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WUSTL Neuroscience Publications Archive - April 2015

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April 5, 2015

April 15, 2015

April 20, 2015

April 27, 2015

April 27, 2015

Bartus, R.T.a g , Kordower, J.H.b , Johnson, E.M.c , Brown, L.g , Kruegel, B.R.g , Chu, Y.b , Baumann, T.L.d g g , Lang, A.E.e , Olanow, C.W.f , Herzog, C.D.g
Post-mortem assessment of the short and long-term effects of the trophic factor neurturin in patients with α-synucleinopathies
(2015) Neurobiology of Disease, 78, pp. 162-171. 

DOI: 10.1016/j.nbd.2015.03.023

a RTBioconsultants Inc.San Diego, CA, United States
b Rush Presbyterian Medical CenterChicago, IL, United States
c Washington University Medical SchoolSt. Louis, MO, United States
d Isis PharmaceuticalsCarlsbad, CA, United States
e Toronto Western HospitalToronto, Canada
f Mount Sinai School of MedicineNYC, United States
g Ceregene Inc, United States

Substantial interest persists for developing neurotrophic factors to treat neurodegenerative diseases. At the same time, significant progress has been made in implementing gene therapy as a means to provide long-term expression of bioactive neurotrophic factors to targeted sites in the brain. Nonetheless, to date, no double-blind clinical trial has achieved positive results on its primary endpoint despite robust benefits achieved in animal models. A major issue with advancing the field is the paucity of information regarding the expression and effects of neurotrophic factors in human neurodegenerative brain, relative to the well-characterized responses in animal models. To help fill this information void, we examined post-mortem brain tissue from four patients with nigrostriatal degeneration who had participated in clinical trials testing gene delivery of neurturin to the putamen of patients. Each had died of unrelated causes ranging from 1.5-to-3-months (2 Parkinson's disease patients), to 4+-years (1 Parkinson's disease and 1 multiple-system atrophy-parkinsonian type patient) following gene therapy.Quantitative and immunohistochemical evaluation of neurturin, alpha-synuclein, tyrosine hydroxylase (TH) and an oligodendroglia marker (Olig 2) were performed in each brain. Comparable volumes-of-expression of neurturin were seen in the putamen in all cases (~. 15-22%; mean. =. 18.5%). TH-signal in the putamen was extremely sparse in the shorter-term cases. A 6-fold increase was seen in longer-term cases, but was far less than achieved in animal models of nigrostriatal degeneration with similar or even far less NRTN exposure. Less than 1% of substantia nigra (SN) neurons stained for neurturin in the shorter-term cases. A 15-fold increase was seen in the longer-term cases, but neurturin was still only detected in ~. 5% of nigral cells.These data provide unique insight into the functional status of advanced, chronic nigrostriatal degeneration in human brain and the response of these neurons to neurotrophic factor stimulation. They demonstrate mild but persistent expression of gene-mediated neurturin over 4-years, with an apparent, time-related amplification of its transport and biological effects, albeit quite weak, and provide unique information to help plan and design future trials. © 2015 Elsevier Inc.

Author Keywords
AAV2;  AAV2 antibodies (Ab);  Alpha-synuclein;  Axonal transport deficiency;  Gene therapy;  Neurotrophic factors;  Parkinson's disease;  Synucleinopathies

Document Type: Article
Source: Scopus

Wang, Y.a b , Ma, M.b , Tang, Q.a b , Zhu, L.a b , Koleini, M.c , Zou, D.c
The effects of different tensile parameters for the neurodynamic mobilization technique on tricipital muscle wet weight and MuRf-1 expression in rabbits with sciatic nerve injury
(2015) Journal of NeuroEngineering and Rehabilitation, pp. 1-7. Article in Press. 

