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WUSTL Neuroscience Publications Archive - December 2013

 December 27, 2013


Cox, J.A.a , LaMora, A.a , Johnson, S.L.b , Voigt, M.M.a
Novel role for carbamoyl phosphate synthetase 2 in cranial sensory circuit formation
(2014) International Journal of Developmental Neuroscience, 33 (1), pp. 41-48. 

a Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 S. Grand Blvd, St. Louis, MO 63104, United States
b Department of Genetics, Washington University of St. Louis, St. Louis, MO 63110, United States

In zebrafish, cranial sensory circuits form by 4 days post-fertilization. We used a forward genetic screen to identify genes involved in the formation of these circuits. In one mutant allele, sl23, axons arising from the epibranchial sensory ganglia do not form their stereotypical terminal fields in the hindbrain. These embryos also had small eyes and deformed jaws, suggesting a pleiotropic effect. Using positional cloning, a 20-nucleotide deletion in the carbamoyl-phosphate-synthetase2-aspartate-transcarbamylase-dihydroorotase (cad) gene was found. Injection of a CAD morpholino phenocopied the mutant and mutants were rescued by injection of cad RNA. Cad activity is required for pyrimidine biosynthesis, and thus is a prerequisite for nucleic acid production and UDP-dependent protein glycosylation. Perturbation of nucleic acid biosynthesis can result in cell death. sl23 mutants did not exhibit elevated cell death, or gross morphological changes, in their hindbrains. To determine if defective protein glycosylation was involved in the aberrant targeting of sensory axons, we treated wild type embryos with tunicamycin, which blocks N-linked protein glycosylation. Interference with glycosylation via tunicamycin treatment mimicked the sl23 phenotype. Loss of cad reveals a critical role for protein glycosylation in cranial sensory circuit formation. © 2013 ISDN.

Author Keywords

Axon guidance;  Epibranchial;  Ganglia;  Glycosylation;  Zebrafish

Document Type: 
Source: Scopus

Shin, J.E., Geisler, S., DiAntonio, A.
Dynamic regulation of SCG10 in regenerating axons after injury
(2014) Experimental Neurology, 252, pp. 1-11. 

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

Peripheral axons can re-extend robustly after nerve injury. Soon after a nerve crush regenerating axons grow through the nerve segment distal to the lesion in close proximity to distal axons that are still morphologically and molecularly preserved. Hence, following the progress of regenerating axons necessitates markers that can distinguish between regenerating and degenerating axons. Here, we show that axonal levels of superior cervical ganglion 10 (SCG10) are dynamically regulated after axonal injury and provide an efficient method to label regenerating axons. In contrast to the rapid loss of SCG10 in distal axons (Shin et al., 2012b), we report that SCG10 accumulates in the proximal axons within an hour after injury, leading to a rapid identification of the lesion site. The increase in SCG10 levels is maintained during axon regeneration after nerve crush or nerve repair and allows for more selective labeling of regenerating axons than the commonly used markers growth-associated protein 43 (GAP43) and YFP. SCG10 is preferentially expressed in regenerating sensory axons rather than motor axons in the sciatic nerve. In a mouse model of slow Wallerian degeneration, SCG10 labeling remains selective for regenerating axons and allows for a quantitative analysis of delayed regeneration in this mutant. Taken together, these data demonstrate the utility of SCG10 as an efficient and selective marker of sensory axon regeneration. © 2013 Elsevier Inc.

Author Keywords
Axon regeneration;  Dorsal root ganglia (DRG);  Marker of regenerating axon;  Nerve repair;  NMNAT;  STMN2

Document Type: Article
Source: Scopus

Rubin, M.A., Dhar, R., Diringer, M.N.
Racial differences in withdrawal of mechanical ventilation do not alter mortality in neurologically injured patients
(2014) Journal of Critical Care, 29 (1), pp. 49-53. 

Neurology/Neurosurgery Intensive Care Unit, Washington University School of Medicine, Department of Neurology, 660 South Euclid Ave Campus Box 8111, St Louis, MO 63110, United States

Purpose: Racial differences in withdrawal of mechanical ventilation (WMV) have been demonstrated among patients with severe neurologic injuries. We ascertained whether such differences might be accounted for by imbalances in socioeconomic status or disease severity, and whether such racial differences impact hospital mortality or result in greater discharge to long-term care facilities. Materials and methods: We evaluated WMV among 1885 mechanically ventilated patients with severe neurologic injury (defined as Glasgow Coma Scale <. 9), excluding those progressing to brain death within the first 48 hours. Results: Withdrawal of mechanical ventilation was less likely in nonwhite patients (22% vs 31%, P < .001). Nonwhites were younger and were more likely to have Medicaid or no insurance, live in ZIP codes with low median household incomes, be unmarried, and have greater illness severity; but after adjustment for these variables, racial difference in WMV persisted (odds ratio, 0.56; 95% confidence interval, 0.42-0.76). Nonwhite patients were more likely to die instead with full support or progress to brain death, resulting in equivalent overall hospital mortality (40% vs 42%, P = .44). Among survivors, nonwhites were more likely to be discharged to long-term care facilities (27% vs 17%, P < .001). Conclusions: Surrogates of nonwhite neurologically injured patients chose WMV less often even after correcting for socioeconomic status and other confounders. This difference in end-of-life decision making does not appear to alter hospital mortality but may result in more survivors left in a disabled state. © 2014 Elsevier Inc.

Author Keywords
Brain injury;  Medical ethics;  Racial disparity;  Withdrawal of ventilation

Document Type: Article
Source: Scopus

Ferradal, S.L.a b , Eggebrecht, A.T.b , Hassanpour, M.b c , Snyder, A.Z.b d , Culver, J.P.a b c
Atlas-based head modeling and spatial normalization for high-density diffuse optical tomography: In vivo validation against fMRI
(2014) NeuroImage, 85, pp. 117-126. Cited 2 times.

a Department of Biomedical Engineering, Washington University, Whitaker Hall, One Brookings Dr., St. Louis, MO, 63130, United States
b Department of Radiology, Washington University School of Medicine, East Bldg., 4525 Scott Ave, St. Louis, MO, 63110, United States
c Department of Physics, Washington University, One Brookings Dr., St. Louis, MO, 63130, United States
d Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, 63110, United States

Diffuse optical imaging (DOI) is increasingly becoming a valuable neuroimaging tool when fMRI is precluded. Recent developments in high-density diffuse optical tomography (HD-DOT) overcome previous limitations of sparse DOI systems, providing improved image quality and brain specificity. These improvements in instrumentation prompt the need for advancements in both i) realistic forward light modeling for accurate HD-DOT image reconstruction, and ii) spatial normalization for voxel-wise comparisons across subjects. Individualized forward light models derived from subject-specific anatomical images provide the optimal inverse solutions, but such modeling may not be feasible in all situations. In the absence of subject-specific anatomical images, atlas-based head models registered to the subject's head using cranial fiducials provide an alternative solution. In addition, a standard atlas is attractive because it defines a common coordinate space in which to compare results across subjects. The question therefore arises as to whether atlas-based forward light modeling ensures adequate HD-DOT image quality at the individual and group level. Herein, we demonstrate the feasibility of using atlas-based forward light modeling and spatial normalization methods. Both techniques are validated using subject-matched HD-DOT and fMRI data sets for visual evoked responses measured in five healthy adult subjects. HD-DOT reconstructions obtained with the registered atlas anatomy (i.e. atlas DOT) had an average localization error of 2.7. mm relative to reconstructions obtained with the subject-specific anatomical images (i.e. subject-MRI DOT), and 6.6. mm relative to fMRI data. At the group level, the localization error of atlas DOT reconstruction was 4.2. mm relative to subject-MRI DOT reconstruction, and 6.1. mm relative to fMRI. These results show that atlas-based image reconstruction provides a viable approach to individual head modeling for HD-DOT when anatomical imaging is not available. © 2013 Published by Elsevier Inc.

Author Keywords
Anatomical atlas;  Brain mapping;  Diffuse optical tomography;  Functional magnetic resonance imaging;  Group analysis;  Non-linear registration;  Spatial normalization

Document Type: Article
Source: Scopus

Hassanpour, M.S.a b , White, B.R.a b , Eggebrecht, A.T.b , Ferradal, S.L.b c , Snyder, A.Z.b d , Culver, J.P.a b c
Statistical analysis of high density diffuse optical tomography
(2014) NeuroImage, 85, pp. 104-116. Cited 1 time.

a Department of Physics, CB 1105, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130-4899, United States
b Department of Radiology, CB 8225, Washington University School of Medicine, 4525 Scott Ave., St. Louis, MO 63110, United States
c Department of Biomedical Engineering, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130, United States
d Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., St Louis, MO, 63110, United States

High density diffuse optical tomography (HD-DOT) is a noninvasive neuroimaging modality with moderate spatial resolution and localization accuracy. Due to portability and wear-ability advantages, HD-DOT has the potential to be used in populations that are not amenable to functional magnetic resonance imaging (fMRI), such as hospitalized patients and young children. However, whereas the use of event-related stimuli designs, general linear model (GLM) analysis, and imaging statistics are standardized and routine with fMRI, such tools are not yet common practice in HD-DOT. In this paper we adapt and optimize fundamental elements of fMRI analysis for application to HD-DOT. We show the use of event-related protocols and GLM de-convolution analysis in un-mixing multi-stimuli event-related HD-DOT data. Statistical parametric mapping (SPM) in the framework of a general linear model is developed considering the temporal and spatial characteristics of HD-DOT data. The statistical analysis utilizes a random field noise model that incorporates estimates of the local temporal and spatial correlations of the GLM residuals. The multiple-comparison problem is addressed using a cluster analysis based on non-stationary Gaussian random field theory. These analysis tools provide access to a wide range of experimental designs necessary for the study of the complex brain functions. In addition, they provide a foundation for understanding and interpreting HD-DOT results with quantitative estimates for the statistical significance of detected activation foci. © 2013 Published by Elsevier Inc.

