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WUSTL Neuroscience Publications Archive - November 2014

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November 26, 2014

Paxilline inhibits BK channels by an almost exclusively closed-channel block mechanism
(2014) Journal of General Physiology, 144 (5), pp. 415-440. 


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


Abstract
Paxilline, a tremorogenic fungal alkaloid, potently inhibits large conductance Ca2+- and voltage-activated K+ (BK)- type channels, but little is known about the mechanism underlying this inhibition. Here we show that inhibition is inversely dependent on BK channel open probability (Po), and is fully relieved by conditions that increase Po, even in the constant presence of paxilline. Manipulations that shift BK gating to more negative potentials reduce inhibition by paxilline in accordance with the increase in channel Po. Measurements of Po times the number of channels at negative potentials support the idea that paxilline increases occupancy of closed states, effectively reducing the closed-open equilibrium constant, L(0). Gating current measurements exclude an effect of paxilline on voltage sensors. Steady-state inhibition by multiple paxilline concentrations was determined for four distinct equilibration conditions, each with a distinct Po. The IC50 for paxilline shifted from around 10 nM when channels were largely closed to near 10 μM as maximal Po was approached. Model-dependent analysis suggests a mechanism of inhibition in which binding of a single paxilline molecule allosterically alters the intrinsic L(0) favoring occupancy of closed states, with affinity for the closed conformation being >500-fold greater than affinity for the open conformation. The rate of inhibition of closed channels was linear up through 2 μM paxilline, with a slope of 2 × 106 M-1s-1. Paxilline inhibition was hindered by either the bulky cytosolic blocker, bbTBA, or by concentrations of cytosolic sucrose that hinder ion permeation. However, paxilline does not hinder MTSET modification of the inner cavity residue, A313C. We conclude that paxilline binds more tightly to the closed conformation, favoring occupancy of closed-channel conformations, and propose that it binds to a superficial position near the entrance to the central cavity, but does not hinder access of smaller molecules to this cavity.


Document Type: Article
Source: Scopus

Gordon, B.A.a , Tse, C.-Y.b , Gratton, G.c , Fabiani, M.c
Spread of activation and deactivation in the brain: Does age matter?
(2014) Frontiers in Aging Neuroscience, 6 (OCT), art. no. 288, . 


a Department of Radiology, Washington University in St. LouisSt. Louis, MO, United States
b Department of Psychology, Chinese University of Hong KongShatin, Hong Kong
c Department of Psychology and Beckman Institute, University of IllinoisUrbana, IL, United States


Abstract
Cross-sectional aging functional MRI results are sometimes difficult to interpret, as standard measures of activation and deactivation may confound variations in signal amplitude and spread, which however, may be differentially affected by age-related changes in various anatomical and physiological factors. To disentangle these two types of measures, here we propose a novel method to obtain independent estimates of the peak amplitude and spread of the BOLD signal in areas activated (task-positive) and deactivated (task-negative) by a Sternberg task, in 14 younger and 28 older adults. The peak measures indicated that, compared to younger adults, older adults had increased activation of the task-positive network, but similar levels of deactivation in the task-negative network. Measures of signal spread revealed that older adults had an increased spread of activation in task-positive areas, but a starkly reduced spread of deactivation in task-negative areas. These effects were consistent across regions within each network. Further, there was greater variability in the anatomical localization of peak points in older adults, leading to reduced cross-subject overlap. These results reveal factors that may confound the interpretation of studies of aging. Additionally, spread measures may be linked to local connectivity phenomena and could be particularly useful to analyze age-related deactivation patterns, complementing the results obtained with standard peak and region of interest analyses.


Author Keywords
Activation;  Aging;  Deactivation;  Default mode network (DMN);  Functional magnetic resonance imaging (fMRI);  Spread;  Task-negative network;  Task-positive network

 


Document Type: Article
Source: Scopus

November 21, 2014

Bolzenius, J.D.a , Laidlaw, D.H.b , Cabeen, R.P.b , Conturo, T.E.c , McMichael, A.R.c , Lane, E.M.d , Heaps, J.M.a , Salminen, L.E.a , Baker, L.M.a , Scott, S.E.a , Cooley, S.A.a , Gunstad, J.e , Paul, R.H.a
Brain structure and cognitive correlates of body mass index in healthy older adults
(2015) Behavioural Brain Research, 278, pp. 342-347. 


a University of Missouri - Saint Louis, One University Boulevard, Stadler Hall 443Saint Louis, MO, United States
b Brown University, Computer Science Department, 115 Waterman St., 4th FloorProvidence, RI, United States
c Washington University School of Medicine, Mallinckrodt Institute of Radiology, 510 S. KingshighwaySaint Louis, MO, United States
d Vanderbilt University Medical Center, 1211 Medical Center DriveNashville, TN, United States
e Kent State University, Department of Psychology, 221 Kent Hall AdditionKent, OH, United States


Abstract
Obesity, commonly measured with body mass index (BMI), is associated with numerous deleterious health conditions including alterations in brain integrity related to advanced age. Prior research has suggested that white matter integrity observed using diffusion tensor imaging (DTI) is altered in relation to high BMI, but the integrity of specific white matter tracts remains poorly understood. Additionally, no studies have examined white matter tract integrity in conjunction with neuropsychological evaluation associated with BMI among older adults. The present study examined white matter tract integrity using DTI and cognitive performance associated with BMI in 62 healthy older adults (20 males, 42 females) aged 51-81. Results revealed that elevated BMI was associated with lower fractional anisotropy (FA) in the uncinate fasciculus, though there was no evidence of an age by BMI interaction relating to FA in this tract. No relationships were observed between BMI and other white matter tracts or cognition after controlling for demographic variables. Findings suggest that elevated BMI is associated with lower structural integrity in a brain region connecting frontal and temporal lobes and this alteration precedes cognitive dysfunction. Future studies should examine biological mechanisms that mediate the relationships between BMI and white matter tract integrity, as well as the evolution of these abnormalities utilizing longitudinal designs.


Author Keywords
Aging;  BMI;  Cognition;  DTI;  Tractography;  White matter


Document Type: Article
Source: Scopus

Sharma, A.K.a , Kim, J.b , Prior, J.T.a , Hawco, N.J.a , Rath, N.P.c , Kim, J.b , Mirica, L.M.a
Small bifunctional chelators that do not disaggregate amyloid β fibrils exhibit reduced cellular toxicity
(2014) Inorganic Chemistry, 53 (21), pp. 11367-11376. 


a Department of Chemistry, Washington University, One Brookings DriveSt. Louis, MO, United States
b Department of Neurology, Washington University, School of MedicineSt. Louis, MO, United States
c Department of Chemistry and Biochemistry, University of Missouri-St. Louis, One University BoulevardSt. Louis, MO, United States


Abstract
Multifunctional metal chelators that can modulate the amyloid β (Aβ) peptide aggregation and its interaction with metal ions such as copper and zinc hold considerable promise as therapeutic agents for Alzheimers disease (AD). However, specific rather than systemic metal chelation by these compounds is needed in order to limit any side effects. Reported herein are two novel small bifunctional chelators, 2-[2-hydroxy-4-(diethylamino)phenyl]benzothiazole (L1) and 2-(2-hydroxy-3-methoxyphenyl)benzothiazole (L2), in which the metal-binding donor atoms are integrated within a molecular framework derived from the amyloid-binding fluorescent dye thioflavin T (ThT). The metal-binding properties of L1 and L2 were probed by pH spectrophotometric titrations to determine their pKa values and the corresponding metal complex stability constants, and the isolated metal complexes were structurally characterized. The amyloid-fibril-binding properties of L1 and L2 were investigated by fluorescence titrations and ThT competition assays. Interestingly, L1 and L2 do not lead to the formation of neurotoxic Aβ42 oligomers in the presence or absence of metal ions, as observed by native gel electrophoresis, Western blotting, and transmission electron microscopy. In addition, L1 and L2 were able to reduce the cell toxicity of preformed Aβ42 oligomers and of the copper-stabilized Aβ42 oligomers. Given their ability to reduce the toxicity of soluble Aβ42 and Cu-Aβ42 species, L1 and L2 are promising lead compounds for the development of chemical agents that can control the neurotoxicity of soluble Aβ42 species in AD.


Document Type: Article
Source: Scopus

Buchan, J.G., Alvarado, D.M., Haller, G., Aferol, H., Miller, N.H., Dobbs, M.B., Gurnett, C.A.
Are copy number variants associated with adolescent idiopathic scoliosis?
(2014) Clinical orthopaedics and related research, 472 (10), pp. 3216-3225. 


Department of Genetics, Washington University School of Medicine, 660 S Euclid Ave, Box 8111, St. Louis, MO, 63110, USA.


Abstract
Adolescent idiopathic scoliosis (AIS) is a complex genetic disorder that causes spinal deformity in approximately 3% of the population. Candidate gene, linkage, and genome-wide association studies have sought to identify genetic variation that predisposes individuals to AIS, but the genetic basis remains unclear. Copy number variants are associated with several isolated skeletal phenotypes, but their role in AIS, to our knowledge, has not been assessed. We determined the frequency of recurrent copy number rearrangements, chromosome aneuploidy, and rare copy number variants in patients with AIS. Between January 2010 and August 2014, we evaluated 150 patients with isolated AIS and spinal curvatures measuring 10° or greater, and 148 agreed to participate. Genomic copy number analysis was performed on patients and 1079 control subjects using the Affymetrix(®) Genome-wide Human SNP Array 6.0. After removing poor quality samples, 143 (97%) patients with AIS were evaluated for copy number variation. We identified a duplication of chromosome 1q21.1 in 2.1% (N = 3/143) of patients with AIS, which was enriched compared with 0.09% (N = 1/1079) of control subjects (p = 0.0057) and 0.07% (N = 6/8329) of a large published control cohort (p = 0.0004). Other notable findings include trisomy X, which was identified in 1.8% (N = 2/114) of female patients with AIS, and rearrangements of chromosome 15q11.2 and 16p11.2 that previously have been associated with spinal phenotypes. Finally, we report rare copy number variants that will be useful in future studies investigating candidate genes for AIS. Copy number variation and chromosomal aneuploidy may contribute to the pathogenesis of adolescent idiopathic scoliosis. Chromosomal microarray may reveal clinically useful abnormalities in some patients with AIS.


Document Type: Article
Source: Scopus

Theodoroff, S.M.a b , Schuette, A.c , Griest, S.a b , Henry, J.A.a b
Individual patient factors associated with effective tinnitus treatment
(2014) Journal of the American Academy of Audiology, 25 (7), pp. 631-643. 


a Veterans Affairs (VA) Rehabilitation Research and Development Service, National Center for Rehabilitative Auditory Research, VA Medical CenterPortland, OR, United States
b Department of Otolaryngology/Head and Neck Surgery, Oregon Health and Science UniversityPortland, OR, United States
c Division of Audiology, Washington UniversitySt. Louis, MO, United States


Abstract
Background: Little is known about patient factors that might influence outcomes of tinnitus interventions. Determining such factors would offer insights into why some individuals benefit from tinnitus intervention whereas others do not. Purpose: The purpose of this study was to evaluate selected patient factors that may be associated with outcomes of tinnitus intervention. Factors studied include demographics, tinnitus characteristics, psychoacoustic tinnitus measures, audiometric data, and overall physical/emotional health status. Research Design: A retrospective analysis was performed on data obtained from a controlled clinical study that compared factors associated with tinnitus relief after tinnitus masking and tinnitus retraining therapy. Study Sample: A total of 126 military veterans participated in this controlled clinical study. Of these, 89 completed outcome measures at both baseline and 12 mo and were included in the present analysis. Data Collection and Analysis: A "responder" to intervention was identified as having a decrease (improvement) of 20 or more points on the Tinnitus Handicap Inventory between baseline and 12 mo. A "nonresponder" did not achieve a 20-point improvement on the Tinnitus Handicap Inventory. Individual patient factors were examined using independent t-tests or χ2 analysis. A logistic regression model was used to determine how well each factor predicted treatment outcome (responder or nonresponder) while controlling for each of the other factors. Results: Five patient factors were significantly different (p ≤ 0.05) between responders and nonresponders. Responders tended to (1) be younger in age; (2) have better low-frequency hearing sensitivity; (3) have greater problems with overall hearing; (4) be more likely to have tinnitus for shorter durations; and (5) perceive their tinnitus to be located "in the head" versus "in the ears." A logistic regression was then performed to determine how well each factor predicted the treatment outcome (responder versus nonresponder) while controlling for each of the other factors. Results from the logistic regression revealed two of the five factors, localization of tinnitus and self-report of hearing problems, to be statistically significant. Conclusions: Examining the association of individual patient factors to a specific tinnitus intervention yielded several significant findings. Although these findings are not definitive, they reveal the capability that exists to perform these kinds of analyses to investigate relationships between individual patient characteristics and outcomes of intervention for tinnitus. Prospective research using systematic approaches is needed to identify these relationships that would contribute toward the ability to differentially predict outcomes of various tinnitus interventions. Obtaining this information would lead to more targeted therapy and ultimately more effective intervention.


Author Keywords
Logistic regression;  Psychoacoustics;  Tinnitus;  Treatment


Document Type: Article
Source: Scopus

Lenze, E.J.a , Hickman, S.b , Hershey, T.a , Wendleton, L.a , Ly, K.b , Dixon, D.a , Doré, P.a , Wetherell, J.L.b c
Mindfulness-based stress reduction for older adults with worry symptoms and co-occurring cognitive dysfunction
(2014) International Journal of Geriatric Psychiatry, 29 (10), pp. 991-1000. 


a Washington University, School of MedicineSt. Louis, MO, United States
b University of California San DiegoSan Diego, CA, United States
c VA San Diego Healthcare SystemSan Diego, CA, United States


Abstract
Background: Mindfulness-based stress reduction (MBSR) has the potential to reduce worry and improve cognitive functioning.

Objectives: In this treatment development project, we examined MBSR in older adults with worry symptoms and co-occurring cognitive dysfunction. We examined (i) acceptability of MBSR, (ii) whether MBSR needs to be lengthened providing more repetition, (iii) MBSR's benefits for worry reduction and cognitive improvements, and (iv) continued use of MBSR techniques during follow-up.

Methods: Two sites (St. Louis and San Diego) enrolled individuals aged 65 years or older with significant anxiety-related distress plus subjective cognitive dysfunction, into traditional 8-session MBSR groups and 12-session groups that had the same content but more repetition of topics and techniques. We examined measures of mindfulness, worry, and a neuropsychological battery focused on memory and executive function before and after the MBSR program, and we followed up participants for 6 months after the completion of MBSR regarding their continued use of its techniques.

Results: Participants (N= 34) showed improvements in worry severity, increases in mindfulness, and improvements in memory as measured by paragraph learning and recall after a delay, all with a large effect size. Most participants continued to use MBSR techniques for 6 months post-instruction and found them helpful in stressful situations. There was no evidence that the extended 12-week MBSR produced superior cognitive or clinical outcomes, greater satisfaction, or greater continuation of MBSR techniques than 8-week MBSR.

Conclusions: These preliminary findings are promising for the further testing and use of MBSR in older adults suffering from clinical worry symptoms and co-occurring cognitive dysfunction. These are common problems in a broad range of older adults, many of whom have anxiety and mood disorders; therefore, stress reduction intervention for them may have great public health value.


Author Keywords
Anxiety;  Meditation;  Memory;  Mindfulness;  Older adults;  Stress;  Yoga


Document Type: Article
Source: Scopus

Heuser, J.E.a b
Some personal and historical notes on the utility of "deep-etch" electron microscopy for making cell structure/function correlations
(2014) Molecular Biology of the Cell, 25 (21), pp. 3273-3276. 


a WPI Institute, Kyoto UniversityKyoto, Japan
b Department of Cell Biology and Physiology, Washington University School of MedicineSt. Louis, MO, United States


Abstract
This brief essay talks up the advantages of metal replicas for electron microscopy and explains why they are still the best way to image frozen cells in the electron microscope. Then it explains our approach to freezing, namely the Van Harreveld trick of "slamming" living cells onto a supercold block of metal sprayed with liquid helium at -269°C, and further talks up this slamming over the alternative of high-pressure freezing, which is much trickier but enjoys greater favor at the moment. This leads me to bemoan the fact that there are not more young investigators today who want to get their hands on electron microscopes and use our approach to get the most "true to life" views of cells out of them with a minimum of hassle. Finally, it ends with a few perspectives on my own career and concludes that, personally, I'm permanently stuck with the view of the "founding fathers" that cell ultrastructure will ultimately display and explain all of cell function, or as Palade said in his Nobel lecture,electron micrographs are "irresistible and half transparent ... their meaning buried under only a few years of work," and "reasonable working hypotheses are already suggested by the ultrastructural organization itself."

 


Document Type: Article
Source: Scopus

 

November 13, 2014

 Hogan, R.E.a , Blatt, I.b , Lawson, B.c , Nagaraddi, V.d , Fakhoury, T.A.e , Anders, B.f , Clark, A.M.f , Laine, D.f , Halvorsen, M.B.f , Chung, S.S.g

Efficacy of once-daily extended-release topiramate (USL255): A subgroup analysis based on the level of treatment resistance
(2014) Epilepsy and Behavior, 41, pp. 136-139. 


a Washington University in St. Louis, Washington University School of Medicine, Adult Epilepsy Center, 660 S Euclid Ave., Campus Box 8St. Louis, MO, United States
b The Chaim Sheba Medical Center, Charles Clore Hospitalization TowerEast Wing, Tel Hashomer, Israel
c Hospital Dr. Sótero del Río, Oficina de Investigaciones MédicasPuente Alto, Chile
d Neurological Clinic of Texas, 12221 Merit Dr., Suite 350Dallas, TX, United States
e Bluegrass Epilepsy Research, 1401 Harrodsburg Rd B280Lexington, KY, United States
f Upsher-Smith Laboratories Inc., 6701 Evenstad DriveMaple Grove, MN, United States
g Barrow Neurological Institute, 500 West Thomas Road, Suite 300Phoenix, AZ, United States


Abstract
Results from a previously conducted global phase III study (PREVAIL; NCT01142193) demonstrate the safety and efficacy of once-daily USL255, Qudexy™ XR (topiramate) extended-release capsules, as adjunctive treatment of drug-resistant partial-onset seizures (POSs). In this study, we report a post hoc analysis of PREVAIL data according to patient level of treatment resistance (based upon the number of concomitant antiepileptic drugs [AEDs] and lifetime AEDs) at baseline, with patients defined as either having "highly" drug-resistant seizures (≥. 2 concurrent AEDs and ≥. 4 lifetime AEDs) or having "less" drug-resistant seizures (1 concurrent AED or <. 4 lifetime AEDs) at baseline. For each subgroup, median percent reduction in POS frequency (primary endpoint), responder rate, Clinical Global Impression of Change (CGI-C), and Quality of Life in Epilepsy - Problems (QOLIE-31-P) survey were assessed. Of 249 PREVAIL patients, 115 were classified as having highly drug-resistant seizures (USL255: n = 52, placebo: n = 63), and 134 were classified as having less drug-resistant seizures (USL255: n = 72, placebo: n = 62) at baseline. For the primary endpoint, USL255 resulted in significantly better seizure outcomes compared with placebo regardless of drug-resistant status (P=.004 and P=.040 for "highly" and "less", respectively). Responder rate was also significantly improved in patients with highly drug-resistant group (P=.023). The CGI-C scores indicated significant improvement in both subgroups (P=.003 and P=.013 for "highly" and "less", respectively). On the QOLIE-31-P, a significant improvement on the seizure worry subscale for the group with less drug-resistant seizures was noted in USL255-treated patients compared with placebo-treated patients (P=.003); the overall score and all other subscales were not significantly different for both subgroups. We conclude that USL255 led to significant improvements across multiple outcomes compared with placebo, including in those patients with highly drug-resistant seizures to prior treatment, making it a valuable treatment option for patients with epilepsy.


