheimer disease with neocortical Aβ and tau deposition does not commonly cause dementia with PD. Furthermore, accumulation of Aβ is associated with lower survival rates in PD patients with dementia. Additional studies are needed to prospectively determine the association between α-synuclein and Aβ accumulation and the role of Aβ in the development and progression of cognitive impairment in PD. ©2012 American Medical Association. All rights reserved.

Document Type: Article
Source: Scopus

 

Leung, Y.W.a , Flora, D.B.b , Gravely, S.a , Irvine, J.a b , Carney, R.M.c , Grace, S.L.a d
The impact of premorbid and postmorbid depression onset on mortality and cardiac morbidity among patients with coronary heart disease: Meta-analysis

(2012) Psychosomatic Medicine, 74 (8), pp. 786-801. 

a Department of Kinesiology and Health Science, Toronto, Canada
b Departments of Psychology, York University, Toronto, Canada
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MI, United States
d University Health Network, Toronto, Canada

Abstract
BACKGROUND: Depression is associated with increased cardiac morbidity and mortality in the general population and in patients with coronary heart disease (CHD). Recent evidence suggests that patients with new-onset depression post-CHD diagnosis have worse outcomes than do those who had previous or recurrent depression. This meta-analysis investigated the timing of depression onset in established CHD and CHD-free cohorts to determine what time frame is associated with greater mortality and cardiac morbidity. METHODOLOGY/PRINCIPAL FINDINGS: The MEDLINE, EMBASE, and PsycINFO databases were searched systematically to identify articles examining a depression time frame that specified an end point of all-cause mortality, cardiac mortality, rehospitalization, or major adverse cardiac events. A meta-analysis was conducted to estimate effect sizes by time frame of depression.Twenty-two prospective cohort studies were identified. Nine studies investigated premorbid depression in CHD-free cohorts in relation to cardiac death. Thirteen studies in patient samples with CHD examined new-onset depression in comparison with previous or recurrent depression. The pooled effect size (risk ratio) was 0.76 (95% confidence interval (CI) = 0.48-1.19) for history of depression only, 1.79 (95% CI = 1.45-2.21) for premorbid depression onset, 2.11 (95% CI = 1.66-2.68) for postmorbid or new depression onset, and 1.59 (95% CI = 1.08-2.34) for recurrent depression. CONCLUSIONS/SIGNIFICANCE: Both premorbid and postmorbid depression onsets are potentially hazardous, and the question of timing may be irrelevant with respect to adverse cardiac outcomes. However, the combination of premorbid depression with the absence of depression at the time of a cardiac event (i.e., historical depression only) is not associated with such outcomes and deserves further investigation. Copyright © 2012 by the American Psychosomatic Society.

Author Keywords
coronary heart disease;  depression;  morbidity;  mortality;  outcome;  timing of onset

Document Type: Article
Source: Scopus

 

Lim, M.H.a b , Gleeson, J.F.c , Jackson, H.J.b
The jumping-to-conclusions bias in new religious movements
(2012) Journal of Nervous and Mental Disease, 200 (10), pp. 868-875. 

a Department of Psychology, Washington University in St. Louis, Campus Box 1125, 1 Brookings Dr, St Louis, MO 63130, United States
b Psychological Sciences, University of Melbourne, Melbourne, Australia
c School of Psychology, Australian Catholic University, Melbourne, Australia

Abstract
The jumping-to-conclusions bias has not been examined in a new religious movement (NRM) group. Twenty-seven delusion-prone NRM individuals were compared with 25 individuals with psychotic disorders and 63 non-delusion-prone individuals on four probabilistic inference tasks, together with measures of psychotic symptoms and delusion proneness. The NRM individuals requested significantly less evidence when compared with the control individuals on both meaningful and nonmeaningful tasks. The NRM individuals requested significantly more evidence on a difficult meaningful task when compared with the individuals with psychotic disorders. A specific reasoning style but not a general reasoning style differentiates the NRM individuals from the individuals with psychotic disorders. These findings may be specific to NRM individuals and may not be generalized to other delusion-prone groups. Copyright © 2001 by Lippincott Williams & Wilkins.

Author Keywords
Delusion prone;  Jumping to conclusions bias;  Probabilistic inference task;  Psychosis continuum

Document Type: Conference Paper
Source: Scopus

 

Hayden, T.a , Perantie, D.C.a , Nix, B.D.a , Barnes, L.D.a , Mostello, D.J.b , Holcomb, W.L.c , Svrakic, D.M.a , Scherrer, J.F.a , Lustman, P.J.a , Hershey, T.a d e
Treating prepartum depression to improve infant developmental outcomes: A study of diabetes in pregnancy
(2012) Journal of Clinical Psychology in Medical Settings, 19 (3), pp. 285-292. 

a Department of Psychiatry, Washington University, School of Medicine, 660 S. Euclid, St. Louis, MO 63110, United States
b Department of Maternal-Fetal Medicine, Saint Louis University, School of Medicine, St. Louis, MO, United States
c St. Joseph Health Center, St. Charles, MO, United States
d Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
e Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Whether and how the co-occurrence of depression and diabetes in pregnancy may worsen infant development has not been reported. Pregnant women with diabetes and with (n = 34) or without (n = 34) major depressive disorder (MDD) were followed during pregnancy and 6-months postpartum. The MDD subset received randomly assigned treatment with cognitive behavior therapy (CBT) or supportive counseling (SC). Depression severity was measured with the Beck Depression Inventory (BDI); infant developmental outcomes were measured with the Bayley Scales of Infant Development (BSID) and its Behavior Rating Scale (BRS). Infants of women with MDD had lower BRS scores (p = .02). Reduction in depression scores was associated with better infant outcomes on the BSID and BRS (p values <.03). These preliminary findings suggest depression occurring in pregnant women with diabetes is associated with poorer infant development and improvement in prepartum depression is associated with improvement in measures of infant development. © Springer Science+Business Media, LLC 2012.

Author Keywords
Depression;  Diabetes;  Infant development;  Pregnancy

Document Type: Article
Source: Scopus

 

Hogan, R.E., English, E.A.
Epilepsy and brain function: common ideas of Hughlings-Jackson and Wilder Penfield.
(2012) Epilepsy & behavior : E&B, 24 (3), pp. 311-313. 

Washington University in St. Louis, Campus Box 8111, 660 S. Euclid Ave., St. Louis, MO 63110, USA.

Abstract
From studies of epilepsy, Hughlings-Jackson proposed a model of brain function including levels of consciousness, a hierarchy of nervous centers, and a sensory-motor relationship. Hughlings-Jackson's ideas influenced Wilder Penfield, a pioneer of electrical stimulation for mapping of the human cerebral cortex. From his work with electrocortical stimulation in patients with epilepsy, Penfield observed what he referred to as a "record of the stream of consciousness," similar to Hughlings-Jackson's "subject consciousness." Penfield expanded upon Hughlings-Jackson's work and suggested that although higher and lower centers explained reflex movements, another separate unaccounted for force controlled voluntary movements. These two functional units he termed the "computer (or automatic sensory-motor mechanism)" and the "mind's mechanism (or highest brain mechanism)." The ideas of John Hughlings-Jackson and Wilder Penfield represent a continuum of thought about the relationship of epilepsy and brain function and continue to be relevant to our current understanding of memory function and the mind-brain relationship. Copyright © 2012 Elsevier Inc. All rights reserved.

Document Type: Review
Source: Scopus

 

Morales, D.M., Townsend, R.R., Malone, J.P., Ewersmann, C.A., Macy, E.M., Inder, T.E., Limbrick Jr., D.D.
Alterations in protein regulators of neurodevelopment in the cerebrospinal fluid of infants with posthemorrhagic hydrocephalus of prematurity.
(2012) Molecular & cellular proteomics : MCP, 11 (6), pp. M111.011973. 

Department of Neurological Surgery, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri 63110, USA.

Abstract
Neurological outcomes of preterm infants with posthemorrhagic hydrocephalus are among the worst in newborn medicine. There remains no consensus regarding the diagnosis or treatment of posthemorrhagic hydrocephalus, and the pathological pathways leading to the adverse neurological sequelae are poorly understood. In the current study, we developed an innovative approach to simultaneously identify potential diagnostic markers of posthemorrhagic hydrocephalus and investigate novel pathways of posthemorrhagic hydrocephalus-related neurological disability. Tandem multi-affinity fractionation for specific removal of plasma proteins from the hemorrhagic cerebrospinal fluid samples was combined with high resolution label-free quantitative proteomics. Analysis of cerebrospinal fluid obtained from infants with posthemorrhagic hydrocephalus demonstrated marked differences in the levels of 438 proteins when compared with cerebrospinal fluid from age-matched control infants. Amyloid precursor protein, neural cell adhesion molecule-L1, neural cell adhesion molecule-1, brevican and other proteins with important roles in neurodevelopment showed profound elevations in posthemorrhagic hydrocephalus cerebrospinal fluid compared with control. Initiation of neurosurgical treatment of posthemorrhagic hydrocephalus resulted in resolution of these elevations. The results from this foundational study demonstrate the significant promise of tandem multi-affinity fractionation-proteomics in the identification and quantitation of protein mediators of neurodevelopment and neurological injury. More specifically, our results suggest that cerebrospinal fluid levels of proteins such as amyloid precursor protein or neural cell adhesion molecule-L1 should be investigated as potential diagnostic markers of posthemorrhagic hydrocephalus. Notably, dysregulation of the levels these and other proteins may directly affect ongoing neurodevelopmental processes in these preterm infants, providing an entirely new hypothesis for the developmental disability associated with posthemorrhagic hydrocephalus.

Document Type: Article
Source: Scopus

 

Boyer, P.a , Petersen, M.B.b
The naturalness of (many) social institutions: Evolved cognition as their foundation
(2012) Journal of Institutional Economics, 8 (1), pp. 1-25. 

a Department of Psychology, Campus Box 1125, Washington University, 1 Brookings Drive, St Louis, MO 63130, United States
b Department of Political Science, Aarhus University, Aarhus, Denmark

Abstract
Most standard social science accounts only offer limited explanations of institutional design, i.e. why institutions have common features observed in many different human groups. Here we suggest that these features are best explained as the outcome of evolved human cognition, in such domains as mating, moral judgment and social exchange. As empirical illustrations, we show how this evolved psychology makes marriage systems, legal norms and commons management systems intuitively obvious and compelling, thereby ensuring their occurrence and cultural stability. We extend this to propose under what conditions institutions can become natural, compelling and legitimate, and outline probable paths for institutional change given human cognitive dispositions. Explaining institutions in terms of these exogenous factors also suggests that a general theory of institutions as such is neither necessary nor in fact possible. What are required are domain-specific accounts of institutional design in different domains of evolved cognition. Copyright © The JOIE Foundation 2011.

Document Type: Article
Source: Scopus

October 17, 2012

Tabaeizadeh, M.a b , Motiei-Langroudi, R.a , Mirbaha, H.a c , Esmaeili, B.d , Tahsili-Fahadan, P.e , Javadi-Paydar, M.a c , Ghaffarpour, M.b , Dehpour, A.R.a f
The differential effects of OX1R and OX2R selective antagonists on morphine conditioned place preference in naïve versus morphine-dependent mice
(2012) Behavioural Brain Research, 237, pp. 41-48. Article in Press. 

a Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
b Iranian Center of Neurological Research, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
c Brain and Spinal Cord Injury Repair Research Center, Tehran University of Medical Sciences, Tehran, Iran
d Department of Neuroscience, University of Pittsburg, Pittsburg, PA, USA
e Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
f Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Abstract
Conditioned place preference (CPP) has been associated with orexinergic (hypocrtinergic) system activation in naïve mice; however, the distinct role of different receptors of orexin in this paradigm has not been characterized yet. Moreover, the relationship between orexins and morphine in dependent mice may not be equal to naïve mice and seems noteworthy to investigate. We investigated the effects of systemic administration of orexin-1-receptor antagonist, SB 334867, and orexin-2 receptor antagonist, TCS-OX2-29 on the acquisition and expression of morphine conditioned place preference (CPP) in both naïve and morphine-dependent mice. We tested SB 334867 in three doses (10, 20 and 30. mg/kg), TCS-OX2-29 in two doses (5 and 10. mg/kg) and morphine with highest effective dose based on our dose-response experiment (5. mg/kg). Our results revealed that while SB 334867 suppressed CPP acquisition and expression in naïve mice, it failed to block CPP acquisition and expression in morphine dependent animals. In contrast, TCS-OX2-29 suppressed CPP acquisition and expression in both naïve and dependent mice significantly. The rewarding effect of morphine has stronger correlation with orexin-2 receptors in morphine-dependent mice while it depends on both kinds of receptors in naïve mice. This finding, if confirmed in other studies, persuades us to further investigate the role of orexin-2 receptor antagonists as potent drugs in addiction treatment. © 2012 Elsevier B.V.

Author Keywords
Dependence;  Mice;  Morphine conditioned place preference;  Orexin;  SB 334867;  TCS-OX2-29

Document Type: Article in Press
Source: Scopus

 

Hightower, G.K.a , Wong, J.K.b , Letendre, S.L.a , Umlauf, A.A.a , Ellis, R.J.a c , Ignacio, C.C.a , Heaton, R.K.a , Collier, A.C.d , Marra, C.M.d , Clifford, D.B.e , Gelman, B.B.f , McArthur, J.C.g , Morgello, S.h , Simpson, D.M.h , McCutchan, J.A.a , Grant, I.a c , Little, S.J.a , Richman, D.D.a c , Kosakovsky Pond, S.L.a , Smith, D.M.a c
Higher HIV-1 genetic diversity is associated with AIDS and neuropsychological impairment
(2012) Virology, 433 (2), pp. 498-505. 

a University of California San Diego, 9500 Gilman Drive # 0679, La Jolla, CA, United States
b San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States
c Veterans Affairs San Diego Healthcare System, San Diego, CA, United States
d University of Washington, Seattle, WA, United States
e Washington University, St. Louis, MO, United States
f University of Texas, Medical Branch, Galveston, TX, United States
g Johns Hopkins University, Baltimore, MD, United States
h Mount Sinai School of Medicine, NY, United States

Abstract
Standard methods used to estimate HIV-1 population diversity are often resource intensive (e.g., single genome amplification, clonal amplification and pyrosequencing) and not well suited for large study cohorts. Additional approaches are needed to address the relationships between intraindividual HIV-1 genetic diversity and 2 disease. With a small cohort of individuals, we validated three methods for measuring diversity: Shannon entropy and average pairwise distance (APD) using single genome sequences, and counts of mixed bases (i.e. ambiguous nucleotides) from population based sequences. In a large cohort, we then used the mixed base approach to determine associations between measure HIV-1 diversity and HIV associated disease. Normalized counts of mixed bases correlated with Shannon Entropy at both the nucleotide (rho=0.72, p=0.002) and amino acid level (rho=0.59, p=0.015), and APD (rho=0.75, p=0.001). Among participants who underwent neuropsychological and clinical assessments (n=187), increased HIV-1 population diversity was associated with both a diagnosis of AIDS and neuropsychological impairment. © 2012.

Author Keywords
AIDS;  Genetic diversity;  HIV;  Neuropsychological impairment;  Viral population dynamics

Document Type: Article
Source: Scopus

 

Rice, J.P.a , Hartz, S.M.a , Agrawal, A.a , Almasy, L.b , Bennett, S.c , Breslau, N.d , Bucholz, K.K.a , Doheny, K.F.e , Edenberg, H.J.f , Goate, A.M.a , Hesselbrock, V.g , Howells, W.B.a , Johnson, E.O.h , Kramer, J.i , Krueger, R.F.p , Kuperman, S.j , Laurie, C.c , Manolio, T.A.k , Neuman, R.J.a , Nurnberger, J.I.l , Porjesz, B.m , Pugh, E.e , Ramos, E.M.k , Saccone, N.n , Saccone, S.a , Schuckit, M.o , Bierut, L.J.a
CHRNB3 is more strongly associated with Fagerström Test for Cigarette Dependence-based nicotine dependence than cigarettes per day: Phenotype definition changes genome-wide association studies results
(2012) Addiction, 107 (11), pp. 2019-2028. 

a Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
b Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX, United States
c Department of Biostatistics, University of Washington, Seattle, WA, United States
d Department of Epidemiology, Michigan State University, East Lansing, MI, United States
e Center for Inherited Disease Research, Johns Hopkins School of Medicine, Baltimore, MD, United States
f Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
g Department of Psychiatry, University of Connecticut, Farmington, CT, United States
h Division of Health, Social and Economic Research, Research Triangle Institute International, Research Triangle Park, NC, United States
i Department of Psychiatry, University of Iowa College of Medicine, Iowa City, IA, United States
j Division of Child Psychiatry, University of Iowa Hospitals, Iowa City, IA, United States
k National Human Genome Research Institute, Bethesda, MD, United States
l Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
m Department of Psychiatry and Behavioral Sciences, State University of New York, Brooklyn, NY, United States
n Department of Genetics, Washington University School of Medicine, St Louis, MO, United States
o Department of Psychiatry, University of California-San Diego, La Jolla, CA, United States
p Department of Psychology, University of Minnesota, Minneapolis, MN, United States

Abstract
Aims: Nicotine dependence is a highly heritable disorder associated with severe medical morbidity and mortality. Recent meta-analyses have found novel genetic loci associated with cigarettes per day (CPD), a proxy for nicotine dependence. The aim of this paper is to evaluate the importance of phenotype definition (i.e. CPD versus Fagerström Test for Cigarette Dependence (FTCD) score as a measure of nicotine dependence) on genome-wide association studies of nicotine dependence. Design: Genome-wide association study. Setting: Community sample. Participants: A total of 3365 subjects who had smoked at least one cigarette were selected from the Study of Addiction: Genetics and Environment (SAGE). Of the participants, 2267 were European Americans, 999 were African Americans. Measurements: Nicotine dependence defined by FTCD score ≥4, CPD. Findings: The genetic locus most strongly associated with nicotine dependence was rs1451240 on chromosome 8 in the region of CHRNB3 [odds ratio (OR)=0.65, P=2.4×10 -8]. This association was further strengthened in a meta-analysis with a previously published data set (combined P=6.7×10 -16, total n=4200). When CPD was used as an alternate phenotype, the association no longer reached genome-wide significance (β=-0.08, P=0.0004). Conclusions: Daily cigarette consumption and the Fagerstrom Test for Cigarette Dependence show different associations with polymorphisms in genetic loci. © 2012 Society for the Study of Addiction.

Author Keywords
CHRNB3;  Genome-wide association studies;  Meta-analysis;  Phenotype definitions

Document Type: Article
Source: Scopus

 

Guinan, J.J.a b , Salt, A.c , Cheatham, M.A.d
Progress in cochlear physiology after Békésy
(2012) Hearing Research, 293 (1-2), pp. 12-20. 

a Eaton Peabody Laboratories, Dept. of Otolaryngology, Mass. Eye and Ear Infirmary, Boston, MA 02114, United States
b Dept. of Otology and Laryngology, Harvard Medical School, Boston, MA 02115, United States
c Department of Otolaryngology, Washington University, School of Medicine, Box 8115, 660 South Euclid Avenue, St. Louis, MO 63110, United States
d Hugh Knowles Center, Department of Communication Sciences and Disorders, Northwestern University, 2240 Campus Drive, Evanston, IL 60208, United States

Abstract
In the fifty years since Békésy was awarded the Nobel Prize, cochlear physiology has blossomed. Many topics that are now current are things Békésy could not have imagined. In this review we start by describing progress in understanding the origin of cochlear gross potentials, particularly the cochlear microphonic, an area in which Békésy had extensive experience. We then review progress in areas of cochlear physiology that were mostly unknown to Békésy, including: (1) stereocilia mechano-electrical transduction, force production, and response amplification, (2) outer hair cell (OHC) somatic motility and its molecular basis in prestin, (3) cochlear amplification and related micromechanics, including the evidence that prestin is the main motor for cochlear amplification, (4) the influence of the tectorial membrane, (5) cochlear micromechanics and the mechanical drives to inner hair cell stereocilia, (6) otoacoustic emissions, and (7) olivocochlear efferents and their influence on cochlear physiology. We then return to a subject that Békésy knew well: cochlear fluids and standing currents, as well as our present understanding of energy dependence on the lateral wall of the cochlea. Finally, we touch on cochlear pathologies including noise damage and aging, with an emphasis on where the field might go in the future. © 2012 Elsevier B.V..

Document Type: Review
Source: Scopus

 

Krug, M.K.a , Carter, C.S.b
Proactive and reactive control during emotional interference and its relationship to trait anxiety
(2012) Brain Research, 1481, pp. 13-36. 

a Cognitive Control and Psychopathology Laboratory, Department of Psychology, Washington University, One Brookings Drive, Saint Louis, MO 63130, United States
b University of California, Davis, United States

Abstract
In classic Stroop paradigms, increasing the proportion of control-demanding incongruent trials results in strategic adjustments in behavior and implementation of cognitive control processes. We manipulated expectancy for incongruent trials in an emotional facial Stroop task to investigate the behavioral and neural effects of proportion manipulation in a cognitively demanding task with emotional stimuli. Subjects performed a high expectancy (HE) task (65 incongruent trials) and a low expectancy (LE) task (35 incongruent trials) during functional magnetic resonance imaging (fMRI). As in standard Stroop tasks, behavioral interference was reduced in the emotional facial Stroop HE task compared to the LE task. Functional MRI data revealed a switch in cognitive control strategy, from a reactive, event-related activation of a medial and lateral cognitive control network and right amygdala in the LE task to a proactive, sustained activation of right dorsolateral prefrontal cortex (DLPFC) in the HE task. Higher trait anxiety was associated with impairment (slower response time and decreased accuracy) as well as reduced activity in left ventrolateral prefrontal cortex, anterior insula, and orbitofrontal cortex in the HE task on high conflict trials with task-irrelevant emotional information, suggesting that individual differences in anxiety may be associated with expectancy-related strategic control adjustments, particularly when emotional stimuli must be ignored. © 2012 Elsevier B.V.

Author Keywords
Amygdala;  Anterior cingulate cortex;  Conflict monitoring;  fMRI;  Prefrontal cortex;  Sustained and transient control

Document Type: Article
Source: Scopus

 

Pierron, F.a , Bayly, P.V.b , Namani, R.b
Application of the virtual fields method to magnetic resonance elastography data
(2012) Conference Proceedings of the Society for Experimental Mechanics Series, 4, pp. 135-142. 

a Laboratoire de Mécanique et Procédés de Fabrication, Arts et Métiers ParisTech, Rue Saint Dominique, 51006 Châlons-en-Champagne, France
b
 Department of Mechanical and Biomechanical Engineering, Washington University, Campus Box 1185, St. Louis, MO, United States

Abstract
This paper deals with the application of the Virtual Fields Method to the identification of the shear modulus of a gel from Magnetic Resonance Elastography data. Volume deformation fields in the cube were recorded at different times during the harmonic loading and the full harmonic response has been reconstructed using Fast Fourier Transform. Strains were then obtained by direct spatial differentiation, without any smoothing. The VFM was then applied with inertial forces balancing out elastic forces, without including the loading force which was not measured here. It has been shown that the choice of the virtual field is critical with such a spatial wave deformation field. A wide range of spatially harmonic virtual fields has been tested at different times within the loading period. The identified shear modulus has been shown to be consistent and to correlate with the value obtained from a simplified approach based on the shear wave solution. This is a feasibility study, it will be extended in the future to heterogeneous materials with a more thorough procedure to build up relevant virtual fields. ©2010 Society for Experimental Mechanics Inc.