Author Keywords
Diffuse optical tomography;  General linear model;  Non-stationary cluster analysis;  Statistical parametric mapping

Document Type: Article
Source: Scopus

Ameis, S.H.a , Ducharme, S.b , Albaugh, M.D.c , Hudziak, J.J.c , Botteron, K.N.d , Lepage, C.b , Zhao, L.b , Khundrakpam, B.b , Collins, D.L.b , Lerch, J.P.e , Wheeler, A.f , Schachar, R.a , Evans, A.C.b , Karama, S.b g
Cortical thickness, cortico-amygdalar networks, and externalizing behaviors in healthy children
(2014) Biological Psychiatry, 75 (1), pp. 65-72. Cited 1 time.

a Department of Psychiatry, Hospital for Sick Children, University of Toronto, Toronto, Canada
b McConnell Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal, Canada
c Vermont Center for Children, Youth and Families, University of Vermont, Burlington, VT, United States
d Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
e Program in Neuroscience and Mental Health, Hospital for Sick Children, University of Toronto, Toronto, Canada
f Kimel Family Translational Imaging-Genetics Lab, Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada
g Douglas Mental Health University Institute, McGill University, Montreal, Canada

Background Fronto-amygdalar networks are implicated in childhood psychiatric disorders characterized by high rates of externalizing (aggressive, noncompliant, oppositional) behavior. Although externalizing behaviors are distributed continuously across clinical and nonclinical samples, little is known about how brain variations may confer risk for problematic behavior. Here, we studied cortical thickness, amygdala volume, and cortico-amygdalar network correlates of externalizing behavior in a large sample of healthy children. Methods Two hundred ninety-seven healthy children (6-18 years; mean = 12 ± 3 years), with 517 magnetic resonance imaging scans, from the National Institutes of Health Magnetic Resonance Imaging Study of Normal Brain Development, were studied. Relationships between externalizing behaviors (measured with the Child Behavior Checklist) and cortical thickness, amygdala volume, and cortico-amygdalar structural networks were examined using first-order linear mixed-effects models, after controlling for age, sex, scanner, and total brain volume. Results significant at p ≤.05, following multiple comparison correction, are reported. Results Left orbitofrontal, right retrosplenial cingulate, and medial temporal cortex thickness were negatively correlated with externalizing behaviors. Although amygdala volume alone was not correlated with externalizing behaviors, an orbitofrontal cortex-amygdala network predicted rates of externalizing behavior. Children with lower levels of externalizing behaviors exhibited positive correlations between orbitofrontal cortex and amygdala structure, while these regions were not correlated in children with higher levels of externalizing behavior. Conclusions Our findings identify key cortical nodes in frontal, cingulate, and temporal cortex associated with externalizing behaviors in children; and indicate that orbitofrontal-amygdala network properties may influence externalizing behaviors, along a continuum and across healthy and clinical samples. © 2014 Society of Biological Psychiatry.

Author Keywords
Amygdala;  cortical thickness;  externalizing behavior;  healthy children and adolescents;  network;  structural magnetic resonance imaging

Document Type: Article
Source: Scopus

Agrawal, A.a , Lynskey, M.T.a b , Bucholz, K.K.a , Kapoor, M.a , Almasy, L.c , Dick, D.M.d , Edenberg, H.J.e , Foroud, T.e , Goate, A.a , Hancock, D.B.f , Hartz, S.a , Johnson, E.O.f , Hesselbrock, V.g , Kramer, J.R.h , Kuperman, S.i , Nurnberger Jr., J.I.e , Schuckit, M.j , Bierut, L.J.a
DSM-5 cannabis use disorder: A phenotypic and genomic perspective
(2014) Drug and Alcohol Dependence, 134 (1), pp. 362-369. 

a Washington University School of Medicine, Department of Psychiatry, St. Louis, MO, United States
b King's College, Institute of Psychiatry, London, United Kingdom
c Texas Biomedical Research Institute, San Antonio, TX, United States
d Virginia Commonwealth University, Virginia Institute of Psychiatric and Behavioral Genetics, VA, United States
e Indiana University School of Medicine, Indianapolis, IN, United States
f RTI International, Behavioral and Health Epidemiology Program, Research Triangle Park, NC, United States
g University of Connecticut, Department of Psychiatry, Farmington, CT, United States
h University of Iowa School of Medicine, Department of Psychiatry, Iowa City, IA, United States
i University of Iowa Hospitals, Division of Child Psychiatry, Iowa City, IA, United States
j University of California at San Diego, Department of Psychiatry, San Diego, CA, United States

Background: We explore the factor structure of DSM-5 cannabis use disorders, examine its prevalence across European- and African-American respondents as well as its genetic underpinnings, utilizing data from a genome-wide study of single nucleotide polymorphisms (SNPs). We also estimate the heritability of DSM-5 cannabis use disorders explained by these common SNPs. Methods: Data on 3053 subjects reporting a lifetime history of cannabis use were utilized. Exploratory and confirmatory factor analyses were conducted to create a factor score, which was used in a genome-wide association analysis. p-values from the single SNP analysis were examined for evidence of gene-based association. The aggregate effect of all SNPs was also estimated using Genome-Wide Complex Traits Analysis. Results: The unidimensionality of DSM-5 cannabis use disorder criteria was demonstrated. Comparing DSM-IV to DSM-5, a decrease in prevalence of cannabis use disorders was only noted in European-American respondents and was exceedingly modest. For the DSM-5 cannabis use disorders factor score, no SNP surpassed the genome-wide significance testing threshold. However, in the European-American subsample, gene-based association testing resulted in significant associations in 3 genes (C17orf58, BPTF and PPM1D) on chromosome 17q24. In aggregate, 21% of the variance in DSM-5 cannabis use disorders was explained by the genome-wide SNPs; however, this estimate was not statistically significant. Conclusions: DSM-5 cannabis use disorder represents a unidimensional construct, the prevalence of which is only modestly elevated above the DSM-IV version. Considerably larger sample sizes will be required to identify individual SNPs associated with cannabis use disorders and unequivocally establish its polygenic underpinnings. © 2013 Elsevier Ireland Ltd.

Author Keywords
Association;  Cannabis;  DSM-5;  Genetics;  GWAS;  Heritability

Document Type: Article
Source: Scopus

Berger, S.S.a b , Elliott, C.a b , Ranzenhofer, L.M.a b , Shomaker, L.B.a b , Hannallah, L.a b , Field, S.E.a b , Young, J.F.c , Sbrocco, T.a , Wilfley, D.E.d , Yanovski, J.A.b , Tanofsky-Kraff, M.a b
Interpersonal problem areas and alexithymia in adolescent girls with loss of control eating
(2014) Comprehensive Psychiatry, 55 (1), pp. 170-178. 

a Department of Medical and Clinical Psychology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, United States
b Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
c Rutgers University, Piscataway, NJ, United States
d Washington University School of Medicine, St. Louis, MO, United States

This study investigated the links among interpersonal problem areas, depression, and alexithymia in adolescent girls at high risk for excessive weight gain and binge eating disorder. Participants were 56 girls (M age = 14.30, SD = 1.56; 53% non-Hispanic White) with a body mass index (BMI, kg/m2) between the 75th and 97th percentiles (M BMI z = 1.57, SD = 0.32). By design, all participants reported loss of control eating patterns in the past month. Adolescents were individually interviewed prior to participating in a group interpersonal psychotherapy obesity and eating disorder prevention program, termed IPT for the prevention of excessive weight gain (IPT-WG). Participants' interpersonal problem areas were coded by trained raters. Participants also completed questionnaires assessing depression and alexithymia. Primary interpersonal problem areas were categorized as interpersonal deficits [as defined in the eating disorders (ED) literature] (n = 29), role disputes (n = 22), or role transitions (n = 5). Girls with interpersonal deficits-ED had greater depressive symptoms and alexithymia than girls with role disputes (p's ≤ 0.01). However, girls with role transitions did not differ from girls with interpersonal deficits-ED or role disputes. Interpersonal problem area had an indirect association with depression via alexithymia; interpersonal deficits-ED were related to greater alexithymia, which in turn, was related to greater depressive symptoms (p = 0.01). Among girls at risk for excess weight gain and eating disorders, those with interpersonal deficits-ED appear to have greater distress as compared to girls with role disputes or role transitions. Future research is required to elucidate the impact of interpersonal problem areas on psychotherapy outcomes. © 2014 Elsevier Inc.