Author Keywords
Antiepileptic drugs;  Drug resistance;  Extended-release;  Partial seizures;  Topiramate


Document Type: Article
Source: Scopus

Kass, A.E.a , Trockel, M.b , Safer, D.L.b , Sinton, M.M.c , Cunning, D.b , Rizk, M.T.d , Genkin, B.H.d , Weisman, H.L.b , Bailey, J.O.b , Jacobi, C.e , Wilfley, D.E.a d , Taylor, C.B.c
Internet-based preventive intervention for reducing eating disorder risk: A randomized controlled trial comparing guided with unguided self-help
(2014) Behaviour Research and Therapy, 63, pp. 90-98. 


a Department of Psychology, Washington University in St. Louis, 660 South Euclid Avenue, Campus Box 8134St. Louis, MO, United States
b Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, MC 5722Stanford, CA, United States
c Department of Psychology, The College of William and Mary, Integrated Science Center, P.O. Box 8795Williamsburg, VA, United States
d Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8134St. Louis, MO, United States
e Technische Universität Dresden, Klinische Psychologie und Psychotherapie, Chemnitzer Str. 46Dresden, Germany


Abstract
Student Bodies, an internet-based intervention, has successfully reduced weight/shape concerns and prevented eating disorders in a subset of college-age women at highest risk for an eating disorder. Student Bodies includes an online, guided discussion group; however, the clinical utility of this component is unclear. This study investigated whether the guided discussion group improves program efficacy in reducing weight/shape concerns in women at high risk for an eating disorder. Exploratory analyses examined whether baseline variables predicted who benefitted most. Women with high weight/shape concerns (N=151) were randomized to Student Bodies with a guided discussion group (n=74) or no discussion group (n=77). Regression analyses showed weight/shape concerns were reduced significantly more among guided discussion group than no discussion group participants (p=0.002; d=0.52); guided discussion group participants had 67% lower odds of having high-risk weight/shape concerns post-intervention (p=0.02). There were no differences in binge eating at post-intervention between the two groups, and no moderators emerged as significant. Results suggest the guided discussion group improves the efficacy of Student Bodies in reducing weight/shape concerns in college students at high risk for an eating disorder.


Author Keywords
Eating disorders;  Guided self-help;  Internet treatment;  Prevention;  Randomized controlled trial


Document Type: Article
Source: Scopus

Aspen, V.a , Weisman, H.a , Vannucci, A.b , Nafiz, N.c , Gredysa, D.d , Kass, A.E.d , Trockel, M.a , Jacobi, C.e , Wilfley, D.E.d , Taylor, C.B.a
Psychiatric co-morbidity in women presenting across the continuum of disordered eating
(2014) Eating Behaviors, 15 (4), pp. 686-693. 


a Department of Psychiatry, Stanford University School of MedicineStanford, CA, United States
b Department of Medical and Clinical Psychology, Uniformed Services University of the Health SciencesBethesda, MD, United States
c Department of Psychology, California State UniversitySacramento, CA, United States
d Department of Psychiatry, Washington University School of MedicineSt. Louis, MO, United States
e Institut für Klinische Psychologie und Psychotherapie, Technische Universität DresdenDresden, Germany


Abstract
Objective: To compare the prevalence and correlates of psychiatric co-morbidity across a large sample of college women without an eating disorder, those at high risk for an eating disorder and women diagnosed using DSM-5 criteria for an eating disorder. Participants: 549 college women aged 18-25. Methods: Data from the Eating Disorder Examination, the Structured Clinical Interview for DSM-IV Axis I disorders and self-report questionnaires were analyzed using logistic regression for categorical data and ANCOVA for continuous measures. Results: Eating disordered symptomatology was strongly associated with anxiety disorders, mood disorders and insomnia. These co-morbidities (type and severity) tend to increase with eating disorder symptom severity. Conclusions: Prevention and treatment programs for eating disorders need to address the high levels of mood, anxiety and sleep problems in this population. The findings on insomnia are novel and suggest that sleep disturbance may play an integral role in eating-related difficulties.


Author Keywords
Co-morbidity;  Eating disorders;  High risk


Document Type: Article
Source: Scopus

Myers, T.A.a b , Ridolfi, D.R.a c , Crowther, J.H.a
Reaction Times to Appearance-Related or Non-appearance-Related Word Choice Among Women With and Without Eating Psychopathology
(2014) Cognitive Therapy and Research, 11 p. Article in Press. 


a Department of Psychology, Kent State UniversityKent, OH, United States
b Department of Psychology, Virginia Wesleyan CollegeNorfolk, VA, United States
c Department of Psychiatry, Washington University in St. LouisSt. Louis, MO, United States


Abstract
Activation of schemas related to one’s appearance has been studied extensively using implicit tasks such as the word stem completion task and the Stoop paradigm. The current study utilized a word stem completion task adapted for presentation on a Personal Data Assistant to examine differences in reaction times to appearance- and non-appearance-related words. Participants were 93 undergraduate women, 30 of whom met criteria for eating psychopathology utilizing the diagnostic algorithm for the Eating Disorder Diagnostic Scale (Stice et al. in Psychol Assess 12:123–131. doi:10.1037/1040-3590.12.2.123, 2000). The remaining 63 participants served as a comparison group. A significant interaction effect indicated that women with eating pathology exhibited significantly longer reaction times when selecting the appearance-related words than those without eating psychopathology. This research introduces a novel method of measuring reaction time to appearance- and non-appearance-related words and demonstrates the relevance of appearance schematicity in the naturalistic environment by showing that these schemas have the potential to impact the way young women process schema-relevant information on a day-to-day basis.


Author Keywords
Cognitive assessment;  Eating disorders;  Schema


Document Type: Article in Press
Source: Scopus

Paul, R.H.a , Joska, J.A.b , Woods, C.c , Seedat, S.d , Engelbrecht, S.e , Hoare, J.b , Heaps, J.a , Valcour, V.f , Ances, B.g , Baker, L.M.a , Salminen, L.E.a , Stein, D.J.b
Impact of the HIV Tat C30C31S dicysteine substitution on neuropsychological function in patients with clade C disease
(2014) Journal of NeuroVirology, 9 p. Article in Press. 


a Department of Psychology and Behavioral Neuroscience, University of Missouri-St. Louis, University BoulevardSt. Louis, United States
b MRC Unit on Anxiety & Stress Disorders, Department of Psychiatry & Mental Health, University of Cape TownCape Town, South Africa
c Department of Psychology, University of KansasKansas, KS, United States
d MRC Unit on Anxiety and Stress Disorders, Department of Psychiatry, University of StellenboschStellenbosch, South Africa
e Division of Medical Virology, Stellenbosch University and National Health Laboratory Services (NHLS)Cape Town, South Africa
f Memory and Aging Center, Department of Neurology, University of CaliforniaSan Francisco, CA, United States
g Department of Neurology, Washington University Medical SchoolSt. Louis, MO, United States


Abstract
Previous animal studies have identified a C31S residue substitution in the C30C31 dicysteine motif of the Tat protein that is associated with reduced neurovirulence in clade C human immunodeficiency virus (HIV). However, clinical studies of patients infected with clade C HIV have reported significant levels of cognitive impairment. To date, no study has specifically examined cognitive function in clade C-infected patients as a function of the presence or absence of the Tat C31 substitution. The present study investigated the impact of the Tat C30C31S genetic substitution among individuals residing in South Africa infected with clade C HIV that either exhibited the C30C31 motif (n = 128) or the C31S motif (n = 46). A control group of seronegative individuals was included to examine the overall impact of HIV on cognitive performance. All individuals completed a comprehensive neuropsychological battery consisting of tests sensitive to HIV. Results revealed that clade C-infected individuals performed significantly worse across cognitive tests compared to seronegative controls. However, there were no significant differences in cognitive performances between individuals with the C31S motif versus those without the C31S substitution. Proximal CD4 cell count and plasma viral load were unrelated to cognitive performances for either group. Results confirm that the C31S dicysteine motif substitution of the Tat protein does not appreciably moderate neuropsychological outcomes in clade C. Further, these findings highlight the importance of clinical management of cognitive symptoms among individuals infected with this viral clade worldwide.


Author Keywords
C31S dicysteine motif;  Clade C;  Cognitive performance;  HIV;  Tat protein


Document Type: Article in Press
Source: Scopus

Jin, H.a , Fan, J.a , Zhang, X.a , Li, J.a , Flores, H.P.b , Perlmutter, J.S.a b , Parsons, S.M.c , Tu, Z.a
Radiosynthesis and in vivo evaluation of a novel σ1 selective PET ligand
(2014) MedChemComm, 5 (11), pp. 1669-1677. 


a Department of Radiology, Washington University, School of MedicineSt. Louis, MO, United States
b Department of Neurology, Washington University, School of MedicineSt. Louis, MO, United States
c Department of Chemistry and Biochemistry, University of CaliforniaSanta Barbara, CA, United States


Abstract
The σ1 receptor is an important target for CNS disorders. We previously identified a σ1 ligand TZ3108 having highly potent (Ki-σ1 = 0.48 nM) and selective affinity for σ1versus σ2 receptors. TZ3108 was 18F-labeled for in vivo evaluation. Biodistribution and blocking studies of [18F]TZ3108 in male Sprague-Dawley rats demonstrated high brain uptake, which was σ1-specific with no in vivo defluorination. MicroPET studies in cynomolgus macaques showed high brain penetration of [18F]TZ3108; the regional brain distribution was consistent with that of the σ1 receptor. Pseudo-equilibrium in the brain was reached
45 min post-injection. Metabolite analysis of [18F]TZ3108 in NHP blood and rodent blood and brain revealed that 70% parent remained in the plasma of NHPs 60 min post-injection and the major radiometabolite did not cross the blood-brain barrier in rats. In summary, the potent, selective and metabolically stable σ1 specific radioligand [18F]TZ3108 represents a potentially useful PET radioligand for quantifying the σ1 receptor in the brain.


Document Type: Article
Source: Scopus

Corley, M., Kroll, K.L.
The roles and regulation of Polycomb complexes in neural development
(2014) Cell and Tissue Research, 21 p. Article in Press. 


Department of Developmental Biology, Washington University School of Medicine, 320 McDonnell Sciences Building, Campus Box 8103, 660 S. Euclid AvenueSt. Louis, United States


Abstract
In the developing mammalian nervous system, common progenitors integrate both cell extrinsic and intrinsic regulatory programs to produce distinct neuronal and glial cell types as development proceeds. This spatiotemporal restriction of neural progenitor differentiation is enforced, in part, by the dynamic reorganization of chromatin into repressive domains by Polycomb repressive complexes, effectively limiting the expression of fate-determining genes. Here, we review the distinct roles that Polycomb repressive complexes play during neurogenesis and gliogenesis, while also highlighting recent work describing the molecular mechanisms that govern their dynamic activity in neural development. Further investigation of the way in which Polycomb complexes are regulated in neural development will enable more precise manipulation of neural progenitor differentiation facilitating the efficient generation of specific neuronal and glial cell types for many biological applications.


Author Keywords
Chromatin;  Epigenetic;  Gliogenesis;  Neurogenesis;  Polycomb


Document Type: Article in Press
Source: Scopus

Crary, J.F.a , Trojanowski, J.Q.b , Schneider, J.A.c , Abisambra, J.F.d , Abner, E.L.e , Alafuzoff, I.f , Arnold, S.E.g , Attems, J.h , Beach, T.G.i , Bigio, E.H.a j , Cairns, N.J.a k , Dickson, D.W.a l , Gearing, M.a m , Grinberg, L.T.a n o , Hof, P.R.a p , Hyman, B.T.a q , Jellinger, K.a r , Jicha, G.A.a s , Kovacs, G.G.b t , Knopman, D.S.b u , Kofler, J.b v , Kukull, W.A.b w , Mackenzie, I.R.b x , Masliah, E.b y , McKee, A.b z , Montine, T.J.b aa , Murray, M.E.a l , Neltner, J.H.b ab , Santa-Maria, I.a , Seeley, W.W.b ac , Serrano-Pozo, A.c ad , Shelanski, M.L.a , Stein, T.c ae , Takao, M.c af , Thal, D.R.c ag , Toledo, J.B.b , Troncoso, J.C.c ah , Vonsattel, J.P.a , White, C.L., 3Rdc ai , Wisniewski, T.c aj , Woltjer, R.L.c ak , Yamada, M.c al , Nelson, P.T.c am
Primary age-related tauopathy (PART): a common pathology associated with human aging
(2014) Acta Neuropathologica, 12 p. Article in Press. 


a Department of Pathology and Cell Biology and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical CenterNew York, NY, United States
b Department of Pathology, Division of Neuropathology, University of PennsylvaniaPhiladelphia, PA, United States
c Departments of Pathology (Neuropathology) and Neurological Sciences, Rush University Medical CenterChicago, IL, United States
d Department of Physiology and Sanders-Brown Center on Aging, University of KentuckyLexington, KY, United States
e Department of Public Health and Sanders-Brown Center on Aging, University of KentuckyLexington, KY, United States
f Department of Immunology, Genetics and Pathology, Uppsala UniversityUppsala, Sweden
g Departments of Psychiatry and Neurology, University of PennsylvaniaPhiladelphia, PA, United States
h Institute for Ageing and Health, Newcastle UniversityNewcastle upon Tyne, United Kingdom
i Civin Laboratory for Neuropathology, Banner Sun Health Research InstituteSun City, AZ, United States
j Department of Pathology (Neuropathology), Northwestern Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of MedicineChicago, IL, United States
k Department of Pathology and Immunology, Washington University School of MedicineSt. Louis, MO, United States
l Department of Neuroscience, Mayo Clinic, 4500 San Pablo RoadJacksonville, FL, United States
m Department of Pathology and Laboratory Medicine (Neuropathology), Emory University School of MedicineAtlanta, GA, United States
n Departments of Neurology and Pathology, UCSan Francisco, CA, United States
o Department of Pathology, University of Sao PauloSao Paulo, Brazil
p Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNew York, NY, United States
q Department of Neurology, Harvard Medical School and Massachusetts General HospitalCharlestown, MA, United States
r Institute of Clinical NeurobiologyVienna, Austria
s Department of Neurology and the Sanders-Brown Center on Aging, University of KentuckyLexington, KY, United States
t Institute of Neurology, Medical University ViennaVienna, Austria
u Department of Neurology, Mayo ClinicRochester, MN, United States
v Department of Pathology (Neuropathology), University of Pittsburgh Medical CenterPittsburgh, PA, United States
w Department of Epidemiology, University of WashingtonSeattle, WA, United States
x Department of Pathology, University of British Columbia, 855 West 12th AvenueVancouver, BC, Canada
y Departments of Neurosciences and Pathology, University of CaliforniaSan Diego, La Jolla, CA, United States
z Department of Pathology (Neuropathology), Boston UniversityBoston, MA, United States
aa Department of Pathology, University of WashingtonSeattle, WA, United States
ab Department of Pathology, University of KentuckyLexington, KY, United States
ac Departments of Neurology and Pathology, University of CaliforniaSan Francisco, CA, United States
ad Department of Neurology, University of Iowa Hospitals and ClinicsIowa city, IA, United States
ae Department of Pathology (Neuropathology), VA Medical Center and Boston University School of MedicineBoston, MA, United States
af Department of Neuropathology, Tokyo Metropolitan Geriatric HospitalTokyo, Japan
ag Laboratory of Neuropathology, University of UlmUlm, Germany
ah Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of MedicinePhiladelphia, PA, United States
ai Department of Pathology (Neuropathology), University of Texas Southwestern Medical SchoolDallas, TX, United States
aj Departments of Neurology, Pathology and Psychiatry, New York University School of MedicineNew York, NY, United States
ak Department of Pathology L113, Oregon Health Sciences UniversityPortland, OR, United States
al Departments of Neurology & Neurobiology of Aging, Kanazawa University Graduate School of Medical SciencesKanazawa, Japan
am Department of Pathology (Neuropathology) and Sanders-Brown Center on Aging, University of KentuckyLexington, KY, United States


Abstract
We recommend a new term, “primary age-related tauopathy” (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer’s disease (AD), in the absence of amyloid (Aβ) plaques. For these “NFT+/Aβ−” brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as “tangle-only dementia” and “tangle-predominant senile dementia”, are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.


Author Keywords
Braak;  Consensus;  Neuropathology;  TOD;  TPSD


Document Type: Article in Press
Source: Scopus

Bista, P.a c , Cerina, M.a , Ehling, P.a b , Leist, M.a , Pape, H.-C.a , Meuth, S.G.b , Budde, T.a
The role of two-pore-domain background K+ (K2P) channels in the thalamus
(2014) Pflugers Archiv European Journal of Physiology, 11 p. Article in Press. 


a Institut für Physiologie I, Westfälische Wilhelms-Universität, Robert-Koch-Str. 27aMünster, Germany
b Klinik für Allgemeine Neurologie und Institut für Physiologie-Abteilung für Neuropathophysiologie, Westfälische Wilhelms-Universität, Albert-Schweitzer-Campus 1Münster, Germany
c Department of Anatomy and Neurobiology, Washington University Medical School, 660 South Euclid AvenueSt. Louis, MO, United States


Abstract
The thalamocortical system is characterized by two fundamentally different activity states, namely synchronized burst firing and tonic action potential generation, which mainly occur during the behavioral states of sleep and wakefulness, respectively. The switch between the two firing modes is crucially governed by the bidirectional modulation of members of the K2P channel family, namely tandem of P domains in a weakly inward rectifying K+ (TWIK)-related acid-sensitive K+ (TASK) and TWIK-related K+ (TREK) channels, in thalamocortical relay (TC) neurons. Several physicochemical stimuli including neurotransmitters, protons, di- and multivalent cations as well as clinically used drugs have been shown to modulate K2P channels in these cells. With respect to modulation of these channels by G-protein-coupled receptors, PLCβ plays a unique role with both substrate breakdown and product synthesis exerting important functions. While the degradation of PIP2 leads to the closure of TREK channels, the production of DAG induces the inhibition of TASK channels. Therefore, TASK and TREK channels were found to be central elements in the control of thalamic activity modes. Since research has yet focused on identifying the muscarinic pathway underling the modulation of TASK and TREK channels in TC neurons, future studies should address other thalamic cell types and members of the K2P channel family.


Author Keywords
Muscarinic modulation;  TASK channels;  Thalamic firing modes;  Thalamocortical network;  TREK channels


Document Type: Article in Press
Source: Scopus

Wojtkiewicz, D.M.a , Saunders, J.b , Domeshek, L.b , Novak, C.B.c , Kaskutas, V.a , Mackinnon, S.E.b
Social impact of peripheral nerve injuries
(2014) Hand, 7 p. Article in Press. 


a Department of Occupational Therapy, Washington University School of MedicineSt. Louis, MO, United States
b Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, Suite 1150, Northwest Tower, 660 South Euclid Avenue, Campus Box 8238St. Louis, MO, United States
c Hand and Upper Extremity Program, Division of Plastic and Reconstructive Surgery, University of TorontoToronto, ON, Canada


Abstract
Background: Disorders involving the peripheral nervous system can have devastating impacts on patients’ daily functions and routines. There is a lack of consideration of the impact of injury on social/emotional well-being and function.

Methods: We performed a retrospective database and chart review of adult patients presenting between 2010 and 2012 with peripheral nerve compression, brachial plexus injury, thoracic outlet syndrome (TOS), or neuromas. At the initial assessment, patients completed a questionnaire used to obtain demographic and psychosocial variable data including the (1) average level of pain over the last month, (2) self-perceived depression, (3) how much pain impacts quality of life (QoL), (4) current level of stress, and (5) ability to cope with stress. Statistical analyses were used to assess the differences between the dependent variables and diagnostic and demographic groups.

Results: This study included 490 patients (mean age 50 ± 15 years); the most common diagnosis was single nerve compression (n = 171). Impact on QoL was significantly greater in patients with TOS, cutaneous peroneal compressions, and neuroma versus single site nerve compressions. Average pain, impact on QoL, and stress at home were significantly higher in females versus males. Impact on QoL was correlated with average pain, depression, stress at home, and ability to cope with stress at home.

Conclusions: Our study demonstrates that patients with single site nerve compression neuropathies experience fewer negative psychosocial effects compared to patients with more proximal upper extremity peripheral nerve disorders and neuromas. The impact on QoL was strongly correlated with pain and depression, where patients with neuromas and painful peroneal nerve entrapments reported greater detriments to QoL.