Document Type: Conference Paper
Source: Scopus

 

Clayton, E.H., Okamoto, R.J., Wilson, K.S., Namani, R., Bayly, P.V.
Comparison of dynamic mechanical testing and MR elastography of biomaterials
(2012) Conference Proceedings of the Society for Experimental Mechanics Series, 4, pp. 143-150. 

Department of Mechanical, Aerospace and Structural Engineering, Department of Biomedical Engineering, Washington University in St. Louis, 1 Brookings Drive, Saint Louis, MO 63130, United States

Abstract
Magnetic resonance elastography (MRE) is a novel experimental technique for estimating the dynamic shear modulus of biological tissue. MRE can be performed non-invasively, in living subjects. Soft biomaterials are notoriously difficult to characterize, since they are typically nonlinear, anisotropic, viscoelastic, and heterogeneous. The ability of MRE to capture the frequency-dependent response of tissue to small amplitude deformation over a range of frequencies was investigated by careful comparison to two different dynamic mechanical tests; direct shear and unconfined compression. The mechanical properties of a standardized gelatin biomaterial were probed over various loading rates. Results confirm direct correlation between estimates of shear modulus obtained by MRE, dynamic shear, and unconfined compression, but quantitative differences between values obtained by MRE compared to direct mechanical test. These results in gelatin are consistent with reports in agar from other groups [1,2]. Differences may be due to non-idealities inherent in loading of soft, wet, material (in mechanical testing), boundary effects (in MRE), or differences in strain amplitude and strain rate. ©2010 Society for Experimental Mechanics Inc.

Document Type: Conference Paper
Source: Scopus

 

Clayton, E.H.a , Wang, Q.a , Song, S.K.b , Okamoto, R.J.a , Bayly, P.V.a c
Magnetic resonance elastography of the mouse vitreous humor in vivo
(2012) Conference Proceedings of the Society for Experimental Mechanics Series, 4, pp. 129-133. 

a Department of Mechanical, Aerospace and Structural Engineering, Washington University in St. Louis, Campus Box 1185, Saint Louis, MO 63130, United States
b Biomedical MR Laboratory, Mallinckrodt Institute of Radiology, Washington University in St. Louis, Saint Louis, MO 63130, United States
c Department of Biomedical Engineering, Washington University in St. Louis, Campus Box 1185, 1 Brookings Drive, Saint Louis, MO 63130, United States

Abstract
Magnetic resonance elastography (MRE) is a novel experimental technique for estimating the dynamic shear modulus of biological tissue in vivo and non-invasively. Propagating acoustic frequency shear waves are launched into biologic tissue via external mechanical actuator and a conventional magnetic resonance imaging (MRI) scanner is used to acquire spatial-temporal measurements of the wave displacement field with micron precision. Local shear modulus estimates are obtained by inverting the equations governing shear wave motion. Changes in tissue pathology may be accompanied by a stark change in tissue elasticity. As a result, MRE has appeal to healthcare practitioners as a non-invasive diagnostic tool. Recently, MRE-based modulus estimates have been obtained in animal liver, brain, and heart [2-7]. Here, for the first time, MRE was used to probe the shear modulus of mouse eye vitreous humor in vivo and non-invasively. ©2010 Society for Experimental Mechanics Inc.

Document Type: Conference Paper
Source: Scopus

 

Bayly, P.V., Clayton, E.H., Feng, Y., Abney, T., Namani, R., Okamoto, R.J., Genin, G.M.
Measurement of brain biomechanics in vivo by magnetic resonance imaging
(2012) Conference Proceedings of the Society for Experimental Mechanics Series, 4, pp. 117-128. 

Department of Mechanical and Biomechanical Engineering, Washington University, Campus Box 1185, St. Louis, MO, United States

Abstract
Computer models of head-brain biomechanics offer enormous potential for improved understanding and prevention of traumatic brain injury (TBI). However existing computer models remain controversial because their predictions have yet to be rigorously compared to measured biomechanical data. The nonlinear, anisotropic, viscoelastic, heterogeneous character of brain tissue, and the intricate connections between the brain and skull, all complicate modeling efforts. In order to make progress toward the goal of accurate simulation of TBI, experimental techniques to address these issues must be developed. In this paper we describe two magnetic resonance (MR) imaging techniques to characterize brain deformation, estimate brain material properties, and illuminate the boundary conditions between brain and skull. MR tagging is used to estimate displacement and strain fields in response to rigid-body acceleration of the skull, and MR elastography is used to visualize shear wave propagation induced by oscillatory loading at the surface of the skull. ©2010 Society for Experimental Mechanics Inc.

Document Type: Conference Paper
Source: Scopus

 

Boxer, A.L.a , Gold, M.b , Huey, E.c , Hu, W.T.d , Rosen, H.a , Kramer, J.a , Gao, F.-B.e , Burton, E.A.f , Chow, T.g , Kao, A.a , Leavitt, B.R.h , Lamb, B.i , Grether, M.j , Knopman, D.k , Cairns, N.J.l , Mackenzie, I.R.m , Mitic, L.j , Roberson, E.D.n , Van Kammen, D.o , Cantillon, M.p , Zahs, K.q , Jackson, G.r , Salloway, S.s , Morris, J.l , Tong, G.t , Feldman, H.u , Fillit, H.v , Dickinson, S.w , Khachaturian, Z.S.x , Sutherland, M.y , Abushakra, S.z , Lewcock, J.aa , Farese, R.ab , Kenet, R.O.ac , LaFerla, F.ad , Perrin, S.ae , Whitaker, S.af , Honig, L.c , Mesulam, M.M.ag , Boeve, B.k , Grossman, M.ah , Miller, B.L.a , Cummings, J.L.ai
The advantages of frontotemporal degeneration drug development (part 2 of frontotemporal degeneration: The next therapeutic frontier)
(2012) Alzheimer's and Dementia, . Article in Press. 

a Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA
b Allon Therapeutics, Vancouver, British Columbia, Canada
c Taub Institute, Department of Neurology, Columbia University, New York, NY, USA
d Department of Neurology, Emory University, Atlanta, GA, USA
e Department of Neurology, University of Massachusetts, Worcester, MA, USA
f Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
g Rotman Research Institute, University of Toronto, Toronto, Ontario, Canada
h Division of Neurology, Department of Medicine, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada
i Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
j Bluefield Project to Cure Frontotemporal Dementia, San Francisco, CA, USA
k Department of Neurology, Mayo Clinic, Rochester, MN, USA
l Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
m Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
n Department of Neurology, University of Alabama School of Medicine, Birmingham, AL, USA
o CNS Drug Development Consultant, Princeton, NJ, USA
p Critical Path Institute, Rockville, MD, USA
q Grossman Center for Memory Research and Care, University of Minnesota School of Medicine, Minneapolis, MN, USA
r Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA
s Department of Neurology, Brown University School of Medicine, Providence, RI, USA
t Bristol Myers Squibb, Princeton, NJ, USA
u Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
v Alzheimer's Drug Discovery Foundation, New York, NY, USA
w Association for Frontotemporal Degeneration, Radnor, PA, USA
x KRA Associates, Potomac, MD, USA
y National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
z Elan Pharmaceuticals, South San Francisco, CA, USA
aa Genentech, South San Francisco, CA, USA
ab Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA
ac Department of Medicine, Weill Cornell Medical College, New York, NY, USA
ad MIND Institute, University of California, Irvine, CA, USA
ae ALS Therapy Development Institute, Cambridge, MA, USA
af Omeros Corporation, Seattle, WA, USA
ag Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
ah Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA
ai Lou Ruvo Center for Brain Health, Cleveland Clinic, Las Vegas, NV, USA

Abstract
Frontotemporal degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language, and motor phenotypes for which there are currently no effective therapies. This is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Degeneration Treatment Study Group, a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This article discusses the current status of FTD clinical research that is relevant to the conduct of clinical trials, and why FTD research may be an attractive pathway for developing therapies for neurodegenerative disorders. The clinical and molecular features of FTD, including rapid disease progression and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared with other dementias. FTD qualifies as orphan indication, providing additional advantages for drug development. Two recent sets of consensus diagnostic criteria will facilitate the identification of patients with FTD, and a variety of neuropsychological, functional, and behavioral scales have been shown to be sensitive to disease progression. Moreover, quantitative neuroimaging measurements demonstrate progressive brain atrophy in FTD at rates that may surpass Alzheimer's disease. Finally, the similarities between FTD and other neurodegenerative diseases with drug development efforts already underway suggest that FTD researchers will be able to draw on this experience to create a road map for FTD drug development. We conclude that FTD research has reached sufficient maturity to pursue clinical development of specific FTD therapies. © 2012 The Alzheimer's Association.

Author Keywords
AD;  Alzheimer's disease;  Biomarker;  Clinical trial;  Corticobasal degeneration;  Drug development;  Frontotemporal degeneration;  FTD;  Progressive supranuclear palsy;  Treatment

Document Type: Article in Press
Source: Scopus

 

van der Fluit, F.a , Gaffrey, M.S.b , Klein-Tasman, B.P.a
Social cognition in Williams syndrome: Relations between performance on the social attribution task and cognitive and behavioral characteristics
(2012) Frontiers in Psychology, 3 (JUN), art. no. Article 197, . 

a Child Neurodevelopment Research Lab, Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, United States
b Early Emotional Development Program, Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Williams syndrome (WS) is a developmental disorder of genetic origin, with characteristic cognitive and personality profiles. Studies of WS point to an outgoing and gregarious personality style, often contrasted with autism spectrum disorders; however, recent research has uncovered underlying social reciprocity difficulties in people withWS. Social information processing difficulties that underlie these social reciprocity difficulties have been sparsely examined. Participants in the current study included 24 children with WS ages 8 through 15. A lab-based measure of social perception and social cognition was administered (Social Attribution Test), as well as an intellectual functioning measure (KBIT-II) and parent reports of communication and reciprocal social skills (Social Communication Questionnaire, Social Responsiveness Scale). Relations between social cognition, cognitive abilities, and socialcommunication were examined. Results demonstrated relations between parent-reported social reciprocity and the typicality of the responses provided in the lab-based measure, even once variability in intellectual functioning was taken into account. Specifically, those individuals who produced narratives in response to the social attribution task (SAT) that were more similar to those described in previous studies of typically developing individuals were also reported to have fewer social reciprocity difficulties in the real world setting as reported by parents. In addition, a significant improvement in performance on the SAT was seen with added scaffolding, particularly for participants with stronger intellectual functioning.These findings indicate that difficulties interpreting the social dynamics between others in ambiguous situations may contribute to the social relationship difficulties observed in people withWS, above and beyond the role of intellectual functioning. Exploratory analyses indicated that performance by individuals with stronger intellectual functioning is improved with additional structure to a greater degree than for those with weaker intellectual functioning. Interventions that specifically target these social information processing of individuals with WS would likely be beneficial. © 2012 van der Fluit, Gaffrey and Klein-Tasman.

Author Keywords
Behavioral phenotype;  Social attribution task;  Social cognition;  Social reciprocity;  Williams syndrome

Document Type: Article
Source: Scopus

 

Bugg, J.M.a b , Crump, M.J.C.a b
In support of a distinction between voluntary and stimulus-driven control: A review of the literature on proportion congruent effects

(2012) Frontiers in Psychology, 3 (SEP), art. no. Article 367, . 

a Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Psychology, Brooklyn College of CUNY, Brooklyn, NY, United States

Abstract
Cognitive control is by nowa large umbrella term referring collectively to multiple processes that plan and coordinate actions to meet task goals. A common feature of paradigms that engage cognitive control is the task requirement to select relevant information despite a habitual tendency (or bias) to select goal-irrelevant information. At least since the 1970s, researchers have employed proportion congruent (PC) manipulations to experimentally establish selection biases and evaluate the mechanisms used to control attention. PC manipulations vary the frequency with which irrelevant information conflicts (i.e., is incongruent) with relevant information. The purpose of this review is to summarize the growing body of literature on PC effects across selective attention paradigms, beginning first with Stroop, and then describing parallel effects in flanker and task-switching paradigms. The review chronologically tracks the expansion of the PC manipulation from its initial implementation at the list-wide level, to more recent implementations at the item-specific and context-specific levels. An important theoretical aim is demonstrating that PC effects at different levels (e.g., list-wide vs. item or context-specific) support a distinction between voluntary forms of cognitive control, which operate based on anticipatory information, and relatively automatic or reflexive forms of cognitive control, which are rapidly triggered by the processing of particular stimuli or stimulus features. A further aim is to highlight those PC manipulations that allow researchers to dissociate stimulus-driven control from other stimulus-driven processes (e.g., S-R responding; episodic retrieval). We conclude by discussing the utility of PC manipulations for exploring the distinction between voluntary control and stimulus-driven control in other relevant paradigms. © 2012 Buggand Crump.

Author Keywords
Cognitive control;  Flanker;  Proportion congruent;  Stimulus-driven control;  Stroop;  Voluntary control

Document Type: Article
Source: Scopus

 

Razafsky, D.a , Blecher, N.a , Markov, A.a , Stewart-Hutchinson, P.J.b , Hodzic, D.a
LINC Complexes Mediate the Positioning of Cone Photoreceptor Nuclei in Mouse Retina
(2012) PLoS ONE, 7 (10), art. no. e47180, . 

a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, MO, United States
b Department of Pathology, New York University School of Medicine, New York, NY, United States

Abstract
It has long been observed that many neuronal types position their nuclei within restricted cytoplasmic boundaries. A striking example is the apical localization of cone photoreceptors nuclei at the outer edge of the outer nuclear layer of mammalian retinas. Yet, little is known about how such nuclear spatial confinement is achieved and further maintained. Linkers of the Nucleoskeleton to the Cytoskeleton (LINC complexes) consist of evolutionary-conserved macromolecular assemblies that span the nuclear envelope to connect the nucleus with the peripheral cytoskeleton. Here, we applied a new transgenic strategy to disrupt LINC complexes either in cones or rods. In adult cones, we observed a drastic nuclear mislocalization on the basal side of the ONL that affected cone terminals overall architecture. We further provide evidence that this phenotype may stem from the inability of cone precursor nuclei to migrate towards the apical side of the outer nuclear layer during early postnatal retinal development. By contrast, disruption of LINC complexes within rod photoreceptors, whose nuclei are scattered across the outer nuclear layer, had no effect on the positioning of their nuclei thereby emphasizing differential requirements for LINC complexes by different neuronal types. We further show that Sun1, a component of LINC complexes, but not A-type lamins, which interact with LINC complexes at the nuclear envelope, participate in cone nuclei positioning. This study provides key mechanistic aspects underlying the well-known spatial confinement of cone nuclei as well as a new mouse model to evaluate the pathological relevance of nuclear mispositioning. © 2012 Razafsky et al.

Document Type: Article
Source: Scopus

 

Taghert, P.a , Nitabach, M.b c d
Peptide Neuromodulation in Invertebrate Model Systems
(2012) Neuron, 76 (1), pp. 82-97. 

a Department of Anatomy and Neurobiology, Washington University Medical School, St. Louis, MO 63110, United States
b Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06520, United States
c Department of Genetics, Yale School of Medicine, New Haven, CT 06520, United States
d Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale School of Medicine, New Haven, CT 06520, United States

Abstract
Neuropeptides modulate neural circuits controlling adaptive animal behaviors and physiological processes, such as feeding/metabolism, reproductive behaviors, circadian rhythms, central pattern generation, and sensorimotor integration. Invertebrate model systems have enabled detailed experimental analysis using combined genetic, behavioral, and physiological approaches. Here we review selected examples of neuropeptide modulation in crustaceans, mollusks, insects, and nematodes, with a particular emphasis on the genetic model organisms Drosophila melanogaster and Caenorhabditis elegans, where remarkable progress has been made. On the basis of this survey, we provide several integrating conceptual principles for understanding how neuropeptides modulate circuit function, and also propose that continued progress in this area requires increased emphasis on the development of richer, more sophisticated behavioral paradigms. Neuropeptides modulate neural circuits controlling adaptive animal behaviors and physiological processes. Here Taghert and Nitabach review selected examples of neuropeptide modulation in invertebrates and provide integrating conceptual principles for understanding how neuropeptides modulate circuit function. © 2012 Elsevier Inc.

Document Type: Review
Source: Scopus

 

Lee, A.G.a b c d e , Oetting, T.A.d , Blomquist, P.H.f , Bradford, G.g , Culican, S.M.h , Kloek, C.i , Krishnan, C.j , Lauer, A.K.k , Levi, L.l , Naseri, A.m , Rubin, S.E.n , Scott, I.U.o , Tao, J.p , Tuli, S.q , Wright, M.M.r , Wudunn, D.s , Zimmerman, M.B.d
A multicenter analysis of the ophthalmic knowledge assessment program and American board of ophthalmology written qualifying examination performance
(2012) Ophthalmology, 119 (10), pp. 1949-1953. 

a Department of Ophthalmology, Methodist Hospital, 6560 Fannin Street, Scurlock 450, Houston, TX 77030, United States
b Department of Ophthalmology, Neurology and Neurosurgery, Weill Cornell Medical College, New York, NY, United States
c Department of Ophthalmology, Baylor College of Medicine, Houston, TX, United States
d Department of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City, IA, United States
e Department of Ophthalmology, University of Texas, Medical Branch, Galveston, TX, United States
f University of Texas, Southwestern Medical Center, Dallas, TX, United States
g West Virginia University, Morgantown, WV, United States
h Washington University, School of Medicine, St. Louis, MO, United States
i Massachusetts Eye and Ear Infirmary, Boston, MA, United States
j Tufts University, Boston, MA, United States
k Casey Eye Institute, Oregon Health and Science University, Portland, OR, United States
l University of California, San Diego, San Diego, CA, United States
m University of California, San Francisco, San Francisco, CA, United States
n North Shore-Long Island Jewish Health System, Great Neck, NY, United States
o Penn State College of Medicine, Hershey, PA, United States
p University of California, Irvine, Irvine, CA, United States
q University of Florida, Gainesville, FL, United States
r University of Minnesota, Minneapolis, MN, United States
s Indiana University, Indianapolis, IN, United States

Abstract
Objective: To compare the performance on the American Board of Ophthalmology Written Qualifying Examination (WQE) with the performance on step 1 of the United States Medical Licensing Examination (USMLE) and the Ophthalmic Knowledge Assessment Program (OKAP) examination for residents in multiple residency programs. Design: Comparative case series. Participants: Fifteen residency programs with 339 total residents participated in this study. The data were extracted from the 5-year American Board of Ophthalmology report to each participating program in 2009 and included residency graduating classes from 2003 through 2007. Residents were included if data were available for the USMLE, OKAP examination in ophthalmology years 1 through 3, and the WQE score. Residents were excluded if one or more of the test scores were not available. Methods: Two-sample t tests, logistic regression analysis, and receiver operating characteristic (ROC) curves were used to examine the association of the various tests (USMLE, OKAP examination year 1, OKAP examination year 2, OKAP examination year 3, and maximum OKAP examination score) as a predictor for a passing or failing grade on the WQE. Main Outcome Measures: The primary outcome measure of this study was first time pass rate for the WQE. Results: Using ROC analysis, the OKAP examination taken at the third year of ophthalmology residency best predicted performance on the WQE. For the OKAP examination taken during the third year of residency, the probability of passing the WQE was at least 80% for a score of 35 or higher and at least 95% for a score of 72 or higher. Conclusions: The OKAP examination, especially in the third year of residency, can be useful to residents to predict the likelihood of success on the high-stakes WQE examination. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. © 2012 American Academy of Ophthalmology.

Document Type: Article
Source: Scopus

 

Caldwell, B.a , Sumner, W.b , Crane, J.a
A systematic review of nicotine by inhalation: Is there a role for the inhaled route?
(2012) Nicotine and Tobacco Research, 14 (10), pp. 1127-1139. 

a Department of Medicine, University of Otago, Wellington, New Zealand
b Division of General Medical Sciences, Department of Medicine, Washington University School of Medicine, St Louis, MO, United States

Abstract
Introduction: A considerable minority of adults remain addicted to smoking cigarettes despite substantial education and public health efforts. Nicotine replacement therapies have only modest long-term quit rates. The pulmonary route of nicotine delivery has advantages over other routes. However, there are regulatory and technical barriers to the development of pulmonary nicotine delivery devices, and hence, none are commercially available. Current knowledge about pulmonary nicotine delivery is scattered throughout the literature and other sources such as patent applications. This review draws together what is currently known about pulmonary nicotine delivery and identifies potential ways that deep lung delivery can be achieved with a simple portable device. Aims: To systematically review clinical trials of nicotine inhalers, determine whether they delivered nicotine via the lung, and identify ways that pulmonary delivery of medicinal nicotine might be achieved and the technical issues involved. Methods: Systematic search of Medline and Embase. Results: Thirty-eight trials met the inclusion criteria. Cough, reflex interruption of smooth inspiration, and throat scratch limited the usefulness of nicotine inhalers. The pharmacokinetic profiles of portable nicotine inhalers were inferior to smoking, but among commercially available products, electronic cigarettes are currently the most promising. Conclusions: Pulmonary nicotine delivery might be maximized by use of nicotine salts, which have a more physiological pH than pure nicotine, by ensuring the mass of the particles is optimal for alveolar absorption, and by adding flavoring agents. Metered-dose inhalers potentially can deliver nicotine more efficiently than other nicotine products, facilitating smoking cessation and improving smokers ' lives. © The Author 2012. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco.