DOI: 10.1186/s12984-015-0034-4

a Rehabilitation medicine center of the second affiliated hospital of Heilongjiang university of Chinese medicine, Harbin, 150001 China
b Rehabilitation medicine college of Heilongjiang university of Chinese medicine, Harbin, 150040 China
c Washington University School of Medicine, Program in Physical Therapy, St. Louis, MO, 63110 USA

Background: After peripheral nerve injury, muscles without innervation begin to undergo atrophy. Research has suggested that MuRf-1 may play a role in muscle atrophy. The neurodynamic mobilization technique (NMT) is a manual therapy method used to elongate a nerve along its long axis, resulting in improved blood flow to the nerve. However, the nerve can be damaged if elongated too much. The purpose of this study is to observe the effect of NMT on muscle wet weight and MuRf-1 expression in rabbits with sciatic nerve injury. Methods: Six adult rabbits were measured to determine the relationship between the joint angle of the lower limb and percent of sciatic nerve elongation to define the tensile parameters of NMT; Thirty adult rabbits were randomly assigned into a sham, model, NMT-A, NMT-B, or NMT-C groups. Four weeks post-treatment, the wet mass of the tricipital muscles and MuRf-1 expression were observed. Results: The wet mass of the tricipital muscles in the NMT-B group was significantly greater than the NMT-A, NMT-C, and model groups. In addition, MuRf-1 expression was significantly reduced in the NMT-B group compared with the NMT-A, NMT-C, and model groups. Conclusions: Elongating the nerve by NMT of 9% in rabbits decreased MuRf-1 expression and decelerated muscle atrophy in the subjects with sciatic nerve injury. © 2015 Wang et al.; licensee BioMed Central.

Author Keywords
MuRf-1;  Neurodynamic mobilization technique (NMT);  Peripheral nerve injury;  Tricipital muscle wet weight

Document Type: Article in Press
Source: Scopus

Das, A.a f , Miller, R.a , Lee, P.a , Holden, C.A.a , Lindhorst, S.M.a , Jaboin, J.b , Vandergrift, W.A., IIIa , Banik, N.L.a c , Giglio, P.a d , Varma, A.K.a , Raizer, J.J.e , Patel, S.J.a
A novel component from citrus, ginger, and mushroom family exhibits antitumor activity on human meningioma cells through suppressing the Wnt/β-catenin signaling pathway
(2015) Tumor Biology, 8 p. Article in Press. 

DOI: 10.1007/s13277-015-3388-0

a Department of Neurosurgery, Medical University of South CarolinaCharleston, SC, United States
b Department of Radiation Oncology, School of Medicine, Washington UniversitySt. Louis, MO, United States
c Ralph H. Johnson VA Medical CenterCharleston, SC, United States
d Department of Neurological Surgery, Wexner Medical College, Ohio State UniversityColumbus, OH, United States
e Department of Neurology and Northwestern Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of MedicineChicago, IL, United States
f Department of Neurosurgery, Neuro-oncology Division, MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina at CharlestonCharleston, SC, United States

Recurrent meningiomas constitute an uncommon but significant problem after standard (surgery and radiation) therapy failure. Current chemotherapies (hydroxyurea, RU-486, and interferon-α) are only of marginal benefit. There is an urgent need for more effective treatments for meningioma patients who have failed surgery and radiation therapy. Limonin, Tangeritin, Zerumbone, 6-Gingerol, Ganoderic Acid A, and Ganoderic Acid DM are some of the plant derivatives that have anti-tumorgenic properties and cause cell death in meningioma cells in vitro. Due to its ease of administration, long-term tolerability, and low incidence of long-term side effects, we explored its potential as a therapeutic agent against meningiomas by examining their efficacy in vitro against meningioma cells. Treatment effects were assessed using MTT assay, Western blot analysis, caspases assay, and DNA fragmentation assay. Results indicated that treatments of IOMM-Lee and CH157MN meningioma cells with Limonin, Tangeritin, Zerumbone, 6-Gingerol, Ganoderic Acid A, and Ganoderic Acid DM induced apoptosis with enhanced phosphorylation of glycogen synthase kinase 3 β (GSK3β) via inhibition of the Wnt5/β-catenin pathway. These drugs did not induce apoptosis in normal human neurons. Other events in apoptosis included downregulation of tetraspanin protein (TSPAN12), survival proteins (Bcl-XL and Mcl-1), and overexpression apoptotic factors (Bax and caspase-3). These results provide preliminary strong evidence that medicinal plants containing Limonin, Tangeritin, 6-Gingerol, Zerumbone, Ganoderic Acid A, and Ganoderic Acid DM can be applied to high-grade meningiomas as a therapeutic agent, and suggests that further in vivo studies are necessary to explore its potential as a therapeutic agent against malignant meningiomas. © 2015 International Society of Oncology and BioMarkers (ISOBM)