Author Keywords
Injury;  Peripheral nerve;  Psychosocial;  Upper extremity


Document Type: Article in Press
Source: Scopus

Randerath, J.a b , Valyear, K.F.b , Hood, A.c , Frey, S.H.b
Two Routes to the Same Action: An Action Repetition Priming Study
(2014) Journal of Motor Behavior, 11 p. Article in Press. 


a Department of Psychology, University of Konstanz, Konstanz, Germany
b Department of Psychological Sciences, University of Missouri, Columbia
c Department of Psychology, Washington University, St. Louis, Missouri


Abstract
ABSTRACT. Action selection can be influenced by preceding movements. The authors investigated how retrospective factors may interact with plan- versus rule-based action selection. Participants completed 2 tasks, both of which involved selecting a pronated or supinated posture. In the plan task, they chose the most comfortable hand orientation. In the rule task, they followed a learned prescription. Trials in both tasks comprised prime-probe pairs that were identical, or differed in the visual stimulus or required motor response. Both tasks showed a response-time advantage for probes that were preceded by identical primes. This effect was greater for the plan task suggesting that plan-based action selection is especially susceptible to recent history, fortifying the idea that differential mechanisms underlie a rule- versus plan-based approach to the same action.


Author Keywords
action planning;  action repetition priming;  action selection;  motor history;  rule-based action


Document Type: Article in Press
Source: Scopus

Craver, C.F.a , Graham, B.b , Rosenbaum, R.S.c d
Remembering Mr B.
(2014) Cortex, 59, pp. 153-184. 


a Philosophy-Neuroscience-Psychology Program, Washington UniversitySt. Louis, United States
b J.D. Candidate, Yale Law School, United States
c Department of Psychology and Neuroscience Graduate Diploma Program, York UniversityToronto, Canada
d Rotman Research Institute, BaycrestToronto, Canada


Abstract
In the accompanying translation and film, Gustav Störring describes the psychological profile of Mr. B. (Franz Breundl), a victim of carbon monoxide poisoning with a nearly complete short-term memory deficit. Störring diagnoses Mr. B. as lacking entirely the capacity to register or retain any information in consciousness for longer than two seconds. Here we introduce these historical documents, describe their historical context, summarize and discuss the central features of the case, and consider the potential significance of the case for contemporary theories of working memory, the self, and personal identity.


Author Keywords
Amnesia;  Carbon monoxide poisoning;  Memory;  Self;  Working memory


Document Type: Article
Source: Scopus

Knutsen, A.K.a , Magrath, E.a , McEntee, J.E.a , Xing, F.b , Prince, J.L.b c , Bayly, P.V.d e , Butman, J.A.a f , Pham, D.L.a
Improved measurement of brain deformation during mild head acceleration using a novel tagged MRI sequence
(2014) Journal of Biomechanics, . Article in Press. 


a Center for Neuroscience and Regenerative Medicine, The Henry M. Jackson Foundation, Bethesda, MD, USA
b Department of Electrical and Computing Engineering, Johns Hopkins University, Baltimore, MD, USA
c Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
d Department of Mechanical Engineering and Materials Science, St. Louis, MO, USA
e Department of Biomedical Engineering, Washington University, St. Louis, MO, USA
f Radiology and Imaging Sciences, Department of Diagnostic Radiology, Clinical Center, National Institutes of Health, Bethesda, MD, USA


Abstract
In vivo measurements of human brain deformation during mild acceleration are needed to help validate computational models of traumatic brain injury and to understand the factors that govern the mechanical response of the brain. Tagged magnetic resonance imaging is a powerful, noninvasive technique to track tissue motion in vivo which has been used to quantify brain deformation in live human subjects. However, these prior studies required from 72 to 144 head rotations to generate deformation data for a single image slice, precluding its use to investigate the entire brain in a single subject. Here, a novel method is introduced that significantly reduces temporal variability in the acquisition and improves the accuracy of displacement estimates. Optimization of the acquisition parameters in a gelatin phantom and three human subjects leads to a reduction in the number of rotations from 72 to 144 to as few as 8 for a single image slice. The ability to estimate accurate, well-resolved, fields of displacement and strain in far fewer repetitions will enable comprehensive studies of acceleration-induced deformation throughout the human brain in vivo.


Author Keywords
Acceleration;  Deformation;  Magnetic resonance imaging (MRI);  Strain;  Traumatic brain injury (TBI)


Document Type: Article in Press
Source: Scopus

Rogers, C.E.a b , Barch, D.M.a c d e , Sylvester, C.M.a , Pagliaccio, D.e , Harms, M.P.a , Botteron, K.N.a c , Luby, J.L.a
Altered gray matter volume and school age anxiety in children born late preterm
(2014) Journal of Pediatrics, 165 (5), pp. 928-935. 


a Department of Psychiatry, Washington University School of Medicine, 660 Scott Ave, Box 8116St. Louis, MO, United States
b Department of Pediatrics, Washington University School of MedicineSt. Louis, MO, United States
c Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of MedicineSt. Louis, MO, United States
d Department of Psychology, Washington University in St. LouisSt. Louis, MO, United States
e Program in Neuroscience, Washington University in St. LouisSt. Louis, MO, United States


Abstract
Objectives To determine if late preterm (LP) children differ from full term (FT) children in volumes of the cortex, hippocampus, corpus callosum, or amygdala and whether these differences are associated with anxiety symptoms at school-age.

Study design LP children born between 34 and 36 weeks gestation and FT children born between 39 and 41 weeks gestation from a larger longitudinal cohort had magnetic resonance imaging scans at school-age. Brain volumes, cortical surface area, and thickness measures were obtained. Anxiety symptoms were assessed using a structured diagnostic interview annually beginning at preschool-age and following the magnetic resonance imaging.

Results LP children (n = 21) had a smaller percentage of total, right parietal, and right temporal lobe gray matter volume than FT children (n = 87). There were no differences in hippocampal, callosal, or amygdala volumes or cortical thickness. LP children also had a relative decrease in right parietal lobe cortical surface area. LP children had greater anxiety symptoms over all assessments. The relationship between late prematurity and school-age anxiety symptoms was mediated by the relative decrease in right temporal lobe volume.

Conclusions LP children, comprising 70% of preterm children, are also at increased risk for altered brain development particularly in the right temporal and parietal cortices. Alterations in the right temporal lobe cortical volume may underlie the increased rate of anxiety symptoms among these LP children. These findings suggest that LP delivery may disrupt temporal and parietal cortical development that persists until school-age with the right temporal lobe conferring risk for elevated anxiety symptoms.


Document Type: Article
Source: Scopus

Nabors, L.B.a , Portnow, J.b , Ammirati, M.c , Brem, H.d , Brown, P.e , Butowski, N.f , Chamberlain, M.C.g , DeAngelis, L.M.h , Fenstermaker, R.A.i , Friedman, A.j , Gilbert, M.R.e , Hattangadi-Gluth, J.k , Hesser, D.l , Holdhoff, M.d , Junck, L.m , Lawson, R.n , Loeffler, J.S.o , Moots, P.L.p , Mrugala, M.M.g , Newton, H.B.c , Raizer, J.J.q , Recht, L.r , Shonka, N.s , Shrieve, D.C.t , Sills, A.K., Jr.p , Swinnen, L.J.d , Tran, D.u , Tran, N.v , Vrionis, F.D.v , Wen, P.Y.w , McMillian, N.R.x , Ho, M.x
Central nervous system cancers, Version 2.2014: Featured updates to the NCCN guidelines
(2014) JNCCN Journal of the National Comprehensive Cancer Network, 12 (11), pp. 1517-1523. 


a University of Alabama at Birmingham Comprehensive Cancer Center, United States
b City of Hope Comprehensive Cancer Center, United States
c Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, United States
d Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, United States
e University of Texas MD Anderson Cancer Center, United States
f UCSF Helen Diller Family Comprehensive Cancer Center, United States
g University of Washington/Seattle Cancer Care Alliance, United States
h Memorial Sloan Kettering Cancer Center, United States
i Roswell Park Cancer Institute, United States
j Duke Cancer Institute, United States
k UC San Diego Moores Cancer Center, United States
l American Brain Tumor Association, United States
m University of Michigan Comprehensive Cancer Center, United States
n St. Jude Children's Research Hospital, University of Tennessee Health Science Center, United States
o Massachusetts General Hospital Cancer Center, United States
p Vanderbilt-Ingram Cancer Center, United States
q Robert H. Lurie Comprehensive Cancer Center of Northwestern University, United States
r Stanford Comprehensive Cancer Center, United States
s Fred and Pamela Buffett Cancer Center, Nebraska Medical Center, United States
t Huntsman Cancer Institute at the University of Utah, United States
u Siteman Cancer Center at Barnes-Jewish Hospital, Washington University School of Medicine, United States
v Moffitt Cancer Center, United States
w Dana-Farber/Brigham and Women's Cancer Center, United States
x National Comprehensive Cancer Network, United States


Abstract
The NCCN Guidelines for Central Nervous System Cancers provide multidisciplinary recommendations for the clinical management of patients with cancers of the central nervous system. These NCCN Guidelines Insights highlight recent updates regarding the management of metastatic brain tumors using radiation therapy. Use of stereotactic radiosurgery (SRS) is no longer limited to patients with 3 or fewer lesions, because data suggest that total disease burden, rather than number of lesions, is predictive of survival benefits associated with the technique. SRS is increasingly becoming an integral part of management of patients with controlled, low-volume brain metastases.


Document Type: Article
Source: Scopus

Milchenko, M.V.a , Rajderkar, D.a , LaMontagne, P.a , Massoumzadeh, P.a , Bogdasarian, R.a , Schweitzer, G.a , Benzinger, T.a , Marcus, D.a , Shimony, J.S.a , Fouke, S.J.b
Comparison of perfusion- and diffusion-weighted imaging parameters in brain tumor studies processed using different software platforms
(2014) Academic Radiology, 21 (10), pp. 1294-1303. 


a Department of Radiology, Washington University School of MedicineSt. Louis, MO, United States
b Department of Neurological Surgery, Swedish Medical CenterSeattle, WA, United States


Abstract
Rationale and Objectives: To compare quantitative imaging parameter measures from diffusion- and perfusion-weighted imaging magnetic resonance imaging (MRI) sequences in subjects with brain tumors that have been processed with different software platforms. Materials and Methods: Scans from 20 subjects with primary brain tumors were selected from the Comprehensive Neuro-oncology Data Repository at Washington University School of Medicine (WUSM) and the Swedish Neuroscience Institute. MR images were coregistered, and each subject's data set was processed by three software packages: 1) vendor-specific scanner software, 2) research software developed at WUSM, and 3) a commercially available, Food and Drug Administration-approved, processing platform (Nordic Ice). Regions of interest (ROIs) were chosen within the brain tumor and normal nontumor tissue. The results obtained using these methods were compared. Results: For diffusion parameters, including mean diffusivity and fractional anisotropy, concordance was high when comparing different processing methods. For perfusion-imaging parameters, a significant variance in cerebral blood volume, cerebral blood flow, and mean transit time (MTT) values was seen when comparing the same raw data processed using different software platforms. Correlation was better with larger ROIs (radii≥5mm). Greatest variance was observed in MTT. Conclusions: Diffusion parameter values were consistent across different software processing platforms. Perfusion parameter values were more variable and were influenced by the software used. Variation in the MTT was especially large suggesting that MTT estimation may be unreliable in tumor tissues using current MRI perfusion methods.


Author Keywords
Cerebral diffusion;  Cerebral perfusion;  MRI;  Tumor imaging


Document Type: Article
Source: Scopus

Milner, E.a , Holtzman, J.C.b , Friess, S.c , Hartman, R.E.d , Brody, D.L.e , Han, B.H.f , Zipfel, G.J.g
Endovascular perforation subarachnoid hemorrhage fails to cause Morris water maze deficits in the mouse.
(2014) Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 34 (9), . 


a 1] Department of Neurological Surgery, Washington University School of Medicine, St Louis, Missouri, USA [2] Program in Neuroscience, Washington University School of Medicine, St Louis, Missouri, USA.
b Department of Neurological Surgery, Washington University School of Medicine, St Louis, Missouri, USA.
c Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA.
d Department of Psychology, Loma Linda University, Loma Linda, California, USA.
e 1] Department of Neurology, Washington University School of Medicine, St Louis, Missouri, USA [2] Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri, USA.
f 1] Department of Neurological Surgery, Washington University School of Medicine, St Louis, Missouri, USA [2] Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri, USA.
g 1] Department of Neurological Surgery, Washington University School of Medicine, St Louis, Missouri, USA [2] Department of Neurology, Washington University School of Medicine, St Louis, Missouri, USA [3] Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri, USA.


Abstract
Cognitive dysfunction is the primary driver of poor long-term outcome in aneurysmal subarachnoid hemorrhage (SAH) survivors; modeling such deficits preclinically is thus key for mechanistic and translational investigation. Although rat SAH causes long-term deficits in learning and memory, it remains unknown whether similar deficits are seen in the mouse, a species particularly amenable to powerful, targeted genetic manipulation. We thus subjected mice to endovascular perforation SAH and assessed long-term cognitive outcome via the Morris water maze (MWM), the most commonly used metric for rodent neurocognition. No significant differences in MWM performance (by either of two protocols) were seen in SAH versus sham mice. Moreover, SAH caused negligible hippocampal CA1 injury. These results undercut the potential of commonly used methods (of SAH induction and assessment of long-term neurocognitive outcome) for use in targeted molecular studies of SAH-induced cognitive deficits in the mouse.


Document Type: Article
Source: Scopus

Li, Y.a , Sands, M.S.a b
Experimental therapies in the murine model of globoid cell leukodystrophy
(2014) Pediatric Neurology, 51 (5), pp. 600-606. Cited 1 time.


a Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid AvenueSt. Louis, MO, United States
b Department of Genetics, Washington University School of MedicineSt. Louis, MO, United States


Abstract
Background Globoid cell leukodystrophy or Krabbe disease, is a rapidly progressive childhood lysosomal storage disorder caused by a deficiency in galactocerebrosidase. Galactocerebrosidase deficiency leads to the accumulation of galactosylsphingosine (psychosine), a cytotoxic lipid especially damaging to oligodendrocytes and Schwann cells. The progressive loss of cells involved in myelination results in a dysmyelinating phenotype affecting both the central and peripheral nervous systems. Current treatment for globoid cell leukodystrophy is limited to bone marrow or umbilical cord blood transplantation. However, these therapies are not curative and simply slow the progression of the disease. The Twitcher mouse is a naturally occurring biochemically faithful model of human globoid cell leukodystrophy that has been used extensively to study globoid cell leukodystrophy pathophysiology and experimental treatments. In this review, we present the major single and combination experimental therapies targeting specific aspects of murine globoid cell leukodystrophy.

Methods Literature review and analysis.

Results The evidence suggests that even with the best available therapies, targeting a single pathogenic mechanism provides minimal clinical benefit. More recently, combination therapies have demonstrated the potential to further advance globoid cell leukodystrophy treatment by synergistically increasing life span. However, such therapies must be designed and evaluated carefully because not all combination therapies yield such positive results.

Conclusions A more complete understanding of the underlying pathophysiology and the interplay between various therapies holds the key to the discovery of more effective treatments for globoid cell leukodystrophy.


Author Keywords
bone marrow transplantation;  galactocerebrosidase;  gene therapy;  globoid cell leukodystrophy;  Krabbe disease;  lysosomal storage disease


Document Type: Review
Source: Scopus

Kapellusch, J.M.a , Gerr, F.E.b , Malloy, E.J.c , Garg, A.a , Harris-Adamson, C.d e , Bao, S.S.f , Burt, S.E.g , Dale, A.M.h , Eisen, E.A.e , Evanoff, B.A.h , Hegmann, K.T.i , Silverstein, B.A.f , Theise, M.S.i , Rempel, D.M.j
Exposure-response relationships for the ACGIH threshold limit value for handactivity level: Results from a pooled data study of carpal tunnel syndrome
(2014) Scandinavian Journal of Work, Environment and Health, 40 (6), pp. 610-620. 


a Department of Occupational Science and Technology, University of WisconsinMilwaukee, WI, United States
b Department of Occupational and Environmental Health, College of Public Health, University of IowaIowa City, IA, United States
c Department of Mathematics and Statistics, American UniversityWashington, DC, United States
d Department of Physical Therapy, Samual Merritt UniversityOakland, CA, United States
e Department of Environmental Health Sciences, University of California BerkeleyBerkeley, United States
f Washington State Department of Labor and IndustriesOlympia, WA, United States
g National Institute for Occupational Safety and Health (NIOSH)Cincinnati, OH, United States
h Washington University School of MedicineSt. Louis, MO, United States
i Rocky Mountain Center for Occupational and Environmental Health (RMCOEH), University of UtahSalt Lake City, UT, United States
j Division of Occupational and Environmental Medicine, University of California, San FranciscoRichmond, CA, United States


Abstract
Objective This paper aimed to quantify exposure-response relationships between the American Conference of Governmental Industrial Hygienists’ (ACGIH) threshold limit value (TLV) for hand-activity level (HAL) and incidence of carpal tunnel syndrome (CTS). Methods Manufacturing and service workers previously studied by six research institutions had their data combined and re-analyzed. CTS cases were defined by symptoms and abnormal nerve conduction. Hazard ratios (HR) were calculated using proportional hazards regression after adjusting for age, gender, body mass index, and CTS predisposing conditions. Results The longitudinal study comprised 2751 incident-eligible workers, followed prospectively for up to 6.4 years and contributing 6243 person-years of data. Associations were found between CTS and TLV for HAL both as a continuous variable [HR 1.32 per unit, 95% confidence interval (95% CI) 1.11-1.57] and when categorized using the ACGIH action limit (AL) and TLV. Those between the AL and TLV and above the TLV had HR of 1.7 (95% CI 1.2-2.5) and 1.5 (95% CI 1.0-2.1), respectively. As independent variables (in the same adjusted model) the HR for peak force (PF) and HAL were 1.14 per unit (95% CI 1.05-1.25), and 1.04 per unit (95% CI 0.93-1.15), respectively. Conclusion Those with exposures above the AL were at increased risk of CTS, but there was no further increase in risk for workers above the TLV. This suggests that the current AL may not be sufficiently protective of workers. Combinations of PF and HAL are useful for predicting risk of CTS.


Author Keywords
American Conference of Governmental Industrial Hygienists;  Biomechanical overload;  CTS;  Epidemiology;  HAL;  Hand force;  MSD;  Musculoskeletal disorder;  Peak force;  Physical exposure;  Repetition;  Threshold limit value;  Upper extremity


Document Type: Article
Source: Scopus

Meuser, T.M.a , Carr, D.B.b , Unger, E.A.c , Ulfarsson, G.F.c
Family reports of medically impaired drivers in Missouri: Cognitive concerns and licensing outcomes
(2014) Accident Analysis and Prevention, 74, pp. 17-23. 


a University of Missouri - St. Louis, Gerontology Program, School of Social Work, 133-134 Bellerive Hall, 1 University Blvd.St. Louis, MO, United States
b Washington University School of Medicine, Department of Medicine and Neurology, 4488 Forest Park Blvd.St. Louis, MO, United States
c University of Iceland, Civil and Environmental Engineering, Hjardarhagi 2-6Reykjavik, Iceland


Abstract
This study investigated reasons why older adults (n = 689) were reported to the Driver License Bureau, Missouri Department of Revenue, by family members as potentially unfit to drive with an emphasis on cognitive concerns and associated licensing outcomes. A total of 448 drivers were reported to have some cognitive issue; common symptoms included confusion, memory loss, and becoming lost while driving. Diagnostic labels (Alzheimer's disease (AD), cognitive impairment/dementia, brain injury/insult) were listed for 365 cases. A physician evaluation is required for license review. Of those with a diagnostic label, half (51%, n = 187) failed to submit this evaluation and almost all were de-licensed immediately. Of those evaluated by a physician, diagnostic agreement between family members and physicians was high for specific conditions (100% for AD, 97% for acute brain injury), and less so for cognitive impairment/dementia (75%). This latter finding suggests that physicians and family members may understand cognitive symptoms differently. Whether cognitively impaired or not, few family reported drivers in this sample (
2%) retained a valid license. Family members may be in the best position to recognize when medical-functional deficits impact on driving safety, and physicians and driver licensing authorities would do well to take their observations into account with respect to older driver fitness.