Document Type: Article
Source: Scopus

Waldron, M.a b , Grant, J.D.b , Bucholz, K.K.b , Lynskey, M.T.c , Slutske, W.S.d , Glowinski, A.L.b , Henders, A.e , Statham, D.J.f , Martin, N.G.e , Heath, A.C.b
Parental separation and early substance involvement: Results from children of alcoholic and cannabis dependent twins
(2014) Drug and Alcohol Dependence, 134 (1), pp. 78-84. 

a Department of Counseling and Educational Psychology, Indiana University School of Education, Bloomington, IN, United States
b Midwest Alcoholism Research Center, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Addictions Department, Institute of Psychiatry, King's College, London, United Kingdom
d Department of Psychology, University of Missouri, Columbia, MO, United States
e Genetic Epidemiology Unit, Queensland Institute of Medical Research, Brisbane, Australia
f Faculty of Arts and Business, University of the Sunshine Coast, Queensland, Australia

Background: Risks associated with parental separation have received limited attention in research on children of parents with substance use disorders. We examined early substance involvement as a function of parental separation during childhood and parental alcohol and cannabis dependence. Method: Data were drawn from 1318 adolescent offspring of monozygotic (MZ) or dizygotic (DZ) Australian twin parents. Cox proportional hazards regression analyses were conducted predicting age at first use of alcohol, first alcohol intoxication, first use and first regular use of cigarettes, and first use of cannabis, from parental separation and both parent and cotwin substance dependence. Parent and cotwin alcohol and cannabis dependence were initially modeled separately, with post hoc tests for equality of effects. Results: With few exceptions, risks associated with parental alcohol versus cannabis dependence could be equated, with results largely suggestive of genetic transmission of risk from parental substance (alcohol or cannabis) dependence broadly defined. Controlling for parental substance dependence, parental separation was a strong predictor for all substance use variables, especially through age 13. Conclusion: Together, findings underscore the importance of parental separation as a risk-factor for early substance involvement over and above both genetic and environmental influences specific to parental alcohol and cannabis dependence. © 2013 Elsevier Ireland Ltd.

Author Keywords
Adolescent substance use;  Children of twins;  Parental separation;  Parental substance dependence

Document Type: Article
Source: Scopus

Chen, L.-S.a , Bloom, A.J.a , Baker, T.B.b , Smith, S.S.b , Piper, M.E.b , Martinez, M.a , Saccone, N.c , Hatsukami, D.d , Goate, A.a , Bierut, L.a
Pharmacotherapy effects on smoking cessation vary with nicotine metabolism gene (CYP2A6)
(2014) Addiction, 109 (1), pp. 128-137. Cited 2 times.

a Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
b Tobacco Research and Intervention, University of Wisconsin, School of Medicine, Madison, WI, United States
c Department of Genetics, Washington University School of Medicine, St Louis, MO, United States
d Department of Psychiatry, University of Minnesota, Minneapolis, MN, United States

Background and aims: Evidence suggests that both the nicotinic receptor α5 subunit (CHRNA5) and Cytochrome P450 2A6 (CYP2A6) genotypes influence smoking cessation success and response to pharmacotherapy. We examine the effect of CYP2A6 genotype on smoking cessation success and response to cessation pharmacotherapy, and combine these effects with those of CHRNA5 genotypes. Design: Placebo-controlled randomized smoking cessation trial. Setting: Ambulatory care facility in Wisconsin, USA. Participants: Smokers (n=709) of European ancestry were randomized to placebo, bupropion, nicotine replacement therapy or combined bupropion and nicotine replacement therapy. Measurements: Survival analysis was used to model time to relapse using nicotine metabolism derived from CYP2A6 genotype-based estimates. Slow metabolism is defined as the lowest quartile of estimated metabolic function. Findings: CYP2A6-defined nicotine metabolic function moderated the effect of smoking cessation pharmacotherapy on smoking relapse over 90 days [hazard ratio (HR)=2.81, 95% confidence interval (CI)=1.32-5.99, P=0.0075], with pharmacotherapy significantly slowing relapse in fast (HR=0.39, 95% CI=0.28-0.55, P=1.97×10-8), but not slow metabolizers (HR=1.09, 95% CI=0.55-2.17, P=0.80). Further, only the effect of nicotine replacement, and not bupropion, varies with CYP2A6-defined metabolic function. The effect of nicotine replacement on continuous abstinence is moderated by the combined genetic risks from CYP2A6 and CHRNA5 (Wald=7.44, d.f.=1, P=0.0064). Conclusions: Nicotine replacement therapy is effective among individuals with fast, but not slow, CYP2A6-defined nicotine metabolism. The effect of bupropion on relapse likelihood is unlikely to be affected by nicotine metabolism as estimated from CYP2A6 genotype. The variation in treatment responses among smokers with genes may guide future personalized smoking cessation interventions. © 2013 Society for the Study of Addiction.

Author Keywords
Metabolism;  Nicotine;  Pharmacogenetics;  Smoking cessation

Document Type: Article
Source: Scopus

Christensen, D.a , Van Naarden Braun, K.a , Doernberg, N.S.a , Maenner, M.J.b c , Arneson, C.L.b , Durkin, M.S.b c , Benedict, R.E.b d , Kirby, R.S.e , Wingate, M.S.f , Fitzgerald, R.g , Yeargin-Allsopp, M.a
Prevalence of cerebral palsy, co-occurring autism spectrum disorders, and motor functioning - Autism and Developmental Disabilities Monitoring Network, USA, 2008
(2014) Developmental Medicine and Child Neurology, 56 (1), pp. 59-65. Cited 1 time.

a Division of Birth Defects and Developmental Disabilities, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, United States
b Waisman Center, University of Wisconsin-Madison, Madison, WI, United States
c Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, United States
d Occupational Therapy Program, Department of Kinesiology, University of Wisconsin-Madison, Madison, WI, United States
e Department of Community and Family Health, College of Public Health, University of South Florida, Tampa, FL, United States
f Department of Health Care Organization and Policy, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, United States
g Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States

Aim: The aim of this study was to report the prevalence and characteristics of children with cerebral palsy (CP). Method: Children with CP (n=451) were ascertained by the Autism and Developmental Disabilities Monitoring (ADDM) Network, a population-based, record-review surveillance system monitoring CP in four areas of the USA. Prevalence was calculated as the number of children with CP among all 8-year-old children residing in these areas in 2008. Motor function was categorized by Gross Motor Function Classification System level and walking ability. Co-occurring autism spectrum disorders (ASD) and epilepsy were ascertained using ADDM Network surveillance methodology. Results: The period prevalence of CP for 2008 was 3.1 per 1000 8-year-old children (95% confidence interval 2.8-3.4). Approximately 58% of children walked independently. Co-occurring ASD frequency was 6.9% and was higher (18.4%) among children with non-spastic CP, particularly hypotonic CP. Co-occurring epilepsy frequency was 41% overall, did not differ by ASD status or CP subtype, and was highest (67%) among children with limited or no walking ability. Interpretation: The prevalence of CP in childhood from US surveillance data has remained relatively constant, in the range of 3.1 to 3.6 per 1000, since 1996. The higher frequency of ASD in non-spastic than in spastic subtypes of CP calls for closer examination. This article is commented on by Zwaigenbaum on pages 7-8 of this issue. © 2013 Mac Keith Press.

Document Type: Article
Source: Scopus

Jackson, K.M.a , Bucholz, K.K.b c , Wood, P.K.c d , Steinley, D.c d , Grant, J.D.b c , Sher, K.J.c d
Towards the characterization and validation of alcohol use disorder subtypes: Integrating consumption and symptom data
(2014) Psychological Medicine, 44 (1), pp. 143-159. 

a Center for Alcohol and Addiction Studies, Brown University, Providence, RI, United States
b Washington University School of Medicine in St Louis, St Louis, MO, United States
c Midwest Alcoholism Research Center, United States
d University of Missouri-Columbia, Columbia, MO, United States

Background There is evidence that measures of alcohol consumption, dependence and abuse are valid indicators of qualitatively different subtypes of alcohol involvement yet also fall along a continuum. The present study attempts to resolve the extent to which variations in alcohol involvement reflect a difference in kind versus a difference in degree. Method Data were taken from the 2001-2002 National Epidemiologic Survey of Alcohol and Related Conditions. The sample (51% male; 72% white/non-Hispanic) included respondents reporting past 12-month drinking at both waves (wave 1: n = 33644; wave 2: n = 25186). We compared factor mixture models (FMMs), a hybrid of common factor analysis (FA) and latent class analysis (LCA), against FA and LCA models using past 12-month alcohol use disorder (AUD) criteria and five indicators of alcohol consumption reflecting frequency and heaviness of drinking. Results Model comparison revealed that the best-fitting model at wave 1 was a one-factor four-class FMM, with classes primarily varying across dependence and consumption indices. The model was replicated using wave 2 data, and validated against AUD and dependence diagnoses. Class stability from waves 1 to 2 was moderate, with greatest agreement for the infrequent drinking class. Within-class associations in the underlying latent factor also revealed modest agreement over time. Conclusions There is evidence that alcohol involvement can be considered both categorical and continuous, with responses reduced to four patterns that quantitatively vary along a single dimension. Nosologists may consider hybrid approaches involving groups that vary in pattern of consumption and dependence symptomatology as well as variation of severity within group. © 2013 Cambridge University Press.