Document Type: Review
Source: Scopus

 

Cruchaga, C.a g , Kauwe, J.S.h , Nowotny, P.a , Bales, K.i , Pickering, E.H.i , Mayo, K.a , Bertelsen, S.a , Hinrichs, A.a , Fagan, A.M.b f g , Holtzman, D.M.b e f g , Morris, J.C.b c f g , Goate, A.M.a b d f g
Cerebrospinal fluid APOE levels: An endophenotype for genetic studies for Alzheimer's disease

(2012) Human Molecular Genetics, 21 (20), art. no. dds296, pp. 4558-4571. 

a Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, United States
b Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, United States
c Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, United States
d Department of Genetics, Washington University School of Medicine, St Louis, MO 63110, United States
e Department of Developmental Biology, Washington University School of Medicine, St Louis, MO 63110, United States
f Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, MO 63110, United States
g Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO 63110, United States
h Department of Biology, Brigham Young University, Provo, UT, United States
i Neuroscience Research Unit, Worldwide Research and Development, Pfizer, Inc., Groton, CT, United States

Abstract
The apolipoprotein E (APOE) genotype is the major genetic risk factor for Alzheimer's disease (AD). We have access to cerebrospinal fluid (CSF) and plasma APOE protein levels from 641 individuals and genome-wide genotyped data from 570 of these samples. The aim of this study was to test whether CSF or plasma APOE levels could be a useful endophenotype for AD and to identify genetic variants associated with APOE levels. We found that CSF (P = 8.15 × 10 -4) but not plasma (P = 0.071) APOE protein levels are significantly associated with CSF Aβ 42 levels. We used Mendelian randomization and genetic variants as instrumental variables to confirm that the association of CSF APOE with CSF Aβ 42 levels and clinical dementia rating (CDR) is not because of a reverse causation or confounding effect. In addition the association of CSF APOE with Aβ 42 levels was independent of the APOE ε4 genotype, suggesting that APOE levels in CSF may be a useful endophenotype for AD. We performed a genome-wide association study to identify genetic variants associated with CSF APOE levels: the APOE ε4 genotype was the strongest single-genetic factor associated with CSF APOE protein levels (P = 6.9 × 10 -13). In aggregate, the Illumina chip single nucleotide polymorphisms explain 72% of the variability in CSF APOE protein levels, whereas the APOE ε4 genotype alone explains 8% of the variability. No other genetic variant reached the genome-wide significance threshold, but nine additional variants exhibited a P-value &lt;10 -6. Pathway mining analysis indicated that these nine additional loci are involved in lipid metabolism (P = 4.49 × 10 -9). © The Author 2012. Published by Oxford University Press. All rights reserved.

Document Type: Article
Source: Scopus

 

Le Glou, E.a , Seugnet, L.a b , Shaw, P.J.c , Preat, T.a , Goguel, V.a
Circadian modulation of consolidated memory retrieval following sleep deprivation in Drosophila
(2012) Sleep, 35 (10), pp. 1377-1384. 

a Genes and Dynamics of Memory Systems, CNRS, ESPCI, Paris, France
b Integrative Physiology of Brain Arousal Systems, Lyon Neuroscience Research Center, CNRS UMR 5292, Lyon, France
c Department of Anatomy and Neurobiology, Washington University, St. Louis, MO, United States

Abstract
Study Objectives: Several lines of evidence indicate that sleep plays a critical role in learning and memory. The aim of this study was to evaluate anesthesia resistant memory following sleep deprivation in Drosophila. Design: Four to 16 h after aversive olfactory training, flies were sleep deprived for 4 h. Memory was assessed 24 h after training. Training, sleep deprivation, and memory tests were performed at different times during the day to evaluate the importance of the time of day for memory formation. The role of circadian rhythms was further evaluated using circadian clock mutants. Results: Memory was disrupted when flies were exposed to 4 h of sleep deprivation during the consolidation phase. Interestingly, normal memory was observed following sleep deprivation when the memory test was performed during the 2 h preceding lights-off, a period characterized by maximum wake in flies. We also show that anesthesia resistant memory was less sensitive to sleep deprivation in flies with disrupted circadian rhythms. Conclusions: Our results indicate that anesthesia resistant memory, a consolidated memory less costly than long-term memory, is sensitive to sleep deprivation. In addition, we provide evidence that circadian factors influence memory vulnerability to sleep deprivation and memory retrieval. Taken together, the data show that memories weakened by sleep deprivation can be retrieved if the animals are tested at the optimal circadian time.

Author Keywords
Activity peak;  Circadian rhythms;  Clock mutant;  Drosophila;  Memory consolidation;  Memory retrieval;  Recall;  Sleep deprivation

Document Type: Article
Source: Scopus

 

Hayashi-Kurahashi, N.a b c , Kidokoro, H.b c d , Kubota, T.b , Maruyama, K.a b , Kato, Y.b , Kato, T.b e , Natsume, J.c , Hayakawa, F.e , Watanabe, K.c f , Okumura, A.g
EEG for predicting early neurodevelopment in preterm infants: An observational cohort study
(2012) Pediatrics, 130 (4), pp. e891-e897. 

a Department of Pediatric Neurology, Central Hospital of Aichi Welfare Center for Persons with Developmental Disabilities, Kasugai, Japan
b Department of Pediatrics, Anjo Kosei Hospital, Anjo, Japan
c Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
d Department of Pediatrics, Washington University in St Louis, 660 South Euclid Ave, St Louis, MO 63110, United States
e Department of Pediatrics, Okazaki City Hospital, Okazaki, Japan
f Faculty of Health and Medical Science, Aichi Shukutoku University, Nagakute, Japan
g Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan

Abstract
OBJECTIVE: To clarify the prognostic value of conventional EEG for the identification of preterm infants at risk for subsequent adverse neurodevelopment in the current perinatal care and medicine setting. METHODS: We studied 780 EEG records of 333 preterm infants born <34 weeks' gestation between 2002 and 2008. Serial EEG recordings were conducted during 3 time periods; at least once each within days 6 (first period), during days 7 to 19 (second period), and days 20 to 36 (third period). The presence and the grade of EEG background abnormalities were assessed according to an established classification system. Neurodevelopmental outcomes were assessed at a corrected age of 12 to 18 months. RESULTS: Of the 333 infants, 33 (10%) had developmental delay and 34 (10%) had cerebral palsy. The presence of EEG abnormalities was significantly predictive of developmental delay and cerebral palsy at all 3 time periods: the first period (n = 265; odds ratio [OR], 4.5; 95% confidence interval [CI], 2.2-9.4), the second period (n = 278; OR, 7.6; 95% CI, 3.6-16), and the third period (n = 237; OR, 5.9; 95% CI, 2.8-13). The grade of EEG abnormalities correlated with the incidence of developmental delay or cerebral palsy in all periods (P < .001). After controlling for other clinical variables, including severe brain injury, EEG abnormality in the second period was an independent predictor of developmental delay (OR, 3.2; 95% CI, 1.1-9.7) and cerebral palsy (OR, 6.8; 95% CI 2.0-23). CONCLUSIONS: EEG abnormalities within the first month of life significantly predict adverse neurodevelopment at a corrected age of 12 to 18 months in the current preterm survivor. Copyright © 2012 by the American Academy of Pediatrics.

Author Keywords
EEG;  Neurodevelopmental;  Preterm

Document Type: Article
Source: Scopus

 

Gilboa, E.a , La Rosa, P.S.b , Nehorai, A.a
Estimating electrical conductivity tensors of biological tissues using microelectrode arrays
(2012) Annals of Biomedical Engineering, 40 (10), pp. 2140-2155. 

a Preston M. Green Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
b Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
Finding the electrical conductivity of tissue is highly important for understanding the tissue's structure and functioning. However, the inverse problem of inferring spatial conductivity from data is highly ill-posed and computationally intensive. In this paper, we propose a novel method to solve the inverse problem of inferring tissue conductivity from a set of transmembrane potential and stimuli measurements made by microelectrode arrays (MEA). We first formalize the discrete forward model of transmembrane potential propagation, based on a reaction- diffusion model with an anisotropic inhomogeneous electrical conductivity-tensor field. Then, we propose a novel parallel optimization algorithm for solving the complex inverse problem of estimating the electrical conductivitytensor field. Specifically, we propose a single-step approximation with a parallel block-relaxation optimization routine that simplifies the joint tensor field estimation problem into a set of computationally tractable subproblems, allowing the use of efficient standard optimization tools. Finally, using numerical examples of several electrical conductivity field topologies and noise levels, we analyze the performance of our algorithm, and discuss its application to real measurements obtained from smooth-muscle cardiac tissue, using data collected with a high-resolution MEA system. © 2012 Biomedical Engineering Society.

Author Keywords
Alternating optimization;  Bidomain model;  Biological tissues;  Electrical conductivity;  Inverse solution;  Microelectrode array;  Parallel optimization;  Tensor field

Document Type: Article
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, 33 (5), pp. 1356-1361. 

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

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.

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

Document Type: Article
Source: Scopus

 

Verweij, K.J.a b c , Yang, J.a , Lahti, J.c , Veijola, J.d , Hintsanen, M.e , Pulkki-Råback, L.e , Heinonen, K.c , Pouta, A.f , Pesonen, A.-K.c , Widen, E.g , Taanila, A.h , Isohanni, M.c , Miettunen, J.d , Palotie, A.g i j , Penke, L.k , Service, S.K.l , Heath, A.C.m , Montgomery, G.W.a , Raitakari, O.n , Kähönen, M.o , Viikari, J.p , Räikkönen, K.c , Eriksson, J.G.f q r s t , Keltikangas-Järvinen, L.e , Lehtimäki, T.u , Martin, N.G.a , Järvelin, M.-R.h v w x , Visscher, P.M.a , Keller, M.C.y z , Zietsch, B.P.a b c z
Maintenance of genetic variation in human personality: Testing evolutionary models by estimating heritability due to common causal variants and investigating the effect of distant inbreeding

(2012) Evolution, 66 (10), pp. 3238-3251. 

a Queensland Statistical Genetics Laboratories, Queensland Institute of Medical Research, Herston 4006, Brisbane, Qld, Australia
b School of Psychology, University of Queensland, St Lucia 4067, Brisbane, Qld, Australia
c Institute of Behavioural Sciences, University of Helsinki, Helsinki 00014, Finland
d Institute of Clinical Medicine, University of Oulu, Oulu 90014, Finland
e Institute of Behavioural Sciences/Psychology, University of Helsinki, Helsinki 00014, Finland
f National Institute for Health and Welfare, Oulu 90101, Finland
g Institute for Molecular Medicine Finland, University of Helsinki, Helsinki 00014, Finland
h Institute of Health Sciences, University of Oulu, Oulu 90014, Finland
i Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10, 1SA, United Kingdom
j Department of Medical Genetics, University of Helsinki, University Central Hospital, Helsinki 00014, Finland
k Department of Psychology, Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom
l University of California Los Angeles, Semel Institute of Neuroscience and Human Behavior, Los Angeles, CA 90095, United States
m Department of Psychiatry, Washington University, School of Medicine, St Louis 63130, MO, United States
n Department of Clinical Physiology, Turku Univ. Hospital and Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20521, Finland
o Department of Clinical Physiology, Tampere University Hospital, University of Tampere School of Medicine, Tampere 33014, Finland
p Department of Medicine, Turku University Hospital, University of Turku, Turku 20521, Finland
q Department of General Practice and Primary health Care, University of Helsinki, Helsinki 00014, Finland
r Helsinki University Central Hospital, Unit of General Practice, Helsinki 00029, Finland
s Folkhälsan Research Centre, Helsinki 00014, Finland
t Vasa Central Hospital, Vasa 65130, Finland
u Department of Clinical Chemistry, Tampere University Hospital, University of Tampere School of Medicine, Tampere 33014, Finland
v Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, MRC-HPA Centre for Environment and Health, Faculty of Medicine, London W2 1PG, United Kingdom
w Biocenter Oulu, University of Oulu, Oulu 90014, Finland
x Department of Lifecourse and Services, National Institute for Health and Welfare, Oulu 90101, Finland
y Department of Psychology and Neuroscience, University of Colorado, Boulder 80309, CO, United States
z Institute for Behavioral Genetics, University of Colorado, Boulder 80303, CO, United States

Abstract
Personality traits are basic dimensions of behavioral variation, and twin, family, and adoption studies show that around 30% of the between-individual variation is due to genetic variation. There is rapidly growing interest in understanding the evolutionary basis of this genetic variation. Several evolutionary mechanisms could explain how genetic variation is maintained in traits, and each of these makes predictions in terms of the relative contribution of rare and common genetic variants to personality variation, the magnitude of nonadditive genetic influences, and whether personality is affected by inbreeding. Using genome-wide single nucleotide polymorphism (SNP) data from > 8000 individuals, we estimated that little variation in the Cloninger personality dimensions (7.2% on average) is due to the combined effect of common, additive genetic variants across the genome, suggesting that most heritable variation in personality is due to rare variant effects and/or a combination of dominance and epistasis. Furthermore, higher levels of inbreeding were associated with less socially desirable personality trait levels in three of the four personality dimensions. These findings are consistent with genetic variation in personality traits having been maintained by mutation-selection balance. © 2012 The Author(s). Evolution © 2012 The Society for the Study of Evolution..

Author Keywords
Antagonistic pleiotropy;  Balancing selection;  Behavioral syndromes;  Correlational selection;  Evolution;  Mutation;  Mutation-selection balance;  Neutral;  Personality;  Temperament;  Trade-offs

Document Type: Article
Source: Scopus

 

Conklyn, D.a , Novak, E.b c , Boissy, A.b , Bethoux, F.b , Chemali, K.b
The effects of modified melodic intonation therapy on nonfluent aphasia: Apilot study
(2012) Journal of Speech, Language, and Hearing Research, 55 (5), pp. 1463-1471. 

a The Music Settlement, Cleveland, OH, United States
b The Cleveland Clinic Foundation, United States
c Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Objective: Positive results have been reported with melodic intonation therapy (MIT) in nonfluent aphasia patientswith damage to their left-brain speech processes, using the patient's intact ability to sing to promote functional language. This pilot study sought to determine the immediate effects of introducing modified melodic intonation therapy (MMIT), a modification of MIT, as an early intervention in stroke patients presenting with Broca's aphasia. Method: After a randomized controlled single-blind design, 30 acute stroke survivors with nonfluent aphasia were randomly assigned to receive MIT treatment or no treatment. A pre/post test, based on the responsive and repetition subsections of the Western Aphasia Battery, was developed for this study. Results: After 1 session, a significant within-subject change was observed for the treatment group's adjusted total score (p =.02), and a significant difference between groups was found for adjusted total score (p =.02) favoring the treatment group. The treatment group also showed a significant change in their responsive subsection scores (p =.01) when their pre-tests from Visit 1 to Visit 2 were compared, whereas the control group showed no change, suggesting a possible carry-over effect of MIT treatment. Conclusion: This study provides preliminary data supporting the possible benefits of utilizing MMIT treatment early in the recovery of nonfluent aphasia patients. © American Speech-Language-Hearing Association.

Author Keywords
Aphasia;  Melodic intonation therapy;  Modified melodic intonation therapy;  Speech rehabilitation;  Stroke

Document Type: Article
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, 14 (10), pp. 1105-1112. 

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

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. © 2012 Macmillan Publishers Limited. All rights reserved.

Document Type: Article
Source: Scopus

 

Mattingly, G.a , Weisler, R.b c , Dirks, B.d , Babcock, T.d , Adeyi, B.d , Scheckner, B.d , Lasser, R.d
Attention deficit hyperactivity disorder subtypes and symptom response in adults treated with lisdexamfetamine dimesylate
(2012) Innovations in Clinical Neuroscience, 9 (5-6), pp. 22-30. 

a Washington University School of Medicine, 330 First Capitol Drive, Suite 390, St. Charles, MO 63301, United States
b Duke University Medical Center in Durham, NC, United States
c University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
d Shire Development LLC, Wayne, PA, United States

Abstract
Objective: To evaluate the efficacy of lisdexamfetamine dimesylate in adults with attention deficit hyperactivity disorder symptom subtypes who exhibit predominantly inattention, hyperactivity/ impulsivity, or combined symptom clusters. Design/Setting/Participants: This is a post-hoc analysis from a multicenter, one-year, open-label lisdexamfetamine dimesylate study in adults with attention deficit hyperactivity disorder previously completing two weeks or more in a four-week, randomized, placebo controlled lisdexamfetamine dimesylate study, using Attention Deficit Hyperactivity Disorder Rating Scale IV symptom ratings as an attention deficit hyperactivity disorder subtype proxy (N=349). Measurements: Attention Deficit Hyperactivity Disorder Rating Scale IV was measured at baseline of prior study and throughout the open-label study. Proxy subtypes were based on item scores of 2 (moderate) or 3 (severe), representing endorsement of at least six of nine symptoms on respective subscales; predominantly combined type endorsed at least six of nine symptoms on each subscale. Overall safety evaluations included treatment-emergent adverse events. Results: At baseline, 93 of 345 participants exhibited predominantly inattention, 13 predominantly hyperactivity/ impulsivity, 236 combined symptom clusters, and three were unassigned. For the three subgroups, respectively, mean (standard deviation) Attention Deficit Hyperactivity Disorder Rating Scale IV total scores at baseline were 34.5 (4.02), 33.8 (3.27), and 43.6 (5.24); change from baseline to endpoint scores were -19.3 (9.48), -24.0 (7.22), and -27.3 (11.78). Mean (standard deviation) end-of-study lisdexamfetamine dimesylate dose was 57.7 (14.75), 53.1 (16.01), and 56.9 (14.94)mg/day, respectively. Treatment-emergent adverse events (<5%) were upper respiratory tract infection (21.8%), insomnia (19.5%), headache (17.2%), dry mouth (16.6%), decreased appetite (14.3%), irritability (11.2%), anxiety (8.3%), nasopharyngitis (7.4%), sinusitis (6.6%), decreased weight (6.0%), back pain (5.4%), and muscle spasms (5.2%). Conclusions: Lisdexamfetamine dimesylate was effective in participants with predominantly inattention, hyperactivity/ impulsivity, and combined attention deficit hyperactivity disorder symptom clusters. Groups exhibiting specific predominant subtype symptoms did not differ in clinical response to lisdexamfetamine dimesylate.

Author Keywords
ADHD-RS-IV symptom subtype;  Adults;  Amphetamine;  Attention-deficit/hyperactivity disorder (ADHD);  Clinical response;  Lisdexamfetamine dimesylate (LDX);  Predominantly combined;  Predominantly hyperactivity/ impulsivity;  Predominantly inattention;  Stimulant

Document Type: Article
Source: Scopus

 

Callejas, A.a , Shulman, G.L.a , Corbetta, M.a b c
False belief vs. false photographs: A test of theory of mind or working memory?
(2011) Frontiers in Psychology, 2 (NOV), art. no. Article 316, . 

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

Document Type: Article
Source: Scopus

 

Bollich, K.L., Johannet, P.M., Vazire, S.
In search of our true selves: Feedback as a path to self-knowledge
(2011) Frontiers in Psychology, 2 (NOV), art. no. Article 312, . 

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

Abstract
How can self-knowledge of personality be improved? What path is the most fruitful source for learning about our true selves? Previous research has noted two main avenues for learning about the self: looking inward (e.g., introspection) and looking outward (e.g., feedback). Although most of the literature on these topics does not directly measure the accuracy of self-perceptions (i.e., self-knowledge), we review these paths and their potential for improving self-knowledge. We come to the conclusion that explicit feedback, a largely unexamined path, is likely a fruitful avenue for learning about one's own personality. Specifically, we suggest that self-knowledge might be fully realized through the use of explicit feedback from close, knowledgeable others. As such, we conclude that the road to self-knowledge likely cannot be traveled alone but must be traveled with close others who can help shed light on our blind spots. © 2011 Bollich, Johannet and Vazire.

Author Keywords
Feedback;  Introspection;  Personality;  Self-knowledge

Document Type: Article
Source: Scopus

 

Du, F.a , Abrams, R.A.b , Kan Zhanga
Spatial distribution of the attentional blink
(2011) Frontiers in Psychology, 2 (DEC), art. no. Article 360, . 

a State Key Laboratory of Brain and Cognitive Science, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
b Department of Psychology, Washington University, St. Louis, MO 63130, United States

Abstract
In the present study subjects viewed streams of rapid serially presented characters and searched for a target digit. After presentation of the target digit, a second target consisting of an orientation singleton (Experiment 1) or a second digit (Experiment 2) was presented at one of several distances from the first target. The attentional blink (AB) impaired performance on the second target with the effect being strongest at distances somewhat removed from the first target location. These results are consistent with lateral inhibition theory and help to resolve some fundamental questions about the spatial distribution of the AB. © 2011 Du, Abrams and Zhang.

Author Keywords
Attention;  Attentional blink;  Spatial attention

Document Type: Article
Source: Scopus

 


October 10, 2012

Han, Y.-P.a b , Sim, A.J.a , Vora, S.C.a , Huang, A.J.W.a
A unique TGFBI protein in granular corneal dystrophy types 1 and 2
(2012) Current Eye Research, 37 (11), pp. 990-996. 

a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Campus Box 8096, 660 S. Euclid Avenue, Saint Louis, MO 63110, United States
b Shanxi Eye Hospital, Taiyuan, China

Abstract
Purpose: Types 1 and 2 granular corneal dystrophies (GCD) are primarily associated with accumulation of the R555W and R124H mutant transforming growth factor β-inducible proteins (TGFBIp) in corneal stroma, respectively. However, specific components of TGFBIp responsible for granular deposits have not been delineated. This study was undertaken to identify the mutant TGFBIp components potentially responsible for GCD. Methods: Recombinant TGFBIp of wild-type (WT) and three mutants, R124C, R124H, and R555W, were generated in HEK293FT cells. WT and TGFBIp mutants were collected from cell lysates. Immunoblot analyses were performed with five different antibodies directed against various regions of WT TGFBIp. Results: WT and TGFBIp mutants showed differential reactivities with these antibodies. In contrast to our prior observation in purified WT and TGFBIp mutants, TGFBIp from cell lysates were less prone to polymerize. A unique 35 kD fragment was detected in cell lysates of R555W and R124H, but not in those of WT or R124C, by a commercial antibody raised against amino acids (a.a.) 199406 of TGFBIp. Conclusions: Monomeric and polymeric WT and TGFBIp mutants were observed in vitro. The 35 kD fragment found only in R555W and R124H, but not in WT and R124C cell lysates, is likely a degraded TGFBIp derived from the central domain of these mutants and this fragment may be contributory to the nonamyloid granular deposits observed in GCD 1 and 2. © 2012 Informa Healthcare USA, Inc.