Author Keywords
Aging;  Alzheimer's disease;  Dementia;  Family input;  Fitness-to-drive;  Medical impairments;  Older drivers


Document Type: Article
Source: Scopus

Victor, M.B.a b , Richner, M.a , Hermanstyne, T.O.a c , Ransdell, J.L.a c , Sobieski, C.b d , Deng, P.-Y.e , Klyachko, V.A.e , Nerbonne, J.M.a c , Yoo, A.S.a
Generation of Human Striatal Neurons by MicroRNA-Dependent Direct Conversion of Fibroblasts
(2014) Neuron, 84 (2), pp. 311-323. 


a Department of Developmental Biology, Washington University School of MedicineSaint Louis, MO, United States
b Washington University School of Medicine, Saint LouisMO, United States
c Center for Cardiovascular Research, Washington University School of MedicineSaint Louis, MO, United States
d Department of Psychiatry, Washington University School of MedicineSaint Louis, MO, United States
e Departments of Biomedical Engineering and Cell Biology and Physiology, CIMED, Washington UniversitySaint Louis, MO, United States


Abstract
The promise of using reprogrammed human neurons for disease modeling and regenerative medicine relies on the ability to induce patient-derived neurons with high efficiency and subtype specificity. We have previously shown that ectopic expression of brain-enriched microRNAs (miRNAs), miR-9/9* and miR-124 (miR-9/9*-124), promoted direct conversion of human fibroblasts into neurons. Here we show that coexpression of miR-9/9*-124 with transcription factors enriched in the developing striatum, BCL11B (also known as CTIP2), DLX1, DLX2, and MYT1L, can guide the conversion of human postnatal and adult fibroblasts into an enriched population of neurons analogous to striatal medium spiny neurons (MSNs). When transplanted in the mouse brain, the reprogrammed human cells persisted insitu for over 6months, exhibited membrane properties equivalent to native MSNs, and extended projections to the anatomical targets of MSNs. These findings highlight the potential of exploiting the synergism between miR-9/9*-124 and transcription factors to generate specific neuronal subtypes.


Document Type: Article
Source: Scopus

Power, R.A.a b , Verweij, K.J.H.c , Zuhair, M.a , Montgomery, G.W.d , Henders, A.K.d , Heath, A.C.e , Madden, P.A.F.e , Medland, S.E.d , Wray, N.R.b , Martin, N.G.d
Genetic predisposition to schizophrenia associated with increased use of cannabis
(2014) Molecular Psychiatry, 19 (11), pp. 1201-1204. 


a Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, DeCrespigny ParkLondon, United Kingdom
b Queensland Brain Institute, University of QueenslandSt Lucia, QLD, Australia
c Department of Developmental Psychology, EMGO Institute for Health and Care Research, VU UniversityAmsterdam, Netherlands
d QIMR Berghofer Medical Research InstituteBrisbane, QLD, Australia
e Department of Psychiatry, Washington University School of MedicineSt Louis, MO, United States


Abstract
Cannabis is the most commonly used illicit drug worldwide. With debate surrounding the legalization and control of use, investigating its health risks has become a pressing area of research. One established association is that between cannabis use and schizophrenia, a debilitating psychiatric disorder affecting
1% of the population over their lifetime. Although considerable evidence implicates cannabis use as a component cause of schizophrenia, it remains unclear whether this is entirely due to cannabis directly raising risk of psychosis, or whether the same genes that increases psychosis risk may also increase risk of cannabis use. In a sample of 2082 healthy individuals, we show an association between an individual's burden of schizophrenia risk alleles and use of cannabis. This was significant both for comparing those who have ever versus never used cannabis (P=2.6 × 10 - 4), and for quantity of use within users (P=3.0 × 10 -3). Although directly predicting only a small amount of the variance in cannabis use, these findings suggest that part of the association between schizophrenia and cannabis is due to a shared genetic aetiology. This form of gene-environment correlation is an important consideration when calculating the impact of environmental risk factors, including cannabis use.


Document Type: Article
Source: Scopus

Kauwe, J.S.K.a , Bailey, M.H.a , Ridge, P.G.a , Perry, R.a , Wadsworth, M.E.a , Hoyt, K.L.a , Staley, L.A.a , Karch, C.M.b c , Harari, O.b , Cruchaga, C.b c , Ainscough, B.J.d , Bales, K.e , Pickering, E.H.e , Bertelsen, S.b , Fagan, A.M.c f g , Holtzman, D.M.c f g h , Morris, J.C.c f g i , Goate, A.M.b c f g j
Genome-Wide Association Study of CSF Levels of 59 Alzheimer's Disease Candidate Proteins: Significant Associations with Proteins Involved in Amyloid Processing and Inflammation
(2014) PLoS Genetics, 10 (10), 16 p. 


a Department of Biology, Brigham Young UniversityProvo, UT, United States
b Department of Psychiatry, Washington University School of MedicineSt Louis, MO, United States
c Hope Center for Neurological Disorders, Washington University School of MedicineSt Louis, MO, United States
d The Genome Institute, Washington University School of MedicineSt Louis, MO, United States
e Neuroscience Research Unit, Worldwide Research and Development, Pfizer IncGroton, CT, United States
f Knight Alzheimer's Disease Research Center, Washington University School of MedicineSt Louis, MO, United States
g Department of Neurology, Washington University School of MedicineSt Louis, MO, United States
h Department of Developmental Biology, Washington University School of MedicineSt Louis, MO, United States
i Department of Pathology and Immunology, Washington University School of MedicineSt Louis, MO, United States
j Department of Genetics, Washington University School of MedicineSt Louis, MO, United States


Abstract
Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Aβ42) and tau levels are strongly correlated with the presence of Alzheimer's disease (AD) neuropathology including amyloid plaques and neurodegeneration and have been successfully used as endophenotypes for genetic studies of AD. Additional CSF analytes may also serve as useful endophenotypes that capture other aspects of AD pathophysiology. Here we have conducted a genome-wide association study of CSF levels of 59 AD-related analytes. All analytes were measured using the Rules Based Medicine Human DiscoveryMAP Panel, which includes analytes relevant to several disease-related processes. Data from two independently collected and measured datasets, the Knight Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), were analyzed separately, and combined results were obtained using meta-analysis. We identified genetic associations with CSF levels of 5 proteins (Angiotensin-converting enzyme (ACE), Chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 4 (CCL4), Interleukin 6 receptor (IL6R) and Matrix metalloproteinase-3 (MMP3)) with study-wide significant p-values (p&lt;1.46×10−10) and significant, consistent evidence for association in both the Knight ADRC and the ADNI samples. These proteins are involved in amyloid processing and pro-inflammatory signaling. SNPs associated with ACE, IL6R and MMP3 protein levels are located within the coding regions of the corresponding structural gene. The SNPs associated with CSF levels of CCL4 and CCL2 are located in known chemokine binding proteins. The genetic associations reported here are novel and suggest mechanisms for genetic control of CSF and plasma levels of these disease-related proteins. Significant SNPs in ACE and MMP3 also showed association with AD risk. Our findings suggest that these proteins/pathways may be valuable therapeutic targets for AD. Robust associations in cognitively normal individuals suggest that these SNPs also influence regulation of these proteins more generally and may therefore be relevant to other diseases.


Document Type: Article
Source: Scopus

Raghavan, R.
Improving the identification of mental health need on college campuses
(2014) Journal of Adolescent Health, 55 (5), pp. 598-599. 


Brown School and Department of Psychiatry, School of Medicine, Washington University in St. LouisSt. Louis, MI, United States


Document Type: Editorial
Source: Scopus

Martinez-Espinosa, P.L., Yang, C., Gonzalez-Perez, V., Xia, X.-M., Lingle, C.J.
Knockout of the BK β2 subunit abolishes inactivation of BK currents in mouse adrenal chromaffin cells and results in slow-wave burst activity
(2014) Journal of General Physiology, 144 (4), pp. 275-295. Cited 1 time.


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


Abstract
Rat and mouse adrenal medullary chromaffin cells (CCs) express an inactivating BK current. This inactivation is thought to arise from the assembly of up to four β2 auxiliary subunits (encoded by the kcnmb2 gene) with a tetramer of pore-forming Slo1 α subunits. Although the physiological consequences of inactivation remain unclear, differences in depolarization-evoked firing among CCs have been proposed to arise from the ability of β2 subunits to shift the range of BK channel activation. To investigate the role of BK channels containing β2 subunits, we generated mice in which the gene encoding β2 was deleted (β2 knockout [KO]). Comparison of proteins from wildtype (WT) and β2 KO mice allowed unambiguous demonstration of the presence of β2 subunit in various tissues and its coassembly with the Slo1 α subunit. We compared current properties and cell firing properties of WT and β2 KO CCs in slices and found that β2 KO abolished inactivation, slowed action potential (AP) repolarization, and, during constant current injection, decreased AP firing. These results support the idea that the β2-mediated shift of the BK channel activation range affects repetitive firing and AP properties. Unexpectedly, CCs from β2 KO mice show an increased tendency toward spontaneous burst firing, suggesting that the particular properties of BK channels in the absence of β2 subunits may predispose to burst firing.


Document Type: Article
Source: Scopus

Sands, M.S.
Mucopolysaccharidosis type VII: A powerful experimental system and therapeutic challenge
(2014) Pediatric Endocrinology Reviews, 12, pp. 159-165. 


Departments of Internal Mediane and Genetics, Washington University, School of Medicine, Campus, Box 8007, 660 South Euclid AvenueSt. Louis, MO, United States


Abstract
Mucopolysaccharidosis type VII (MPSVII) is an inborn error of metabolism caused by a deficiency in the lysosomal enzyme B-glucuronidase (GUSB). As such, MPSVII is one of a larger class of inherited diseases referred to as lysosomal storage diseases (LSD). (1) The absence of GUSB activity leads to the progressive accumulation of undegraded glycosaminoglycans (GAGs) in many tissues of the body. Mucopolysaccharidosis VII has a complex clinical phenotype, including skeletal dysplasia, hepatosplenomegally, sensory deficits, cognitive impairment, and premature death. Although the natural history of the human disease is not precisely defined, small and large animal models of MPSVII have played a major role in our understanding of the disease process and towards effective treatments. The mouse model of MPSVII is a particularly powerful system due to its similarity to the human disease and the ability to generate large numbers of genetically defined animals. It has been shown in the murine model of MPSVII that recombinant enzyme replacement therapy (ERT) can ameliorate most of the clinical signs of disease if initiated during the neonatal period. Progenitor cell transplantation (hematopoietic, neuronal, mesenchymal) can correct many of the pathological signs of disease in MPSVII mice. Viral-mediated gene therapy has also been shown to decrease the severity of the disease in both the murine and canine models of MPSVII. Although pre-clinical experiments have shown that a number of approaches can effectively treat MPSVII, translation of those therapies into the clinic has lagged behind other LSDs. This is due in large part to the ultra-rare nature of MPSVII. Encouragingly, a clinical trial of ERT for MPSVII has recently been initiated. It will be interesting to determine if the positive pre-clinical data gathered in animal models of MPSVII translate to affected children. This clinical trial may also establish a paradigm for the i treatment of other ultra-rare disorders.


Author Keywords
Animal models;  Enzyme replacement therapy;  Gene therapy;  Inherited metabolic disease;  Lysosomal storage disease;  Mucopolysaccharidosis VII;  Stem cell therapy


Document Type: Article
Source: Scopus

Kelly, M.P.a , Wall, L.B.a , Stoker, G.E.b , Daniel Riew, K.a
Myeloradiculopathy: C8 and T1 radiculopathy
(2014) Seminars in Spine Surgery, 26 (2), pp. 100-105. 


a Department of Orthopedic Surgery, Washington University School of Medicine, IOH 5th Floor, 660 South Euclid Ave, Box 8233Saint Louis, MO, United States
b Washington University School of MedicineSaint Louis, MO, United States


Abstract
Due to rarity and overlap in sensory and motor contributions, diagnosis of C8 and T1 radiculopathies may be difficult. This may also be due, in part, to an incomplete knowledge and understanding of the brachial plexus and peripheral nerve anatomy. The C8 and T1 nerves provide sensory innervation proximal to the wrist, which is important when distinguishing between these radiculopathies and an ulnar compressive lesion. Understanding plexus anatomy will allow surgeons to distinguish between C8 and T1 radiculopathies, with particular attention to other pathologies that present with similar complaints.


Document Type: Article
Source: Scopus

Musiek, E.
Neuroprotective drug gives a nod to NAD
(2014) Science Translational Medicine, 6 (256), art. no. 256ec169, . 


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


Document Type: Note
Source: Scopus

Aleem, A.W., Krogue, J.D., Calfee, R.P.
Outcomes of revision surgery for cubital tunnel syndrome
(2014) Journal of Hand Surgery, 39 (11), pp. 2141-2149. 


Department of Orthopaedic Surgery, Washington University School of Medicine, 660 S. Euclid Ave.St. Louis, MO, United States


Abstract
Purpose To compare both validated patient-rated and objective outcomes of patients following revision cubital tunnel surgery to a similar group of patients who underwent primary surgery.

Methods This case-control investigation enrolled 56 patients treated surgically for cubital tunnel syndrome (28 revision cases, 28 primary controls) at a tertiary center. Patients with a minimum of 2 years of follow-up were eligible. All patients completed an in-office study evaluation. Revision participants represented 55% of potential patients in our practice and controls (treated only with primary surgery) were chosen at random from our practice to reach a 1:1 case to control ratio. Preoperative McGowan grading was confirmed similar between the groups. Outcome measures included validated patient outcome questionnaires (Patient-Rated Elbow Evaluation, Levine-Katz questionnaire), symptoms, and physical examination findings. Statistical analyses were conducted to compare the patient groups.

Results Despite 79% of revision patients reporting symptomatic improvement, revision patients reported worse outcomes on all measured standardized questionnaires compared with primary patients. The Levine-Katz questionnaire indicated mild residual symptoms in the primary group (1.6) versus moderate remaining symptoms following revision surgery (2.3). The Patient-Rated Elbow Evaluation also indicated superior results for the control group (9 ± 10) compared with the revision group (32 ± 22). Revision patients had a higher frequency of constant symptoms, elevated 2-point discrimination, and diminished pinch strength. McGowan grading improved after 25% of revision surgeries versus 64% of primary surgeries, and 21% of revision patients had deterioration of their McGowan grade.

Conclusions Subjective and objective outcomes of revision patients in this cohort were inferior to outcomes of similar patients following primary surgery. Revision surgery can be offered in the setting of persistent or recurrent symptoms that are unexplained by an alternative diagnosis, but patients should be counseled that complete resolution of symptoms is unlikely. Type of study/level of evidence Therapeutic III.


Author Keywords
Cubital tunnel syndrome;  outcomes;  prognosis;  revision


Document Type: Article
Source: Scopus

Matthieu, M.M., PhDa b , Gardiner, G.c , Ziegemeier, E.c , Buxton, M.c , Han, L.c , Cross, W.d e
Personal and Professional Knowledge of and Experience With Suicide and Suicide Prevention Among Stakeholders in Clinical and Community Practice
(2014) Social Work in Mental Health, 12, pp. 443-456. 


a Department of Veterans Affairs, St. Louis Healthcare System, Mental Health ServiceSaint Louis, MO, United States
b Saint Louis University, College for Public Health and Social Justice, School of Social WorkSaint Louis, MO, United States
c George Warren Brown School of Social Work and Public Health, Washington University in St. LouisSt. Louis, MO, United States
d University of Rochester Medical CenterRochester, NY, United States
e Center of Excellence at Canandaigua, Canandaigua VA Medical CenterCanandaigua, NY, United States


Abstract
Community-dwelling veterans at risk for suicide may be in contact with a variety of providers in agency-based settings that offer health and human services. The study aim is to describe the perspective of agency-based clinical and community providers who may come into contact with veterans in need of suicide prevention services and to examine the nature of their personal and professional relationships to individuals at risk for suicide among this sample.

This study reports on qualitative data from a sample of Veterans’ Affairs (VA) and community providers serving veterans and military families in one Midwestern state (N = 70). Providers completed a survey assessing exposure to suicide, including contact with and relationship to someone suicidal, and organizational characteristics of the providers’ employing agencies. Semi-structured interview questions probed for the nature of how they would react with suicidal individuals. Most providers (94%) had some prior contact with someone who was suicidal, and nearly three quarters (77%) knew someone who had died by suicide. Providers reported powerful emotional responses of sadness and remorse to suicidal experiences. While these providers interact with veterans and military families as part of their jobs, they may have their own history of being exposed to suicide, both professionally and personally.


Author Keywords
health personnel;  health service;  prevention;  qualitative research;  suicide;  United States Department of Veterans Affairs;  veterans


Document Type: Article
Source: Scopus

Pence, M.A., Burnham, C.-A.D.
Photo quiz: A 58-year-old female with altered mental status
(2014) Journal of Clinical Microbiology, 52 (11), p. 3835. 


Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of MedicineSt. Louis, MO, United States


Document Type: Article
Source: Scopus

Garsa, A.A.a , Badiyan, S.N.b , Dewees, T.b , Simpson, J.R.b , Huang, J.b , Drzymala, R.E.b , Barani, I.J.a , Dowling, J.L.c , Rich, K.M.c , Chicoine, M.R.c , Kim, A.H.c , Leuthardt, E.C.c , Robinson, C.G.b
Predictors of individual tumor local control after stereotactic radiosurgery for non-small cell lung cancer brain metastases
(2014) International Journal of Radiation Oncology Biology Physics, 90 (2), pp. 407-413. 


a Department of Radiation Oncology, University of California, San FranciscoSan Francisco, CA, United States
b Department of Radiation Oncology, Washington University, School of Medicine, 4921 Parkview Place- LLSt. Louis, MO, United States
c Department of Neurosurgery, Washington University, School of MedicineSt. Louis, MO, United States


Abstract
Purpose: To evaluate local control rates and predictors of individual tumor local control for brain metastases from non-small cell lung cancer (NSCLC) treated with stereotactic radiosurgery (SRS).

Methods and Materials: Between June 1998 and May 2011, 401 brain metastases in 228 patients were treated with Gamma Knife single-fraction SRS. Local failure was defined as an increase in lesion size after SRS. Local control was estimated using the Kaplan-Meier method. The Cox proportional hazards model was used for univariate and multivariate analysis. Receiver operating characteristic analysis was used to identify an optimal cutpoint for conformality index relative to local control. A P value <.05 was considered statistically significant.

Results: Median age was 60 years (range, 27-84 years). There were 66 cerebellar metastases (16%) and 335 supratentorial metastases (84%). The median prescription dose was 20 Gy (range, 14-24 Gy). Median overall survival from time of SRS was 12.1 months. The estimated local control at 12 months was 74%. On multivariate analysis, cerebellar location (hazard ratio [HR] 1.94, P=.009), larger tumor volume (HR 1.09, P<.001), and lower conformality (HR 0.700, P=.044) were significant independent predictors of local failure. Conformality index cutpoints of 1.4-1.9 were predictive of local control, whereas a cutpoint of 1.75 was the most predictive (P=.001). The adjusted Kaplan-Meier 1-year local control for conformality index ≥1.75 was 84% versus 69% for conformality index <1.75, controlling for tumor volume and location. The 1-year adjusted local control for cerebellar lesions was 60%, compared with 77% for supratentorial lesions, controlling for tumor volume and conformality index.

Conclusions: Cerebellar tumor location, lower conformality index, and larger tumor volume were significant independent predictors of local failure after SRS for brain metastases from NSCLC. These results warrant further investigation in a prospective setting.