Author Keywords
Apoptosis;  Catenin;  Ginger;  Lemon;  Meningioma;  Mushroom;  Wnt

Document Type: Article in Press
Source: Scopus

Salminen, L.E.a , Conturo, T.E.b , Laidlaw, D.H.c , Cabeen, R.P.c , Akbudak, E.b , Lane, E.M.d , Heaps, J.M.e , Bolzenius, J.D.a , Baker, L.M.a , Cooley, S.a , Scott, S.a , Cagle, L.M.a , Phillips, S.a , Paul, R.H.a e
Regional age differences in gray matter diffusivity among healthy older adults
(2015) Brain Imaging and Behavior, 9 p. Article in Press. 

DOI: 10.1007/s11682-015-9383-7

a Department of Psychology, University of Missouri- Saint Louis, 1 University Boulevard, Stadler Hall 442 ASaint Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. KingshighwaySt. Louis, MO, United States
c Computer Science Department, Brown UniversityProvidence, RI, United States
d Vanderbilt University Medical Center, 1211 Medical Center DriveNashville, TN, United States
e Missouri Institute of Mental Health, 4633 World Parkway CircleBerkeley, MO, United States

Aging is associated with microstructural changes in brain tissue that can be visualized using diffusion tensor imaging (DTI). While previous studies have established age-related changes in white matter (WM) diffusion using DTI, the impact of age on gray matter (GM) diffusion remains unclear. The present study utilized DTI metrics of mean diffusivity (MD) to identify age differences in GM/WM microstructure in a sample of healthy older adults (N = 60). A secondary aim was to determine the functional significance of whole-brain GM/WM MD on global cognitive function using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Participants were divided into three age brackets (ages 50–59, 60–69, and 70+) to examine differences in MD and cognition by decade. MD was examined bilaterally in the frontal, temporal, parietal, and occipital lobes for the primary analyses and an aggregate measure of whole-brain MD was used to test relationships with cognition. Significantly higher MD was observed in bilateral GM of the temporal and parietal lobes, and in right hemisphere WM of the frontal and temporal lobes of older individuals. The most robust differences in MD were between the 50–59 and 70+ age groups. Higher whole-brain GM MD was associated with poorer RBANS performance in the 60–69 age group. Results suggest that aging has a significant and differential impact on GM/WM diffusion in healthy older adults, which may explain a modest degree of cognitive variability at specific time points during older adulthood. © 2015 Springer Science+Business Media New York

Author Keywords
Aging;  Cognition;  Diffusivity;  DTI;  Gray matter;  White matter

Document Type: Article in Press
Source: Scopus

Semenkovich, K.a b , Brown, M.E.c , Svrakic, D.M.b c , Lustman, P.J.b c
Depression in Type 2 Diabetes Mellitus: Prevalence, Impact, and Treatment
(2015) Drugs, 11 p. Article in Press. 

DOI: 10.1007/s40265-015-0347-4

a Department of Pediatrics, Washington University School of MedicineSt. Louis, MO, United States
b Bell Street Clinic, Mental Health Service, St. Louis Veterans Administration Medical CenterSt. Louis, MO, United States
c Department of Psychiatry, Washington University School of MedicineSt. Louis, MO, United States