Author Keywords
Amyloid;  Anti-TGFBIp;  Corneal dystrophies;  Protein misfolding;  TGFBIp

Document Type: Article
Source: Scopus

 

Boxer, A.L.a , Gold, M.b , Huey, E.c , Gao, F.-B.d , Burton, E.A.e , Chow, T.f , Kao, A.a , Leavitt, B.R.g , Lamb, B.h , Grether, M.i , Knopman, D.j , Cairns, N.J.k , Mackenzie, I.R.l , Mitic, L.i , Roberson, E.D.m , Van Kammen, D.n , Cantillon, M.o , Zahs, K.p , Salloway, S.q , Morris, J.k , Tong, G.r , Feldman, H.s , Fillit, H.t , Dickinson, S.u , Khachaturian, Z.v , Sutherland, M.w , Farese, R.x , Miller, B.L.a , Cummings, J.y
Frontotemporal degeneration, the next therapeutic frontier: Molecules and animal models for frontotemporal degeneration drug development
(2012) Alzheimer's and Dementia, . Article in Press. 

a Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA
b Allon Therapeutics, Vancouver, British Columbia, Canada
c Department of Neurology, Taub Institute, Columbia University, New York, NY, USA
d Department of Neurology, University of Massachusetts, Worcester, MA, USA
e Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
f Rotman Research Institute, University of Toronto, Toronto, Ontario, Canada
g Division of Neurology, Department of Medicine, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada
h Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
i Bluefield Project to Cure Frontotemporal Dementia, San Francisco, CA, USA
j Department of Neurology, Mayo Clinic, Rochester, MN, USA
k Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
l Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
m Department of Neurology, University of Alabama School of Medicine, Birmingham, AL, USA
n CNS Drug Development Consultant, Princeton, NJ, USA
o Critical Path Institute, Rockville, MD, USA
p Grossman Center for Memory Research and Care, University of Minnesota School of Medicine, Minneapolis, MN, USA
q Department of Neurology, Brown University School of Medicine, Providence, RI, USA
r Bristol Myers Squibb, Princeton, NJ, USA
s Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
t Alzheimer's Drug Discovery Foundation, New York, NY, USA
u Association for Frontotemporal Degeneration, Radnor, PA, USA
v KRA Associates, Potomac, MD, USA
w National Institutes of Health/National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
x Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA
y Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA

Abstract
Frontotemporal degeneration (FTD) is a common cause of dementia for which there are currently no approved therapies. Over the past decade, there has been an explosion of knowledge about the biology and clinical features of FTD that has identified a number of promising therapeutic targets as well as animal models in which to develop drugs. The close association of some forms of FTD with neuropathological accumulation of tau protein or increased neuroinflammation due to progranulin protein deficiency suggests that a drug's success in treating FTD may predict efficacy in more common diseases such as Alzheimer's disease. A variety of regulatory incentives, clinical features of FTD such as rapid disease progression, and relatively pure molecular pathology suggest that there are advantages to developing drugs for FTD as compared with other more common neurodegenerative diseases such as Alzheimer's disease. In March 2011, the Frontotemporal Degeneration Treatment Study Group sponsored a conference entitled "FTD, the Next Therapeutic Frontier," which focused on preclinical aspects of FTD drug development. The goal of the meeting was to promote collaborations between academic researchers and biotechnology and pharmaceutical researchers to accelerate the development of new treatments for FTD. Here we report the key findings from the conference, including the rationale for FTD drug development; epidemiological, genetic, and neuropathological features of FTD; FTD animal models and how best to use them; and examples of successful drug development collaborations in other neurodegenerative diseases. © 2012 The Alzheimer's Association.

Author Keywords
Frontotemporal degeneration;  Progranulin;  Tau;  TDP-43;  Treatment

Document Type: Article in Press
Source: Scopus

 

He, X.a , Haselhorst, T.b , Von Itzstein, M.b , Kolarich, D.c g , Packer, N.H.c , Gloster, T.M.d h , Vocadlo, D.J.d , Clarke, L.A.e , Qian, Y.f , Kermode, A.R.a
Production of α-L-iduronidase in maize for the potential treatment of a human lysosomal storage disease
(2012) Nature Communications, 3, art. no. 1062, . 

a Department of Biological Sciences, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada
b Institute for Glycomics, Griffith University, Gold Coast Campus, QLD 4222, Australia
c Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW 2109, Australia
d Department of Chemistry, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada
e Department of Medical Genetics, University of British Columbia, Child and Family Research Institute, 950 W 28th Avenue, Vancouver, BC, V5Z 4H4, Canada
f Department of Internal Medicine, Washington University School of Medicine, St Louis, MI 63110, United States
g Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, 14424 Potsdam, Germany
h School of Chemistry, University of St Andrews, Biomolecular Sciences Building, North Haugh, St Andrews KY16 9ST, United Kingdom

Abstract
Lysosomal storage diseases are a class of over 70 rare genetic diseases that are amenable to enzyme replacement therapy. Towards developing a plant-based enzyme replacement therapeutic for the lysosomal storage disease mucopolysaccharidosis I, here we expressed α-L-iduronidase in the endosperm of maize seeds by a previously uncharacterized mRNA-targeting-based mechanism. Immunolocalization, cellular fractionation and in situ RT-PCR demonstrate that the α-L-iduronidase protein and mRNA are targeted to endoplasmic reticulum (ER)-derived protein bodies and to protein body-ER regions, respectively, using regulatory (5′-and 3′-UTR) and signal-peptide coding sequences from the γ-zein gene. The maize α-L-iduronidase exhibits high activity, contains high-mannose N-glycans and is amenable to in vitro phosphorylation. This mRNA-based strategy is of widespread importance as plant N-glycan maturation is controlled and the therapeutic protein is generated in a native form. For our target enzyme, the N-glycan structures are appropriate for downstream processing, a prerequisite for its potential as a therapeutic protein. ©2012 Macmillan Publishers Limited. All rights reserved.

Document Type: Article
Source: Scopus

 

Malcolm, H.R.a , Heo, Y.-Y.b , Caldwell, D.B.a , McConnell, J.K.a , Hawkins, J.F.b , Guayasamin, R.C.b , Elmore, D.E.b , Maurer, J.A.a
Ss-bCNGa: a unique member of the bacterial cyclic nucleotide gated (bCNG) channel family that gates in response to mechanical tension
(2012) European Biophysics Journal, pp. 1-11. Article in Press. 

a Department of Chemistry, Washington University in St. Louis, St. Louis, 63130, United States
b Department of Chemistry, Wellesley College, Wellesley, 02481, United States

Abstract
Bacterial cyclic nucleotide gated (bCNG) channels are generally a nonmechanosensitive subset of the mechanosensitive channel of small conductance (MscS) superfamily. bCNG channels are composed of an MscS channel domain, a linking domain, and a cyclic nucleotide binding domain. Among bCNG channels, the channel domain of Ss-bCNGa, a bCNG channel from Synechocystis sp. PCC 6803, is most identical to Escherichia coli (Ec) MscS. This channel also exhibits limited mechanosensation in response to osmotic downshock assays, making it the only known full-length bCNG channel to respond to hypoosmotic stress. Here, we compare and contrast the ability of Ss-bCNGa to gate in response to mechanical tension with Se-bCNG, a nonmechanosensitive bCNG channel, and Ec-MscS, a prototypical mechanosensitive channel. Compared with Ec-MscS, Ss-bCNGa only exhibits limited mechanosensation, which is most likely a result of the inability of Ss-bCNGa to form the strong lipid contacts needed for significant function. Unlike Ec-MscS, Ss-bCNGa displays a mechanical response that increases with protein expression level, which may result from channel clustering driven by interchannel cation-π interactions. © 2012 European Biophysical Societies' Association.

Author Keywords
Bacterial cyclic nucleotide gated (bCNG) channels;  Cation-π interactions;  Lipid interactions;  Mechanosensation;  Mechanosensitive channel of small conductance (MscS);  Osmotic downshock

Document Type: Article in Press
Source: Scopus

 

Joseph, N.M.a , Phillips, J.b c , Dahiya, S.d , M Felicella, M.a , Tihan, T.a , Brat, D.J.e , Perry, A.b c
Diagnostic implications of IDH1-R132H and OLIG2 expression patterns in rare and challenging glioblastoma variants
(2012) Modern Pathology, . Article in Press. 

a Department of Pathology, University of California San Francisco (UCSF), San Francisco, CA, USA
b 1] Department of Pathology, University of California San Francisco (UCSF), San Francisco, CA, USA
c Department of Neurological Surgery, University of California San Francisco (UCSF), San Francisco, CA, USA
d Department of Pathology and Immunology, Division of Neuropathology, Washington University School of Medicine, St Louis, MO, USA
e Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA

Abstract
Recent work has demonstrated that nearly all diffuse gliomas display nuclear immunoreactivity for the bHLH transcription factor OLIG2, and the R132H mutant isocitrate dehydrogenase 1 (IDH1) protein is expressed in the majority of diffuse gliomas other than primary glioblastoma. However, these antibodies have not been widely applied to rarer glioblastoma variants, which can be diagnostically challenging when the astrocytic features are subtle. We therefore surveyed the expression patterns of OLIG2 and IDH1 in 167 non-conventional glioblastomas, including 45 small cell glioblastomas, 45 gliosarcomas, 34 glioblastomas with primitive neuroectodermal tumor-like foci (PNET-like foci), 23 with an oligodendroglial component, 11 granular cell glioblastomas, and 9 giant cell glioblastomas. OLIG2 was strongly expressed in all glioblastomas with oligodendroglial component, 98% of small cell glioblastomas, and all granular cell glioblastomas, the latter being particularly helpful in ruling out macrophage-rich lesions. In 74% of glioblastomas with PNET-like foci, OLIG2 expression was retained in the PNET-like foci, providing a useful distinction from central nervous system PNETs. The glial component of gliosarcomas was OLIG2 positive in 93% of cases, but only 14% retained focal expression in the sarcomatous component; as such this marker would not reliably distinguish these from pure sarcoma in most cases. OLIG2 was expressed in 67% of giant cell glioblastomas. IDH1 was expressed in 55% of glioblastomas with oligodendroglial component, 15% of glioblastomas with PNET-like foci, 7% of gliosarcomas, and none of the small cell, granular cell, or giant cell glioblastomas. This provides further support for the notion that most glioblastomas with oligodendroglial component are secondary, while small cell glioblastomas, granular cell glioblastomas, and giant cell glioblastomas are primary variants. Therefore, in one of the most challenging differential diagnoses, IDH1 positivity could provide strong support for glioblastoma with oligodendroglial component, while essentially excluding small cell glioblastoma.Modern Pathology advance online publication, 5 October 2012; doi:10.1038/modpathol.2012.173.

Document Type: Article in Press
Source: Scopus

 

Finn, B., Roediger III, H.L., Rosenzweig, E.
Reconsolidation from negative emotional pictures: Is successful retrieval required?
(2012) Memory and Cognition, 40 (7), pp. 1031-1045. 

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

Abstract
Finn and Roediger (Psychological Science 22:781-786, 2011) found that when a negative emotional picture was presented immediately after a successful retrieval, later test performance was enhanced as compared to when a neutral picture or a blank screen had been shown. This finding implicates the period immediately following retrieval as playing an important role in determining later retention via reconsolidation. In two new experiments, we investigated whether successful retrieval was required to show the enhancing effect of negative emotion on later recall. In both experiments, the participants studied Swahili-English vocabulary pairs, took an intervening cued-recall test, and were given a final cued-recall test on all items. In Experiment 1, we tested a distinctiveness explanation of the effect. The results showed that neither presentation of a negative picture just prior to successful retrieval nor presentation of a positive picture after successful retrieval produced the enhancing effect that was seen when negative pictures were presented after successful retrieval. In Experiment 2, we tested whether the enhancing effect would occur when a negative picture followed an unsuccessful retrieval attempt with feedback, and a larger enhancement effect occurred after errors of commission than after errors of omission. These results indicate that effort in retrieving is critical to the enhancing effect shown with negative pictures; whether the target is produced by the participant or given by an external source following a commission error does not matter. We interpret these results as support for semantic enrichment as a key element in producing the enhancing effect of negative pictures that are presented after a retrieval attempt. © 2012 Psychonomic Society, Inc.

Author Keywords
Emotion and memory;  Memory retrieval;  Reconsolidation

Document Type: Article
Source: Scopus

 

Rodebaugh, T.L., Fernandez, K.C., Levinson, C.A.
Testing the effects of social anxiety disorder on friendship quality across gender and ethnicity
(2012) Cognitive Behaviour Therapy, 41 (2), pp. 130-139. 

Department of Psychology, Washington University in St Louis, 1 Brookings Drive, Campus Box 1125, St Louis, MO 63130, United States

Abstract
Previous research suggests that social anxiety disorder (SAD) has a specific relationship with impairment in friendship quality; however, potential moderators of this relationship have not been tested. The current study examines whether the specific effect of SAD on friendship quality is stable or varies across gender and ethnicity in a large epidemiological dataset. Results indicate that the underlying construct of friendship quality differed slightly but significantly between men and women; as a result, effects of SAD were tested in men and women separately. After partially constraining friendship quality across ethnic groups, our results indicated that the relationship between SAD and friendship quality remained robust in all groups. In addition to replicating the finding that SAD specifically relates to perceived friendship quality, the current study highlights the need to test whether underlying constructs such as friendship quality are consistent across the groups that make up heterogeneous samples. © 2012 Swedish Association for Behaviour Therapy.

Author Keywords
Friendship;  Interpersonal processes;  Social anxiety disorder;  Social phobia

Document Type: Article
Source: Scopus

 

Roediger III, H.L., Smith, M.A.
The "pure-study" learning curve: The learning curve without cumulative testing
(2012) Memory and Cognition, 40 (7), pp. 989-1002. 

Department of Psychology, Box 1125, Washington University, One Brookings Drive, St. Louis, MO 63130-4899, United States

Abstract
The customary assumption in the study of human learning using alternating study and test trials is that learning occurs during study trials and that test trials are useful only to measure learning. In fact, tests seem to play little role in the development of learning, because the learning curve is similar even when the number of test trials varies widely (Tulving, Journal of Verbal Learning and Verbal Behavior 6:175-184, 1967). However, this outcome seems odd, because other research has shown that testing fosters greater long-term learning than does studying. We report three experiments addressing whether tests affect the shape of the learning curve. In two of the experiments, we examined this issue by varying the number of spaced study trials in a sequence and examining performance on only a single test trial at the end of the series (a "pure-study" learning curve). We compared these pure-study learning curves to standard learning curves and found that the standard curves increase more rapidly and reach a higher level in both free recall (Exp. 1) and paired-associate learning (Exp. 2). In Experiment 3, we provided additional study trials in the "pure-study" condition to determine whether the standard (study-test) condition would prove superior to a study-study condition. The standard condition still produced better retention on both immediate and delayed tests. Our experiments show that test trials play an important role in the development of learning using both free-recall (Exps. 1 and 3) and paired-associate (Exp. 2) procedures. Theories of learning have emphasized processes that occur during study, but our results show that processes engaged during tests are also critical. © 2012 Psychonomic Society, Inc.

Author Keywords
Learning;  Memory;  Recall;  Testing effect

Document Type: Article
Source: Scopus

 

Haque, O.S.a , De Freitas, J.b , Viani, I.c , Niederschulte, B.d , Bursztajn, H.J.e
Why did so many German doctors join the Nazi Party early?
(2012) International Journal of Law and Psychiatry, . Article in Press. 

a Program in Psychiatry and the Law, Harvard Medical School, 96 Larchwood Drive, Cambridge, MA 02138, USA
b Department of Psychology, Yale University, P.O. BOX 204181, New Haven, CT 06520-4181, USA
c School of Natural Sciences, Fairleigh Dickinson University, 1000 River Rd, Teaneck, NJ 07666, USA
d Department of Political Science, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130, USA
e Program in Psychiatry and the Law at BIDMC Psychiatry of Harvard Medical School, 96 Larchwood Drive, Cambridge, MA 02138, USA

Abstract
During the Weimar Republic in the mid-twentieth century, more than half of all German physicians became early joiners of the Nazi Party, surpassing the party enrollments of all other professions. From early on, the German Medical Society played the most instrumental role in the Nazi medical program, beginning with the marginalization of Jewish physicians, proceeding to coerced "experimentation," "euthanization," and sterilization, and culminating in genocide via the medicalization of mass murder of Jews and others caricatured and demonized by Nazi ideology. Given the medical oath to "do no harm," many postwar ethical analyses have strained to make sense of these seemingly paradoxical atrocities. Why did physicians act in such a manner? Yet few have tried to explain the self-selected Nazi enrollment of such an overwhelming proportion of the German Medical Society in the first place. This article lends insight into this paradox by exploring some major vulnerabilities, motives, and rationalizations that may have predisposed German physicians to Nazi membership-professional vulnerabilities among physicians in general (valuing conformity and obedience to authority, valuing the prevention of contamination and fighting against mortality, and possessing a basic interest in biomedical knowledge and research), economic factors and motives (related to physician economic insecurity and incentives for economic advancement), and Nazi ideological and historical rationalizations (beliefs about Social Darwinism, eugenics, and the social organism as sacred). Of particular significance for future research and education is the manner in which the persecution of Jewish physician colleagues was rationalized in the name of medical ethics itself. Giving proper consideration to the forces that fueled "Nazi Medicine" is of great importance, as it can highlight the conditions and motivations that make physicians susceptible to misapplications of medicine, and guide us toward prevention of future abuse. © 2012.

Author Keywords
Ethical rationalizations;  Holocaust;  Nazi physicians;  Shoah

Document Type: Article in Press
Source: Scopus

 

Nimmakayalu, M.a , Noble, N.a , Horton, V.K.a , Willing, M.b , Copeland, S.c , Sheffield, V.a , Nagy, P.L.d , Wassink, T.a , Patil, S.a , Shchelochkov, O.A.a
2q24 deletions: Further characterization of clinical findings and their relation to the SCN cluster
(2012) American Journal of Medical Genetics, Part A, . Article in Press. 

a Division of Medical Genetics, Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, Iowa
b Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri
c Genetic Services Branch, Division of Services for Children with Special Health Needs, Maternal and Child Health Bureau, Rockville, Maryland
d Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York

Abstract
As the resolution of molecular cytogenetic methods continues to improve, it has become increasingly possible to refine genotype-phenotype correlations based upon gene involvement. We report three new patients with nonrecurrent deletions involving subbands of 2q24. These patients were referred for evaluation of developmental delay, but were found to have unique, nonoverlapping clinical features. Patient 1 presented with infantile seizures, microcephaly, and brain anomalies, along with facial dysmorphism, growth retardation, neuromuscular scoliosis, and later with developmental regression. Array comparative genomic hybridization (aCGH) detected an 8Mb interstitial deletion encompassing the neuronal sodium channel (SCN) gene cluster. Patient 2 presented with growth retardation, congenital heart defect, and hypotonia. Patient 3 presented with developmental delay and behavioral problems. Patients 2 and 3 had no history of seizures, microcephaly, or brain anomalies and were found to have deletions of 2q24,
8Mb and <500kb respectively, centromeric to and outside the SCN cluster. It has been demonstrated that mutations and copy number variants (CNVs) affecting the SCN gene cluster result in severe, early-onset seizures. It is however, less clear whether haploinsufficiency of regions outside the SCN cluster may result in phenotypically recognizable and clinically significant features. We discuss additional dosage sensitive genes that may exist outside the SCN cluster. Our and published data indicate that 2q24 deletions not involving the SCN cluster are associated with fewer neurobehavioral problems, but may predispose to congenital malformations. © 2012 Wiley Periodicals, Inc.

Author Keywords
2q24;  2q31.1;  Array comparative genomic hybridization (aCGH);  Dravet syndrome;  FIGN;  Growth retardation;  Microcephaly;  SCN cluster;  SCN1A;  SCN2A;  SCN3A;  SCN7A;  SCN9A;  Seizures;  SLC4A10

Document Type: Article in Press
Source: Scopus

 

Pineda, R.G.a b , Tjoeng, T.H.c , Vavasseur, C.d , Kidokoro, H.b , Neil, J.J.b e f , Inder, T.b e f
Patterns of Altered Neurobehavior in Preterm Infants within the Neonatal Intensive Care Unit
(2012) Journal of Pediatrics, . Article in Press. 

a Program in Occupational Therapy, Washington University School of Medicine, St Louis, MO; Washington University School of Medicine, St Louis, MO
b Department of Pediatrics, Washington University School of Medicine, St Louis, MO; Washington University School of Medicine, St Louis, MO
c Department of Pediatrics, University of Hawaii, Honolulu, HI; Washington University School of Medicine, St Louis, MO
d National Maternity Hospital, Dublin, Ireland
e Department of Neurology, Washington University School of Medicine, St Louis, MO
f Department of Radiology, Washington University School of Medicine, St Louis, MO

Abstract
Objective: To investigate differences in neurobehavior between preterm infants at term and full-term infants, changes in neurobehavior between 34 weeks postmenstrual age (PMA) and term equivalent in the preterm infant, and the relationship of neurobehavior to perinatal exposures. Study design: In this prospective cohort study, 75 infants were tested at 34 weeks PMA and again at term using the Neonatal Intensive Care Unit Network Neurobehavioral Scale. Infants underwent magnetic resonance imaging at term equivalent. Regression was used to investigate differences in the scale's domains of function across time and in relation to perinatal exposures. Results: At term equivalent, preterm infants exhibited altered behavior compared with full-term infants, with poorer orientation (P < .001), lower tolerance of handling (P < .001), lower self-regulation (P < .001), poorer reflexes (P < .001), more stress (P < .001), hypertonicity (P < .001), hypotonia (P < .001), and more excitability (P = .007). Preterm infants from 34 weeks PMA to term equivalent, demonstrated changes in motor functions with declining quality of movement (P = .006), increasing hypertonia (P < .001), decreasing hypotonia (P = .001), and changes in behavior with increasing arousal (P < .001), increasing excitability (P < .001), and decreasing lethargy (P < .001). Cerebral injury was associated with more excitability (P = .002). However, no associations were detected between any of the perinatal exposures and developmental change from 34 weeks PMA to term equivalent. Conclusion: Preterm infants have altered neurobehavior in a broad number of domains at term equivalent. Cerebral injury alters neurobehavior but does not appear to impair early neurobehavioral changes. Important neurobehavioral changes occur before term, and this provides an opportunity for interventions in the neonatal intensive care unit. © 2012 Mosby, Inc. All rights reserved.

Document Type: Article in Press
Source: Scopus

 

Firszt, J.B.a , Holden, L.K.a , Reeder, R.M.a , Waltzman, S.B.b , Arndt, S.c
Auditory abilities after cochlear implantation in adults with unilateral deafness: A pilot study
(2012) Otology and Neurotology, 33 (8), pp. 1339-1346. 

a Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, Campus Box 8115, 660 South Euclid Avenue, St. Louis, MO, 63110, United States
b Department of Otolaryngology, New York University School of Medicine, New York, NY, United States
c Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center Freiburg, Freiburg, Germany

Abstract
Objective: This pilot study examined speech recognition, localization, temporal and spectral discrimination, and subjective reports of cochlear implant (CI) recipients with unilateral deafness. Study Design: Three adult male participants with short-term unilateral deafness (<5 yr) participated. All had sudden onset of severe-to-profound hearing loss in 1 ear, which then received a CI, and normal or near normal hearing in the other ear. Speech recognition in quiet and noise, localization, discrimination of temporal and spectral cues, and a subjective questionnaire were obtained over several days. Listening conditions were CI, normal hearing (NH) ear, and bilaterally (CI and NH). Results: All participants had open-set speech recognition and excellent audibility (250-6,000 Hz) with the CI. Localization improved bilaterally compared with the NH ear alone. Word recognition in noise was significantly better bilaterally than with the NH ear for 2 participants. Sentence recognition in various noise conditions did not show significant bilateral improvement; however, the CI did not hinder performance in noise even when noise was toward the CI side. The addition of the CI improved temporal difference discrimination for 2 participants and spectral difference discrimination for all participants. Participants wore the CI full time, and subjective reports were positive. Conclusion: Overall, the CI recipients with unilateral deafness obtained open-set speech recognition, improved localization, improved word recognition in noise, and improved perception of their ability to hear in everyday life. A larger study is warranted to further quantify the benefits and limitations of cochlear implantation in individuals with unilateral deafness. © 2012, Otology & Neurotology, Inc.