Document Type: Article
Source: Scopus

Wu, X.a , Eggebrecht, A.T.b , Ferradal, S.L.b c , Culver, J.P.b c , Dehghani, H.a
Quantitative evaluation of atlas-based highdensity diffuse optical tomography for imaging of the human visual cortex
(2014) Biomedical Optics Express, 5 (11), pp. 3882-3900. 


a School of Computer Science, University of BirminghamBirmingham, United Kingdom
b Department of Radiology, Washington University School of Medicine, 4525 Scott AvenueSt Louis, MO, United States
c Department of Biomedical Engineering, Washington University, One Brookings DriveSt. Louis, MO, United States


Abstract
Image recovery in diffuse optical tomography (DOT) of the human brain often relies on accurate models of light propagation within the head. In the absence of subject specific models for image reconstruction, the use of atlas based models are showing strong promise. Although there exists some understanding in the use of some limited rigid model registrations in DOT, there has been a lack of a detailed analysis between errors in geometrical accuracy, light propagation in tissue and subsequent errors in dynamic imaging of recovered focal activations in the brain. In this work 11 different rigid registration algorithms, across 24 simulated subjects, are evaluated for DOT studies in the visual cortex. Although there exists a strong correlation (R2 = 0.97) between geometrical surface error and internal light propagation errors, the overall variation is minimal when analysing recovered focal activations in the visual cortex. While a subject specific mesh gives the best results with a 1.2 mm average location error, no single algorithm provides errors greater than 4.5 mm. This work demonstrates that the use of rigid algorithms for atlas based imaging is a promising route when subject specific models are not available.


Document Type: Article
Source: Scopus

Kim, A.H.a , Thompson, E.A.a , Governale, L.S.b , Santa, C.c , Cahill, K.c , Kieran, M.W.e , Chi, S.N.e , Ullrich, N.J.d e e , Scott, R.M.c e e , Goumnerova, L.C.c e e
Recurrence after gross-total resection of low-grade pediatric brain tumors: The frequency and timing of postoperative imaging
(2014) Journal of Neurosurgery: Pediatrics, 14 (4), pp. 356-364. 


a Department of Neurosurgery, Washington UniversitySt. Louis, MI, United States
b Department of Neurosurgery, Ohio State UniversityColumbus, OH, United States
c Department of Neurosurgery, Boston Children's Hospital, 300 Longwood Ave.Boston, MA, United States
d Department of Neurology, Boston Children's HospitalBoston, MA, United States
e Pediatric Neuro-Oncology Center, Dana-Farber Cancer InstituteBoston, MA, United States


Abstract
Object. Low-grade glial and glioneuronal brain tumors are frequently encountered in the pediatric population and can be effectively treated by resection. The authors aimed to use imaging to evaluate how often tumors recurred and to determine if recurrences were associated with any clinical symptoms, along with the financial costs of imaging, in patients with radiographically proven gross-total resection (GTR) at Boston Children's Hospital. These data were assessed to propose guidelines regarding postoperative surveillance.

Methods. The authors performed a retrospective cohort analysis of the Pediatric Brain Tumor Program database from 1993 to 2003 to identify patients with glial or glioneuronal tumors initially evaluated at Boston Children's Hospital. Among the 888 patients evaluated for any type of brain tumor during this period, 67 patients had WHO Grade I glial or glioneuronal lesions with radiographically proven GTR and available follow-up data. The frequency and timing of postoperative imaging was compared with the institutional protocol. Recurrence-free survival was calculated using the Kaplan-Meier method. Financial costs of imaging were available from 2001 to 2009 and were averaged to extrapolate the postoperative surveillance costs.

Results. Among the 67 patients with GTR, 13 recurrences were detected radiographically with a mean time to recurrence of 32.4 months (range 2.9-128.5 months). The mean duration of follow-up after surgery was 6.6 years. The recurrence-free survival at 2 and 5 years after GTR for all low-grade glial and glioneuronal tumors was 0.90 (95% CI 0.82-0.97) and 0.82 (95% CI 0.73-0.92), respectively. No clinical symptoms were associated with any of the recurrences, and no deaths occurred. Under the institutional protocol of surveillance imaging, the estimated cost per recurrence at 5 years was $104,094 per patient. The proposed protocol would reduce the number of MR scans in the first 5 years from 10 to 5, providing a potential cost savings of $52,047 per recurrence.

Conclusions. Given the slow-growing, clinically asymptomatic nature of low-grade glial and glioneuronal tumors coupled with the financial and psychological costs of repeated imaging, the authors propose a postoperative surveillance MRI schedule that is less intensive than current institutional practice. © AANS, 2014.


Author Keywords
Glioma;  Magnetic resonance imaging;  Oncology;  Pediatric brain tumor;  Pilocytic astrocytoma;  Recurrence


Document Type: Article
Source: Scopus

Kamran, M.a , Hacker, C.D.b , Allen, M.G.c , Mitchell, T.J.c , Leuthardt, E.C.d , Snyder, A.Z.e , Shimony, J.S.a
Resting-state blood oxygen level-dependent functional magnetic resonance imaging for presurgical planning
(2014) Neuroimaging Clinics of North America, 24 (4), pp. 655-669. 


a Mallinckrodt Institute of Radiology, Washington University School of Medicine, 4525 Scott AvenueSt Louis, MO, United States
b Medical Student Training Program, Washington University School of Medicine, 4525 Scott AvenueSt Louis, MO, United States
c Department of Neurological Surgery, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 4525 Scott AvenueSt Louis, MO, United States
d Department of Neurological Surgery, Washington University School of Medicine, 4525 Scott AvenueSt Louis, MO, United States
e Department of Neurology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 4525 Scott AvenueSt Louis, MO, United States


Abstract
Resting-state functional MR imaging (rsfMR imaging) measures spontaneous fluctuations in the blood oxygen level-dependent (BOLD) signal and can be used to elucidate the brain's functional organization. It is used to simultaneously assess multiple distributed resting-state networks. Unlike task-based functional MR imaging, rsfMR imaging does not require task performance. This article presents a brief introduction of rsfMR imaging processing methods followed by a detailed discussion on the use of rsfMR imaging in presurgical planning. Example cases are provided to highlight the strengths and limitations of the technique.


Author Keywords
Eloquent cortex;  Functional MR imaging;  MLP;  Multilayered perceptron;  Resting-state functional MR imaging;  Resting-state networks;  RsfMR imaging;  RSNs


Document Type: Article
Source: Scopus

Hilbert, A.a , Pike, K.M.b , Goldschmidt, A.B.c , Wilfley, D.E.d , Fairburn, C.G.e , Dohm, F.-A.f , Walsh, B.T.b , Striegel Weissman, R.g
Risk factors across the eating disorders
(2014) Psychiatry Research, 220 (1-2), pp. 500-506. 


a Integrated Research and Treatment Center AdiposityDiseases, Department of Medical Psychology and Medical Sociology, University of Leipzig Medical Center, Philipp-Rosenthal-Strasse 27Leipzig, Germany
b Department of Psychiatry, Columbia UniversityNew York, NY, United States
c Department of Psychiatry and Behavioral Neuroscience, University of ChicagoChicago, IL, United States
d Department of Psychiatry, Washington University in St. LouisSt. Louis, MO, United States
e Department of Psychiatry, Oxford University, Warneford HospitalOxford, United Kingdom
f Graduate School of Education and oAllied Professions, Fairfield UniversityFairfield, CT, United States
g Department of Psychology, Wesleyan UniversityMiddletown, CT, United States


Abstract
This study sought to examine risk and onset patterns in anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). Women with AN (n=71), BN (n=66), BED (n=160) and non-psychiatric controls (n=323) were compared retrospectively on risk factors, symptom onset, and diagnostic migration. Eating disorder groups reported greater risk exposure than non-psychiatric controls. AN and BED differed on premorbid personality/behavioral problems, childhood obesity, and family overeating. Risk factors for BN were shared with AN and BED. Dieting was the most common onset symptom in AN, whereas binge eating was most common in BN and BED. Migration between AN and BED was rare, but more frequent between AN and BN and between BN and BED. AN and BED have distinct risk factors and onset patterns, while BN shares similar risk factors and onset patterns with both AN and BED. Results should inform future classification schemes and prevention programs.


Author Keywords
Anorexia nervosa;  Binge eating disorder;  Bulimia nervosa;  Eating disorders;  Risk factors


Document Type: Article
Source: Scopus

Stein, K.C., True, H.L.
Structural variants of yeast prions show conformer-specific requirements for chaperone activity
Molecular Microbiology, 93 (6), pp. 1156-1171. 


Department of Cell Biology and Physiology, Washington University School of MedicineSt. Louis, MO, United States


Abstract
Molecular chaperones monitor protein homeostasis and defend against the misfolding and aggregation of proteins that is associated with protein conformational disorders. In these diseases, a variety of different aggregate structures can form. These are called prion strains, or variants, in prion diseases, and cause variation in disease pathogenesis. Here, we use variants of the yeast prions [RNQ+] and [PSI+] to explore the interactions of chaperones with distinct aggregate structures. We found that prion variants show striking variation in their relationship with Hsp40s. Specifically, the yeast Hsp40 Sis1 and its human orthologue Hdj1 had differential capacities to process prion variants, suggesting that Hsp40 selectivity has likely changed through evolution. We further show that such selectivity involves different domains of Sis1, with some prion conformers having a greater dependence on particular Hsp40 domains. Moreover, [PSI+] variants were more sensitive to certain alterations in Hsp70 activity as compared to [RNQ+] variants. Collectively, our data indicate that distinct chaperone machinery is required, or has differential capacity, to process different aggregate structures. Elucidating the intricacies of chaperone-client interactions, and how these are altered by particular client structures, will be crucial to understanding how this system can go awry in disease and contribute to pathological variation.


Document Type: Article
Source: Scopus

Tupal, S.a , Rieger, M.A.b c , Ling, G..-Y.a , Park, T.J.d , Dougherty, J.D.b c , Goodchild, A.K.e , Gray, P.A.a
Testing the role of preBötzinger complex somatostatin neurons in respiratory and vocal behaviors
European Journal of Neuroscience, 40 (7), pp. 3067-3077. 


a Department of Anatomy and Neurobiology, Washington University School of MedicineSt. Louis, MO, United States
b Department of Genetics, Washington University School of MedicineSt. Louis, MO, United States
c Department of Psychiatry, Washington University School of MedicineSt. Louis, MO, United States
d Laboratory of Integrative Neuroscience and Department of Biological Sciences, University of Illinois at ChicagoChicago, IL, United States
e The Australian School of Advanced Medicine, Macquarie University SydneySydney, NSW, Australia


Abstract
Identifying neurons essential for the generation of breathing and related behaviors such as vocalisation is an important question for human health. The targeted loss of preBötzinger Complex (preBötC) glutamatergic neurons, including those that express high levels of somatostatin protein (SST neurons), eliminates normal breathing in adult rats. Whether preBötC SST neurons represent a functionally specialised population is unknown. We tested the effects on respiratory and vocal behaviors of eliminating SST neuron glutamate release by Cre-Lox-mediated genetic ablation of the vesicular glutamate transporter 2 (VGlut2). We found the targeted loss of VGlut2 in SST neurons had no effect on viability in vivo, or on respiratory period or responses to neurokinin 1 or μ-opioid receptor agonists in vitro. We then compared medullary SST peptide expression in mice with that of two species that share extreme respiratory environments but produce either high or low frequency vocalisations. In the Mexican free-tailed bat, SST peptide-expressing neurons extended beyond the preBötC to the caudal pole of the VII motor nucleus. In the naked mole-rat, however, SST-positive neurons were absent from the ventrolateral medulla. We then analysed isolation vocalisations from SST-Cre;VGlut2F/F mice and found a significant prolongation of the pauses between syllables during vocalisation but no change in vocalisation number. These data suggest that glutamate release from preBötC SST neurons is not essential for breathing but play a species- and behavior-dependent role in modulating respiratory networks. They further suggest that the neural network generating respiration is capable of extensive plasticity given sufficient time.


Author Keywords
Bat;  Naked mole-rat;  PreBötzinger complex;  Respiratory rhythm;  Vocalisation


Document Type: Article
Source: Scopus

Park, K.W.a b , Boyer, M.I.a b , Calfee, R.P.a b , Goldfarb, C.A.a b , Osei, D.A.a b
The efficacy of 95-Hz topical vibration in pain reduction for trigger finger injection: A placebo-controlled, prospective, randomized trial
(2014) Journal of Hand Surgery, 39 (11), pp. 2203-2207. 


a Department of Orthopedic Surgery, Washington University School of Medicine, 660 South Euclid AvenueSt. Louis, MO, United States
b Washington University, Institute of Clinical and Translational SciencesSt. Louis, MO, United States


Abstract
Methods A total of 90 trigger finger injections were randomized to 1 of 3 cohorts. With the injection, patients received no vibration (control group), ultrasound vibration (sham control group), or vibration (experimental group). We used a commercial handheld massaging device to provide a vibratory stimulus for the experimental group. We obtained visual analog scale (VAS) pain scores before and after injection to assess anticipated pain and actual pain experienced.

Results Anticipated pain and actual pain did not differ significantly among groups. Anticipated VAS pain scores were 45, 48, and 50 and actual VAS pain scores were 56, 56, and 63 for the vibration, control, and sham control groups, respectively. When normalized using anchoring VAS pain scores for "stubbing a toe" or "paper cut," no between-group differences remained in injection pain scores.

Conclusions Concomitant vibratory stimulation does not reduce pain experienced during corticosteroid injections for trigger finger. Type of study/level of evidence Therapeutic I.

Purpose To determine whether vibratory stimulation would decrease pain experienced by patients during corticosteroid injection for trigger finger.


Author Keywords
Injection;  pain;  steroid;  trigger finger;  vibration anesthesia


Document Type: Article
Source: Scopus

He, X.a , Zhang, L.b , Chen, Y.c , Remke, M.d , Shih, D.d , Lu, F.b , Wang, H.b , Deng, Y.b , Yu, Y.e , Xia, Y.f , Wu, X.d , Ramaswamy, V.d , Hu, T.g , Wang, F.h , Zhou, W.i , Burns, D.K.g , Kim, S.H.j , Kool, M.k , Pfister, S.M.k , Weinstein, L.S.l , Pomeroy, S.L.m , Gilbertson, R.J.n , Rubin, J.B.o , Hou, Y.h , Wechsler-Reya, R.p , Taylor, M.D.d , Lu, Q.R.q
The G protein α subunit Gαs is a tumor suppressor in Sonic hedgehog-driven medulloblastoma.
(2014) Nature medicine, 20 (9), pp. 1035-1042. 


a 1] Department of Forensic Medicine, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, School of Preclinical and Forensic Medicine, West China Second Hospital, Sichuan University, Chengdu, China. [2] Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
b Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
c School of Life Sciences, Xiamen University, Fujian, China.
d The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
e Department of Pediatrics, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Second Hospital, Sichuan University, Chengdu, China.
f Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China.
g Department of Pathology, University of Texas Southwestern Medical Center, Dallas, USA.
h Department of Forensic Medicine, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, School of Preclinical and Forensic Medicine, West China Second Hospital, Sichuan University, Chengdu, China.
i Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China.
j Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
k Division of Pediatric Neurooncology, German Cancer Research Center, Heidelberg, Germany.
l Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
m Department of Neurology, Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
n Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
o Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
p Tumor Development Program, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
q 1] Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. [2] Department of Pediatrics, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Second Hospital, Sichuan University, Chengdu, China. [3] Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China.


Abstract
Medulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving medulloblastoma initiation and progression remain poorly understood. Herein, we identify GNAS, encoding the G protein Gαs, as a potent tumor suppressor gene that, when expressed at low levels, defines a subset of aggressive Sonic hedgehog (SHH)-driven human medulloblastomas. Ablation of the single Gnas gene in anatomically distinct progenitors in mice is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. Gαs is highly enriched at the primary cilium of granule neuron precursors and suppresses Shh signaling by regulating both the cAMP-dependent pathway and ciliary trafficking of Hedgehog pathway components. Elevation in levels of a Gαs effector, cAMP, effectively inhibits tumor cell proliferation and progression in Gnas-ablated mice. Thus, our gain- and loss-of-function studies identify a previously unrecognized tumor suppressor function for Gαs that can be found consistently across Shh-group medulloblastomas of disparate cellular and anatomical origins, highlighting G protein modulation as a potential therapeutic avenue.


Document Type: Article
Source: Scopus

Malcolm, H.R.a b , Blount, P.b , Maurer, J.A.a
The mechanosensitive channel of small conductance (MscS) functions as a Jack-In-The Box
(2014) Biochimica et Biophysica Acta - Biomembranes, 1848 (1), pp. 159-166. 


a Department of Chemistry, Washington UniversitySt. Louis, MO, United States
b Department of Physiology, University of Texas Southwestern Medical CenterDallas, TX, United States


Abstract
Phenotypical analysis of the lipid interacting residues in the closed state of the mechanosensitive channel of small conductance (MscS) from Escherichia coli (E. coli) has previously shown that these residues are critical for channel function. In the closed state, mutation of individual hydrophobic lipid lining residues to alanine, thus reducing the hydrophobicity, resulted in phenotypic changes that were observable using in vivo assays. Here, in an analogous set of experiments, we identify eleven residues in the first transmembrane domain of the open state of MscS that interact with the lipid bilayer. Each of these residues was mutated to alanine and leucine to modulate their hydrophobic interaction with the lipid tail-groups in the open state. The effects of these changes on channel function were analyzed using in vivo bacterial assays and patch clamp electrophysiology. Mutant channels were found to be functionally indistinguishable from wildtype MscS. Thus, mutation of open-state lipid interacting residues does not differentially stabilize or destabilize the open, closed, intermediate, or transition states of MscS. Based on these results and other data from the literature, we propose a new gating paradigm for MscS where MscS acts as a "Jack-In-The-Box" with the intrinsic bilayer lateral pressure holding the channel in the closed state. In this model, upon application of extrinsic tension the channel springs into the open state due to relief of the intrinsic lipid bilayer pressure.


Author Keywords
Bacterial ion channel;  conductance (MscS);  Gating mechanism;  Jack-In-The-Box;  Lipid interaction;  Mechanosensitive channel of small


Document Type: Article
Source: Scopus

Zheng, Q.a , Ahlawat, S.b , Schaefer, A.a c , Mahoney, T.a d , Koushika, S.P.e , Nonet, M.L.a
The Vesicle Protein SAM-4 Regulates the Processivity of Synaptic Vesicle Transport
(2014) PLoS Genetics, 10 (10), 15 p. 


a Department of Anatomy and Neurobiology, Washington University Medical SchoolSt. Louis, MO, United States
b National Centre for Biological Sciences, Tata Institute of Fundamental ResearchBangalore, India
c Department of Neurology, Washington University Medical SchoolSt. Louis, MO, United States
d Huffington Center On Aging, Baylor College of MedicineHouston, TX, United States
e Department of Biological Sciences, Tata Institute of Fundamental ResearchColaba, Mumbai, India


Abstract
Axonal transport of synaptic vesicles (SVs) is a KIF1A/UNC-104 mediated process critical for synapse development and maintenance yet little is known of how SV transport is regulated. Using C. elegans as an in vivo model, we identified SAM-4 as a novel conserved vesicular component regulating SV transport. Processivity, but not velocity, of SV transport was reduced in sam-4 mutants. sam-4 displayed strong genetic interactions with mutations in the cargo binding but not the motor domain of unc-104. Gain-of-function mutations in the unc-104 motor domain, identified in this study, suppress the sam-4 defects by increasing processivity of the SV transport. Genetic analyses suggest that SAM-4, SYD-2/liprin-α and the KIF1A/UNC-104 motor function in the same pathway to regulate SV transport. Our data support a model in which the SV protein SAM-4 regulates the processivity of SV transport.


Document Type: Article
Source: Scopus

Perez-Torres, C.J.a , Engelbach, J.A.a , Cates, J.b , Thotala, D.b , Yuan, L.c , Schmidt, R.E.e , Rich, K.M.b c , Drzymala, R.E.b , Ackerman, J.J.H.a d f , Garbow, J.R.a
Toward distinguishing recurrent tumor from radiation necrosis: DWI and MTC in a gamma knife-irradiated mouse glioma model
(2014) International Journal of Radiation Oncology Biology Physics, 90 (2), pp. 446-453. 


a Department of Radiology, Biomedical MR Laboratory, Washington University School of Medicine, 4525 Scott AveSt. Louis, MO, United States
b Department of Radiation Oncology, Washington UniversitySt. Louis, MO, United States
c Department of Neurosurgery, Washington UniversitySt. Louis, MO, United States
d Department of Chemistry, Washington UniversitySt. Louis, MO, United States
e Department of Neuropathology, Washington UniversitySt. Louis, MO, United States
f Department of Internal Medicine, Washington UniversitySt. Louis, MO, United States


Abstract
Results: MTR was found to be consistently decreased in all lesions compared to nonlesion brain tissue (contralateral hemisphere), with limited specificity between lesion types. In contrast, ADC, though less sensitive to the presence of pathology, was increased in radiation injury and decreased in tumors. In the irradiated glioma model, ADC also increased immediately after irradiation, but decreased as the tumor regrew.