Author Keywords
Alcohol;  categorical;  consumption;  dependence;  typology

Document Type: Article
Source: Scopus

Cohn, B.a , Keim, S.M.b , Sanders, A.B.b
Can Anticoagulated Patients be Discharged Home Safely from the Emergency Department after Minor Head Injury?
(2013) Journal of Emergency Medicine, . Article in Press. 

a Division of Emergency Medicine, Washington University School of Medicine, St. Louis, Missouri
b Department of Emergency Medicine, University of Arizona College of Medicine, Phoenix, Arizona

Background: Anticoagulated patients have increased risk for bleeding, and serious outcomes could occur after head injury. Controversy exists regarding the utility of head computed tomography (CT) in allowing safe discharge dispositions for anticoagulated patients suffering minor head injury. Clinical Question: What is the risk of delayed intracranial hemorrhage in anticoagulated patients with minor head injury and a normal initial head CT scan? Evidence Review: Four observational studies were reviewed that investigated the outcomes of anticoagulated patients who presented after minor head injury. Results: Overall incidence of death or neurosurgical intervention ranged from 0 to 1.1% among the patients investigated. The studies did not clarify which patients were at highest risk. Conclusion: The literature does not support mandatory admission for all anticoagulated patients after minor head injury, but further studies are needed to identify the higher-risk patients for delayed bleeding to determine appropriate management. © 2013 Elsevier Inc. All rights reserved.

Author Keywords
anticoagulation;  head injury;  medical imaging;  prognosis

Document Type: Article in Press
Source: Scopus

Barcroft, J., Sommers, M.S.
(2013) Studies in Second Language Acquisition, pp. 1-27. Article in Press. 

Washington University in St. Louis

Previous studies (Barcroft & Sommers, 2005 Sommers & Barcroft, 2007) have demonstrated that variability in talker, speaking style, and speaking rate positively affect second language vocabulary learning, whereas variability in overall amplitude and fundamental frequency (F0) do not, at least for native English speakers. Sommers and Barcroft (2007) hypothesized that English speakers do not benefit (with regard to second language vocabulary learning) from amplitude and F0 variability because these are not phonetically relevant to them. The present study further tested this hypothesis by examining effects of F0 variability among adults who speak a tone language (Zapotec-Spanish bilinguals) and those who do not speak a tone language (Spanish speakers with substantial knowledge of English). Participants attempted to learn 24 Russian words while hearing the words and viewing their corresponding pictures. Three levels of F0 variability were compared. Fundamental frequency variability significantly improved vocabulary learning for speakers of the tone language (Zapotec) but not for the Spanish speakers. This result provides strong evidence that effects of acoustic variability on learning new word forms depend on phonetic relevance. Copyright © Cambridge University Press 2013.

Document Type: Article in Press
Source: Scopus

Powell, B.J.a , Hausmann-Stabile, C.a , McMillen, J.C.b
Mental health clinicians' experiences of implementing evidence-based treatments
(2013) Journal of Evidence-Based Social Work, 10 (5), pp. 396-409. 

a George Warren Brown School of Social Work, Washington University, St. Louis, MO, United States
b School of Social Service Administration, The University of Chicago, Chicago, IL, United States

Implementation research has tremendous potential to bridge the research-practice gap; however, we know more about barriers to evidence-based care than the factors that contribute to the adoption and sustainability of evidence-based treatments. In this qualitative study the authors explore the experiences of clinicians (N D 11) who were implementing evidence-based treatments, highlighting the factors that they perceived to be most critical to successful implementation. The clinicians' narratives reveal many leverage points that can inform administrators, clinical supervisors, and clinicians who wish to implement evidence-based treatments, as well as other stakeholders who wish to develop and test strategies for moving evidence-based treatments into routine care. © Taylor & Francis Group, LLC.

Author Keywords
Evidence-based practice;  Implementation research;  Qualitative research

Document Type: Article
Source: Scopus

Mailhot Vega, R.B.a , Kim, J.b , Bussière, M.c , Hattangadi, J.d , Hollander, A.e , Michalski, J.a , Tarbell, N.J.c , Yock, T.c , MacDonald, S.M.c
Cost effectiveness of proton therapy compared with photon therapy in the management of pediatric medulloblastoma
(2013) Cancer, 119 (24), pp. 4299-4307. 

a Department of Radiation Oncology, Washington University, St. Louis School of Medicine, St. Louis, MO, United States
b Harvard School of Public Health, Boston, MA, United States
c Department of Radiation Oncology, Harvard Medical School, Massachusetts General Hospital, 100 Blossom Street, Boston, MA 02114, United States
d Department of Radiation Oncology, University California San Diego, San Diego, CA, United States
e Department of Pediatric Endocrinology, Washington University, St. Louis School of Medicine, St. Louis, MO, United States

BACKGROUND Proton therapy has been a hotly contested issue in both scientific publications and lay media. Proponents cite the modality's ability to spare healthy tissue, but critics claim the benefit gained from its use does not validate its cost compared with photon therapy. The objective of this study was to evaluate the cost effectiveness of proton therapy versus photon therapy in the management of pediatric medulloblastoma. METHODS A cost-effective analysis was performed from the societal perspective using a Monte Carlo simulation model. A population of pediatric medulloblastoma survivors aged 18 years was studied who had received treatment at age 5 years and who were at risk of developing 10 adverse events, such as growth hormone deficiency, coronary artery disease, ototoxicity, secondary malignant neoplasm, and death. Costing data included the cost of investment and the costs of diagnosis and management of adverse health states from institutional and Medicare data. Longitudinal outcomes data and recent modeling studies informed risk parameters for the model. Incremental cost-effectiveness ratios were used to measure outcomes. RESULTS Results from the base case demonstrated that proton therapy was associated with higher quality-adjusted life years and lower costs; therefore, it dominated photon therapy. In 1-way sensitivity analyses, proton therapy remained the more attractive strategy, either dominating photon therapy or having a very low cost per quality-adjust life year gained. Probabilistic sensitivity analysis illustrated the domination of proton therapy over photon therapy in 96.4% of simulations. CONCLUSIONS By using current risk estimates and data on required capital investments, the current study indicated that proton therapy is a cost-effective strategy for the management of pediatric patients with medulloblastoma compared with standard of care photon therapy.

Author Keywords
comparative effectiveness;  cost effectiveness;  medulloblastoma;  Monte Carlo;  proton

Document Type: Article
Source: Scopus

Harris-Adamson, C.a b , Eisen, E.A.b , Dale, A.M.c , Evanoff, B.c , Hegmann, K.T.d , Thiese, M.S.d , Kapellusch, J.e , Garg, A.e , Burt, S.f , Bao, S.g , Silverstein, B.g , Gerr, F.h , Merlino, L.h , Rempel, D.i j
The impact of gender on personal, health and workplace psychosocial risk factors for carpal tunnel syndrome: A pooled study cohort
(2013) Proceedings of the Human Factors and Ergonomics Society, pp. 911-914. 

a Department of Physical Therapy, Samuel Merritt University, United States
b School of Public Health ,Occupational, Social, and Environmental Medicine, University of California Berkeley, United States
c Division of General Medical Science, Washington University School of Medicine, United States
d Rocky Mountain Center for Occupational and Environmental Health (RMCOEH), University of Utah, United States
e Center for Ergonomics, University of Wisconsin-Milwaukee, United States
f National Institute for Occupational Safety and Health (NIOSH), United States
g Washington State Department of Labor and Industries, Safety and Health Assessment and Research for Prevention (SHARP) Program, United States
h Department of Occupational and Environmental Health, University of Iowa, United States
i Division of Occupational and Environmental Medicine, University of California at San Francisco, United States
j Department of Bioengineering, University of California Berkeley, United States

Between 2001 and 2010 six research groups conducted coordinated multi-year, prospective studies of upper extremity musculoskeletal disorders in US workers from various industries and collected detailed subjectlevel exposure information with follow-up symptom, physical examination, electrophysiological measures, and job changes. Objective. This analysis of the pooled cohort examined the incidence of dominant-hand carpal tunnel syndrome (CTS) in relation to demographic characteristics and estimated associations with occupational psychosocial factors, adjusting for confounding by personal risk factors. Methods. 3,515 participants, without baseline CTS, were followed up to 7 years. Case criteria included symptoms and an electrodiagnostic study consistent with CTS. Adjusted hazard ratios were estimated in Cox proportional hazard models. Workplace biomechanical factors were collected but not evaluated in this analysis. Results. Females were at elevated, though statistically non-significant, risk for CTS (HR=1.30; 95%CI: 0.98-1.72). The incidence of CTS increased linearly with both age and BMI over most of the observed range. High job strain increased risk (HR=1.86; 95%CI: 1.11-3.14) and social support was protective (HR=0.43; 95%CI: 0.23-0.78). There was no effect modification of gender on age, BMI or high job strain. Conclusions. Personal factors associated with an increased risk of developing CTS were BMI, age and being female, though no effect modification by gender was evident. Workplace risk factors were high job strain while social support was protective. Copyright 2013 by Human Factors and Ergonomics Society, Inc.

Document Type: Conference Paper
Source: Scopus

Shiau, C.a , Monk, K.a b , Joo, W.a c , Talbot, W.a
An anti-inflammatory nod-like receptor is required for microglia development
(2013) Cell Reports, 5 (5), pp. 1342-1352. 

a Department of Developmental Biology, Stanford University, Stanford, CA 94305, United States
b Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Biology, Stanford University, Stanford, CA 94305, United States

Microglia are phagocytic cells that form the basis of the brain's immune system. They derive from primitive macrophages that migrate into the brain during embryogenesis, but the genetic control of microglial development remains elusive. Starting with a genetic screen in zebrafish, we show that the noncanonical NOD-like receptor (NLR) nlrc3-like is essential for microglial formation. Although most NLRs trigger inflammatory signaling, nlrc3-like acts cell autonomously in microglia precursor cells to suppress unwarranted inflammation in the absence of overt immune challenge. In nlrc3-like mutants, primitive macrophages initiate a systemic inflammatory response with increased proinflammatory cytokines and actively aggregate instead of migrating into thebrain to form microglia. NLRC3-like requires both its pyrin and NACHT domains, and it can bind the inflammasome component apoptosis-associated speck-like protein. Our studies suggest that NLRC3-like may regulate the inflammasome and other inflammatory pathways. Together, these results demonstrate that NLRC3-like prevents inappropriate macrophage activation, thereby allowing normal microglial development. © 2013 The Authors.