Author Keywords
Cochlear implant;  Localization;  Single-sided deafness;  Speech recognition;  Unilateral deafness

Document Type: Article
Source: Scopus

 

Wells, A.a , Lagomasino, I.T.b , Palinkas, L.A.c , Green, J.M.b , Gonzalez, D.d
Barriers to Depression Treatment Among Low-Income, Latino Emergency Department Patients
(2012) Community Mental Health Journal, pp. 1-7. Article in Press. 

a Brown School of Social Work, Washington University in St. Louis, One Brookings Drive, Campus Box 1196, St. Louis, 63130-4899, United States
b Department of Psychiatry and Behavioral Sciences, Keck School of Medicine at USC, 2250 Alcazar Street, Suite 2200, Los Angeles, 90033, United States
c School of Social Work, University of Southern California, MRF 339, Los Angeles, 90089-0411, United States
d Special Service for Groups, Weber Community Center, 5849 Crocker St., Los Angeles, 90003, United States

Abstract
Low-income and Latinos use the emergency department (ED) as a primary source of care. Also, the depression prevalence in ED patients is high, making the ED a compelling venue for depression screening and intervention. This study examined barriers and facilitators to depression treatment among low-income, predominantly Latino ED patients. We conducted telephone interviews with 24 ED patients (18-62 years of age, 79 % female) who dropped out of a depression treatment intervention. Using grounded theory, we analyzed perceptions of depression and treatment, and barriers and facilitators to mental health treatment. Although most patients acknowledged signs of depression, there was a lack of readiness to seek help. Patients reported negative perceptions about anti-depressant medication, even if they had no previous use. Barriers to treatment included transportation concerns, employment/unemployment, patient-provider issues, and immigrant documentation. Identified facilitators included consistent provider advice and "talking." This study introduced new misunderstanding and miscommunication barriers. © 2012 Springer Science+Business Media New York.

Author Keywords
Depression;  Emergency department;  Latino;  Low-income;  Minority

Document Type: Article in Press
Source: Scopus

 

Fiorella, D.a , Derdeyn, C.P.b , Lynn, M.J.c , Barnwell, S.L.d , Hoh, B.L.f , Levy, E.I.h , Harrigan, M.R.i , Klucznik, R.P.k , McDougall, C.G.m , Pride, G.L.o , Zaidat, O.O.p , Lutsep, H.L.e , Waters, M.F.g , Hourihane, J.M.q , Alexandrov, A.V.j , Chiu, D.l , Clark, J.M.n , Johnson, M.D.r , Torbey, M.T.s , Rumboldt, Z.t , Cloft, H.J.v , Turan, T.N.u , Lane, B.F.c , Janis, L.S.w , Chimowitz, M.I.u
Detailed analysis of periprocedural strokes in patients undergoing intracranial stenting in stenting and aggressive medical management for preventing recurrent stroke in intracranial stenosis (SAMMPRIS)

(2012) Stroke, 43 (10), pp. 2682-2688. 

a Department of Neurosurgery, State University of New York, Health Sciences Center, Stony Brook, NY 11794-8122, United States
b Mallinckrodt Institute of Radiology, Department of Neurology and Neurosurgery, Washington University School of Medicine, St Louis, MO, United States
c Department of Biostatistics and Bioinformatics, Emory University Rollins School of Public Health, Atlanta, GA, United States
d Department of Neurological Surgery, Dotter Interventional Institute, United States
e Department of Neurology, Oregon Health Sciences University, Portland, OR, United States
f Department of Neurosurgery, University of Florida, Gainesville, FL, United States
g Department of Neurology and Neuroscience, University of Florida, Gainesville, FL, United States
h Department of Neurosurgery, University of Buffalo, Buffalo, NY, United States
i Department of Neurosurgery, University of Alabama, Birmingham, AL, United States
j Department of Neurology, University of Alabama, Birmingham, AL, United States
k Department of Radiology, Methodist Hospital, Houston, TX, United States
l Department of Neurology, Methodist Hospital, Houston, TX, United States
m Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, United States
n Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, United States
o Department of Radiology and Neurosurgery, University of Texas Southwestern Medical Center, Dallas, TX, United States
p Department of Neurology, Radiology and Neurosurgery, Medical College of Wisconsin, Milwaukee, WI, United States
q Dent Neurological Institute, Buffalo, NY, United States
r Department of Neurology and Neurotherapeutics, University of Texas Southwestern, Dallas, TX, United States
s Department of Neurology, Medical College of Wisconsin, Milwaukee, WI, United States
t Department of Radiology, Medical University of South Carolina, Charleston, SC, United States
u Department of Neurosciences, Medical University of South Carolina, Charleston, SC, United States
v Department of Radiology, Mayo Clinic, Rochester, MN, United States
w National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda, MD, United States

Abstract
BACKGROUND AND PURPOSE-: Enrollment in the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) trial was halted due to the high risk of stroke or death within 30 days of enrollment in the percutaneous transluminal angioplasty and stenting arm relative to the medical arm. This analysis focuses on the patient and procedural factors that may have been associated with periprocedural cerebrovascular events in the trial. METHODS-: Bivariate and multivariate analyses were performed to evaluate whether patient and procedural variables were associated with cerebral ischemic or hemorrhagic events occurring within 30 days of enrollment (termed periprocedural) in the percutaneous transluminal angioplasty and stenting arm. RESULTS-: Of 224 patients randomized to percutaneous transluminal angioplasty and stenting, 213 underwent angioplasty alone (n=5) or with stenting (n=208). Of these, 13 had hemorrhagic strokes (7 parenchymal, 6 subarachnoid), 19 had ischemic stroke, and 2 had cerebral infarcts with temporary signs within the periprocedural period. Ischemic events were categorized as perforator occlusions (13), embolic (4), mixed perforator and embolic (2), and delayed stent occlusion (2). Multivariate analyses showed that higher percent stenosis, lower modified Rankin score, and clopidogrel load associated with an activated clotting time above the target range were associated (P≤0.05) with hemorrhagic stroke. Nonsmoking, basilar artery stenosis, diabetes, and older age were associated (P≤0.05) with ischemic events. CONCLUSIONS-: Periprocedural strokes in SAMMPRIS had multiple causes with the most common being perforator occlusion. Although risk factors for periprocedural strokes could be identified, excluding patients with these features from undergoing percutaneous transluminal angioplasty and stenting to lower the procedural risk would limit percutaneous transluminal angioplasty and stenting to a small subset of patients. Moreover, given the small number of events, the present data should be used for hypothesis generation rather than to guide patient selection in clinical practice. © 2012 American Heart Association, Inc.

Author Keywords
angioplasty and stenting;  clinical trial;  intracranial stenosis

Document Type: Article
Source: Scopus

 

Bugg, J.M.
Dissociating Levels of Cognitive Control: The Case of Stroop Interference
(2012) Current Directions in Psychological Science, 21 (5), pp. 302-309. 

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

Abstract
Attention is often imperfect; cognitive control is needed to counteract the tendency to attend to distractors that are incompatible with current goals. Cognitive psychologists have long explored cognitive control by examining Stroop interference-the slowed naming of colors on incongruent trials (e.g., "RED" displayed in blue ink), as compared to congruent trials (e.g., "RED" displayed in red ink), in the color-word Stroop task. The magnitude of interference reflects the effectiveness of cognitive control, but it does not reveal the precise processes used to minimize attention to the distracting word. The need for experimental approaches that accomplish this objective is underscored by the existence of qualitatively different cognitive control processes. Prior accounts stressed the use of top-down filtering processes at a task- or list-wide level to avoid word reading, but recent findings have shown that control of word reading is sometimes stimulus-driven-that is, triggered by the processing of stimuli or stimulus features. In this article, I highlight the critical findings that dissociate top-down and stimulus-driven control in the Stroop task, dissociations that are central to the view that cognitive control operates at multiple levels. © The Author(s) 2012.

Author Keywords
cognitive control;  proportion congruence;  stimulus-driven control;  Stroop;  top-down control

Document Type: Article
Source: Scopus

 

Lenze, E.J.a , Host, H.H.b c , Hildebrand, M.W.d , Morrow-Howell, N.e , Carpenter, B.f , Freedland, K.E.a , Baum, C.A.g , Dixon, D.a , Doré, P.a e , Wendleton, L.a , Binder, E.F.c g
Enhanced Medical Rehabilitation Increases Therapy Intensity and Engagement and Improves Functional Outcomes in Postacute Rehabilitation of Older Adults: A Randomized-Controlled Trial
(2012) Journal of the American Medical Directors Association, 13 (8), pp. 708-712. 

a Department of Psychiatry, Washington University, St Louis, MO, United States
b Program in Physical Therapy, Washington University, St Louis, MO, United States
c Department of Internal Medicine, Washington University, St Louis, MO, United States
d Department of Occupational Therapy, East Carolina University, Greenville, NC, United States
e School of Social Work, Washington University, St Louis, MO, United States
f Department of Psychology, Washington University, St Louis, MO, United States
g Program in Occupational Therapy, Washington University, St Louis, MO, United States

Abstract
Objectives: For millions of disabled older adults each year, postacute care in skilled nursing facilities is a brief window of opportunity to regain enough function to return home and live independently. Too often this goal is not achieved, possibly because of therapy that is inadequately intense or engaging. This study tested Enhanced Medical Rehabilitation, an intervention designed to increase patient engagement in, and intensity of, daily physical and occupational therapy sessions in postacute-care rehabilitation. Design: Randomized controlled trial of Enhanced Medical Rehabilitation versus standard-of-care rehabilitation. Setting: Postacute care unit of a skilled nursing facility in St Louis, MO. Participants: Twenty-six older adults admitted from a hospital for postacute rehabilitation. Intervention: Based on models of motivation and behavior change, Enhanced Medical Rehabilitation is a set of behavioral skills for physical and occupational therapists that increase patient engagement and intensity, with the goal of improving functional outcome, through (1) a patient-directed, interactive approach, (2) increased rehabilitation intensity, and (3) frequent feedback to patients on their effort and progress. Measurements: Therapy intensity: assessment of patient active time in therapy sessions. Therapy engagement: Rehabilitation Participation Scale. Functional and performance outcomes: Barthel Index, gait speed, and 6-minute walk. Results: Participants randomized to Enhanced Medical Rehabilitation had higher intensity therapy and were more engaged in their rehabilitation sessions; they had more improvement in gait speed (improving from 0.08 to 0.38 m/s versus 0.08 to 0.22 in standard of care, P = .003) and 6-minute walk (from 73 to 266 feet versus 40 to 94 feet in standard of care, P = .026), with a trend for better improvement of Barthel Index (+43 points versus 26 points in standard of care, P = .087), compared with participants randomized to standard-of-care rehabilitation. Conclusion: Higher intensity and patient engagement in the postacute rehabilitation setting is achievable, with resultant better functional outcomes for older adults. Findings should be confirmed in a larger randomized controlled trial. © 2012 American Medical Directors Association, Inc.

Author Keywords
Geriatrics;  Intensity;  Motivation;  Nursing home;  Post-acute;  Rehabilitation

Document Type: Article
Source: Scopus

 

Galvan, A.a , Fladvad, T.b , Skorpen, F.b , Gao, X.c , Klepstad, P.b d , Kaasa, S.b e , Dragani, T.A.a
Genetic clustering of European cancer patients indicates that opioid-mediated pain relief is independent of ancestry
(2012) Pharmacogenomics Journal, 12 (5), pp. 412-416. 

a Department of Predictive and Preventive Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, Milan 20133, Italy
b European Palliative Care Research Center, Medical Faculty, Norwegian University of Science and Technology, Trondheim, Norway
c Division of Statistical Genomics, Washington University School of Medicine, St Louis, MO, United States
d Department of Intensive Care, St Olav University Hospital, Trondheim, Norway
e Department of Oncology, St Olav University Hospital, Trondheim, Norway

Abstract
The European Pharmacogenetic Opioid Study (EPOS) of a large series of European cancer patients treated with opioids was carried out to assess the influence of genetics on cancer pain relief. As response to opioid therapy was associated with the patients country of origin, we tested whether population stratification might represent a confounding factor in the analysis of genetic control of response to opioid therapy. From the whole EPOS series representing 2294 patients genotypes for 379 single-nucleotide polymorphisms (SNPs), we extracted 117 autosomal SNPs with minor allele frequency<0.28 to obtain highly informative genetic markers, and analyzed the SNPs in 1724 individuals showing <20% missing genotypes. Use of the AWclust program to detect clusters of genetically related individuals in the EPOS series showed that the 117-SNP panel distinguished four main European subgroups statistically associated with ethnicity, but not with country of origin or with the pain relief phenotype. Subethnic European groups of genetically related individuals exist that can be correctly identified using an
100-SNP panel. Such genetic clustering may control for admixture in association studies and may allow discrimination between genetic and environmental effects on phenotypes showing association with country of origin, as in the case of pain relief. © 2012 Macmillan Publishers Limited. All rights reserved.

Author Keywords
opioids;  pharmacogenomics;  polygenic diseases;  single-nucleotide polymorphisms

Document Type: Article
Source: Scopus

 

Mashour, G.A.a , Shanks, A.a , Tremper, K.K.a , Kheterpal, S.a , Turner, C.R.b , Ramachandran, S.K.a , Picton, P.a , Schueller, C.c , Morris, M.a , Vandervest, J.C.a , Lin, N.d , Avidan, M.S.d
Prevention of intraoperative awareness with explicit recall in an unselected surgical population: A randomized comparative effectiveness trial
(2012) Anesthesiology, 117 (4), pp. 717-725. 

a Department of Anesthesiology, University of Michigan, Medical School, 1H247 UH/SPC-5048, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5048, United States
b Anesthesia Service, Bay Area Medical Center, Marinette, WI, United States
c Wayne State University, Detroit, MI, United States
d Department of Anesthesiology, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Background: Intraoperative awareness with explicit recall occurs in approximately 0.15% of all surgical cases. Efficacy trials based on the Bispectral Index® (BIS) monitor (Covidien, Boulder, CO) and anesthetic concentrations have focused on high-risk patients, but there are no effectiveness data applicable to an unselected surgical population. Methods: We conducted a randomized controlled trial of unselected surgical patients at three hospitals of a tertiary academic medical center. Surgical cases were randomized to alerting algorithms based on either BIS values or anesthetic concentrations. The primary outcome was the incidence of definite intraoperative awareness; prespecified secondary outcomes included postanesthetic recovery variables. Results: The study was terminated because of futility. At interim analysis the incidence of definite awareness was 0.12% (11/9,376) (95% CI: 0.07-0.21%) in the anesthetic concentration group and 0.08% (8/9,460) (95% CI: 0.04-0.16%) in the BIS group (P = 0.48). There was no significant difference between the two groups in terms of meeting criteria for recovery room discharge or incidence of nausea and vomiting. By post hoc secondary analysis, the BIS protocol was associated with a 4.7-fold reduction in definite or possible awareness events compared with a cohort receiving no intervention (P = 0.001; 95% CI: 1.7-13.1). Conclusion: This negative trial could not detect a difference in the incidence of definite awareness or recovery variables between monitoring protocols based on either BIS values or anesthetic concentration. By post hoc analysis, a protocol based on BIS monitoring reduced the incidence of definite or possible intraoperative awareness compared with routine care. Copyright © 2012, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins.

Document Type: Article
Source: Scopus

 

Chimowitz, M.I.a , Fiorella, D.b , Derdeyn, C.P.c , Turan, T.N.a , Lane, B.F.d , Janis, L.S.e , Lynn, M.J.d
Response to critique of the stenting and aggressive medical management for preventing recurrent stroke in intracranial stenosis (SAMMPRIS) trial by abou-chebl and steinmetz
(2012) Stroke, 43 (10), pp. 2806-2809. 

a Department of Neurosciences, Medical University of South Carolina, Stroke Program, 19 Hagood Avenue, Charleston, SC 29425, United States
b Department of Neurosurgery, State University of New York, Stony Brook, NY, United States
c Mallinckrodt Institute of Radiology, Department of Neurology and Neurosurgery, Washington University School of Medicine, St Louis, MO, United States
d Department of Biostatistics and Bioinformatics, Emory University Rollins School of Public, Health, Atlanta, GA, United States
e National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda, MD, United States

Author Keywords
angioplasty and stenting;  clinical trial;  intracranial stenosis

Document Type: Note
Source: Scopus

 

Piasecki, T.M.a , Wood, P.K.a , Shiffman, S.b , Sher, K.J.a , Heath, A.C.c
Responses to alcohol and cigarette use during ecologically assessed drinking episodes
(2012) Psychopharmacology, 223 (3), pp. 331-344. 

a Department of Psychological Sciences and Midwest Alcoholism Research Center, University of Missouri, 210 McAlester Hall, Columbia, MO 65211, United States
b Department of Psychology, University of Pittsburgh, 130 N. Bellefield Avenue, Pittsburgh, PA 15260, United States
c Department of Psychiatry and Midwest Alcoholism Research Center, Washington University, School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, United States

Abstract
Rationale Tobacco and alcohol are frequently used together, and this may be partly explained by a distinct profile of subjective effects associated with co-administration. Ecological momentary assessment studies have examined effects of naturally occurring co-use, but, to date, have not assessed differing effects as alcohol levels rise and fall. Objectives The objective of the study was to describe subjective states and appraisals of cigarette and alcohol effects reported during the entirety of real-world drinking episodes. Methods Currently-smoking frequent drinkers (N0255) carried electronic diaries for 21 days. Analyses focused on reports made during 2,046 drinking episodes. Signaled prompts intensively oversampled moments in the hours following consumption of the first drink in an episode. Multilevel regression analyses were used to predict ratings of buzz, dizziness, excitement, and sluggishness as a function of person-level and contextual covariates, estimated blood alcohol concentration (eBAC) level, ascending vs. descending eBAC, smoking, and their interactions. Appraisals of cigarette and alcohol effects were also examined within this framework. Results Buzz, excitement, and pleasure from alcohol and cigarettes were prominent features of real-world drinking episodes. Smoking was associated with enhanced buzz and excitement when eBAC was high and descending. Smoking slightly accentuated the relation between eBAC and ratings of drinking pleasure among women, but this relation was somewhat weakened by smoking among men. Conclusions Smoking during drinking episodes may be partly explained by a persistence of stimulant alcohol effects beyond the blood alcohol concentration peak. Acute effects of nicotine and tobacco use on the descending limb deserve further scrutiny in experimental alcohol challenge research. © Springer-Verlag 2012.

Author Keywords
Alcohol;  Craving;  Ecological momentary assessment;  Reinforcement;  Smoking;  Subjective states;  Tobacco

Document Type: Review
Source: Scopus

 

Barbour, J., Yee, A., Kahn, L.C., MacKinnon, S.E.
Supercharged end-to-side anterior interosseous to ulnar motor nerve transfer for intrinsic musculature reinnervation
(2012) Journal of Hand Surgery, 37 (10), pp. 2150-2159. 

Division of Plastic and Reconstructive Surgery, Rehabilitation Institute of Saint Louis, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Functional motor recovery after peripheral nerve injury is predominantly determined by the time to motor end plate reinnervation and the absolute number of regenerated motor axons that reach target. Experimental models have shown that axonal regeneration occurs across a supercharged end-to-side (SETS) nerve coaptation. In patients with a recovering proximal ulnar nerve injury, a SETS nerve transfer conceptually is useful to protect and preserve distal motor end plates until the native axons fully regenerate. In addition, for nerve injuries in which incomplete regeneration is anticipated, a SETS nerve transfer may be useful to augment the regenerating nerve with additional axons and to more quickly reinnervate target muscle. We describe our technique for a SETS nerve transfer of the terminal anterior interosseous nerve (AIN) to the pronator quadratus muscle (PQ) end-to-side to the deep motor fascicle of the ulnar nerve in the distal forearm. In addition, we describe our postoperative therapy regimen for these transfers and an evaluation tool for monitoring progressive muscle reinnervation. Although the AIN-to-ulnar motor group SETS nerve transfer was specifically designed for ulnar nerve injuries, we believe that the SETS procedure might have broad clinical utility for second- and third-degree axonotmetic nerve injuries, to augment partial recovery and/or "babysit" motor end plates until the native parent axons regenerate to target. We would consider all donor nerves currently utilized in end-to-end nerve transfers for neurotmetic injuries as candidates for this SETS technique. © 2012 American Society for Surgery of the Hand.

Author Keywords
Intrinsic ulnar neuropathy;  nerve transfer;  supercharge end-to-side

Document Type: Article
Source: Scopus

 

Epstein, L.H.a f , Raja, S.b , Daniel, T.O.a , Paluch, R.A.a , Wilfley, D.E.c , Saelens, B.E.d , Roemmich, J.N.e
The built environment moderates effects of family-based childhood obesity treatment over 2 years
(2012) Annals of Behavioral Medicine, 44 (2), pp. 248-258. 

a University at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY, United States
b University at Buffalo, School of Architecture and Planning, Buffalo, NY, United States
c Washington University, School of Medicine, St. Louis, MO, United States
d Seattle Children's Hospital, University of Washington, Seattle, WA, United States
e USDA-ARS-NPA Grand Forks Human Nutrition Research Center, 2420 2ND Avenue North, Grand Forks, ND 58202-9034, United States
f Department of Pediatrics, School of Medicine and Biomedical Sciences, University at Buffalo, 3435 Main Street, Building 26, Buffalo, NY 14214-3000, United States

Abstract
Background Research suggests the neighborhood built environment is related to child physical activity and eating. Purpose The purpose of this study was to determine if characteristics of the neighborhood environment moderate the relationship between obesity treatment and weight loss, and if outcomes of particular treatments are moderated by built environment characteristics. Method The relationship between the built environment and standardized BMI (zBMI) changes for 191 8-12-year-old children who participated in one of four randomized, controlled trials of pediatric weight management was assessed using mixed models analysis of covariance. Results At 2-year follow-up, greater parkland, fewer convenience stores, and fewer supermarkets were associated with greater zBMI reduction across all interventions. No treatments interacted with characteristics of the built environment. Conclusions Activity- and eating-related built neighborhood characteristics are associated with child success in behavioral obesity treatments. Efficacy may be improved by individualizing treatments based on built environment characteristics. © The Society of Behavioral Medicine 2012.

Author Keywords
Built environment;  Convenience stores;  Neighborhood block size;  Parkland;  Supermarkets;  Weight loss

Document Type: Article
Source: Scopus

 

Murray, D.J.
The simulation-derived algorithm: A better method to achieve a performance consensus
(2012) Anesthesiology, 117 (4), pp. 701-702. 