Conclusions: ADC is a better metric than MTR for differentiating glioma from radiation injury. However, MTR was more sensitive to both tumor and radiation injury than ADC, suggesting a possible role in detecting lesions that do not enhance strongly on T1-weighted images.

Purpose: Accurate noninvasive diagnosis is vital for effective treatment planning. Presently, standard anatomical magnetic resonance imaging (MRI) is incapable of differentiating recurring tumor from delayed radiation injury, as both lesions are hyperintense in both postcontrast T1- and T2-weighted images. Further studies are therefore necessary to identify an MRI paradigm that can differentially diagnose these pathologies. Mouse glioma and radiation injury models provide a powerful platform for this purpose.

Methods and Materials: Two MRI contrasts that are widely used in the clinic were chosen for application to a glioma/radiation-injury model: diffusion weighted imaging, from which the apparent diffusion coefficient (ADC) is obtained, and magnetization transfer contrast, from which the magnetization transfer ratio (MTR) is obtained. These metrics were evaluated longitudinally, first in each lesion type alone-glioma versus irradiation - and then in a combined irradiated glioma model.


Document Type: Article
Source: Scopus

Wein, N.a , Vulin, A.a , Falzarano, M.S.b , Szigyarto, C.A.c , Maiti, B.d , Findlay, A.e , Heller, K.N.e , Uhlén, M.c , Bakthavachalu, B.f , Messina, S.g , Vita, G.g , Passarelli, C.h , Gualandi, F.b , Wilton, S.D.i , Rodino-Klapac, L.R.j , Yang, L.k , Dunn, D.M.l , Schoenberg, D.R.f , Weiss, R.B.l , Howard, M.T.l , Ferlini, A.b , Flanigan, K.M.m
Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice.
(2014) Nature medicine, 20 (9), pp. 992-1000. 


a 1] The Center for Gene Therapy, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA. [2].
b Section of Microbiology and Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
c Department of Proteomics and Nanobiotechnology, School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Sweden.
d Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
e The Center for Gene Therapy, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
f 1] Center for RNA Biology, The Ohio State University, Columbus, Ohio, USA. [2] Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio, USA.
g Department of Neuroscience, University of Messina and Centro Clinico Nemo Sud, Messina, Italy.
h Bambino Gesù Children's Hospital, Rome, Italy.
i Centre for Comparative Genomics, Murdoch University, Perth, Western Australia, Australia.
j 1] The Center for Gene Therapy, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA. [2] Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.
k Division of Biomedical Informatics, Department of Computer Science, University of Kentucky Lexington, Kentucky, USA.
l Department of Human Genetics, The University of Utah School of Medicine, Salt Lake City, Utah, USA.
m 1] The Center for Gene Therapy, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA. [2] Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA. [3] Department of Neurology, The Ohio State University, Columbus, Ohio, USA.


Abstract
Most mutations that truncate the reading frame of the DMD gene cause loss of dystrophin expression and lead to Duchenne muscular dystrophy. However, amelioration of disease severity has been shown to result from alternative translation initiation beginning in DMD exon 6 that leads to expression of a highly functional N-truncated dystrophin. Here we demonstrate that this isoform results from usage of an internal ribosome entry site (IRES) within exon 5 that is glucocorticoid inducible. We confirmed IRES activity by both peptide sequencing and ribosome profiling in muscle from individuals with minimal symptoms despite the presence of truncating mutations. We generated a truncated reading frame upstream of the IRES by exon skipping, which led to synthesis of a functional N-truncated isoform in both human subject-derived cell lines and in a new DMD mouse model, where expression of the truncated isoform protected muscle from contraction-induced injury and corrected muscle force to the same level as that observed in control mice. These results support a potential therapeutic approach for patients with mutations within the 5' exons of DMD.


Document Type: Article
Source: Scopus

Cohen, I.J.a , Baris, H.a , Mistry, P.K.b c , Sands, M.S.d
Treatment for LSDs: Real options for several diseases
(2014) Pediatric Endocrinology Reviews, 12, p. 71. 


a Sackler Faculty of Medicine, Tel Aviv University, Raphael Recanati Genetic Institute Rabin Medical CenterPetah Tikva, Israel
b Department of Medicine, Pediatrics and Cellular and Molecular Physiology, Yale School of MedicineNew Haven, CT, United States
c Gaucher Disease Treatment Center, Yale School of MedicineNew Haven, CT, United States
d Department of Internal Medicine, Washington University, School of MedicineSt. Louis, MO, United States


Document Type: Editorial
Source: Scopus

November 6, 2014

Lilienthal, L.a , Rose, N.S.b , Tamez, E.a , Myerson, J.a , Hale, S.a
Individuals with low working memory spans show greater interference from irrelevant information because of poor source monitoring, not greater activation
(2014) Memory and Cognition, 10 p. Article in Press. 


a Department of Psychology, Washington University in St. LouisSt. Louis, MO, United States
b Department of Psychiatry, University of Wisconsin-MadisonMadison, WI, United States


Abstract
Although individuals with high and low working memory (WM) span appear to differ in the extent to which irrelevant information interferes with their performance on WM tasks, the locus of this interference is not clear. The present study investigated whether, when performing a WM task, high- and low-span individuals differ in the activation of formerly relevant, but now irrelevant items, and/or in their ability to correctly identify such irrelevant items. This was done in two experiments, both of which used modified complex WM span tasks. In Experiment 1, the span task included an embedded lexical decision task designed to obtain an implicit measure of the activation of both currently and formerly relevant items. In Experiment 2, the span task included an embedded recognition judgment task designed to obtain an explicit measure of both item and source recognition ability. The results of these experiments indicate that low-span individuals do not hold irrelevant information in a more active state in memory than high-span individuals, but rather that low-span individuals are significantly poorer at identifying such information as irrelevant at the time of retrieval. These results suggest that differences in the ability to monitor the source of information, rather than differences in the activation of irrelevant information, are the more important determinant of performance on WM tasks.


Author Keywords
Individual differences;  Irrelevant information;  Source memory;  Working memory


Document Type: Article in Press
Source: Scopus

Kamath, A.A., Limbrick, D.L., Smyth, M.D.
Characterization of postoperative fevers after hemispherotomy
(2014) Child's Nervous System, 6 p. Article in Press. 


Department of Neurological Surgery, St. Louis Children’s Hospital, Washington University School of Medicine, One Children’s Place, Suite 4S20St. Louis, MO, United States


Abstract
Objective: Patients who have undergone hemispherotomy for intractable epilepsy tend to develop postoperative fevers, which can be severe and/or prolonged, for unclear reasons. The purpose of this paper is to characterize postoperative fever curves after hemispherotomy based on factors including seizure etiology, perioperative blood loss, and the presence or absence of ventricular drainage.

Methods: We present 72 patients who underwent hemispherotomy at our institution between 1995 and 2013 by four surgeons. Data including daily maximum body temperature, seizure etiology, ventricular drain use, steroid and antipyretic use, and seizure control were gathered retrospectively based on electronic records including operative summaries, nursing notes, discharge summaries, and follow-up clinic notes.

Results: Seventy-two patients from 11 weeks to 21 years old (mean 7.4 years old) underwent hemispherotomy between 1995 and 2013. Sixty (83 %) had fevers postoperatively, while the remainder were afebrile. Patients without external ventricular drains had higher and more prolonged fevers compared to those with drains (p = 0.003). Patients with Rasmussen’s encephalitis tended to have higher postoperative fevers than patients with other seizure etiologies (p = 0.005), while patients with cortical dysplasia and polymicrogyria tended to have less severe fevers (p = 0.027 and 0.017, respectively). Fifty-five patients (76 %) had freedom from disabling seizures (Engel class I), and 96 % showed worthwhile improvement or better (Engel classes I–III).

Conclusion: Postoperative fever can be anticipated in hemispherotomy patients, may vary based on certain seizure etiologies, and may be mitigated by routinely utilizing external ventricular drainage. Hemispherotomy is an effective surgical procedure for intractable epilepsy in selected patients.


Author Keywords
Epilepsy;  Hemispherectomy;  Hemispherotomy;  Postoperative fever;  Ventriculostomy


Document Type: Article in Press
Source: Scopus

Kang, Y.a , Ge, Y.a , Cassidy, R.M.a , Lam, V.a , Luo, L.a , Moon, K.-M.b , Lewis, R.c , Molday, R.S.d , Wong, R.O.L.e , Foster, L.J.b , Craig, A.M.a
A combined transgenic proteomic analysis and regulated trafficking of neuroligin-2
(2014) Journal of Biological Chemistry, 289 (42), pp. 29350-29364. 


a Brain Research Centre and Department of Psychiatry, University of British Columbia, 2211 Wesbrook MallVancouver, BC, Canada
b Department of Biochemistry and Molecular Biology and Centre for High-throughput Biology, Canada
c Department of Biochemistry and Molecular Biology and Centre for Macular Research, University of British ColumbiaVancouver, Canada
d Department of Anatomy and Neurobiology, Washington UniversitySt. Louis, MI, United States
e Department of Biological Structure, University of WashingtonSeattle, WA, United States


Abstract
Synapses, the basic units of communication in the brain, require complex molecular machinery for neurotransmitter release and reception. Whereas numerous components of excitatory postsynaptic sites have been identified, relatively few proteins are known that function at inhibitory postsynaptic sites.Onesuch component is neuroligin-2 (NL2), an inhibitory synapse-specific cell surface protein that functions in cell adhesion and synaptic organization via binding to neurexins. In this study,weused a transgenictandem affinity purification and mass spectrometry strategy to isolate and characterize NL2-associated complexes. Complexes purified from brains of transgenic His6-FLAG-YFP-NL2 mice showed enrichment in the Gene Ontology terms cell-cell signaling and synaptic transmission relative to complexes purified from wild type mice as a negative control. In addition to expected components including GABAreceptor subunits and gephyrin, several novel proteins were isolated in association with NL2. Based on the presence of multiple components involved in trafficking and endocytosis, we showed that NL2 undergoes dynamin-dependent endocytosis in response to soluble ligand and colocalizes with VPS35 retromer in endosomes. Inhibitory synapses in brain also present a particular challenge for imaging. Whereas excitatory synapses on spines can be imaged with a fluorescent cell fill, inhibitory synapses require a molecular tag. We find the His6-FLAG-YFP-NL2 to be a suitable tag, with the unamplified YFP signal localizing appropriately to inhibitory synapses in multiple brain regions including cortex, hippocampus, thalamus, and basal ganglia. Altogether, we characterize NL2-associated complexes, demonstrate regulated trafficking of NL2, and provide tools for further proteomic and imaging studies of inhibitory synapses.


Document Type: Article
Source: Scopus

Garai, K.a c , Verghese, P.B.b d , Baban, B.a , Holtzman, D.M.b , Frieden, C.a
The binding of apolipoprotein e to oligomers and fibrils of amyloid-β alters the kinetics of amyloid aggregation
(2014) Biochemistry, 53 (40), pp. 6323-6331. 


a Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660 South Euclid AvenueSt. Louis, MO, United States
b Department of Neurology, Hope Center for Neurological Disorders, Washington University School of MedicineSt. Louis, MO, United States
c TIFR Centre for Interdisciplinary Sciences, 21 Brundavan ColonyNarsingi, Hyderabad, India
d C2N Diagnostics, Center for Emerging TechnologiesSt. Louis, MO, United States


Abstract
Deposition of amyloid-β (Aβ) in Alzheimers disease (AD) is strongly correlated with the APOE genotype. However, the role of apolipoprotein E (apoE) in Aβ aggregation has remained unclear. Here we have used different apoE preparations, such as recombinant protein or protein isolated from cultured astrocytes, to examine the effect of apoE on the aggregation of both Aβ1-40 and Aβ1-42. The kinetics of aggregation, measured by the loss of fluorescence of tetramethylrhodamine-labeled Aβ, is shown to be dramatically slowed by the presence of substoichiometric concentrations of apoE. Using these concentrations, we conclude that apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth. At higher apoE concentrations, the protein also binds to Aβ fibrils, resulting in fibril stabilization and a slower rate of fibril growth. The aggregation of Aβ1-40 is dependent on the apoE isoform, being the most dramatic for apoE4 and less so for apoE3 and apoE2. Our results indicate that the detrimental role of apoE4 in AD could be related to apoE-induced stabilization of the soluble but cytotoxic oligomeric forms and intermediates of Aβ, as well as fibril stabilization.


Document Type: Article
Source: Scopus

Sturm, I.a b c , Biankertz, B.b d , Potes, C.e f , Schaik, G.e f g h i j , Curio, G.a c d
ECoG high gamma activity reveals distinct cortical representations of lyrics passages, Harmonic and timbre-related changes in a rock song
(2014) Frontiers in Human Neuroscience, 8 (OCT), art. no. 798, 14 p. 


a Berlin School of Mind and Brain, Humboldt Universitat zu BerlinBerlin, Germany
b Neurotechnology Group, Department of Electrical Engineering and Computer Science, Berlin Institute of TechnologyBerlin, Germany
c Neurophysics Group, Department of Neurology and Clinical Neurophysiology, Charite—University Medicine BerlinBerlin, Germany
d Bernstein Focus: NeurotechnologyBerlin, Germany
e National Resource Center for Adaptive Neurotechnologies, Wadsworth Center, New York State Department of HealthAlbany, NY, United States
f Department of Electrical and Computer Engineering, University of Texas at El PasoEl Paso, TX, United States
g Department of Neurosurgery, Washington University in St. LouisSt. Louis, MO, United States
h Department of Biomedical Engineering, Rensselaer Polytechnic InstituteTroy, NY, United States
i Department of Neurology, Albany Medical CollegeAlbany, NY, United States
j Department of Neurosurgery, Washington University in St. LouisSt. Louis, MO, United States


Abstract
Listening to music moves our minds and moods, stirring interest in its neural underpinnings. A multitude of compositional features drives the appeal of natural music. How such original music, where a composer's opus is not manipulated for experimental purposes, engages a listener's brain has not been studied until recently. Here, we report an in-depth analysis of two electrocorticographic (ECoG) data sets obtained over the left hemisphere in ten patients during presentation of either a rock song or a read-out narrative. First, the time courses of five acoustic features (intensity, presence/absence of vocals with lyrics, spectral centroid, harmonic change, and pulse clarity) were extracted from the audio tracks and found to be correlated with each other to varying degrees. In a second step, we uncovered the specific impact of each musical feature on ECoG high-gamma power (70-170 Hz) by calculating partial correlations to remove the influence of the other four features. In the music condition, the onset and offset of vocal lyrics in ongoing instrumental music was consistently identified within the group as the dominant driver for ECoG high-gamma power changes over temporal auditory areas, while concurrently subject-individual activation spots were identified for sound intensity, timbral, and harmonic features. The distinct cortical activations to vocal speech-related content embedded in instrumental music directly demonstrate that song integrated in instrumental music represents a distinct dimension in complex music. In contrast, in the speech condition, the full sound envelope was reflected in the high gamma response rather than the onset or offset of the vocal lyrics. This demonstrates how the contributions of stimulus features that modulate the brain response differ across the two examples of a full-length natural stimulus, which suggests a context-dependent feature selection in the processing of complex auditory stimuli.


Author Keywords
Acoustic features;  Electrocorticography (ECoG);  High gamma;  Music processing;  Natural music


Document Type: Article
Source: Scopus

Phillips, B.Z.a , Stockburger, C.b , Mackinnon, S.E.a
Ulnar nerve transection during Tommy John surgery: novel findings and approach to treatment
(2014) Hand, 4 p. Article in Press. 


a Division of Plastic and Reconstructive Surgery, Washington University School of MedicineSt. Louis, MO, United States
b Department of Orthopedic Surgery, Washington University School of MedicineSt. Louis, MO, United States


Document Type: Article in Press
Source: Scopus

Furman, J.L.b , Norris, C.M.a
Calcineurin and glial signaling: Neuroinflammation and beyond
(2014) Journal of Neuroinflammation, 11 (1), art. no. 158, . 


a Pharmacology and Nutritional Sciences and the Sanders-Brown Center on Aging, University of Kentucky College of Medicine, 800 South Limestone St.Lexington, KY, United States
b Department of Neurology, School of Medicine, Washington University, 660 South EuclidSt. Louis, MO, United States


Abstract
Similar to peripheral immune/inflammatory cells, neuroglial cells appear to rely on calcineurin (CN) signaling pathways to regulate cytokine production and cellular activation. Several studies suggest that harmful immune/inflammatory responses may be the most impactful consequence of aberrant CN activity in glial cells. However, newly identified roles for CN in glutamate uptake, gap junction regulation, Ca2+ dyshomeostasis, and amyloid production suggest that CN's influence in glia may extend well beyond neuroinflammation. The following review will discuss the various actions of CN in glial cells, with particular emphasis on astrocytes, and consider the implications for neurologic dysfunction arising with aging, injury, and/or neurodegenerative disease.


Author Keywords
Alzheimer's disease;  Amyloid;  Astrocytes;  Ca2+ regulation;  Calcineurin;  Gap junction;  Glutamate;  Neurodegeneration;  Neuroinflammation


Document Type: Review
Source: Scopus

Brenner, D.S.a b c , Golden, J.P.a , Vogt, S.K.a , Dhaka, A.d e , Story, G.M.a , Gereau, R.W., IVa b
A dynamic set point for thermal adaptation requires phospholipase C-mediated regulation of TRPM8 in vivo
(2014) Pain, 155 (10), pp. 2124-2133. 


a Washington University Pain Center, Department of Anesthesiology, Washington University School of MedicineSt. Louis, MO, United States
b Neuroscience Program, Washington University School of MedicineSt. Louis, MO, United States
c Medical Scientist Training Program, Washington University School of MedicineSt. Louis, MO, United States
d Department of Biological Structure, University of WashingtonSeattle, WA, United States
e Neurobiology and Behavior Graduate Program, University of WashingtonSeattle, WA, United States


Abstract
The ability to sense and respond to thermal stimuli at varied environmental temperatures is essential for survival in seasonal areas. In this study, we show that mice respond similarly to ramping changes in temperature from a wide range of baseline temperatures. Further investigation suggests that this ability to adapt to different ambient environments is based on rapid adjustments made to a dynamic temperature set point. The adjustment of this set point requires transient receptor potential cation channel, subfamily member 8 (TRPM8), but not transient receptor potential cation channel, subfamily A, member 1 (TRPA1), and is regulated by phospholipase C (PLC) activity. Overall, our findings suggest that temperature response thresholds in mice are dynamic, and that this ability to adapt to environmental temperature seems to mirror the in vitro findings that PLC-mediated hydrolysis of phosphoinositol 4,5-bisphosphate modulates TRPM8 activity and thereby regulates the response thresholds to cold stimuli.