Document Type: Article
Source: Scopus

Crick, S.L.a , Ruff, K.M.a , Garai, K.a b , Frieden, C.b , Pappu, R.V.a
Unmasking the roles of N- and C-terminal flanking sequences from exon 1 of huntingtin as modulators of polyglutamine aggregation
(2013) Proceedings of the National Academy of Sciences of the United States of America, 110 (50), pp. 20075-20080. 

a Department of Biomedical Engineering, Center for Biological Systems Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
b Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States

Huntington disease is caused by mutational expansion of the CAG trinucleotide within exon 1 of the huntingtin (Htt) gene. Exon 1 spanning N-terminal fragments (NTFs) of the Htt protein result from aberrant splicing of transcripts of mutant Htt. NTFs typically encompass a polyglutamine tract fl anked by an N-terminal 17-residue amphipathic stretch (N17) and a C-terminal 38-residue proline-rich stretch (C38). We present results from in vitro biophysical studies that quantify the driving forces for and mechanisms of polyglutamine aggregation as modulated by N17 and C38. Although N17 is highly soluble by itself, it lowers the saturation concentration of soluble NTFs and increases the driving force, vis-à-vis homopolymeric polyglutamine, for forming insoluble aggregates. Kinetically, N17 accelerates fi bril formation and destabilizes nonfibrillar intermediates. C38 is also highly soluble by itself, and it lends its high intrinsic solubility to lower the driving force for forming insoluble aggregates by increasing the saturation concentration of soluble NTFs. In NTFs with both modules, N17 and C38 act synergistically to destabilize nonfibrillar intermediates (N17 effect) and lower the driving force for forming insoluble aggregates (C38 effect). Morphological studies show that N17 and C38 promote the formation of ordered fibrils by NTFs. Homopolymeric polyglutamine forms a mixture of amorphous aggregates and fi brils, and its aggregation mechanisms involve early formation of heterogeneous distributions of nonfibrillar species. We propose that N17 and C38 act as gatekeepers that control the intrinsic heterogeneities of polyglutamine aggregation. This provides a biophysical explanation for the modulation of in vivo NTF toxicities by N17 and C38.

Author Keywords
Phase separation;  Subsaturation;  Supersaturation;  Tetramethyl rhodamine

Document Type: Article
Source: Scopus

Maggio, N.a b , Shavit-Stein, E.a , Dori, A.a b c , Blatt, I.a d , Chapman, J.a d
Prolonged systemic inflammation persistently modifies synaptic plasticity in the hippocampus: Modulation by the stress hormones
(2013) Frontiers in Molecular Neuroscience, 6 (DEC), art. no. 46, . 

a Department of Neurology, The Joseph Sagol Neuroscience Center, The Chaim Sheba Medical Center, Tel HaShomer, Israel
b The Chaim Sheba Medical Center, Tel HaShomer, Israel
c Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
d Department of Neurology, Tel Aviv University, Tel Aviv, Israel

Transient systemic inflammation has been shown to cause altered behavior both in humans and in laboratory animals through activation of microglia and heightened level of cytokines detected in the brain and in the body. Furthermore, both activated microglia and the increased cytokines level have been associated with the sudden clinical deterioration in demented people or in aged patients upon systemic inflammation. Whilst it is increasingly becoming clear the role of transient systemic inflammation in promoting dementia in aged individuals, it is still a matter of debate whether prolonged systemic inflammation might persistently modify the brain. In this study, we examined the influence of a systemic long term inflammatory event on synaptic plasticity. We report that while a short exposure to LPS produces transient deficit in long term potentiation (LTP) expression, systemic prolonged inflammation impairs LTP in slices of animals previously primed by a Complete Freund's adjuvant injection. Interestingly, steroids are able to modulate this effect: whereas glucocorticosteroid (GR) activation further reduces LTP, mineralocorticosteroid receptors (MR) activation promotes the full recovery of LTP. We believe that this research advances the current understandings on the role of the immune system in the onset and progression of cognitive deficits following long lasting systemic inflammation, and proposes possible insights on future strategies in order to prevent early dementia in these predisposed individuals. © 2013 Maggio, Shavit-Stein, Dori, Blatt and Chapman.

Author Keywords
Corticosterone;  Glucocorticosteroid receptors;  Hippocampus;  Inflammation;  LPS;  LTP;  Mineralocorticosteroid receptors;  Synaptic plasticity

Document Type: Article
Source: Scopus

Musiek, E.S.a , Lim, M.M.b , Yang, G.c , Bauer, A.Q.d , Qi, L.a , Lee, Y.c , Roh, J.H.a , Ortiz-Gonzalez, X.e , Dearborn, J.T.f , Culver, J.P.d , Herzog, E.D.g , Hogenesch, J.B.c , Wozniak, D.F.f , Dikranian, K.h , Giasson, B.I.i , Weaver, D.R.j , Holtzman, D.M.a , FitzGerald, G.A.c
Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration
(2013) Journal of Clinical Investigation, 123 (12), pp. 5389-5400. Cited 2 times.

a Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease Research Center, St. Louis, MI 63110, United States
b Division of Sleep Medicine, Philadelphia, PA, United States
c Institute for Translational Medicine and Therapeutics, Department of Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
d Department of Radiology, Washington University School of Medicine, St. Louis, MI, United States
e Department of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, United States
f Department of Psychiatry, Washington University School of Medicine, St. Louis, MI, United States
g Department of Biology, Washington University, St. Louis, MI, United States
h Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MI, United States
i Department of Neuroscience and Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, United States
j Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA, United States

Brain aging is associated with diminished circadian clock output and decreased expression of the core clock proteins, which regulate many aspects of cellular biochemistry and metabolism. The genes encoding clock proteins are expressed throughout the brain, though it is unknown whether these proteins modulate brain homeostasis. We observed that deletion of circadian clock transcriptional activators aryl hydrocarbon receptor nuclear translocator-like (Bmal1) alone, or circadian locomotor output cycles kaput (Clock) in combination with neuronal PAS domain protein 2 (Npas2), induced severe age-dependent astrogliosis in the cortex and hippocampus. Mice lacking the clock gene repressors period circadian clock 1 (Per1) and period circadian clock 2 (Per2) had no observed astrogliosis. Bmal1 deletion caused the degeneration of synaptic terminals and impaired cortical functional connectivity, as well as neuronal oxidative damage and impaired expression of several redox defense genes. Targeted deletion of Bmal1 in neurons and glia caused similar neuropathology, despite the retention of intact circadian behavioral and sleep-wake rhythms. Reduction of Bmal1 expression promoted neuronal death in primary cultures and in mice treated with a chemical inducer of oxidative injury and striatal neurodegeneration. Our findings indicate that BMAL1 in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration.

Document Type: Article
Source: Scopus

Fu, M.a , Landreville, S.b , Agapova, O.A.b , Wiley, L.A.b , Shoykhet, M.a , Harbour, J.W.b c , Heuckeroth, R.O.a d
Retinoblastoma protein prevents enteric nervous system defects and intestinal pseudo-Obstruction
(2013) Journal of Clinical Investigation, 123 (12), pp. 5152-5164. 

a Department of Pediatrics, United States
b Department of Ophthalmology and Visual Sciences, Washington University School of Medicine in St. Louis, St. Louis, MI, United States
c Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, United States
d Department of Developmental, Regenerative and Stem Cell Biology, Washington University School of Medicine in St. Louis, St. Louis, MI, United States

The retinoblastoma 1 (RB1) tumor suppressor is a critical regulator of cell cycle progression and development. To investigate the role of RB1 in neural crest-derived melanocytes, we bred mice with a floxed Rb1 allele with mice expressing Cre from the tyrosinase (Tyr) promoter. TyrCre+;Rb1fl/fl mice exhibited no melanocyte defects but died unexpectedly early with intestinal obstruction, striking defects in the enteric nervous system (ENS), and abnormal intestinal motility. Cre-induced DNA recombination occurred in all enteric glia and most small bowel myenteric neurons, yet phenotypic effects of Rb1 loss were cell-type specific. Enteric glia were twice as abundant in mutant mice compared with those in control animals, while myenteric neuron number was normal. Most myenteric neurons also appeared normal in size, but NO-producing myenteric neurons developed very large nuclei as a result of DNA replication without cell division (i.e., endoreplication). Parallel studies in vitro found that exogenous NO and Rb1 shRNA increased ENS precursor DNA replication and nuclear size. The large, irregularly shaped nuclei in NO-producing neurons were remarkably similar to those in progeria, an early-onset aging disorder that has been linked to RB1 dysfunction. These findings reveal a role for RB1 in the ENS.