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

Document Type: Note
Source: Scopus

 

Xiao, Q., Ford, A.L., Xu, J., Yan, P., Lee, K.-Y., Gonzales, E., West, T., Holtzman, D.M., Lee, J.-M.
Bcl-x Pre-mRNA splicing regulates brain injury after neonatal hypoxia-ischemia
(2012) Journal of Neuroscience, 32 (39), pp. 13587-13596. 

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

Abstract
The bcl-x gene appears to play a critical role in regulating apoptosis in the developing and mature CNS and following CNS injury. Two isoforms of Bcl-x are produced as a result of alternative pre-mRNA splicing: Bcl-x L (the long form) is anti-apoptotic, while Bcl-x S (short form) is pro-apoptotic. Despite the antagonistic activities of these two isoforms, little is known about how regulation of alternative splicing of bcl-x may mediate neural cell apoptosis. Here, we report that apoptotic stimuli (staurosporine or C2-ceramide) reciprocally altered Bcl-x splicing in neural cells, decreasing Bcl-x L while increasing Bcl-x S. Specific knockdown of Bcl-x S attenuated apoptosis. To further define regulatory elements that influenced Bcl-x splicing, a Bcl-x minigene was constructed. Deletional analysis revealed several consensus sequences within intron 2 that altered splicing.Wefound that the splicing factor, CUG-binding-protein-1 (CUGBP1), bound to a consensus sequence close to the Bcl-x L 5′ splice site, altering the Bcl-x L /Bcl-x S ratio and influencing cell death. In vivo, neonatal hypoxia-ischemia reciprocally altered Bcl-x pre-mRNA splicing, similar to the in vitro studies. Manipulation of the splice isoforms using viral gene transfer of Bcl-x S shRNA into the hippocampus of rats before neonatal hypoxia-ischemia decreased vulnerability to injury. Moreover, alterations in nuclear CUGBP1 preceded Bcl-x splicing changes. These results suggest that alternative pre-mRNA splicing may be an important regulatory mechanism for cell death after acute neurological injury and may potentially provide novel targets for intervention. ©2012 the authors.

Document Type: Article
Source: Scopus

 

Roberts, M.S.a , Macauley, S.L.a , Wong, A.M.b , Yilmas, D.b , Hohm, S.a , Cooper, J.D.b , Sands, M.S.a
Combination small molecule PPT1 mimetic and CNS-directed gene therapy as a treatment for infantile neuronal ceroid lipofuscinosis
(2012) Journal of Inherited Metabolic Disease, 35 (5), pp. 847-857. 

a Department of Internal Medicine, Washington University School of Medicine, Campus Box 8007, 660 S. Euclid Ave., St. Louis, MO 63110, United States
b Pediatric Storage Disorders Laboratory, Department of Neuroscience, Institute of Psychiatry, London SE5 9NU, United Kingdom

Abstract
Infantile neuronal ceroid lipofuscinosis (INCL) is a profoundly neurodegenerative disease of children caused by a deficiency in the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1). There is currently no effective therapy for this invariably fatal disease. To date, preclinical experiments using single treatments have resulted in incremental clinical improvements. Therefore, we determined the efficacy of CNS-directed AAV2/5-mediated gene therapy alone and in combination with the systemic delivery of the lysosomotropic PPT1 mimetic phosphocysteamine. Since CNS-directed gene therapy provides relatively high levels of PPT1 activity to specific regions of the brain, we hypothesized that phosphocysteamine would complement that activity in regions expressing subtherapeutic levels of the enzyme. Results indicate that CNS-directed gene therapy alone provided the greatest improvements in biochemical and histological measures as well as motor function and life span. Phosphocysteamine alone resulted in only minor improvements in motor function and no increase in lifespan. Interestingly, phosphocysteamine did not increase the biochemical and histological response when combined with AAV2/5-mediated gene therapy, but it did result in an additional improvement in motor function. These data suggest that a CNS-directed gene therapy approach provides significant clinical benefit, and the addition of the small molecule PPT1 mimetic can further increase that response. © SSIEM and Springer 2012.

Document Type: Article
Source: Scopus

 

Christ, S.E.a , Moffitt, A.J.a , Peck, D.b , White, D.A.c , Hilgard, J.a
Decreased functional brain connectivity in individuals with early-treated phenylketonuria: Evidence from resting state fMRI
(2012) Journal of Inherited Metabolic Disease, 35 (5), pp. 807-816. 

a Department of Psychological Sciences, University of Missouri, 210 McAlester Hall, Columbia, MO 65203, United States
b Department of Child Health, University of Missouri, Columbia, MO, United States
c Department of Psychology, Washington University, St. Louis, MO, United States

Abstract
Previous histological and neuroimaging studies have documented structural abnormalities in the white matter of the brain in individuals with early-treated phenylketonuria (ETPKU). It remains unclear, however, the extent to which the function of the brain's interconnections are impacted by this condition. Presently, we utilized functional magnetic resonance imaging (fMRI) to evaluate the synchronization of neural signals (i.e., functional connectivity) among brain regions comprising the default mode network (DMN) in a sample of 11 individuals with ETPKU and 11 age-and gender-matched neurologically intact controls. The DMN is a group of interconnected brain regions that are known to be generally more active during rest than during task performance. Data analysis revealed decreased functional connectivity among DMN regions for the ETPKU group compared with the control group. Within the PKU group, we also found a significant relationship between blood phenylalanine (phe) levels and the functional connectivity between select regions of the DMN. In conjunction with findings from another recent fMRI study (Christ, Moffitt et al. 2010), the present results suggest that ETPKU-related deficiencies in functional connectivity are pervasive. The current findings also provide initial evidence that the extent of such impairment may be moderated in part by blood phe levels. © SSIEM and Springer 2012.

Document Type: Article
Source: Scopus

 

Anticevic, A.a , Repovs, G.b , Barch, D.M.a
Emotion effects on attention, amygdala activation, and functional connectivity in schizophrenia
(2012) Schizophrenia Bulletin, 38 (5), pp. 967-980. 

a Department of Psychology, Washington University, St. Louis, MO, United States
b Department of Psychology, University of Ljubljana, Ljubljana, Slovenia

Abstract
Emotional abnormalities are a critical clinical feature of schizophrenia (SCZ), but complete understanding of their underlying neuropathology is lacking. Numerous studies have examined amygdala activation in response to affective stimuli in SCZ, but no consensus has emerged. However, behavioral studies examining 'in-the-moment' processing of affect have suggested intact emotional processing in SCZ. To examine which aspects of emotional processing may be impaired in SCZ, we combined behavior and neuroimaging to investigate effects of aversive stimuli during minimal cognitive engagement, at the level of behavior, amygdala recruitment, and its whole-brain task-based functional connectivity (tb-fcMRI) because impairments may manifest when examining across-region functional integration. Twenty-eight patients and 24 matched controls underwent rapid event-related fMRI at 3 T while performing a simple perceptual decision task with negative or neutral distraction. We examined perceptual decision slowing, amygdala activation, and whole-brain amygdala tb-fcMRI, while ensuring group signal-to-noise profile matching. Following scanning, subjects rated all images for experienced arousal and valence. No significant group differences emerged for negative vs neutral reaction time, emotional ratings across groups, or amygdala activation. However, even in the absence of behavioral or activation differences, SCZ subjects demonstrated significantly weaker amygdala-prefrontal cortical coupling, specifically during negative distraction. Whereas in-the-moment perception, behavioral response, and amygdala recruitment to negative stimuli during minimal cognitive load seem to be intact, there is evidence of aberrant amygdala-prefrontal integration in SCZ subjects. Such abnormalities may prove critical for understanding disturbances in patients' ability to use affective cues when guiding higher level cognitive processes needed in social interactions. © 2012 The Author.

Author Keywords
amygdala;  attention;  emotion;  fMRI;  functional connectivity;  IAPS;  schizophrenia

Document Type: Article
Source: Scopus

 

Jayaraman, M.V.a , Meyers, P.M.b , Derdeyn, C.P.c , Fraser, J.F.d , Hirsch, J.A.e , Hussain, M.S.f , Blackham, K.A.g , Eskey, C.J.h , Jensen, M.E.i , Moran, C.J.c , Prestigiacomo, C.J.j , Rasmussen, P.A.k , McDougall, C.G.l
Reporting standards for angiographic evaluation and endovascular treatment of cerebral arteriovenous malformations

(2012) Journal of NeuroInterventional Surgery, 4 (5), pp. 325-330. 

a Departments of Diagnostic Imaging and Neurosurgery, Alpert Medical School, Brown University, Providence, RI, United States
b Department of Radiology and Neurological Surgery, Columbia University, New York, NY, United States
c Neuroradiology Department, Washington University in St Louis, St Louis, MO, United States
d Department of Neurological Surgery, University of Kentucky, Louisville, KY, United States
e Department of Interventional and Diagnostic Neuroradiology, Massachusetts General Hospital, Boston, MA, United States
f Cerebrovascular Center, Cleveland Clinic, Cleveland, OH, United States
g University Hospitals Department of Radiology, Case Western Reserve University, Cleveland, OH, United States
h Department of Radiology, Neurology and Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
i Department of Radiology and Neurological Surgery, University of Virginia, Charlottesville, VA, United States
j Department of Neurological Surgery, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, United States
k Neurosurgery Department, Cleveland Clinic, Cleveland, OH, United States
l Neurosurgery Department, Barrow Neurological Institute, Phoenix, AZ, United States

Abstract
These guidelines were developed by consensus of a multidisciplinary panel of specialists interested in the evaluation and treatment of patients with arteriovenous malformations (AVMs) of the CNS. The reporting criteria described will serve as a template for trial design and for clinical investigators who wish to report on endovascular therapy of cerebral AVMs. Direct comparison of various treatment paradigms is important to standardization of care, maximization of good treatment outcomes, assessment of new methods and technologies.

Document Type: Review
Source: Scopus

 
Kadkhodayan, Y.a , Somogyi, C.T.a , Cross III, D.T.a , Derdeyn, C.P.a , Zipfel, G.J.b , Chicoine, M.R.b , Rich, K.M.b , Grubb Jr., R.L.b , Dacey Jr., R.G.b , Moran, C.J.a
Technical, angiographic and clinical outcomes of Neuroform 1, 2, 2 Treo and 3 devices in stent-assisted coiling of intracranial aneurysms
(2012) Journal of NeuroInterventional Surgery, 4 (5), pp. 368-374. 

a Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd, St Louis, MO 63110, United States
b Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO, United States

Abstract
Background and purpose: Since 2002 the Neuroform stent has expanded endovascular treatment of widenecked intracranial aneurysms. A study was undertaken to assess the technical success rates and angiographic and clinical outcomes in stent-assisted coiling with Neuroform 1, 2, 2 Treo and 3. Methods: Patients undergoing Neuroform stent-assisted coiling were enrolled in a prospective registry that included 156 stent deployment attempts in 113 consecutive patients (mean age 53, range 25-78). Deployment success and difficulty, stent movement, procedural complications, immediate/delayed aneurysm occlusion and in-stent stenosis on angiographic follow-up were compared among Neuroform 1, 2, 2 Treo and 3 stents using a log likelihood ratio χ 2 test. Results: Of 156 stent attempts, 123 (79%) were deployed (Neuroform 1: 8/9 (89%), Neuroform 2: 50/66 (76%), Neuroform 2 Treo: 9/11 (82%), Neuroform 3: 56/70 (80%)) with a symptomatic complication rate of 1.9% (3/156; 2 transient ischemic attacks, 1 stroke, no deaths). Non-target stent placement (1/8 (13%), 6/50 (12%), 2/9 (22%), 3/56 (5%)), difficult placement (2/8 (25%), 10/50 (20%), 5/9 (56%), 6/56 (11%)), stent movement (1/8 (13%), 4/50 (8%), 0/9 (0%), 4/56 (7%)), procedural complications (1/9 (11%), 7/66 (11%), 2/11 (18%), 2/70 (3%)) and immediate near complete aneurysm occlusion (6/6 (100%), 24/37 (65%), 5/7 (71%), 40/45 (89%)) trended towards improvement with each generation. Improvements in difficult stent placement and immediate aneurysm occlusion were significant (p=0.01 and 0.03, respectively). Conclusion: Neuroform stent-assisted coiling has evolved through four generations as a safe and effective means of treating wide-necked intracranial aneurysms.

Document Type: Article
Source: Scopus

 

Kadkhodayan, Y., Delgado Almandoz, J.E., Kelly, J.E., Kale, S.P., Jagadeesan, B.D., Moran, C.J., Cross III, D.T., Derdeyn, C.P.
Yield of catheter angiography in patients with intracerebral hemorrhage with and without intraventricular extension
(2012) Journal of NeuroInterventional Surgery, 4 (5), pp. 358-363. 

Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd, St Louis 63110, MO, United States

Abstract
Background and aim: The role of imaging for the detection of vascular lesions in patients with intracerebral hemorrhage (ICH) is poorly defined. A study was undertaken to compare the yield of digital subtraction angiography (DSA) in patients with ICH with intraventricular hemorrhage (IVH) and those without IVH. Methods: The DSA database at our institution was reviewed for patients who underwent DSA for acute spontaneous ICH over a period of 68 months. Patients with known vascular malformation or brain neoplasm, prior surgery, ischemic infarction, subarachnoid hemorrhage or isolated IVH were excluded. Patients were grouped into those with associated IVH (group A) and those without (group B). Baseline demographic and clinical data, non-contrast head CT (NCCT) probability for a vascular lesion and angiographic results were compared. Results: 293 patients met the inclusion and exclusion criteria (141 women, 152 men, mean age 57, range 18-88), 139 in group A and 154 in group B. Age and sex distributions were similar (p7gt;0.05). Group A patients were more likely to be hypertensive or coagulopathic (p=0.001). Group B had more patients with high probability NCCT scans (p<0.001). Underlying vascular lesions were found in 21 patients (15.1%) in group A and 34 (22.1%) in group B (p>0.05). Conclusion: The presence of IVH in patients with acute spontaneous ICH is not associated with an increased risk of an underlying vascular lesion and should not be used to select patients for neurovascular evaluation.

Document Type: Article
Source: Scopus

 

Bowland, S.a , Edmond, T.b , Fallot, R.D.c
Evaluation of a spiritually focused intervention with older trauma survivors
(2012) Social Work (United States), 57 (1), pp. 73-82. 

a Kent School of Social Work, University of Louisville, Patterson Hall 300, Louisville, KY 40292, United States
b Brown School of Social Work, Washington University, St. Louis, MO, United States
c Community Connections, Washington, DC, United States

Abstract
This study evaluated the effectiveness of an 11-session, spiritually focused group intervention with older women survivors (age 55 years and older) of interpersonal trauma (child abuse, sexual assault, or domestic violence) in reducing trauma-related depressive symptoms, posttraumatic stress, and anxiety. Forty-three community-dwelling women survivors of interpersonal trauma were randomized into treatment (n = 21) or control (n = 22) groups. Participants in group psychotherapy discussed spiritual struggles related to abuse and developed spiritual coping resources. The treatment group had significantly lower depressive symptoms, anxiety, and physical symptoms at posttest compared with the control group. In a separate analysis, posttraumatic stress symptoms also dropped significantly in the treatment group. Gains were maintained at three-month follow-up. This study provides strong initial support for the effectiveness of spiritually focused group intervention for older survivors of interpersonal trauma from a Christian background. © 2012 National Association of Social Workers.

Author Keywords
Interpersonal trauma;  Intervention;  Older women;  Spirituality;  Trauma symptoms

Document Type: Article
Source: Scopus

 

Raichle, M.E.
Intrinsic activity and consciousness
(2011) Research and Perspectives in Neurosciences, 18, pp. 147-160. 

Departments of Radiology, Neurology, Neurobiology and Biomedical Engineering, Washington University School of Medicine, 4525. Scott Avenue, St Louis, MO 63110, United States

Abstract
Traditionally, studies of brain function have focused on task-evoked responses. By their very nature, such experiments tacitly encourage a reflexive view of brain function. While such an approach has been remarkably productive, it ignores the alternative possibility: that brain functions are mainly intrinsic, involving information processing for interpreting, responding to and predicting environmental demands. I shall argue that the latter view best captures the essence of brain function, a position that accords well with the allocation of the brain's energy resources. Understanding intrinsic activity will require integrating knowledge from cognitive, systems, cellular and molecular neuroscience. Ultimately, understanding conscious awareness will require an appreciation of the fundamental role played by intrinsic activity in brain function. © Springer-Verlag Berlin Heidelberg 2011.

Document Type: Article
Source: Scopus

 

 

October 3, 2012

Giraudeau, M.a , Toomey, M.B.a b , McGraw, K.J.a
Can House Finches (Carpodacus mexicanus) use non-visual cues to discriminate the carotenoid content of foods?
(2012) Journal of Ornithology, 153 (4), pp. 1017-1023. 

a School of Life Sciences, Arizona State University, Tempe, AZ 85287-4501, United States
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Carotenoid pigments are involved in different physiological processes (e. g., immunoenhancement, antioxidant activity) in addition to coloring plumage and integuments. As animals cannot synthesize these pigments de novo, it has been proposed that carotenoids constitute a limiting resource that birds may specifically seek in their food. Confirming this hypothesis, it was recently found that birds can discriminate between carotenoid-enriched diets and control diets, even if both have the same color, suggesting that there may be underlying non-visual (e. g., olfactory, taste) mechanisms for detecting carotenoid presence or enrichment in foods. In this study, we performed two experiments with male House Finches (Carpodacus mexicanus) to test if this species is able to discriminate between (1) carotenoid-enriched and plain sunflower seeds (while controlling for food coloration), and (2) plain seeds scented with β-ionone, which is a carotenoid-degradation product that is common in many fruits and is one of the most powerful flavor-active organic compounds, or a sham odorant. We found that finches did not show significant food preferences in either experiment, indicating that they did not use odor or flavor cues associated with carotenoids to discriminate between foods. However, our results do not rule out the possibilities that other flavors or odors can be used in discrimination or that finches may learn to discriminate flavors and odors over longer periods of time or at other times of year through post-ingestive feedback mechanisms. © 2012 Dt. Ornithologen-Gesellschaft e.V.

Author Keywords
Carotenoids;  Foraging;  House Finch;  Olfaction

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, 158 A (10), pp. 2602-2605. 

a Greenwood Genetic Center, Greenwood, SC, United States
b Baylor College of Medicine, Houston, TX, United States
c Washington University School of Medicine, St. Louis, MO, United States

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
Source: Scopus

 

Webb, B.T.a , Guo, A.-Y.b , Maher, B.S.c , Zhao, Z.b , Van Den Oord, E.J.d , Kendler, K.S.a , Riley, B.P.a , Gillespie, N.A.a , Prescott, C.A.e , Middeldorp, C.M.f , Willemsen, G.f , De Geus, E.J.C.f , Hottenga, J.-J.f , Boomsma, D.I.f , Slagboom, E.P.g , Wray, N.R.h , Montgomery, G.W.i , Martin, N.G.i , Wright, M.J.i , Heath, A.C.j , Madden, P.A.j , Gelernter, J.k , Knowles, J.A.l , Hamilton, S.P.m , Weissman, M.M.n o , Fyer, A.J.n o , Huezo-Diaz, P.p , McGuffin, P.p , Farmer, A.p , Craig, I.W.p , Lewis, C.p , Sham, P.q , Crowe, R.R.r , Flint, J.s , Hettema, J.M.a
Meta-analyses of genome-wide linkage scans of anxiety-related phenotypes
(2012) European Journal of Human Genetics, 20 (10), pp. 1078-1084. 

a Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, PO Box 980126, Richmond, VA 23298-0126, United States
b Departments of Biomedical Informatics and Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, United States
c Department of Mental Health, Johns Hopkins School of Public Health, Baltimore, MD, United States
d School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States
e Department of Psychology, University of Southern California, Los Angeles, CA, United States
f Department of Biological Psychology, VU University, Amsterdam, Netherlands
g Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, Netherlands
h Queensland Brain Institute, University of Queensland, St Lucia, QLD, Australia
i Queensland Institute of Medical Research, Brisbane, QLD, Australia
j Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
k Departments of Psychiatry, Genetics and Neurobiology, Yale University School of Medicine, New Haven, CT, United States
l Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
m Department of Psychiatry, University of California, San Francisco, CA, United States
n Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, United States
o New York State Psychiatric Institute, New York, NY, United States
p Institute of Psychiatry, King's College London, London, United Kingdom
q Department of Psychiatry, University of Hong Kong, Hong Kong
r Department of Psychiatry, University of Iowa, Iowa City, IA, United States
s Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom

Abstract
Genetic factors underlying trait neuroticism, reflecting a tendency towards negative affective states, may overlap genetic susceptibility for anxiety disorders and help explain the extensive comorbidity amongst internalizing disorders. Genome-wide linkage (GWL) data from several studies of neuroticism and anxiety disorders have been published, providing an opportunity to test such hypotheses and identify genomic regions that harbor genes common to these phenotypes. In all, 11 independent GWL studies of either neuroticism (n8) or anxiety disorders (n3) were collected, which comprised of 5341 families with 15 529 individuals. The rank-based genome scan meta-analysis (GSMA) approach was used to analyze each trait separately and combined, and global correlations between results were examined. False discovery rate (FDR) analysis was performed to test for enrichment of significant effects. Using 10 cM intervals, bins nominally significant for both GSMA statistics, P SR and P OR, were found on chromosomes 9, 11, 12, and 14 for neuroticism and on chromosomes 1, 5, 15, and 16 for anxiety disorders. Genome-wide, the results for the two phenotypes were significantly correlated, and a combined analysis identified additional nominally significant bins. Although none reached genome-wide significance, an excess of significant P SR P-values were observed, with 12 bins falling under a FDR threshold of 0.50. As demonstrated by our identification of multiple, consistent signals across the genome, meta-analytically combining existing GWL data is a valuable approach to narrowing down regions relevant for anxiety-related phenotypes. This may prove useful for prioritizing emerging genome-wide association data for anxiety disorders. © 2012 Macmillan Publishers Limited. All rights reserved.