Author Keywords
Adaptation;  Cold;  Heat;  Pain;  Phospholipase C;  PIP2;  Thermosensation;  TRPA1;  TRPM8


Document Type: Article
Source: Scopus

Mcnicol, E.D.a , Schumann, R.b , Haroutounian, S.c
A systematic review and meta-analysis of ketamine for the prevention of persistent post-surgical pain
(2014) Acta Anaesthesiologica Scandinavica, 58 (10), pp. 1199-1213. 


a Departments of Anesthesiology and Pharmacy, Tufts Medical Center, 800 Washington Street, Box 420Boston, MA, United States
b Department of Anesthesiology, Tufts Medical CenterBoston, MA, United States
c Department of Anesthesiology, Washington University in St LouisSt Louis, MO, United States


Abstract
While post-operative pain routinely resolves, persistent post-surgical pain (PPSP) is common in certain surgeries; it causes disability, lowers quality of life and has economic consequences. The objectives of this systematic review and meta-analysis were to evaluate the effectiveness of ketamine in reducing the prevalence and severity of PPSP and to assess safety associated with its use. We searched the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE through December 2012 for articles in any language. We included randomized, controlled trials in adults in which ketamine was administered perioperatively via any route. Seventeen studies, the majority of which administered ketamine intravenously, met all inclusion criteria. The overall risk of developing PPSP was not significantly reduced at any time point in the ketamine group vs. placebo, nor did comparisons of pain severity scores reach statistical significance. Sensitivity analysis of exclusively intravenous ketamine studies included in this meta-analysis demonstrated statistically significant reductions in risk of developing PPSP at 3 and 6 months (P = 0.01 and P = 0.04, respectively). Adverse event rates were similar between ketamine and placebo groups. The study data from our review are heterogeneous and demonstrate efficacy of intravenously administered ketamine only in comparison with placebo. Highly variable timing and dosing of ketamine in these studies suggest that no unifying effective regimen has emerged. Future research should focus on clinically relevant outcomes, should stratify patients with pre-existing pain and possible central sensitization and should enroll sufficiently large numbers to account for loss to follow-up in long-term studies.


Document Type: Review
Source: Scopus

Voils, S.A.a , Human, T.b , Brophy, G.M.c
Adverse neurologic effects of medications commonly used in the intensive care unit
(2014) Critical Care Clinics, 30 (4), pp. 795-811. 


a Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, 1225 Center Drive, HPNP Building, Room 3315, PO Box100486Gainesville, FL, United States
b Barnes-Jewish Hospital, Washington University in St. LouisSt. Louis, MO, United States
c Departments of Pharmacotherapy and Outcomes Science and Neurosurgery, Medical College of Virginia Campus, Virginia Commonwealth University, 410 North, 12th StreetRichmond, VA, United States


Abstract
Adverse drug effects often complicate the care of critically ill patients. Therefore, each patient's medical history, maintenance medication, and new therapies administered in the intensive care unit must be evaluated to prevent unwanted neurologic adverse effects. Optimization of pharmacotherapy in critically ill patients can be achieved by considering the need to reinitiate home medications, and avoiding drugs that can decrease the seizure threshold, increase sedation and cognitive deficits, induce delirium, increase intracranial pressure, or induce fever. Avoiding medication-induced neurologic adverse effects is essential in critically ill patients, especially those with neurologic injury.


Author Keywords
Adverse effects;  Critical care;  Drug interactions;  Neurocritical care;  Neurologic complications


Document Type: Review
Source: Scopus

Avidan, M.S.a , Sleigh, J.W.b
Beware the Boojum: The NAP5 audit of accidental awareness during intended general anaesthesia
(2014) Anaesthesia, 69 (10), pp. 1065-1068. 


a Department of Anesthesiology, Surgery Washington University, School of MedicineSt. Louis, MO, United States
b Department of Anaesthesia, Waikato Clinical School University of AucklandHamilton, New Zealand


Document Type: Review
Source: Scopus

Barch, D.M., Sheffield, J.M.
Cognitive impairments in psychotic disorders: Common mechanisms and measurement
(2014) World Psychiatry, 13 (3), pp. 224-232. 


Departments of Psychology, Psychiatry and Radiology, Washington University in St. Louis, 1 Brookings Dr.St. Louis, MO, United States


Abstract
Decades of research have provided robust evidence of cognitive impairments in psychotic disorders. Individuals with schizophrenia appear to be impaired on the majority of neuropsychological tasks, leading some researchers to argue for a "generalized deficit", in which the multitude of cognitive impairments are the result of a common neurobiological source. One such common mechanism may be an inability to actively represent goal information in working memory as a means to guide behavior, with the associated neurobiological impairment being a disturbance in the function of the dorsolateral prefrontal cortex. Here, we provide a discussion of the evidence for such impairment in schizophrenia, and how it manifests in domains typically referred to as cognitive control, working memory and episodic memory. We also briefly discuss cognitive impairment in affective psychoses, reporting that the degree of impairment is worse in schizophrenia than in bipolar disorder and psychotic major depression, but the profile of impairment is similar, possibly reflecting common mechanisms at the neural level. Given the recent release of the DSM-5, we end with a brief discussion on assessing cognition in the context of diagnosis and treatment planning in psychotic disorders.


Author Keywords
Cognitive control;  Cognitive deficits;  DSM-5;  Episodic memory;  Generalized deficit;  Psychotic disorders;  Schizophrenia;  Working memory


Document Type: Article
Source: Scopus

Waters, E.A.a , Kincaid, C.a , Kaufman, A.R.b , Stock, M.L.c , Peterson, L.M.d , Muscanell, N.L.e , Guadagno, R.E.e
Concerns about unintended negative consequences of informing the public about multifactorial risks may be premature for young adult smokers
(2014) British Journal of Health Psychology, 19 (4), pp. 720-736. 


a Division of Public Health Sciences, Department of Surgery, Washington UniversitySt. Louis, MO, United States
b Division of Cancer Control and Population Sciences, National Cancer InstituteRockville, MD, United States
c Department of Psychology, George Washington UniversityWashington, DC, United States
d Department of Psychiatry, University of PittsburghPA, United States
e Department of Psychology, University of AlabamaTuscaloosa, AL, United States


Abstract
Background Many health risks are associated with both genetic and behavioural factors. Concerns have been raised that learning about such multifactorial risks might have detrimental effects on health-related beliefs, cognitions, and affect. However, experimental evidence is sparse. Objective To explore the effects of reading an online news article about the discovery of a genetic basis for nicotine addiction.

Methods Smokers (N = 333) were recruited from the psychology subject pools of two major universities. Participants were randomly assigned to read one of three news articles: one describing a genetic basis for nicotine addiction and lung cancer obtained from a national news source, one altered to indicate no genetic basis for nicotine addiction and lung cancer, or one unrelated attention control. Participants then completed an online questionnaire, which assessed smoking-related cognitions and affect, and beliefs about nicotine addiction, quitting smoking, and whether the harms of tobacco use are delayed.

Results There was no statistically significant influence of experimental condition on smoking-related cognitions/affect (ps &gt;.05, η2 &lt;.002), beliefs about addiction and quitting (Wilks' λ =.98, p =.66, η2 =.01), or delayed harm (ps &gt;.05, η2 &lt;.002). Conclusion Reading an online news article about the presence or absence of a genetic basis for nicotine addiction was not found to change smoking-related cognitions/affect or beliefs among young adult smokers. Concerns about negative effects of multifactorial risk information on health beliefs may be premature. Nevertheless, to effectively translate basic genomics research into effective public health practice, further research should investigate these issues in different populations, via different communication modalities, and for different health outcomes. Statement of contribution What is already known on this subject? Information about the health implications of the interaction between genetics and behaviour is becoming prevalent. Learning about these interactions may reduce perceived risk and intentions to engage in health behaviours. What does this study add? Informing young adult smokers about the genetic basis for nicotine addiction does not affect health beliefs negatively. Responses are not moderated by endorsing the idea of genetic causation or current/experimenter smoking status.


Author Keywords
attitudes;  behaviour;  gene-by-environment;  genetic;  multifactorial;  smoking;  tobacco use


Document Type: Article
Source: Scopus

Schwedt, T.J.a , Chong, C.D.a , Chiang, C.-C.a , Baxter, L.b , Schlaggar, B.L.c , Dodick, D.W.a
Enhanced pain-induced activity of pain-processing regions in a case-control study of episodic migraine
(2014) Cephalalgia, 34 (12), pp. 947-958. 


a Mayo Clinic, 5777 E. Mayo Blvd.Phoenix, AZ, United States
b Barrow Neurological InstitutePhoenix, AZ, United States
c Washington University School of MedicineSt. Louis, MO, United States


Abstract
Objective: The objective of this study was to identify brain regions having aberrant pain-induced activation in migraineurs, thereby gaining insight into particular aspects of pain processing that are atypical in migraineurs.

Methods: Functional magnetic resonance imaging assessed whole brain responses to painful heat in 24 adult episodic migraineurs who were at least 48 hours pain free and 27 healthy controls. Regions differentially activated in migraineurs compared to controls were identified. Activation intensities in these regions were correlated with headache frequency, number of migraine years, and time to next migraine attack.

Results: Migraineurs had greater pain-induced activation of lentiform nucleus, fusiform gyrus, subthalamic nucleus, hippocampus, middle cingulate cortex, premotor cortex, somatosensory cortex, and dorsolateral prefrontal cortex, and less activation in precentral gyrus and superior temporal gyrus. There were significant correlations between activation strength and headache frequency for middle cingulate (r= 0.627, p= 0.001), right dorsolateral prefrontal cortex (r= 0.568, p= 0.004), left fusiform gyrus (r= 0.487, p= 0.016), left precentral gyrus (r= 0.415, p= 0.044), and left hippocampus (r= 0.404, p= 0.050) and with number of migraine years for left fusiform gyrus (r= 0.425, p= 0.038). There were no significant correlations between activation strength and time to next migraine attack.

Conclusions: The majority of regions with enhanced pain-induced activation in headache-free migraineurs participate in cognitive aspects of pain perception such as attending to pain and pain memory. Enhanced cognitive pain processing by migraineurs might reflect cerebral hypersensitivity related to high expectations and hypervigilance for pain.


Author Keywords
cognitive pain processing;  functional magnetic resonance imaging;  headache;  Migraine;  pain


Document Type: Article
Source: Scopus

McClintick, J.N.a , Brooks, A.I.b , Deng, L.b , Liang, L.b , Wang, J.C.c , Kapoor, M.c , Xuei, X.a , Foroud, T.d , Tischfield, J.A.b , Edenberg, H.J.a d
Ethanol treatment of lymphoblastoid cell lines from alcoholics and non-alcoholics causes many subtle changes in gene expression
(2014) Alcohol, 48 (6), pp. 603-610. 


a Department of Biochemistry and Molecular Biology, Indiana University School of MedicineIndianapolis, IN, United States
b Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers UniversityPiscataway, NJ, United States
c Department of Psychiatry, Washington University School of Medicine, B8134, 660 S. Euclid Ave.St. Louis, MO, United States
d Department of Medical and Molecular Genetics, Indiana University School of MedicineIndianapolis, IN, United States


Abstract
To elucidate the effects of a controlled exposure to ethanol on gene expression, we studied lymphoblastoid cell lines (LCLs) from 21 alcoholics and 21 controls. We cultured each cell line for 24h with and without 75mM ethanol and measured gene expression using microarrays. Differences in expression between LCLs from alcoholics and controls included 13 genes previously identified as associated with alcoholism or related traits, including KCNA3, DICER1, ZNF415, CAT, SLC9A9, and PPARGC1B. The paired design allowed us to detect very small changes due to ethanol treatment: ethanol altered the expression of 37% of the probe sets (51% of the unique named genes) expressed in these LCLs, most by modest amounts. Ninety-nine percent of the named genes expressed in the LCLs were also expressed in brain. Key pathways affected by ethanol include cytokine, TNF, and NFκB signaling. Among the genes affected by ethanol were ANK3, EPHB1, SLC1A1, SLC9A9, NRD1, and SH3BP5, which were reported to be associated with alcoholism or related phenotypes in 2 genome-wide association studies. Genes that either differed in expression between alcoholics and controls or were affected by ethanol exposure are candidates for further study.


Author Keywords
Alcoholism;  Cytokines;  Gene expression;  Lymphoblastoid cell lines;  NFkappaB;  TNF


Document Type: Article
Source: Scopus

Fitzsimmons-Craft, E.E.a , Bardone-Cone, A.M.b , Bulik, C.M.c d e , Wonderlich, S.A.f g , Crosby, R.D.f g , Engel, S.G.f g
Examining an elaborated sociocultural model of disordered eating among college women: The roles of social comparison and body surveillance
(2014) Body Image, 11 (4), pp. 488-500. 


a Department of Psychiatry, Washington University School of MedicineSt. Louis, MO, United States
b Department of Psychology, University of North Carolina at Chapel HillChapel Hill, NC, United States
c Department of Psychiatry, University of North Carolina at Chapel HillChapel Hill, NC, United States
d Department of Nutrition, University of North Carolina at Chapel HillChapel Hill, NC, United States
e Department of Medical Epidemiology and Biostatistics, Karolinska InstitutetStockholm, Sweden
f Neuropsychiatric Research InstituteFargo, ND, United States
g Department of Clinical Neuroscience, University of North Dakota School of Medicine and Health SciencesGrand Forks, ND, United States


Abstract
Social comparison (i.e., body, eating, exercise) and body surveillance were tested as mediators of the thin-ideal internalization-body dissatisfaction relationship in the context of an elaborated sociocultural model of disordered eating. Participants were 219 college women who completed two questionnaire sessions 3 months apart. The cross-sectional elaborated sociocultural model (i.e., including social comparison and body surveillance as mediators of the thin-ideal internalization-body dissatisfaction relation) provided a good fit to the data, and the total indirect effect from thin-ideal internalization to body dissatisfaction through the mediators was significant. Social comparison emerged as a significant specific mediator while body surveillance did not. The mediation model did not hold prospectively; however, social comparison accounted for unique variance in body dissatisfaction and disordered eating 3 months later. Results suggest that thin-ideal internalization may not be "automatically" associated with body dissatisfaction and that it may be especially important to target comparison in prevention and intervention efforts.


Author Keywords
Body dissatisfaction;  Body surveillance;  Disordered eating;  Social comparison;  Sociocultural model;  Thin-ideal internalization


Document Type: Article
Source: Scopus

Gubler, T., Pierce, L.
Healthy, Wealthy, and Wise: Retirement Planning Predicts Employee Health Improvements
(2014) Psychological Science, 25 (9), pp. 1822-1830. 


Olin Business School, Washington University in St. Louis, United States


Abstract
Are poor physical and financial health driven by the same underlying psychological factors? We found that the decision to contribute to a 401(k) retirement plan predicted whether an individual acted to correct poor physical-health indicators revealed during an employer-sponsored health examination. Using this examination as a quasi-exogenous shock to employees’ personal-health knowledge, we examined which employees were more likely to improve their health, controlling for differences in initial health, demographics, job type, and income. We found that existing retirement-contribution patterns and future health improvements were highly correlated. Employees who saved for the future by contributing to a 401(k) showed improvements in their abnormal blood-test results and health behaviors approximately 27% more often than noncontributors did. These findings are consistent with an underlying individual time-discounting trait that is both difficult to change and domain interdependent, and that predicts long-term individual behaviors in multiple dimensions.


Author Keywords
domain interdependence;  employee health;  field data;  intertemporal choice;  retirement savings;  time discounting


Document Type: Article
Source: Scopus

De Los Rios, F.a f , Kleindorfer, D.O.a , Guzik, A.b , Ortega-Gutierrez, S.e , Sangha, N.c , Kumar, G.d , Grotta, J.C.c , Lee, J.-M.d , Meyer, B.C.b , Schwamm, L.H.g , Khatri, P.a
Intravenous fibrinolysis eligibility: A survey of stroke clinicians' practice patterns and review of the literature
(2014) Journal of Stroke and Cerebrovascular Diseases, 23 (8), pp. 2130-2138. 


a Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of MedicineCincinnati, OH, United States
b Department of Neuroscience, University of California San DiegoSan Diego, CA, United States
c Department of Neurology, University of TexasHouston, TX, United States
d Department of Neurology, Washington UniversitySt. Louis, MI, United States
e Department of Neurology, Columbia UniversityNew York, NY, United States
f Department of Neurology, Sanna Healthcare Network, Av. Aurelio Miro Quesada 1030San-Isidro, Lima 27, Peru
g Department of Neurology, Harvard Medical SchoolBoston, MA, United States


Abstract
Background The indications and contraindications for intravenous (IV) recombinant tissue plasminogen activator (rtPA) use in ischemic stroke can be confusing to the practicing neurologist. Here we seek to describe practice patterns regarding decision-making among US stroke clinicians.

Methods Stroke clinicians (attending and fellow) from the 8 National Institutes of Health SPOTRIAS (Specialized Programs of Translational Research in Acute Stroke) centers were asked to complete a survey ahead of the 2012 SPOTRIAS Investigators' meeting.

Results A total of 51 surveys were collected (71% response rate). Most of the responders were attending physicians (68%). Only 18% of clinicians reported strictly adhering to current American Heart Association guidelines for treatment within 3 hours from symptom onset; this increased to 51% for the European Cooperative Acute Stroke Study (ECASS) III criteria in the 3 to 4.5 hours time frame. All clinicians treat eligible patients in the 3 to 4.5 hours time frame. The great majority will recommend rtPA in the following scenarios: (1) elderly individuals irrespective of age (97%); (2) severe stroke irrespective of National Institutes of Health Stroke Scale (NIHSS) (95%); or (3) suspected stroke with seizures at symptom onset (91%). None recommended rtPA in the setting of an international normalized ratio >1.7. Most clinicians defined mild strokes as an exclusion based on the perceived disability of the deficit (80%) rather than on a specific NIHSS threshold.

Conclusions Most surveyed stroke clinicians seem to find that the current IV rtPA eligibility criteria for the 3-hour time frame too restrictive. All would recommend rtPA to eligible patients in the 3 to 4.5 hours time frame despite the absence of an U.S. Food and Drug Administration (FDA)-approved indication.


Author Keywords
infarction;  rtPA;  Stroke;  stroke treatment;  thrombolysis;  tissue plasminogen activator


Document Type: Article
Source: Scopus

Hoekel, J.a m , Chisholm, S.A.a , Al-Lozi, A.b , Hershey, T.b c d , Earhart, G.f g , Hullar, T.h , Karzon, R.i j , Lugar, H.M.b , Manwaring, L.e , Marshall, B.e , Paciorkowski, A.R.k , Pepino, Y.l , Pickett, K.g , Permutt, A.l , Ranck, S.b , Reiersen, A.b , Tychsen, L.a e , Viehoever, A.c , White, N.H.e , Urano, F.l , Wasson, J.l
Ophthalmologic correlates of disease severity in children and adolescents with Wolfram syndrome
(2014) Journal of AAPOS, 18 (5), pp. 461-465.e1. 


a Department of Ophthalmology, Washington University School of Medicine, St. Louis Children's Hospital, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis Children's Hospital, United States
c Department of Neurology, Washington University School of Medicine, St. Louis Children's Hospital, United States
d Department of Radiology, Washington University School of Medicine, St. Louis Children's Hospital, United States
e Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, United States
f Department of Surgery, United States
g Department of Physical Therapy, United States
h Department of Otolaryngology, United States
i Department of Audiology, United States
j Department of Communication Sciences, United States
k Department of Neurology, U Rochester, United States
l Department of Medicine, United States


Abstract
PURPOSE: To describe an ophthalmic phenotype in children at relatively early stages of Wolfram syndrome.

METHODS Quantitative ophthalmic testing of visual acuity, color vision, automated visual field sensitivity, optic nerve pallor and cupping, and retinal nerve fiber layer (RNFL) thickness assessed by optical coherence tomography (OCT) was performed in 18 subjects 5-25 years of age. Subjects were also examined for presence or absence of afferent pupillary defects, cataracts, nystagmus, and strabismus.

RESULTS: Subnormal visual acuity was detected in 89% of subjects, color vision deficits in 94%, visual field defects in 100%, optic disk pallor in 94%, abnormally large optic nerve cup:disk ratio in 33%, thinned RNFL in 100%, afferent pupillary defects in 61%, cataracts in 22%, nystagmus in 39%, and strabismus in 39% of subjects. RNFL thinning (P≤lt; 0.001), afferent pupillary defects (P = 0.01), strabismus (P = 0.04), and nystagmus (P = 0.04) were associated with more severe disease using the Wolfram United Rating Scale.

CONCLUSIONS: Children and adolescents with Wolfram syndrome have multiple ophthalmic markers that correlate with overall disease severity. RNFL thickness measured by OCT may be the most reliable early marker.