Document Type: Article
Source: Scopus

Iltis, A.S.a , Misra, S.b c , Dunn, L.B.d , Brown, G.K.e , Campbell, A.f , Earll, S.A.g , Glowinski, A.h , Hadley, W.B.i , Pies, R.j , Du Bois, J.M.k l
Addressing risks to advance mental health research
(2013) JAMA Psychiatry, 70 (12), pp. 1363-1371. 

a Center for Bioethics, Health, and Society, Department of Philosophy, Wake Forest University, Winston-Salem, NC, United States
b Mental Health and Clinical Neurosciences Division, Portland VA Medical Center, Portland, OR, United States
c Department of Psychiatry, Oregon Health and Science University, Portland, United States
d Department of Psychiatry and Psycho-Oncology, UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, United States
e Clinical Psychology in Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
f Center for Bioethics and Humanities, SUNY Upstate Medical University, Syracuse, NY, United States
g St Louis Empowerment, St Louis, MO, United States
h Department of Psychiatry, Washington University, School of Medicine, St Louis, MO, United States
i Falk College for Sports and Human Dynamics, Syracuse University, Syracuse, NY, United States
j Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, United States
k Department of Medicine, Washington University, School of Medicine, St Louis, MO, United States
l Albert Gnaegi Center for Health Care Ethics, St Louis University, Salus Center, 3545 Lafayette, St Louis, MO 63104, United States

IMPORTANCE: Risk communication and management are essential to the ethical conduct of research, yet addressing risks may be time consuming for investigators and institutional review boards may reject study designs that seem too risky. This can discourage needed research, particularly in higher-risk protocols or those enrolling potentially vulnerable individuals, such as those with some level of suicidality. Improved mechanisms for addressing research risks may facilitate much needed psychiatric research. OBJECTIVE: To provide mental health researchers with practical approaches to (1) identify and define various intrinsic research risks, (2) communicate these risks to others (eg, potential participants, regulatory bodies, and society), (3) manage these risks during the course of a study, and (4) justify the risks. EVIDENCE REVIEW: As part of a National Institute of Mental Health-funded scientific meeting series, a public conference and a closed-session expert panel meeting were held on managing and disclosing risks in mental health clinical trials. The expert panel reviewed the literature with a focus on empirical studies and developed recommendations for best practices and further research on managing and disclosing risks in mental health clinical trials. No institutional review board-review was required because there were no human subjects. FINDINGS Challenges, current data, practical strategies, and topics for future research are addressed for each of 4 key areas pertaining to management and disclosure of risks in clinical trials: identifying and defining risks, communicating risks, managing risks during studies, and justifying research risks. CONCLUSIONS AND RELEVANCE: Empirical data on risk communication, managing risks, and the benefits of research can support the ethical conduct of mental health research and may help investigators better conceptualize and confront risks and to gain institutional review board-approval. © Copyright 2013 American Medical Association. All rights reserved.

Document Type: Article
Source: Scopus

Mills, S.M., Mallmann, J., Santacruz, A.M., Fuqua, A., Carril, M., Aisen, P.S., Althage, M.C., Belyew, S., Benzinger, T.L., Brooks, W.S., Buckles, V.D., Cairns, N.J., Clifford, D., Danek, A., Fagan, A.M., Farlow, M., Fox, N., Ghetti, B., Goate, A.M., Heinrichs, D., Hornbeck, R., Jack, C., Jucker, M., Klunk, W.E., Marcus, D.S., Martins, R.N., Masters, C.M., Mayeux, R., McDade, E., Morris, J.C., Oliver, A., Ringman, J.M., Rossor, M.N., Salloway, S., Schofield, P.R., Snider, J., Snyder, P., Sperling, R.A., Stewart, C., Thomas, R.G., Xiong, C., Bateman, R.J.
Erratum: Preclinical trials in autosomal dominant AD: Implementation of the DIAN-TU trial (Rev. Neurol. (2013) 169 (10) (737-743))
(2013) Revue Neurologique, 169 (12), p. 1018. 

DIAN-TU, Washington University in St. Louis, Campus B. 8111, 660 S. Euclid Ave., St. Louis, MO 63108, United States

Document Type: Erratum
Source: Scopus

Vaughn, K.E.a c , Rawson, K.A.a , Pyc, M.A.b
Repeated retrieval practice and item difficulty: Does criterion learning eliminate item difficulty effects?
(2013) Psychonomic Bulletin and Review, 20 (6), pp. 1239-1245. 

a Kent State University, Kent, OH, United States
b Washington University, St. Louis, MO, United States
c Department of Psychology, Kent State University, P.O. Box 5190, Kent, OH, 44242-0001, United States

A wealth of previous research has established that retrieval practice promotes memory, particularly when retrieval is successful. Although successful retrieval promotes memory, it remains unclear whether successful retrieval promotes memory equally well for items of varying difficulty. Will easy items still outperform difficult items on a final test if all items have been correctly recalled equal numbers of times during practice? In two experiments, normatively difficult and easy Lithuanian-English word pairs were learned via test-restudy practice until each item had been correctly recalled a preassigned number of times (from 1 to 11 correct recalls). Despite equating the numbers of successful recalls during practice, performance on a delayed final cued-recall test was lower for difficult than for easy items. Experiment 2 was designed to diagnose whether the disadvantage for difficult items was due to deficits in cue memory, target memory, and/or associative memory. The results revealed a disadvantage for the difficult versus the easy items only on the associative recognition test, with no differences on cue recognition, and even an advantage on target recognition. Although successful retrieval enhanced memory for both difficult and easy items, equating retrieval success during practice did not eliminate normative item difficulty differences. © 2013 Psychonomic Society, Inc.

Author Keywords
Human memory

Document Type: Article
Source: Scopus

Minelli, A.a , Maffioletti, E.a , Cloninger, C.R.b , Magri, C.a , Sartori, R.c , Bortolomasi, M.d , Congiu, C.a , Bignotti, S.e , Segala, M.d , Giacopuzzi, M.d , Gennarelli, M.a f
Role of allelic variants of FK506-binding protein 51 (FKBP5) gene in the development of anxiety disorders
(2013) Depression and Anxiety, 30 (12), pp. 1170-1176. 

a Department of Molecular and Translational Medicine, Biology and Genetic Division, University of Brescia, Viale Europa, 11, 25123 Brescia, Italy
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Department of Philosophy, Education, and Psychology, University of Verona, Verona, Italy
d Psychiatric Hospital Villa Santa Chiara, Verona, Italy
e Psychiatric Unit, I.R.C.C.S. San Giovanni di Dio - Fatebenefratelli, Brescia, Italy
f Genetic Unit, I.R.C.C.S. San Giovanni di Dio - Fatebenefratelli, Brescia, Italy

Background Anxiety disorders exhibit remarkably high rates of comorbidity with major depressive disorder (MDD). Mood and anxiety disorders are considered stress-related diseases. Genetic variations in the co-chaperone FK506-binding protein 51, FKBP5, which modulates the function of glucocorticoid receptors, have been associated with an increased risk for the development of posttraumatic stress disorder, but data regarding its role in MDD are controversial. The aims of this study were to clarify the role of the FKBP5 gene in depression and anxiety disorders through a case-control study and an association study with personality traits using the Temperament and Character Inventory (TCI) in healthy subjects. Methods Six hundred fifty-seven MDD patients, with or without an anxiety disorder in comorbidity, and 462 healthy volunteers were enrolled in the study. Two hundred fifty-six controls agreed to fill out the TCI. Results The results showed that the T allele of rs1360780 was more frequent among the patients affected by MDD with a comorbidity of anxiety disorders, compared to those without (P <.001). Among the controls, we found that the T allele more often exhibited personality traits associated with an increased vulnerability to anxiety. Conclusions These results support the hypothesis that allelic variants of FKBP5 are a risk factor for anxiety disorders. The identification of genetic variants involved in anxiety may have implications for the optimization of therapeutic interventions. © 2013 Wiley Periodicals, Inc.

Author Keywords
anxiety;  FKBP5;  harm avoidance;  major depressive disorder;  temperament & character inventory

Document Type: Article
Source: Scopus

Cheng, H.a , Wang, M.a , Li, J.-L.a , Cairns, N.J.b , Han, X.a
Specific changes of sulfatide levels in individuals with pre-clinical Alzheimer's disease: An early event in disease pathogenesis
(2013) Journal of Neurochemistry, 127 (6), pp. 733-738. 

a Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL 32827, United States
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States

To explore the hypothesis that alterations in cellular membrane lipids are present at the stage of pre-clinical Alzheimer's disease (AD) (i.e., cognitively normal at death, but with AD neuropathology), we performed targeted shotgun lipidomics of lipid extracts from post-mortem brains of subjects with pre-clinical AD. We found sulfatide levels were significantly lower in subjects with pre-clinical AD compared to those without AD neuropathology. We also found that the level of ethanolamine glycerophospholipid was marginally lower at this stage of AD, whereas changes of the ceramide levels were undetectable with the available samples. These results indicate that cellular membrane defects are present at the earliest stages of AD pathogenesis and also suggest that sulfatide loss is among the earliest events of AD development, while alterations in the levels of ethanolamine glycerophospholipid and ceramide occur relatively later in disease. To determine lipid changes at the stage of pre-clinical Alzheimer's disease (AD) (i.e., cognitively normal at death, but with AD neuropathology), we performed lipidomics analysis and found that sulfatide levels were significantly lower in subjects with pre-clinical AD compared to those without AD neuropathology. The results suggest that sulfatide loss is among the earliest events of AD development. © 2013 International Society for Neurochemistry.