Author Keywords
anxiety;  linkage;  meta-analysis;  neuroticism;  panic disorder

Document Type: Article
Source: Scopus

 

Palmer, R.H.C.a b c , McGeary, J.E.a b c , Francazio, S.a d , Raphael, B.J.e , Lander, A.D.f , Heath, A.C.g , Knopik, V.S.a b
The genetics of alcohol dependence: Advancing towards systems-based approaches
(2012) Drug and Alcohol Dependence, 125 (3), pp. 179-191. 

a Division of Behavioral Genetics, Department of Psychiatry, Rhode Island Hospital, United States
b Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, United States
c Department of Veterans Affairs, Providence, RI, United States
d Providence College, Providence, United States
e Department of Computer Science, Center for Computational Molecular Biology, Brown University, United States
f Department of Developmental and Cell Biology, University of California, Irvine, United States
g Department of Psychiatry, Washington University School of Medicine, St. Louis, United States

Abstract
Background: Personalized treatment for psychopathologies, in particular alcoholism, is highly dependent upon our ability to identify patterns of genetic and environmental effects that influence a person's risk. Unfortunately, array-based whole genome investigations into heritable factors that explain why one person becomes dependent upon alcohol and another does not, have indicated that alcohol's genetic architecture is highly complex. That said, uncovering and interpreting the missing heritability in alcohol genetics research has become all the more important, especially since the problem may extend to our inability to model the cumulative and combinatorial relationships between common and rare genetic variants. As numerous studies begin to illustrate the dependency of alcohol pharmacotherapies on an individual's genotype, the field is further challenged to identify new ways to transcend agnostic genomewide association approaches. We discuss insights from genetic studies of alcohol related diseases, as well as issues surrounding alcohol's genetic complexity and etiological heterogeneity. Finally, we describe the need for innovative systems-based approaches (Systems Genetics) that can provide additional statistical power that can enhance future gene-finding strategies and help to identify heretofore-unrealized mechanisms that may provide new targets for prevention/treatments efforts. Emerging evidence from early studies suggest that Systems Genetics has the potential to organize our neurological, pharmacological, and genetic understanding of alcohol dependence into a biologically plausible framework that represents how perturbations across evolutionarily robust biological systems determine susceptibility to alcohol dependence. © 2012 Elsevier Ireland Ltd.

Author Keywords
Alcohol dependence;  Alcoholism;  Genetics;  GWAS;  Systems Genetics

Document Type: Review
Source: Scopus

 

Bergin, J.E.a , Neale, M.C.a , Eaves, L.J.a , Martin, N.G.b , Heath, A.C.c , Maes, H.H.a
Genetic and Environmental Transmission of Body Mass Index Fluctuation
(2012) Behavior Genetics, pp. 1-8. Article in Press. 

a Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, MCV, Richmond, 23298, United States
b Queensland Institute of Medical Research and Joint Genetics Program, University of Queensland, Brisbane, Australia
c Department of Psychiatry, Washington University School of Medicine, St. Louis, United States

Abstract
This study sought to determine the relationship between body mass index (BMI) fluctuation and cardiovascular disease phenotypes, diabetes, and depression and the role of genetic and environmental factors in individual differences in BMI fluctuation using the extended twin-family model (ETFM). This study included 14,763 twins and their relatives. Health and Lifestyle Questionnaires were obtained from 28,492 individuals from the Virginia 30,000 dataset including twins, parents, siblings, spouses, and children of twins. Self-report cardiovascular disease, diabetes, and depression data were available. From self-reported height and weight, BMI fluctuation was calculated as the difference between highest and lowest BMI after age 18, for individuals 18-80 years. Logistic regression analyses were used to determine the relationship between BMI fluctuation and disease status. The ETFM was used to estimate the significance and contribution of genetic and environmental factors, cultural transmission, and assortative mating components to BMI fluctuation, while controlling for age. We tested sex differences in additive and dominant genetic effects, parental, non-parental, twin, and unique environmental effects. BMI fluctuation was highly associated with disease status, independent of BMI. Genetic effects accounted for ~34 % of variance in BMI fluctuation in males and ~43 % of variance in females. The majority of the variance was accounted for by environmental factors, about a third of which were shared among twins. Assortative mating, and cultural transmission accounted for only a small proportion of variance in this phenotype. Since there are substantial health risks associated with BMI fluctuation and environmental components of BMI fluctuation account for over 60 % of variance in males and over 50 % of variance in females, environmental risk factors may be appropriate targets to reduce BMI fluctuation. © 2012 Springer Science+Business Media New York.

Author Keywords
BMI;  Chronic disease;  Family studies;  Heritability;  Weight change

Document Type: Article in Press
Source: Scopus

 

Mitchell, T.J.a , Neil, J.J.a b c , Zempel, J.M.a b , Thio, L.L.a b , Inder, T.E.a b c , Bretthorst, G.L.c
Automating the analysis of EEG recordings from prematurely-born infants: A Bayesian approach
(2012) Clinical Neurophysiology, . Article in Press. 

a Department of Pediatrics, Washington University, St. Louis, MO 63110, USA
b Department of Pediatric Neurology, Washington University, St. Louis, MO 63110, USA
c Department of Radiology, Washington University, St. Louis, MO 63110, USA

Abstract
Objective: To implement an automated analysis of EEG recordings from prematurely-born infants and thus provide objective, reproducible results. Methods: Bayesian probability theory is employed to compute the posterior probability for developmental features of interest in EEG recordings. Currently, these features include smooth delta waves (0.5-1.5 Hz, >100 μV), delta brushes (delta portion: 0.5-1.5 Hz, >100 μV; "brush" portion: 8-22 Hz, <75 μV), and interburst intervals (<10 μV), though the approach taken can be generalized to identify other EEG features of interest. Results: When compared with experienced electroencephalographers, the algorithm had a true positive rate between 72% and 79% for the identification of delta waves (smooth or "brush") and interburst intervals, which is comparable to the inter-rater reliability. When distinguishing between smooth delta waves and delta brushes, the algorithm's true positive rate was between 53% and 88%, which is slightly less than the inter-rater reliability. Conclusion: Bayesian probability theory can be employed to consistently identify features of EEG recordings from premature infants. Significance: The identification of features in EEG recordings provides a first step towards the automated analysis of EEG recordings from premature infants. © 2012.

Author Keywords
Bayesian;  EEG;  Neonatal

Document Type: Article in Press
Source: Scopus

 

Liu, T.a , Daniels, C.K.b c , Cao, S.d
Comprehensive review on the HSC70 functions, interactions with related molecules and involvement in clinical diseases and therapeutic potential

(2012) Pharmacology and Therapeutics, . Article in Press. 

a Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA
b Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, Idaho State University, Pocatello, ID, USA
c The ISU Biomedical Research Institute, Idaho State University, Pocatello, ID, USA
d Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA

Abstract
Heat shock cognate protein 70 (HSC70) is a constitutively expressed molecular chaperone which belongs to the heat shock protein 70 (HSP70) family. HSC70 shares some of the structural and functional similarity with HSP70. HSC70 also has different properties compared with HSP70 and other heat shock family members. HSC70 performs its full functions by the cooperation of co-chaperones. It interacts with many other molecules as well and regulates various cellular functions. It is also involved in various diseases and may become a biomarker for diagnosis and potential therapeutic targets for design, discovery, and development of novel drugs to treat various diseases. In this article, we provide a comprehensive review on HSC70 from the literatures including the basic general information such as classification, structure and cellular location, genetics and function, as well as its protein association and interaction with other proteins. In addition, we also discussed the relationship of HSC70 and related clinical diseases such as cancer, cardiovascular, neurological, hepatic and many other diseases and possible therapeutic potential and highlight the progress and prospects of research in this field. Understanding the functions of HSC70 and its interaction with other molecules will help us to reveal other novel properties of this protein. Scientists may be able to utilize this protein as a biomarker and therapeutic target to make significant advancement in scientific research and clinical setting in the future. © 2012 Elsevier Inc. All rights reserved.

Author Keywords
HSC70;  HSP70;  HSPa8;  Molecular chaperone;  Protein folding;  Ubiquitination

Document Type: Article in Press
Source: Scopus

 

Bodner, K.E.a , Aldridge, K.b , Moffitt, A.J.a , Peck, D.c , White, D.A.d , Christ, S.E.a
A volumetric study of basal ganglia structures in individuals with early-treated phenylketonuria
(2012) Molecular Genetics and Metabolism, . Article in Press. 

a Department of Psychological Sciences, University of Missouri, Columbia, MO, USA
b Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, MO, USA
c Department of Child Health, University of Missouri School of Medicine, Columbia, MO, USA
d Department of Psychology, Washington University, St. Louis, MO, USA

Abstract
Whereas the impact of early-treated phenylketonuria (ETPKU) on cortical white matter is well documented, relatively little is known regarding the potential impact of this metabolic disorder on deep gray matter structures such as the basal ganglia. The current study used high-resolution (1 mm 3) magnetic resonance imaging to investigate bilateral basal ganglia structures (i.e., putamen, caudate nucleus, and nucleus accumbens) in a sample of 13 individuals with ETPKU and a demographically-matched sample of 13 neurologically intact individuals without PKU. Consistent with previous research, we found smaller whole brain volumes in the ETPKU group compared with the non-PKU group. Individuals with ETPKU also had significantly larger putamen volumes than non-PKU individuals. In addition, the degree of putamen enlargement was correlated with blood phenylalanine levels and full scale IQ in the ETPKU group. These findings are consistent with the hypothesis that ETPKU-related increases in phenylalanine lead to decreased central dopamine levels thus impacting dopamine-dependent brain regions such as the putamen that play an important role in cognition. © 2012 Elsevier Inc. All rights reserved.

Author Keywords
Basal ganglia;  Caudate;  Magnetic resonance imaging;  Phenylketonuria;  Putamen;  Striatum

Document Type: Article in Press
Source: Scopus

 

Agrawal, A.a , Madden, P.A.F.a , Martin, N.G.b , Lynskey, M.T.a
Do early experiences with cannabis vary in cigarette smokers?
(2012) Drug and Alcohol Dependence, . Article in Press. 

a Washington University School of Medicine, Department of Psychiatry, 660 S. Euclid, CB 8134, Saint Louis, MO 63110, USA
b Queensland Institute of Medical Research, Brisbane, Australia

Abstract
Introduction: We examine whether regular cigarette smokers were more likely to be exposed to and use cannabis at an earlier age, and further, upon initiation, whether their initial experiences with cannabis varied from those reported by never/non-regular cigarette smokers. Method: A sample of 3797 Australian twins and siblings aged 21-46 years was used. Survival analyses examined whether cigarette smokers were at increased likelihood of early opportunity to use cannabis and early onset of cannabis use. Logistic regression examined whether cigarette smokers reported greater enjoyment of their cannabis experience, inhaling on the first try, differing positive and negative initial subjective reactions, smoked cigarettes with cannabis the first time and were more likely to try cannabis again within a week. Results: Regular cigarette smokers were more likely to report an earlier opportunity to use cannabis and early onset of cannabis use. Regular cigarette smokers were also considerably more likely to have enjoyed their first experience with cannabis and reported higher rates of positive initial reactions. They were more likely to report inhaling on the first try and smoking cigarettes with cannabis. Potentially negative subjective reactions were also elevated in regular cigarette smokers. Importantly, cigarette smokers were at 1.87 increased odds of smoking cannabis within a week of their initial use. Conclusion: These findings indicate that the well-known overlap in cannabis and cigarette smoking behaviors may evolve as early as opportunity to use and extend through the course of the substance use trajectory. © 2012.

Author Keywords
Cannabis;  Cigarette;  Initial reaction;  Onset;  Opportunity

Document Type: Article in Press
Source: Scopus

 

Anderson, N.R.a , Blakely, T.b , Schalk, G.c , Leuthardt, E.C.d , Moran, D.W.e
Electrocorticographic (ECoG) correlates of human arm movements
(2012) Experimental Brain Research, pp. 1-10. Article in Press. 

a Department of Biomedical Engineering, Cortech Solutions and Washington University in Saint Louis, 1409 Audubon Blvd, Wilmington, 28403, United States
b Department of Computer Science and Engineering, Washington University in Saint Louis, 1815 E Calhoun, Seattle, 98112, United States
c Wadsworth Center, C650 Empire State Plaza, Albany, 12201, United States
d School of Neurosurgery and Department of Biomedical Engineering, Washington University in Saint Louis, 660 S. Euclid Avenue, Campus Box 8057, St. Louis, 63110, United States
e Department of Biomedical Engineering, Washington University in Saint Louis, 300F Whitaker Hall, Campus Box 1097, St. Louis, 63021, United States

Abstract
Invasive and non-invasive brain-computer interface (BCI) studies have long focused on the motor cortex for kinematic control of artificial devices. Most of these studies have used single-neuron recordings or electroencephalography (EEG). Electrocorticography (ECoG) is a relatively new recording modality in BCI research that has primarily been built on successes in EEG recordings. We built on prior experiments related to single-neuron recording and quantitatively compare the extent to which different brain regions reflect kinematic tuning parameters of hand speed, direction, and velocity in both a reaching and tracing task in humans. Hand and arm movement experiments using ECoG have shown positive results before, but the tasks were not designed to tease out which kinematics are encoded. In non-human primates, the relationships among these kinematics have been more carefully documented, and we sought to begin elucidating that relationship in humans using ECoG. The largest modulation in ECoG activity for direction, speed, and velocity representation was found in the primary motor cortex. We also found consistent cosine tuning across both tasks, to hand direction and velocity in the high gamma band (70-160 Hz). Thus, the results of this study clarify the neural substrates involved in encoding aspects of motor preparation and execution and confirm the important role of the motor cortex in BCI applications. © 2012 Springer-Verlag.

Author Keywords
Arm tuning;  Brain-computer interfaces;  Cosine tuning;  Electrocorticography;  Motor cortex;  Subdural electroencephalography

Document Type: Article in Press
Source: Scopus

 

Demarzo, M.M.P.a , Stein, P.K.b
Mental stress and exercise training response: Stress-sleep connection may be involved
(2012) Frontiers in Physiology, 3 JUN, art. no. Article 178, . 

a Department of Preventive Medicine, Center for Mindfulness and Health Promotion, Universidade Federal de São Paulo, São Paulo, Brazil
b Division of Cardiology, Heart Rate Variability Laboratory, Washington University School of Medicine, Saint Louis, MO, United States

Document Type: Article
Source: Scopus

 

Krug, M.K.a , Carter, C.S.b
Proactive and reactive control during emotional interference and its relationship to trait anxiety
(2012) Brain Research, . Article in Press. 

a Cognitive Control and Psychopathology Laboratory, Department of Psychology, Washington University, Campus Box 1125, One Brookings Drive, Saint Louis, MO 63130, USA
b University of California, Davis, USA

Abstract
In classic Stroop paradigms, increasing the proportion of control-demanding incongruent trials results in strategic adjustments in behavior and implementation of cognitive control processes. We manipulated expectancy for incongruent trials in an emotional facial Stroop task to investigate the behavioral and neural effects of proportion manipulation in a cognitively demanding task with emotional stimuli. Subjects performed a high expectancy (HE) task (65% incongruent trials) and a low expectancy (LE) task (35% incongruent trials) during functional magnetic resonance imaging (fMRI). As in standard Stroop tasks, behavioral interference was reduced in the emotional facial Stroop HE task compared to the LE task. Functional MRI data revealed a switch in cognitive control strategy, from a reactive, event-related activation of a medial and lateral cognitive control network and right amygdala in the LE task to a proactive, sustained activation of right dorsolateral prefrontal cortex (DLPFC) in the HE task. Higher trait anxiety was associated with impairment (slower response time and decreased accuracy) as well as reduced activity in left ventrolateral prefrontal cortex, anterior insula, and orbitofrontal cortex in the HE task on high conflict trials with task-irrelevant emotional information, suggesting that individual differences in anxiety may be associated with expectancy-related strategic control adjustments, particularly when emotional stimuli must be ignored. © 2012 Elsevier B.V. All rights reserved.

Author Keywords
Amygdala;  Anterior cingulate cortex;  Conflict monitoring;  fMRI;  Prefrontal cortex;  Sustained and transient control

Document Type: Article in Press
Source: Scopus

 

Malcolm, H.R., Maurer, J.A.
The Mechanosensitive Channel of Small Conductance (MscS) Superfamily: Not Just Mechanosensitive Channels Anymore
(2012) ChemBioChem, 13 (14), pp. 2037-2043. 

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

Author Keywords
Bacterial ion channels;  Bioinformatics;  Mechanosensitive channel of small conductance (MscS);  Mechanosensitive channels;  MscS superfamily

Document Type: Short Survey
Source: Scopus

 

Schwartz, G.W.a , Okawa, H.a , Dunn, F.A.a , Morgan, J.L.b , Kerschensteiner, D.c , Wong, R.O.a , Rieke, F.d e
The spatial structure of a nonlinear receptive field
(2012) Nature Neuroscience, . Article in Press. 

a Department of Physiology and Biophysics, University of Washington, Seattle, Seattle, Washington, USA
b Department of Molecular and Cell Biology, Harvard University, Cambridge, Massachusetts, USA
c Department of Ophthalmolgy and Visual Sciences, and Department of Anatomy and Neurobiology, Washington University, St. Louis, Missouri, USA
d 1] Department of Physiology and Biophysics, University of Washington, Seattle, Seattle, Washington, USA
e Howard Hughes Medical Institute, Seattle, Washington, USA

Abstract
Understanding a sensory system implies the ability to predict responses to a variety of inputs from a common model. In the retina, this includes predicting how the integration of signals across visual space shapes the outputs of retinal ganglion cells. Existing models of this process generalize poorly to predict responses to new stimuli. This failure arises in part from properties of the ganglion cell response that are not well captured by standard receptive-field mapping techniques: nonlinear spatial integration and fine-scale heterogeneities in spatial sampling. Here we characterize a ganglion cell's spatial receptive field using a mechanistic model based on measurements of the physiological properties and connectivity of only the primary excitatory circuitry of the retina. The resulting simplified circuit model successfully predicts ganglion-cell responses to a variety of spatial patterns and thus provides a direct correspondence between circuit connectivity and retinal output.

Document Type: Article in Press
Source: Scopus

 

Babu, M.M.a , Kriwacki, R.W.b , Pappu, R.V.c
Versatility from protein disorder

(2012) Science, 337 (6101), pp. 1460-1461. 

a MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, United Kingdom
b Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, United States
c Department of Biomedical Engineering, Washington University of St. Louis, St. Louis, MO 63130, United States

Abstract
Synergy between disordered regions and structured domains increases the functional versatility of proteins and their interaction networks.

Document Type: Short Survey
Source: Scopus

 

Guerin, S.A.a , Robbins, C.A.b , Gilmore, A.W.c , Schacter, D.L.b
Interactions between Visual Attention and Episodic Retrieval: Dissociable Contributions of Parietal Regions during Gist-Based False Recognition
(2012) Neuron, 75 (6), pp. 1122-1134. 

a School of Psychological Sciences, University of Melbourne, Carlton, VIC 3010, Australia
b Department of Psychology, Harvard University, Cambridge, MA 02138, United States
c Department of Psychology, Washington University, St. Louis, MO 63110, United States

Abstract
The interaction between episodic retrieval and visual attention is relatively unexplored. Given that systems mediating attention and episodic memory appear to be segregated, and perhaps even in competition, it is unclear how visual attention is recruited during episodic retrieval. We investigated the recruitment of visual attention during the suppression of gist-based false recognition, the tendency to falsely recognize items that are similar to previously encountered items. Recruitment of visual attention was associated with activity in the dorsal attention network. The inferior parietal lobule, often implicated in episodic retrieval, tracked veridical retrieval of perceptual detail and showed reduced activity during the engagement of visual attention, consistent with a competitive relationship with the dorsal attention network. These findings suggest that the contribution of the parietal cortex to interactions between visual attention and episodic retrieval entails distinct systems that contribute to different components of the task while also suppressing each other. Guerin et al. report neuroimaging findings indicating that the contribution of the parietal cortex to interactions between visual attention and episodic retrieval entails distinct systems that contribute to different components of the task while also suppressing each other. © 2012 Elsevier Inc.

Document Type: Article
Source: Scopus

 

Crawford, D.C.a b , Jiang, X.b , Taylor, A.b , Mennerick, S.b c
Astrocyte-derived thrombospondins mediate the development of hippocampal presynaptic plasticity in vitro
(2012) Journal of Neuroscience, 32 (38), pp. 13100-13110. 

a Graduate Program in Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
b Departments of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
c Departments of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Astrocytes contribute to many neuronal functions, including synaptogenesis, but their role in the development of synaptic plasticity remains unclear. Presynaptic muting of hippocampal glutamatergic terminals defends against excitotoxicity. Here we studied the role of astrocytes in the development of presynaptic muting at glutamatergic synapses in rat hippocampal neurons. We found that astrocytes were critical for the development of depolarization-dependent and G i/o-dependent presynaptic muting. The ability of cAMP analogues to modulate presynaptic function was also impaired by astrocyte deficiency. Although astrocyte deprivation resulted in postsynaptic glutamate receptor deficits, this effect appeared independent of astrocytes' role in presynaptic muting. Muting was restored with chronic, but not acute, treatment with astrocyte-conditioned medium, indicating that a soluble factor is permissive for muting. Astrocyte-derived thrombospondins (TSPs) are likely responsible because TSP1 mimicked the effect of conditioned medium, and gabapentin, a highaffinity antagonist of TSP binding to the α2δ-1 calcium channel subunit, mimicked astrocyte deprivation. We found evidence that protein kinase A activity is abnormal in astrocyte-deprived neurons but restored by TSP1, so protein kinase A dysfunction may provide a mechanism by which muting is disrupted during astrocyte deficiency. In summary our results suggest an important role for astrocytederived TSPs, acting through α2δ-1, in maturation of a potentially important form of presynaptic plasticity. © 2012 the authors.

Document Type: Article
Source: Scopus

 

Johnson, J.R.a , Kocher, B.a , Barnett, E.M.b , Marasa, J.a , Piwnica-Worms, D.a
Caspase-activated cell-penetrating peptides reveal temporal coupling between endosomal release and apoptosis in an RGC-5 cell model
(2012) Bioconjugate Chemistry, 23 (9), pp. 1783-1793. 

a Departments of Cell Biology and Physiology, Molecular Imaging Center, Mallinckrodt Institute of Radiology, St. Louis, MO 63110, United States
b Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Caspase-activatable cell-penetrating peptide (CPP) probes, designed for efficient cell uptake and specificity via cleavable intramolecular quenched-fluorophore strategies, show promise for identifying and imaging retinal ganglion cell apoptosis in vivo. However, initial cell uptake and trafficking events cannot be visualized because the probes are designed to be optically quenched in the intact state. To visualize subcellular activation events in real-time during apoptosis, a new series of matched quenched and nonquenched CPP probes were synthesized. In both native and staurosporine- differentiated RGC-5 cells, probe uptake was time- and concentration-dependent through clathrine-, caveolin-, and pinocytosis-mediated endocytic mechanisms. During apoptosis, KcapTR488, a novel dual fluorophore CPP probe, revealed by multispectral imaging a temporal coupling of endosomal release and effector caspase activation in RGC-5 cells. The novel CPPs described herein provide new tools to study spatial and temporal regulation of endosomal permeability during apoptosis. © 2012 American Chemical Society.