Document Type: Article
Source: Scopus

Lak, A.a c , Costa, G.M.a b , Romberg, E.a d , Koulakov, A.A.a , Mainen, Z.F.b , Kepecs, A.a
Orbitofrontal cortex is required for optimal waiting based on decision confidence
(2014) Neuron, 84 (1), pp. 190-201. 


a Cold Spring Harbor Laboratory, Cold Spring Harbor, 1 Bungtown RoadNY, United States
b Champalimaud Centre for the Unknown, Avenue Brasília s/nLisbon, Portugal
c Department of Physiology, Development, and Neuroscience, University of CambridgeCambridge, United Kingdom
d Washington University School of Medicine in St. Louis, Mallinckrodt Institute of Radiology, 510 S. Kingshighway BoulevardSt. Louis, MO, United States


Abstract
Confidence judgments are a central example of metacognition-knowledge about one's own cognitive processes. According to this metacognitive view, confidence reports are generated by a second-order monitoring process based on the quality of internal representations about beliefs. Although neural correlates of decision confidence have been recently identified in humans and other animals, it is not well understood whether there are brain areas specifically important for confidence monitoring. To address this issue, we designed a postdecision temporal wagering task in which rats expressed choice confidence by the amount of time they were willing to wait for reward. We found that orbitofrontal cortex inactivation disrupts waiting-based confidence reports without affecting decision accuracy. Furthermore, we show that a normative model can quantitatively account for waiting times based on the computation of decision confidence. These results establish an anatomical locus for a metacognitive report, confidence judgment, distinct from the processes required for perceptual decisions.


Document Type: Article
Source: Scopus

Moore, A., Vachharajani, A.
Preparing for the delivery of a neonate with neural tube defect
(2014) NeoReviews, 15 (10), pp. e461-e462. 


Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis Children’s HospitalSt Louis, MT, United States


Document Type: Note
Source: Scopus

Badiyan, S.N.a , Markovina, S.a , Simpson, J.R.a , Robinson, C.G.a , DeWees, T.a , Tran, D.D.c , Linette, G.c , Jalalizadeh, R.a , Dacey, R.b , Rich, K.M.b , Chicoine, M.R.b , Dowling, J.L.b , Leuthardt, E.C.b , Zipfel, G.J.b , Kim, A.H.b , Huang, J.a
Radiation therapy dose escalation for glioblastoma multiforme in the era of temozolomide
(2014) International Journal of Radiation Oncology Biology Physics, 90 (4), pp. 877-885. 


a Department of Radiation Oncology, Washington University School of Medicine, 4921 Parkview PlaceSt. Louis, MO, United States
b Department of Neurosurgery, Washington University School of MedicineSt. Louis, MO, United States
c Division of Medical Oncology, Department of Medicine, Washington University School of MedicineSt. Louis, MO, United States


Abstract
Purpose: To review clinical outcomes of moderate dose escalation using high-dose radiation therapy (HDRT) in the setting of concurrent temozolomide (TMZ) in patients with newly diagnosed glioblastoma multiforme (GBM), compared with standard-dose radiation therapy (SDRT).

Methods and Materials: Adult patients aged <70 years with biopsy-proven GBM were treated with SDRT (60 Gy at 2 Gy per fraction) or with HDRT (>60 Gy) and TMZ from 2000 to 2012. Biological equivalent dose at 2-Gy fractions was calculated for the HDRT assuming an α/β ratio of 5.6 for GBM.

Results: Eighty-one patients received SDRT, and 128 patients received HDRT with a median (range) biological equivalent dose at 2-Gy fractions of 64 Gy (61-76 Gy). Overall median follow-up time was 1.10 years, and for living patients it was 2.97 years. Actuarial 5-year overall survival (OS) and progression-free survival (PFS) rates for patients that received HDRT versus SDRT were 12.4% versus 13.2% (P=.71), and 5.6% versus 4.1% (P=.54), respectively. Age (P=.001) and gross total/near-total resection (GTR/NTR) (P=.001) were significantly associated with PFS on multivariate analysis. Younger age (P<.0001), GTR/NTR (P<.0001), and Karnofsky performance status ≥80 (P=.001) were associated with improved OS. On subset analyses, HDRT failed to improve PFS or OS for those aged <50 years or those who had GTR/NTR.

Conclusion: Moderate radiation therapy dose escalation above 60 Gy with concurrent TMZ does not seem to improve clinical outcomes for patients with GBM.


Document Type: Article
Source: Scopus

Johnson, R.E.a , Kerschensteiner, D.a b c
Retrograde plasticity and differential competition of bipolar cell dendrites and axons in the developing retina
(2014) Current Biology, 24 (19), pp. 2301-2306. Cited 1 time.


a Department of Ophthalmology and Visual Sciences, Washington University School of MedicineSaint Louis, MO, United States
b Department of Anatomy and Neurobiology, Washington University School of MedicineSaint Louis, MO, United States
c Hope Center for Neurological Disorders, Washington University School of MedicineSaint Louis, MO, United States


Abstract
Most neurons function in the context of pathways that process and propagate information through a series of stages, e.g., from the sensory periphery to cerebral cortex [1]. Because activity at each stage of a neural pathway depends on connectivity at the preceding one, we hypothesized that during development, axonal output of a neuron may regulate synaptic development of its dendrites (i.e., retrograde plasticity). Within pathways, neurons often receive input from multiple partners and provide output to targets shared with other neurons (i.e., convergence) [2]. Converging axons can intermingle or occupy separate territories on target dendrites. Activity-dependent competition has been shown to bias target innervation by overlapping axons in several systems [3-8]. By contrast, whether territorial axons or dendrites compete for targets and inputs, respectively, has not been tested. Here, we generate transgenic mice in which glutamate release from specific sets of retinal bipolar cells (BCs) is suppressed. We find that dendrites of silenced BCs recruit fewer inputs when their neighbors are active and that dendrites of active BCs recruit more inputs when their neighbors are silenced than either active or silenced BCs with equal neighbors. By contrast, axons of silenced BCs form fewer synapses with their targets, irrespective of the activity of their neighbors. These findings reveal that retrograde plasticity guides BC dendritic development in vivo and demonstrate that dendrites, but not territorial axons, in a convergent neural pathway engage in activity-dependent competition. We propose that at a population level, retrograde plasticity serves to maximize functional representation of inputs.


Document Type: Article
Source: Scopus

King, A.A.a , Rodeghier, M.J.b , Panepinto, J.A.c , Strouse, J.J.d , Casella, J.F.d , Quinn, C.T.e , Dowling, M.M.f , Sarnaik, S.A.g , Thompson, A.A.h , Woods, G.M.i , Minniti, C.P.j , Redding-Lallinger, R.C.k , Kirby-Allen, M.l , Kirkham, F.J.m , Mckinstry, R.n , Noetzel, M.J.o , White, D.A.p , Kwiatkowski, J.K.q , Howard, T.H.r , Kalinyak, K.A.e , Inusa, B.s , Rhodes, M.M.t , Heiny, M.E.u , Fuh, B.v , Fixler, J.M.w , Gordon, M.O.x , Debaun, M.R.y
Silent cerebral infarction, income, and grade retention among students with sickle cell anemia
American Journal of Hematology, 89 (10), pp. E188-E192. 


a Program in Occupational Therapy and Department of Pediatrics Hematology Oncology, Washington University School of MedicineSt. Louis, MO, United States
b Rodeghier ConsultantsChicago, IL, United States
c Division of Hematology/Oncology, Department of Pediatrics, Medical College of WisconsinMilwaukee, WI, United States
d Division of Hematology/Oncology, Department of Pediatrics, Hematology/Oncology Johns Hopkins University School of MedicineBaltimore, MD, United States
e Division of Hematology/Oncology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of CincinnatiCincinnati, OH, United States
f Departments of Pediatrics, Neurology and Neurotherapeutics, University of Texas Southwestern Medical SchoolDallas, TX, United States
g Division of Hematology/Oncology, Department of Pediatrics, Wayne State UniversityDetroit, MI, United States
h Division of Hematology/Oncology, Department of Pediatrics, Northwestern UniversityChicago, IL, United States
i Division of Hematology/Oncology, Department of Pediatrics, University of Missouri-Kansas CityKansas City, MO, United States
j National Heart, Lung and Blood Institute, National Institutes of HealthBethesda, MD, United States
k Division of Hematology/Oncology, Department of Pediatrics, University of North Carolina at Chapel HillChapel Hill, NC, United States
l Hospital for Sick Children, University of TorontoToronto, ON, Canada
m Neurosciences Unit, Institute of Child Health, University College London, United Kingdom
n Department of Radiology, Washington University School of MedicineSt. Louis, MO, United States
o Departments of Neurology and Pediatrics, Washington University School of MedicineSt. Louis, MO, United States
p Department of Psychology, Washington UniversitySt. Louis, MO, United States
q Division of Hematology/Oncology, Department of Pediatrics, University of Pennsylvania, Children's Hospital of PhiladelphiaPhiladelphia, PA, United States
r Division of Hematology/Oncology, Department of Pediatrics, University of Alabama at BirminghamBirmingham, AL, United States
s Department of Paediatrics, Evelina Children's Hospital, St Thomas' Hospital National Health Service TrustLondon, United Kingdom
t Division of Hematology/Oncology, Department of Pediatrics, The Ohio State UniversityColumbus, OH, United States
u Division of Hematology/Oncology, Department of Pediatrics, Indiana University-Purdue University IndianaIndianapolis, IN, United States
v Division of Hematology/Oncology, Department of Pediatrics, Brody School of MedicineGreenville, NC, United States
w Division of Hematology/Oncology, Department of Pediatrics, Sinai HospitalBaltimore, MD, United States
x Department of Ophthalmology and Visual Sciences, Biostatistics, Washington University School of MedicineSt. Louis, MO, United States
y Vanderbilt-Meharry Center of Excellence in Sickle Cell Disease, Division of Hematology/Oncology, Department of Pediatrics, Vanderbilt UniversityNashville, TN, United States


Abstract
Children with sickle cell anemia have a higher-than-expected prevalence of poor educational attainment. We test two key hypotheses about educational attainment among students with sickle cell anemia, as measured by grade retention and use of special education services: (1) lower household per capita income is associated with lower educational attainment; (2) the presence of a silent cerebral infarct is associated with lower educational attainment. We conducted a multicenter, cross-sectional study of cases from 22 U.S. sites included in the Silent Infarct Transfusion Trial. During screening, parents completed a questionnaire that included sociodemographic information and details of their child's academic status. Of 835 students, 670 were evaluable 536 had data on all covariates and were used for analysis. The students' mean age was 9.4 years (range: 5-15) with 52.2% male 17.5% of students were retained one grade level and 18.3% received special education services. A multiple variable logistic regression model identified that lower household per capita income (odds ratio [OR] of quartile 1 = 6.36, OR of quartile 2 = 4.7, OR of quartile 3 = 3.87; P = 0.001 for linear trend), age (OR = 1.3; P < 0.001), and male gender (OR, 2.2; P = 0.001) were associated with grade retention; silent cerebral infarct (P = 0.31) and painful episodes (P = 0.60) were not. Among students with sickle cell anemia, household per capita income is associated with grade retention, whereas the presence of a silent cerebral infarct is not. Future educational interventions will need to address both the medical and socioeconomic issues that affect students with sickle cell anemia.


Document Type: Article
Source: Scopus

Kishore, S.a , Bagnall, M.W.a b , McLean, D.L.a
Systematic shifts in the balance of excitation and inhibition coordinate the activity of axial motor pools at different speeds of locomotion
(2014) Journal of Neuroscience, 34 (42), pp. 14046-14054. 


a Department of Neurobiology, Northwestern UniversityEvanston, IL, United States
b Department of Anatomy and Neurobiology, Washington University School of MedicineSt. Louis, MO, United States


Abstract
An emerging consensus from studies of axial and limb networks is that different premotor populations are required for different speeds of locomotion. An important but unresolved issue is why this occurs. Here, we perform voltage-clamp recordings from axial motoneu-rons in larval zebra fish during “fictive” swimming to test the idea that systematic differences in the biophysical properties of axial motoneurons are associated with differential tuning in the weight and timing of synaptic drive, which would help explain premotor population shifts. We find that increases in swimming speed are accompanied by increases in excitation preferentially to lower input resistance (Rin) motoneurons, whereas inhibition uniformly increases with speed to all motoneurons regardless of Rin. Additionally, while the timing of rhythmic excitatory drive sharpens within the pool as speed increases, there are shifts in the dominant source of inhibition related to Rin. At slow speeds, anti-phase inhibition is larger throughout the pool.However,as swimming speedsup, inhibition arriving in-phase with local motor activity increases, particularly in higher Rin motoneurons. Thus, in addition to systematic differences in the weight and timing of excitation related to Rin and speed, there are also speed-dependent shifts in the balance of different sources of inhibition, which is most obvious in more excitable motor pools. We conclude that synaptic drive is differentially tuned to the biophysical properties of motoneurons and argue that differences in premotor circuits exist to simplify the coordination of activity within spinal motor pools during changes in locomotor speed.


Author Keywords
Excitation;  Inhibition;  Locomotion;  Motoneurons;  Recruitment;  Spinal cord


Document Type: Article
Source: Scopus

Luo, S.a c , Schaefer, A.M.a b , Dour, S.a , Nonet, M.L.a
The conserved lim domain-containing focal adhesion protein zyx-1 regulates synapse maintenance in caenorhabditis elegans
(2014) Development (Cambridge), 141 (20), pp. 3922-3933. 


a Department of Anatomy and Neurobiology, Washington University Medical School, 660 S Euclid AveSt Louis, MO, United States
b Department of Neurology, Washington University Medical School, 660 S Euclid AveSt Louis, MO, United States
c Department of Biology, Massachusetts Institute of TechnologyCambridge, MA, United States


Abstract
We describe the identification of zyxin as a regulator of synapse maintenance in mechanosensory neurons in C. elegans. zyx-1 mutants lacked PLM mechanosensory synapses as adult animals. However, most PLM synapses initially formed during development but were subsequently lost as the animals developed. Vertebrate zyxin regulates cytoskeletal responses to mechanical stress in culture. Our work provides in vivo evidence in support of such a role for zyxin. In particular, zyx-1 mutant synaptogenesis phenotypes were suppressed by disrupting locomotion of the mutant animals, suggesting that zyx-1 protects mechanosensory synapses from locomotion-induced forces. In cultured cells, zyxin is recruited to focal adhesions and stress fibers via C-terminal LIM domains and modulates cytoskeletal organization via the N-terminal domain. The synapse-stabilizing activity was mediated by a short isoform of ZYX-1 containing only the LIM domains. Consistent with this notion, PLM synaptogenesis was independent of α-actinin and ENA-VASP, both of which bind to the N-terminal domain of zyxin. Our results demonstrate that the LIM domain moiety of zyxin functions autonomously to mediate responses to mechanical stress and provide in vivo evidence for a role of zyxin in neuronal development.


Author Keywords
Axon retraction;  Cytoskeleton;  Stress fiber;  Synaptogenesis


Document Type: Article
Source: Scopus

Dissel, S.a b , Hansen, C.N.a , Özkaya, Ö.a , Hemsley, M.a , Kyriacou, C.P.a , Rosato, E.a
The logic of circadian organization in drosophila
(2014) Current Biology, 24 (19), pp. 2257-2266. 


a Department of Genetics, University of LeicesterLeicester, United Kingdom
b Department of Anatomy and Neurobiology, Washington University in St Louis, 660 South Euclid AvenueSt Louis, MO, United States


Abstract
Background In the fruit fly Drosophila melanogaster, interlocked negative transcription/translation feedback loops provide the core of the circadian clock that generates rhythmic phenotypes. Although the current molecular model portrays the oscillator as cell autonomous, cross-talk among clock neurons is essential for robust cycling behavior. Nevertheless, the functional organization of the neuronal network remains obscure.

Results Here we show that shortening or lengthening of the circadian period of locomotor activity can be obtained either by targeting different groups of clock cells with the same genetic manipulation or by challenging the same group of cells with activators and repressors of neuronal excitability.

Conclusions Based on these observations we interpret circadian rhythmicity as an emerging property of the circadian network and we propose an initial model for its architectural design.


Document Type: Article
Source: Scopus

Raya, A.K., Diringer, M.N.
Treatment of subarachnoid hemorrhage
(2014) Critical Care Clinics, 30 (4), pp. 719-733. 


Neurocritical Care Section, Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box8111St Louis, MO, United States


Abstract
Nontraumatic subarachnoid hemorrhage from intracranial aneurysm rupture presents with sudden severe headache. Initial treatment focuses on airway management, blood pressure control, and extraventricular drain for hydrocephalus. After identifying the aneurysm, they may be clipped surgically or endovascularly coiled. Nimodipine is administered to maintain a euvolemic state and prevent delayed cerebral ischemia (DCI). Patients may receive anticonvulsants. Monitoring includes serial neurologic assessments, transcranial Doppler ultrasonography, computed tomography perfusion, and angiographic studies. Treatment includes augmentation of blood pressure and cardiac output, cerebral angioplasty, and intra-arterial infusions of vasodilators. Although early mortality is high, about one half of survivors recover with little disability.


Author Keywords
Aneurysm;  Delayed cerebral ischemia;  Subarachnoid hemorrhage;  Transcranial doppler ultrasonography;  Vasospasm


Document Type: Review
Source: Scopus

Martin, C.S.a b , Langenbucher, J.W.b , Chung, T.a , Sher, K.J.c d
Truth or consequences in the diagnosis of substance use disorders
Addiction, 109 (11), pp. 1773-1778. Cited 4 times.


a Western Psychiatric Institute and Clinic, University of Pittsburgh School of MedicinePittsburgh, PA, United States
b Center of Alcohol Studies, Rutgers UniversityPiscataway, NJ, United States
c University of Missouri-ColumbiaColumbia, MO, United States
d Midwest Alcohol Research Center, Washington University School of MedicineSt Louis, MO, United States


Abstract
Aims: This commentary critically evaluates the use of substance-related negative psychosocial and health consequences to define and diagnose alcohol and other substance use disorders. Methods: Narrative review. Results: The consequences of substance use cause much suffering and are major public health and economic problems. However, there are a number of conceptual and measurement problems with using consequences as diagnostic criteria for substance disorders. Data indicate that substance-related consequences introduce systematic bias and degrade the validity of diagnostic systems. Conclusions: Negative psychosocial and health consequences of substance use should play a fundamentally reduced role in modern diagnostic systems for, and definitions of, addictive disorders.


Author Keywords
Addiction;  Alcohol Use Disorders;  Diagnosis;  Health consequences;  Psychosocial consequences;  Substance Use Disorders


Document Type: Article
Source: Scopus

Fischer, C., Lieu, J.
Unilateral hearing loss is associated with a negative effect on language scores in adolescents
(2014) International Journal of Pediatric Otorhinolaryngology, 78 (10), pp. 1611-1617. 


Department of Otolaryngology, Washington University School of MedicineSt. Louis, MO, United States


Abstract
Objective: To determine if adolescents with unilateral hearing loss (UHL) demonstrate worse language skills than their siblings with normal hearing (NH). Design: Case-control study of 12-17-year-old adolescents with UHL (20 cases) compared with sibling controls with NH (13 controls). Methods: Scores on the oral portion of the Oral and Written Language Scales (OWLS) and the Clinical Evaluation of Language Fundamentals (CELF) were the primary outcome measure. Wechsler's Abbreviated Scales of Intelligence (WASI) scores were also used as an outcome measure. Results: Adolescents with UHL demonstrated worse overall and expressive language scores than controls, (98 vs. 114, P= 0.001; 100 vs. 114, P= 0.006) and had significantly lower full scale (98 vs. 112, P= 0.017), verbal (101 vs. 113, P= 0.032), and performance IQ (95 vs. 107, P= 0.037). Conclusions: These findings suggest that UHL in adolescents is associated with a negative effect on standardized language scores and IQ. They also demonstrate that the developmental gap between children with UHL and children with NH does not resolve as the children progress into adolescence and may even widen as the children grow older. Therefore, these results strongly encourage implementation of early intervention for children with UHL to prevent speech-language delays. More studies in adolescents are warranted to evaluate educational outcomes.


Author Keywords
Adolescents;  Cognition;  Speech or language delay;  Unilateral hearing loss

 
Document Type: Article
Source: Scopus