Author Keywords
ceramide;  membrane lipids;  plasmalogen;  pre-clinical Alzheimer's disease;  shotgun lipidomics;  sulfatide

Document Type: Article
Source: Scopus

Karimi, M.a , Moerlein, S.M.b c , Videen, T.O.a b , Su, Y.b , Flores, H.P.a , Perlmutter, J.S.a b d e f
Striatal dopamine D1-like receptor binding is unchanged in primary focal dystonia
(2013) Movement Disorders, 28 (14), pp. 2002-2006. 

a Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, United States
c Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO, United States
d Department of Neurobiology, Washington University School of Medicine, Saint Louis, MO, United States
e Occupational Therapy Program, Washington University School of Medicine, Saint Louis, MO, United States
f Physical Therapy Program, Washington University School of Medicine, Saint Louis, MO, United States

Background: Multiple studies have demonstrated decreases in striatal D2-like (D2, D3) radioligand binding in primary focal dystonias. Although most investigations have focused on D2-specific receptors (D2R), a recent study suggests that the decreased D2-like binding may be due to a D3-specific (D3R) abnormality. However, only limited data exist on the role of D1-specific receptors (D1R) and the D1R-mediated pathways within basal ganglia in dystonia. Metabolic positron emission tomography (PET) data in primary generalized dystonia suggest resting state over activity in the D1R-mediated direct pathway, leading to excessive disinhibition of motor cortical areas. This work investigated whether striatal D1-like receptors are affected in primary focal dystonias. Methods: Striatal-specific (caudate and putamen) binding of the D1-like radioligand [11C]NNC 112 was measured using PET in 19 patients with primary focal dystonia (cranial, cervical, or arm) and 18 controls. Results: No statistically significant difference was detected in striatal D1-like binding between the two groups. The study had 91% power to detect a 20% difference, indicating that false-negative results were unlikely. Conclusions: Because [11C]NNC 112 has high affinity for D1-like receptors, very low affinity for D2-like receptors, and minimal sensitivity to endogenous dopamine levels, we conclude that D1-like receptor binding is not impaired in these primary focal dystonias. © 2013 Movement Disorder Society.

Author Keywords
[11C]NNC 112;  D1 receptor;  Focal dystonia;  Positron emission tomography

Document Type: Article
Source: Scopus

Rodrigue, J.a , Hanto, D.c , Curry, M.a b
The alcohol relapse risk assessment: A scoring system to predict the risk of relapse to any alcohol use after liver transplant
(2013) Progress in Transplantation, 23 (4), pp. 310-318. 

a Transplant Institute, Beth Israel Deaconess Medical Center, 110 Francis Street, Boston, MA 02215, United States
b Washington University, School of Medicine, St Louis, MO, United States

Context-Alcohol relapse after liver transplant heightens concern about recurrent disease, nonadherence to the immunosuppression regimen, and death.Objectives-To develop a scoring system to stratify risk of alcohol relapse after liver transplant.Design-Retrospective medical record review.Setting and Participants-All adult liver transplants performed from May 2002 to February 2011 at a single center in the United States.Main Outcome Measure-The incidence of return to any alcohol consumption after liver transplant.Results-Thirty-four percent (40/118) of patients with a history of alcohol abuse/dependency relapsed to use of any alcohol after liver transplant. Nine of 25 hypothesized risk factors were predictive of alcohol relapse after liver transplant: absence of hepatocellular carcinoma, tobacco dependence, continued alcohol use after liver disease diagnosis, low motivation for alcohol treatment, poor stress management skills, no rehabilitation relationship, limited social support, lack of nonmedical behavioral consequences, and continued engagement in social activities with alcohol present. Each independent predictor was assigned an Alcohol Relapse Risk Assessment (ARRA) risk value of 1 point, and patients were classified into 1 of 4 groups by ARRA score: ARRA I = 0, ARRA II = 1 to 3, ARRA III = 4 to 6, and ARRA IV = 7 to 9. Patients in the 2 higher ARRA classifications had significantly higher rates of alcohol relapse and were more likely to return to pretransplant levels of drinking.Conclusion-Alcohol relapse rates are moderately high after liver transplant. The ARRA is a valid and practical tool for identifying pretransplant patients with alcohol abuse or dependency at elevated risk of any alcohol use after liver transplant. © 2013 NATCO.

Document Type: Article
Source: Scopus

Luby, J.a e , Belden, A.a , Botteron, K.a b , Marrus, N.a , Harms, M.P.a , Babb, C.a , Nishino, T.a , Barch, D.a b c d
The effects of poverty on childhood brain development: The mediating effect of caregiving and stressful life events
(2013) JAMA Pediatrics, 167 (12), pp. 1135-1142. 

a Department of Psychiatry, Washington University, School of Medicine in St Louis, MO, United States
b Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine in St Louis, MO, United States
c Department of Psychology, Washington University in St Louis, MO, United States
d Program in Neuroscience, Washington University in St Louis, MO, United States
e Early Emotional Development Program, Department of Psychiatry, Washington University School of Medicine in St LouisWashington, 660 S Euclid Ave, St Louis, MO 63110-1093, United States

ImportanceThe study provides novel data to inform the mechanisms by which poverty negatively impacts childhood brain development. OBJECTIVE To investigate whether the income-to-needs ratio experienced in early childhood impacts brain development at school age and to explore the mediators of this effect. DESIGN, SETTING, AND PARTICIPANTS This studywas conducted at an academic research unit at theWashington University School of Medicine in St Louis. Data from a prospective longitudinal study of emotion development in preschool children who participated in neuroimaging at school age were used to investigate the effects of poverty on brain development. Children were assessed annually for 3 to 6 years prior to the time of amagnetic resonance imaging scan, during which they were evaluated on psychosocial, behavioral, and other developmental dimensions. Preschoolers included in the study were 3 to 6 years of age and were recruited from primary care and day care sites in the St Louis metropolitan area; they were annually assessed behaviorally for 5 to 10 years. Healthy preschoolers and those with clinical symptoms of depression participated in neuroimaging at school age/early adolescence. EXPOSURE Household poverty as measured by the income-to-needs ratio. MAIN OUTCOMES AND MEASURES Brain volumes of children's white matter and cortical gray matter, as well as hippocampus and amygdala volumes, obtained usingmagnetic resonance imaging. Mediators of interest were caregiver support/hostility measured observationally during the preschool period and stressful life events measured prospectively. RESULTS Poverty was associated with smaller white and cortical gray matter and hippocampal and amygdala volumes. The effects of poverty on hippocampal volume were mediated by caregiving support/hostility on the left and right, as well as stressful life events on the left. CONCLUSIONS AND RELEVANCE The finding that exposure to poverty in early childhood materially impacts brain development at school age further underscores the importance of attention to the well-established deleterious effects of poverty on child development. Findings that these effects on the hippocampus are mediated by caregiving and stressful life events suggest that attempts to enhance early caregiving should be a focused public health target for prevention and early intervention. Findings substantiate the behavioral literature on the negative effects of poverty on child development and provide new data confirming that effects extend to brain development. Mechanisms for these effects on the hippocampus are suggested to inform intervention. Copyright 2013 American Medical Association.

Document Type: Article
Source: Scopus

Pien, G.W.a b c , Pack, A.I.a b , Jackson, N.a , Maislin, G.a , Macones, G.A.d , Schwab, R.J.a b c
Risk factors for sleep-disordered breathing in pregnancy
(2013) Thorax, . Article in Press. 

a Center for Sleep and Circadian Neurobiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
b Sleep Medicine Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
c Pulmonary and Critical Care Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
d Department of Obstetrics and Gynecology, Washington University School of Medicine, St Louis, Missouri, USA

Rationale: Symptoms of sleep-disordered breathing (SDB) are common among pregnant women, and several studies link SDB symptoms with gestational hypertension and preeclampsia. However, few prospective studies objectively measuring SDB during pregnancy have been performed. Objectives: We performed a prospective cohort study examining risk factors for third trimester SDB in pregnant women. Measurements and methods: 105 pregnant women from the Hospital of the University of Pennsylvania obstetrics practices completed first and third trimester overnight polysomnography studies. We examined whether the number of SDB events per hour of sleep increased during pregnancy. We performed unadjusted and multivariable logistic regression analyses to estimate the effects of usual and pregnancy-specific characteristics on development of third trimester obstructive sleep apnoea (OSA). In secondary analyses, we examined the relationship between objectively measured SDB, hypertensive disorders of pregnancy, and other adverse maternal-fetal outcomes. Main results: Mean Apnoea-Hypopnoea Index increased from 2.07 (SD 3.01) events/h at baseline (first trimester) to 3.74 (SD 5.97) in the third trimester (p=0.009). 10.5% of women had OSA in the first trimester. By the third trimester, 26.7% of women had OSA. In multivariable analyses, first trimester body mass index (BMI) and maternal age were significantly associated with third trimester OSA. Conclusions: Third trimester OSA is common. Risk factors for third trimester OSA among women without baseline SDB include higher baseline BMI and maternal age. © 2013 BMJ Publishing Group Ltd & British Thoracic Society.