Document Type: Article
Source: Scopus

 

Castellano, J.M.a , Deane, R.b , Gottesdiener, A.J.a , Verghese, P.B.a , Stewart, F.R.a , West, T.c , Paoletti, A.C.c , Kasper, T.R.b , DeMattos, R.B.d , Zlokovic, B.V.e , Holtzman, D.M.a f
Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Aβ clearance in a mouse model of β-amyloidosis
(2012) Proceedings of the National Academy of Sciences of the United States of America, 109 (38), pp. 15502-15507. 

a Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, St. Louis, MO 63110, United States
b Department of Neurosurgery, Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, United States
c C2N Diagnostics, Center for Emerging Technologies, St. Louis, MO 63108, United States
d Lilly Research Labs., Eli Lilly and Co., Indianapolis, IN 46285, United States
e Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, United States
f Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
The apolipoprotein E (APOE)-ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease, likely increasing risk by altering amyloid-β (Aβ) accumulation. We recently demonstrated that the low-density lipoprotein receptor (LDLR) is a major apoE receptor in the brain that strongly regulates amyloid plaque deposition. In the current study, we sought to understand the mechanism by which LDLR regulates Aβ accumulation by altering Aβ clearance from brain interstitial fluid. We hypothesized that increasing LDLR levels enhances blood-brain barrier-mediated Aβ clearance, thus leading to reduced Aβ accumulation. Using the brain Aβ efflux index method, we found that blood-brain barrier-mediated clearance of exogenously administered Aβ is enhanced with LDLR overexpression. We next developed a method to directly assess the elimination of centrally derived, endogenous Aβ into the plasma of mice using an anti-Aβ antibody that prevents degradation of plasma Aβ, allowing its rate of appearance from the brain to be measured. Using this plasma Aβ accumulation technique, we found that LDLR overexpression enhances brain-to-blood Aβ transport. Together, our results suggest a unique mechanism by which LDLR regulates brain-to-blood Aβ clearance, which may serve as a useful therapeutic avenue in targeting Aβ clearance from the brain.

Author Keywords
Dementia;  In vivo microdialysis;  Low-density lipoprotein-related protein 1;  Peripheral;  Sequestration

Document Type: Article
Source: Scopus

 

Dougherty, J.D.a , Fomchenko, E.I.d , Akuffo, A.A.a , Schmidt, E.h , Helmy, K.Y.d , Bazzoli, E.e , Brennan, C.W.b c , Holland, E.C.b c d e f , Milosevic, A.g
Candidate pathways for promoting differentiation or quiescence of oligodendrocyte progenitor-like cells in glioma
(2012) Cancer Research, 72 (18), pp. 4856-4868. 

a Departments of Genetics and Psychiatry, Washington University, St. Louis, MO, United States
b Department of Neurosurgery, Rockefeller University, New York, NY, United States
c Brain Tumor Center, Rockefeller University, New York, NY, United States
d Department of Cancer Biology and Genetics, Rockefeller University, New York, NY, United States
e Department of Neurology, Rockefeller University, New York, NY, United States
f Department of Surgery, Memorial Sloan Kettering Cancer Center, Rockefeller University, New York, NY, United States
g GENSAT Project, Rockefeller University, New York, NY, United States
h Laboratory of Molecular Biology, Rockefeller University, New York, NY, United States

Abstract
Platelet-derived growth factor receptor alpha-positive oligodendrocyte progenitor cells (OPC) located within the mature central nervous system may remain quiescent, proliferate, or differentiate into oligodendrocytes. Human glioblastoma multiforme tumors often contain rapidly proliferating oligodendrocyte lineage transcription factor 2 (Olig2)-positive cells that resemble OPCs. In this study, we sought to identify candidate pathways that promote OPC differentiation or quiescence rather than proliferation. Gene expression profiling conducted in both normal murine OPCs and highly proliferative Olig2-positive glioma cells identified all the transcripts associated with the highly proliferative state of these cells and showed that among the various cell types found within the brain, Olig2-positive tumor cells are most similar to OPCs. We then subtracted OPC transcripts found in tumor samples from those found in normal brain samples and identified 28 OPC transcripts as candidates for promoting differentiation or quiescence. Systematic analysis of human glioma data revealed that these genes have similar expression pro files in human tumors and were significantly enriched in genomic deletions, suggesting an antiproliferative role. Treatment of primary murine glioblastoma cells with agonists of one candidate gene, Gpr17, resulted in a decreased number of neurospheres. Together, our findings show that comparison of the molecular phenotype of progenitor cells in tumors to the equivalent cells in the normal brain represents a novel approach for the identification of targeted therapies. ©2012 AACR.

Document Type: Article
Source: Scopus

 

Pandey, N., Fahey, M.T., Jong, Y.-J.I., O'Malley, K.L.
Sequences Located within the N-Terminus of the PD-Linked LRRK2 Lead to Increased Aggregation and Attenuation of 6-Hydroxydopamine-Induced Cell Death
(2012) PLoS ONE, 7 (9), art. no. e45149, . 

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

Abstract
Clinical symptoms of Parkinson's disease (PD) arise from the loss of substantia nigra neurons resulting in bradykinesia, rigidity, and tremor. Intracellular protein aggregates are a pathological hallmark of PD, but whether aggregates contribute to disease progression or represent a protective mechanism remains unknown. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been linked to PD in both familial cases and idiopathic cases and aggregates of the LRRK2 protein are present in postmortem PD brain samples. To determine whether LRRK2 contains a region of protein responsible for self-aggregation, two independent, bioinformatic algorithms were used to identify an N-terminal amino acid sequence as being aggregation-prone. Cells subsequently transfected with a construct containing this domain were found to have significantly increased protein aggregation compared to wild type protein or a construct containing only the last half of the molecule. Finally, in support of the hypothesis that aggregates represent a self-protection strategy, aggregated N-terminal LRRK2 constructs significantly attenuated cell death induced by the PD-mimetic, 6-hydroxydopamine (6-OHDA). © 2012 Pandey et al.

Document Type: Article
Source: Scopus

 

Klein, S.E.a , Dale, A.M.b , Hayes, M.H.c , Johnson, J.E.a , McCormick, J.J.a , Racette, B.A.d
Clinical presentation and self-reported patterns of pain and function in patients with plantar heel pain
(2012) Foot and Ankle International, 33 (9), pp. 693-698. 

a Department of Orthopaedic Surgery, Washington University School of Medicine, Campus Box 8233, 660 South Euclid Avenue, St. Louis, MO, United States
b General Medical Sciences, Washington University School of Medicine, St. Louis, MO, United States
c Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Plantar heel pain is a common disorder of the foot. The purpose of this study was to explore the relationship between duration of symptoms in plantar fasciitis patients and demographic factors, the intensity and location of pain, extent of previous treatment, and self-reported pain and function. Methods: The charts of patients presenting with plantar heel pain between June 2008 and October 2010 were reviewed retrospectively and 182 patients with a primary diagnosis of plantar fasciitis were identified. Patients with symptoms less than 6 months were identified as acute and patients with symptoms greater than or equal to 6 months were defined as having chronic symptoms. Comparisons based on duration of symptoms were performed for age, gender, body mass index (BMI), comorbidities, pain location and intensity, and a functional score measured by the Foot and Ankle Ability Measure (FAAM). Results: The two groups were similar in age, BMI, gender, and comorbidities. Pain severity, as measured by a visual analog scale, was not statistically significant between the two groups (6.6 and 6.2). The acute and chronic groups of patients reported similar levels of function on both the activity of daily living (62 and 65) and sports (47 and 45) subscales of the FAAM. Patients in the chronic group were more likely to have seen more providers and tried more treatment options for this condition. Conclusion: As plantar fasciitis symptoms extend beyond 6 months, patients do not experience increasing pain intensity or functional limitation. No specific risk factors have been identified to indicate a risk of developing chronic symptoms. Copyright © 2012 by the American Orthopaedic Foot & Ankle Society.

Author Keywords
Functional limitation;  Heel pain;  Plantar fasciitis

Document Type: Article
Source: Scopus

 

Tse, S.a , Hong, S.-I.b , Wang, C.-W.c , Cunningham-Williams, R.M.d
Gambling behavior and problems among older adults: A systematic review of empirical studies
(2012) Journals of Gerontology - Series B Psychological Sciences and Social Sciences, 67 B (5), pp. 639-652. 

a Department of Social Work and Social Administration, University of Hong Kong, Pokfulam Road, Hong Kong, Hong Kong
b Department of Social Work, National University of Singapore, Singapore
c Centre for Behavioral Health, University of Hong Kong, China
d George Warren Brown School of Social Work, Washington University, St Louis, MO, United States

Abstract
Objectives. With the rapid aging of the population and the increased availability of gambling facilities over the past three decades, older adults may gamble more and may be increasingly at risk for problem gambling (PG) or pathological gambling disorder (PGD). To facilitate a better understanding of gambling behavior among older adults that will inform preventive strategies, this article systematically examined empirical studies on issues related to older adults' gambling. Method. This article reviewed 75 empirical studies including data on the distribution and determinants of PG and PGD and the outcomes of gambling.Results.This review used the broad term of "disordered gambling" as a means to explain a continuum of problems caused by PG and PGD. The analyses covered seven topics concerning older adults' gambling behaviors: Participation rates for gambling, prevalence rates of disordered gambling, motivation for initially beginning to gamble, risk and protective factors for disordered gambling, and negative and positive health outcomes from gambling. Discussion. Based on research gaps identified in the review, this article proposes six recommendations for future studies focusing on well-being of older adults who gamble, research method issues, and taking into account older adults' inspirations and adjustment to the aging process in the 21st century. © 2012 The Author.

Author Keywords
Activity levels;  Behavioral addiction;  Lifestyle;  Mental health

Document Type: Review
Source: Scopus

 

Sheline, C.T.a d , Zhu, J.d , Zhang, W.d , Shi, C.b d d , Cai, A.-L.c d d
Mitochondrial inhibitor models of Huntington's disease and Parkinson's disease induce zinc accumulation and are attenuated by inhibition of zinc neurotoxicity in vitro or in vivo

(2013) Neurodegenerative Diseases, 11 (1), pp. 49-58. 

a Department of Ophthalmology, Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, 2020 Gravier St., New Orleans, LA 70112, United States
b Department of Surgery, Washington University, Saint Louis, MO, United States
c Department of Biomedical Engineering, Washington University, Saint Louis, MO, United States
d Department of Neurology, Washington University, Saint Louis, MO, United States

Abstract
Background: Inhibition of mitochondrial function occurs in many neurodegenerative diseases, and inhibitors of mitochondrial complexes I and II are used to model them. The complex II inhibitor, 3-nitroproprionic acid (3-NPA), kills the striatal neurons susceptible in Huntington's disease. The complex I inhibitor N-methyl-4-phenylpyridium (MPP +) and 6-hydroxydopamine (6-OHDA) are used to model Parkinson's disease. Zinc (Zn 2+) accumulates after 3-NPA, 6-OHDA and MPP + in situ or in vivo. Objective: We will investigate the role of Zn 2+ neurotoxicity in 3-NPA, 6-OHDA and MPP +. Methods: Murine striatal/midbrain tyrosine hydroxylase positive, or near-pure cortical neuronal cultures, or animals were exposed to 3-NPA or MPP + and 6-OHDA with or without neuroprotective compounds. Intracellular zinc ([Zn 2+] i), nicotinamide adenine dinucleotide (NAD +), NADH, glycolytic intermediates and neurotoxicity were measured. Results: We showed that compounds or genetics which restore NAD + and attenuate Zn 2+ neurotoxicity (pyruvate, nicotinamide, NAD +, increased NAD + synthesis, sirtuin inhibition or Zn 2+ chelation) attenuated the neuronal death induced by these toxins. The increase in [Zn 2+] i preceded a reduction in the NAD +/NADH ratio that caused a reversible glycolytic inhibition. Pyruvate, nicotinamide and NAD + reversed the reductions in the NAD +/NADH ratio, glycolysis and neuronal death after challenge with 3-NPA, 6-OHDA or MPP +, as was previously shown for exogenous Zn 2+. To test efficacy in vivo, we injected 3-NPA into the striatum of rats and systemically into mice, with or without pyruvate. We observed early striatal Zn 2+ fluorescence, and pyruvate significantly attenuated the 3-NPA-induced lesion and restored behavioral scores. Conclusions: Together, these studies suggest that Zn 2+ accumulation caused by MPP + and 3-NPA is a novel preventable mechanism of the resultant neurotoxicity. © 2012 S. Karger AG, Basel.

Author Keywords
3-Nitropropionic acid;  6-Hydroxydopamine;  Glycolytic inhibition;  N-methyl-4-phenylpyridium;  Zinc neurotoxicity

Document Type: Article
Source: Scopus

 

Maddox, G.B., Balota, D.A.
Self control of when and how much to test face-name pairs in a novel spaced retrieval paradigm: An examination of age-related differences
(2012) Aging, Neuropsychology, and Cognition, 19 (5), pp. 620-643. 

Department of Psychology, Washington University, Box 1125, St. Louis, MO, 63130, United States

Abstract
Although the mnemonic benefit of spaced retrieval is well established, the way in which participants naturally space their own retrieval is relatively unexplored. To examine this question, a novel experimental paradigm was developed in which young and healthy older adults were given control over the frequency and timing of retrieval practice in the context of an ongoing reading task. Results showed that both age groups naturally expanded the intervals of their retrieval practice. When instructed, younger adults but not older adults were better able to employ equal spaced retrieval during retrieval practice. However, even under equal spaced retrieval instructions, young adults included an early retrieval attempt prior to equally spacing their retrieval. Although memory performance was equivalent, secondary task performance was reduced in the experimenter-instructed condition compared with the participant-selected condition. The results overall indicate that both younger and older participants naturally monitor their memory and efficiently use testing to titrate the number and timing of retrieval attempts used during the acquisition phase. © 2012 Psychology Press.

Author Keywords
Aging;  Memory;  Metacognition;  Retrieval;  Testing effect

Document Type: Article
Source: Scopus

 

MacAr, 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, 42 (5), pp. 732-742. 

a Department of Psychology, University of Bonn, Kaiser-Karl-Ring 9, 53111 Bonn, Germany
b Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom
c Department of Psychiatry, Washington University Medical School, St Louis, MO, United States
d Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, QLD, 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. © Springer Science+Business Media, LLC 2012.

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

Document Type: Article
Source: Scopus

 

Schoeller, E.L.a , Schon, S.a , Moley, K.H.a b
The effects of type 1 diabetes on the hypothalamic, pituitary and testes axis
(2012) Cell and Tissue Research, 349 (3), pp. 839-847.

a Departments of Obstetrics and Gynecology, Washington University, School of Medicine, St. Louis MO 63110, United States
b Cell Biology and Physiology, Washington University, School of Medicine, St. Louis MO 63110, United States

Abstract
Type 1 diabetes is an autoimmune disorder characterized by a lack of insulin production by the beta cells of the pancreas. This lack of insulin causes a variety of systemic effects on whole-body metabolism. Poorly managed type 1 diabetes can lead to cardiovascular disease, diabetic neuropathy, and diabetic retinopathy. Increasingly, even well-managed type 1 diabetic patients show damage to peripheral organs related to complications from the disease. The central role of insulin in energy homeostasis also renders it an important signaling factor in the reproductive tract. type 1 diabetes has now been demonstrated to cause defects in sperm and testes. The aim of this review is to present the known effects of insulin's role in the function of the male reproductive tract. These effects might be mediated through hormonal alterations in the hypothalamic pituitary gonadal axis or through the direct interaction of insulin on the testes and sperm cells. Although fertility complications also occur in type 2 diabetic males, this review will focus on the defects specifically linked with the lack of insulin seen in type 1 diabetes. © Springer-Verlag 2012.

Author Keywords
Diabetes;  Insulin;  Reproduction;  Sperm;  Testes

Document Type: Review
Source: Scopus

 

Tye-Murray, N.a , Sommers, M.S.b , Mauze, E.a , Schroy, C.a , Barcroft, J.c , Spehar, B.a
Using patient perceptions of relative benefit and enjoyment to assess auditory training
(2012) Journal of the American Academy of Audiology, 23 (8), pp. 623-634. 

a Department of Otolaryngology, Washington University School of Medicine, Campus Box 8115, 660 South Euclid Avenue, St. Louis, MO 63110, United States
b Department of Psychology, Washington University, St. Louis, MO, United States
c Department of Romance Languages and Literatures, Washington University, St. Louis, MO, United States

Abstract
Background: Patients seeking treatment for hearing-related communication difficulties are often disappointed with the eventual outcomes, even after they receive a hearing aid or a cochlear implant. One approach that audiologists have used to improve communication outcomes is to provide auditory training (AT), but compliance rates for completing AT programs are notoriously low. Purpose: The primary purpose of the investigation was to conduct a patient-based evaluation of the benefits of an AT program, I Hear What You Mean, in order to determine how the AT experience might be improved. A secondary purpose was to examine whether patient perceptions of the AT experience varied depending on whether they were trained with a single talker's voice or heard training materials from multiple talkers. Research Design: Participants completed a 6 wk auditory training program and were asked to respond to a posttraining questionnaire. Half of the participants heard the training materials spoken by six different talkers, and half heard the materials produced by only one of the six talkers. Study Sample: Participants included 78 adult hearing-aid users and 15 cochlear-implant users for a total of 93 participants who completed the study, ages 18 to 89 yr (M = 66 yr, SD = 16.67 yr). Forty-three females and 50 males participated. The mean better ear pure-tone average for the participants was 56 dB HL (SD = 25 dB). Intervention: Participants completed the single- or multiple-talker version of the 6 wk computerized AT program, I Hear What You Mean, followed by completion of a posttraining questionnaire in order to rate the benefits of overall training and the training activities and to describe what they liked best and what they liked least. Data Collection and Analysis: After completing a 6 wk computerized AT program, participants completed a posttraining questionnaire. Seven-point Likert scaled responses to whether understanding spoken language had improved were converted to individualized z scores and analyzed for changes due to AT. Written responses were coded and categorized to consider both positive and negative subjective opinions of the AT program. Regression analyses were conducted to examine the relationship between perceived effort and perceived benefit and to identify factors that predict overall program enjoyment. Results: Participants reported improvements in their abilities to recognize spoken language and in their self-confidence as a result of participating in AT. Few differences were observed between reports from those trained with one versus six different talkers. Correlations between perceived benefit and enjoyment were not significant, and only participant age added unique variance to predicting program enjoyment. Conclusions: Participants perceived AT to be beneficial. Perceived benefit did not correlate with perceived enjoyment. Compliance with computerized AT programs might be enhanced if patients have regular contact with a hearing professional and train with meaning-based materials. An unheralded benefit of AT may be an increased sense of control over the hearing loss. In future efforts, we might aim to make training more engaging and entertaining, and less tedious.

Author Keywords
Auditory training;  Cochlear implants;  Hearing aids;  Hearing loss;  Self-assessment

Document Type: Article
Source: Scopus

 

Chappell, M.C.a g , Char, D.H.a b e , Cole, T.B.a , Harbour, J.W.f , Mishra, K.c , Weinberg, V.K.c d , Phillips, T.L.c
Uveal melanoma: Molecular pattern, clinical features, and radiation response
(2012) American Journal of Ophthalmology, 154 (2), pp. 227-332.e2. 

a California Pacific Medical Center, 45 Castro St, San Francisco, CA 94114, United States
b Tumori Foundation, San Francisco, CA, United States
c Department of Ophthalmology, UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, United States
d Department of Radiation Oncology, UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, United States
e Department of Ophthalmology, Stanford School of Medicine, Stanford, CA, United States
f Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MI, United States
g University of Washington Medical Center, Seattle, WA, United States

Abstract
• PURPOSE: To characterize the clinical spectrum of class 1 and class 2 uveal melanomas and their relationship with intraocular proton radiation response. • DESIGN: Masked retrospective case series of uveal melanoma patients with fine needle biopsy- based molecular profiles. • METHODS: A total of 197 uveal melanoma patients from a single institution were analyzed for pathology, clinical characteristics, and response to radiation therapy. • RESULTS: A total of 126 patients (64%) had class 1 tumors and 71 (36%) had class 2 tumors. Patients with class 2 tumors had more advanced age (mean: 64 years vs 57 years; P = .001), had thicker initial mean ultrasound measurements (7.4 mm vs 5.9 mm; P = .0007), and were more likely to have epithelioid or mixed cells on cytopathology (66% vs 38%; P = .0004). Although mean pretreatment and posttreatment ultrasound thicknesses were significantly different between class 1 and class 2 tumors, there was no difference in the mean change in thickness 24 months after radiation therapy (mean difference: class 1=-1.64 mm, class 2=-1.47; P = .47) or in the overall rate of thickness change (slope: P = .64). Class 2 tumors were more likely to metastasize and cause death than class 1 tumors (DSS: P < .0001). • CONCLUSIONS: At the time of radiation therapy, thicker tumors, epithelioid pathology, and older patient age are significantly related to class 2 tumors, and class 2 tumors result in higher tumor-related mortality. We found no definitive clinical marker for differentiating class 1 and class 2 tumors. © 2012 by Elsevier Inc. All rights reserved.

Document Type: Article
Source: Scopus

 

Wells, A.A.a , Palinkas, L.A.b , Qiu, X.c , Ell, K.b
Cancer patients' perspectives on discontinuing depression treatment: The "drop out" phenomenon
(2011) Patient Preference and Adherence, 5, pp. 465-470. 

a George Warren Brown School of Social Work, Washington University, 210 Brown Hall, Campus Box 1196, One Brookings Drive, St Louis, MO 63130-4899, United States
b School of Social Work, University of Southern California, Los Angeles, CA, United States
c School of Social Work, Saint Louis University, St Louis, MO, United States

Abstract
Background: Adherence is a critical component of clinical intervention utility, but little is known about how cancer patients with depression, particularly low-income, ethnic minority patients, perceive adherence to and drop out from treatment. Aim: To explore low-income, minority cancer patient perspectives about not adhering or dropping out of depression treatment. Methods: A qualitative substudy was conducted within the Alleviating Depression among Patients with Cancer (ADAPt-C) study. The intervention was an individualized stepped care depression treatment program provided by a clinical social worker in collaboration with a study psychiatrist. Patients randomized to the intervention were offered antidepressant medication and/or 8-10 sessions of problem solving treatment talk therapy. In-depth telephone interviews were conducted with 20 patients who had dropped out of depression treatment, using a grounded theory qualitative methodological approach. Results: Enrolled intervention patients were predominately Latina, Spanish-speaking, and foreign born. Most patients (12/20) acknowledged they had dropped out of treatment for a variety of reasons, including dissatisfaction with treatment, poor patient-provider relations, logistical and financial barriers, cancer treatment commitments, and language barriers. However, other patients (8/20) denied they had dropped out of treatment and/or became confused about being labeled as a "dropout." Conclusion: A substantial percentage of low-income, ethnic minority patients who drop out of treatment for depression appear not to realize they have dropped out of treatment. Improving treatment adherence requires explanation of what constitutes adherence and the consequences of failing to do so from the perspective of both patient and provider. © 2011 Wells et al, publisher and licensee Dove Medical Press Ltd.

Author Keywords
Adherence;  Cancer;  Compliance;  Depression;  Dropout;  Minority

Document Type: Article
Source: Scopus