Document Type: Article in Press
Source: Scopus

Sumner, C.J.a b , D'Ydewalle, C.a c , Wooley, J.a , Fawcett, K.A.d e , Hernandez, D.f , Gardiner, A.R.d e , Kalmar, B.e , Baloh, R.H.g , Gonzalez, M.h , Züchner, S.h , Stanescu, H.C.i , Kleta, R.i , Mankodi, A.j , Cornblath, D.R.a , Boylan, K.B.k , Reilly, M.M.d e , Greensmith, L.e , Singleton, A.B.f , Harms, M.B.l , Rossor, A.M.e , Houlden, H.d e
A dominant mutation in FBXO38 causes distal spinal muscular atrophy with calf predominance
(2013) American Journal of Human Genetics, 93 (5), pp. 976-983. 

a Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States
b Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States
c Laboratory for Neurobiology, Vesalius Research Center, VIB and KU Leuven, 3000 Leuven, Belgium
d Department of Molecular Neuroscience, National Hospital for Neurology and Neurosurgery and UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom
e MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery and UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom
f Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda,MD 20892, United States
g Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA 90095, United States
h Dr. John T. MacDonald Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, FL 33136, United States
i Center for Nephrology, University College London, London WC1N 3BG, United Kingdom
j Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, United States
k Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, United States
l Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States

Spinal muscular atrophies (SMAs) are a heterogeneous group of inherited disorders characterized by degeneration of anterior horn cells and progressive muscle weakness. In two unrelated families affected by a distinct form of autosomal-dominant distal SMA initially manifesting with calf weakness, we identified by genetic linkage analysis and exome sequencing a heterozygous missense mutation, c.616T>C (p.Cys206Arg), in F-box protein 38 (FBXO38). FBXO38 is a known coactivator of the transcription factor Krüppel-like factor 7 (KLF7), which regulates genes required for neuronal axon outgrowth and repair. The p.Cys206Arg substitution did not alter the subcellular localization of FBXO38 but did impair KLF7-mediated transactivation of a KLF7-responsive promoter construct and endogenous KLF7 target genes in both heterologously expressing human embryonic kidney 293T cells and fibroblasts derived from individuals with the FBXO38 missense mutation. This transcriptional dysregulation was associated with an impairment of neurite outgrowth in primary motor neurons. Together, these results suggest that a transcriptional regulatory pathway that has a well-established role in axonal development could also be critical for neuronal maintenance and highlight the importance of FBXO38 and KLF7 activity in motor neurons. © 2013 by The American Society of Human Genetics. All rights reserved.

Document Type: Article
Source: Scopus

Cheuy, V.A.a , Hastings, M.K.b , Commean, P.K.c , Ward, S.R.d , Mueller, M.J.e
Intrinsic foot muscle deterioration is associated with metatarsophalangeal joint angle in people with diabetes and neuropathy
(2013) Clinical Biomechanics, 28 (9-10), pp. 1055-1060. 

a Applied Biomechanics Laboratory, Movement Science Program, Washington University School of Medicine, 4444 Forest Park Ave., St. Louis, MO 63108, United States
b Human Biodynamics Laboratory, Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
c Electronic Radiology Laboratory, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Muscle Physiology Laboratory, Department of Orthopaedic Surgery, University of California San Diego, San Diego, CA, United States
e Applied Biomechanics Laboratory, Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States

Background Metatarsophalangeal joint deformity is associated with skin breakdown and amputation. The aims of this study were to compare intrinsic foot muscle deterioration ratios (ratio of adipose to muscle volume), and physical performance in subjects with diabetic neuropathy to controls, and determine their associations with 1) metatarsophalangeal joint angle and 2) history of foot ulcer. Methods 23 diabetic, neuropathic subjects [59 (SD 10) years] and 12 age-matched controls [57 (SD 14) years] were studied. Radiographs and MRI were used to measure metatarsophalangeal joint angle and intrinsic foot muscle deterioration through tissue segmentation by image signal intensity. The Foot and Ankle Ability Measure evaluated physical performance. Findings The diabetic, neuropathic group had a higher muscle deterioration ratio [1.6 (SD 1.2) vs. 0.3 (SD 0.2), P < 0.001], and lower Foot and Ankle Ability Measure scores [65.1 (SD 24.4) vs. 98.3 (SD 3.3) %, P < 0.01]. The correlation between muscle deterioration ratio and metatarsophalangeal joint angle was r = - 0.51 (P = 0.01) for all diabetic, neuropathic subjects, but increased to r = - 0.81 (P < 0.01) when only subjects with muscle deterioration ratios > 1.0 were included. Muscle deterioration ratios in individuals with diabetic neuropathy were higher for those with a history of ulcers. Interpretation Individuals with diabetic neuropathy had increased intrinsic foot muscle deterioration, which was associated with second metatarsophalangeal joint angle and history of ulceration. Additional research is required to understand how foot muscle deterioration interacts with other impairments leading to forefoot deformity and skin breakdown. © 2013 Elsevier Ltd.

Author Keywords
Foot deformity;  Intermuscular adipose tissue;  Muscle

Document Type: Article
Source: Scopus

Mahajan, P.a , Jaffe, D.M.d e , Olsen, C.S.f , Leonard, J.R.e g , Nigrovic, L.E.h , Rogers, A.J.b c , Kuppermann, N.i j , Leonard, J.C.d e
Spinal cord injury without radiologic abnormality in children imaged with magnetic resonance imaging
(2013) Journal of Trauma and Acute Care Surgery, 75 (5), pp. 843-847. 

a Department of Pediatrics, Children's Hospital of Michigan, Wayne State University School of Medicine, 3901 Beaubien Blvd, Detroit, MI 48201, United States
b Department of Emergency Medicine, University of Michigan Medical Center, University of Michigan School of Medicine, Ann Arbor, MI, United States
c Department of Pediatrics, University of Michigan Medical Center, University of Michigan School of Medicine, Ann Arbor, MI, United States
d Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
e St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO, United States
f Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, United States
g Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States
h Division of Emergency Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
i Department of Emergency Medicine, University of California, Davis, School of Medicine, Davis, CA, United States
j Department of Pediatrics, University of California, Davis, School of Medicine, Davis, CA, United States

BACKGROUND: This study aimed to compare children diagnosed with cervical spinal cord injury without radiographic abnormality (SCIWORA) relative to whether there is evidence of cervical spinal cord abnormalities on magnetic resonance imaging (MRI). METHODS: We conducted a planned subanalysis of a cohort of children younger than 16 years with blunt cervical spine injury presenting to Pediatric Emergency Care Applied Research Network centers from January 2000 to December 2004 who underwent cervical MRI and did not have bony or ligamentous injury identified on neuroimaging. We defined SCIWORA with normal MRI finding as children with clinical evidence of cervical cord injury and a normal MRI finding and compared them with children with SCIWORA who had cervical cord signal changes on MRI (abnormal MRI finding). RESULTS: Of the children diagnosed with cervical spine injury, 55% (297 of 540) were imaged with MRI; 69 had no bony or ligamentous injuries and were diagnosed with SCIWORA by clinical evaluation; 54 (78%) had normal MRI finding, and 15 (22%) had cervical cord signal changes on MRI (abnormal MRI finding). Children with abnormal MRI findings were more likely to receive operative stabilization (0% normal MRI finding vs. 20% abnormal MRI finding) and have persistent neurologic deficits at initial hospital discharge (6% normal MRI finding vs. 67% abnormal MRI finding). CONCLUSION: Children diagnosed with SCIWORA but with normal MRI finding in our cohort presented differently and had substantially more favorable clinical outcomes than those with cervical cord abnormalities on MRI. Copyright © 2013 by Lippincott Williams & Wilkins.

Author Keywords
Emergency medicine;  MRI;  Pediatric;  Radiology;  Spinal cord

Document Type: Article
Source: Scopus

Brown, C.A.a , Karimi, M.K.a , Tian, L.a , Flores, H.a , Su, Y.b , Tabbal, S.D.c , Loftin, S.K.a , Moerlein, S.M.b d , Perlmutter, J.S.a b e f g
Validation of midbrain positron emission tomography measures for nigrostriatal neurons in macaques
(2013) Annals of Neurology, 74 (4), pp. 602-610. 

a Department of Neurology, Washington University of Medicine, St Louis, MO, United States
b Department of Radiology, Washington University of Medicine, St Louis, MO, United States
c Department of Neurology, American University of Beirut, Beirut, Lebanon
d Department of Biochemistry and Molecular Biophysics, Washington University of Medicine, St Louis, MO, United States
e Department of Neurobiology, Washington University of Medicine, St Louis, MO, United States
f Department of Occupational Therapy, Washington University of Medicine, St Louis, MO, United States
g Department of Physical Therapy, Washington University of Medicine, St Louis, MO, United States

Objective: Development of an effective therapy to slow the inexorable progression of Parkinson disease requires a reliable, objective measurement of disease severity. In the present study, we compare presynaptic positron emission tomography (PET) tracer uptake in the substantia nigra (SN) to cell loss and motor impairment in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primates. Methods: Presynaptic PET tracers 6-[18F]- fluorodopa (FD), [11C]-2β-methoxy-3β-4-fluorophenyltropane (CFT), and [11C]-dihydrotetrabenazine (DTBZ) were used to measure specific uptake in the SN and striatum before and after a variable dose of MPTP in nonhuman primates. These in vivo PET-based measures were compared with motor impairment, as well as postmortem tyrosine hydroxylase-positive cell counts and striatal dopamine concentration. Results: We found the specific uptake of both CFT and DTBZ in the SN had a strong, significant correlation with dopaminergic cell counts in the SN (R2 = 0.77, 0.53, respectively, p &lt; 0.001), but uptake of FD did not. Additionally, both CFT and DTBZ specific uptake in the SN had a linear relationship with motor impairment (rs = -0.77, -0.71, respectively, p &lt; 0.001), but FD uptake did not. Interpretation: Our findings demonstrate that PET-measured binding potentials for CFT and DTBZ for a midbrain volume of interest targeted at the SN provide faithful correlates of nigral neuronal counts across a full range of lesion severity. Because these measures correlate with both nigral cell counts and parkinsonian ratings, we suggest that these SN PET measures are relevant biomarkers of nigrostriatal function. © 2013 American Neurological Association.


Document Type: Article
Source: Scopus