Clinically significant depression is present in one of every four people with type 2 diabetes mellitus (T2DM). Depression increases the risk of the development of T2DM and the subsequent risks of hyperglycemia, insulin resistance, and micro- and macrovascular complications. Conversely, a diagnosis of T2DM increases the risk of incident depression and can contribute to a more severe course of depression. This linkage reflects a shared etiology consisting of complex bidirectional interactions among multiple variables, a process that may include autonomic and neurohormonal dysregulation, weight gain, inflammation, and hippocampal structural alterations. Two recent meta-analyses of randomized controlled depression treatment trials in patients with T2DM concluded that psychotherapy and antidepressant medication (ADM) were each moderately effective for depression and that cognitive behavior therapy (CBT) had beneficial effects on glycemic control. However, the number of studies (and patients exposed to randomized treatment) included in these analyses is extremely small and limits the certainty of conclusions that can be drawn from the data. Ultimately, there is no escaping the paucity of the evidence base and the need for additional controlled trials that specifically address depression management in T2DM. Future trials should determine both the effects of treatment and the change in depression during treatment on measures of mood, glycemic control, and medical outcome. © 2015 Springer International Publishing Switzerland (outside the USA)

Document Type: Article in Press
Source: Scopus

Corral-Frías, N.S.a , Nikolova, Y.S.b , Michalski, L.J.c , Baranger, D.A.A.c d , Hariri, A.R.b , Bogdan, R.a c d
Stress-related anhedonia is associated with ventral striatum reactivity to reward and transdiagnostic psychiatric symptomatology
(2015) Psychological Medicine, 13 p. Article in Press. 

DOI: 10.1017/S0033291715000525

a Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA
b Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Duke University, Durham, NC, USA
c BRAIN Laboratory, Department of Psychology, Washington University in St Louis, St Louis, MO, USA
d Division of Biology and Biomedical Sciences, Washington University in St Louis, St Louis, MO, USA

Background: Early life stress (ELS) is consistently associated with increased risk for subsequent psychopathology. Individual differences in neural response to reward may confer vulnerability to stress-related psychopathology. Using data from the ongoing Duke Neurogenetics Study, the present study examined whether reward-related ventral striatum (VS) reactivity moderates the relationship between retrospectively reported ELS and anhedonic symptomatology. We further assessed whether individual differences in reward-related VS reactivity were associated with other depressive symptoms and problematic alcohol use via stress-related anhedonic symptoms and substance use-associated coping. Method: Blood oxygen level-dependent functional magnetic resonance imaging (fMRI) was collected while participants (n = 906) completed a card-guessing task, which robustly elicits VS reactivity. ELS, anhedonic symptoms, other depressive symptoms, coping behavior, and alcohol use behavior were assessed with self-report questionnaires. Linear regressions were run to examine whether VS reactivity moderated the relationship between ELS and anhedonic symptoms. Structural equation models examined whether this moderation was indirectly associated with other depression symptoms and problematic alcohol use through its association with anhedonia. Results: Analyses of data from 820 participants passing quality control procedures revealed that the VS × ELS interaction was associated with anhedonic symptoms (p = 0.011). Moreover, structural equation models indirectly linked this interaction to non-anhedonic depression symptoms and problematic alcohol use through anhedonic symptoms and substance-related coping. Conclusions: These findings suggest that reduced VS reactivity to reward is associated with increased risk for anhedonia in individuals exposed to ELS. Such stress-related anhedonia is further associated with other depressive symptoms and problematic alcohol use through substance-related coping. Copyright © Cambridge University Press 2015

Author Keywords
Alcohol;  anhedonia;  depression;  early life stress;  fMRI;  reward;  ventral striatum

Document Type: Article in Press
Source: Scopus

Lewczuk, P.a , Mroczko, B.b c , Fagan, A.d , Kornhuber, J.a
Biomarkers of Alzheimer's disease and mild cognitive impairment: A current perspective
(2015) Advances in Medical Sciences, 60 (1), pp. 76-82. Cited 1 time.

DOI: 10.1016/j.advms.2014.11.002

a Department of Psychiatry and Psychotherapy, Universita Tsklinikum Erlangen and Friedrich-Alexander Universitat Erlangen-Nurnberg, Schwaba-chanlage 691054 Erlangen, Germany
b Department of Neurodegeneration Diagnostics, Medical University of BialystokBialystok, Poland
c Department of Biochemical Diagnostics, University Hospital in BialystokBialystok, Poland
d Knight Alzheimer's Disease Research Center, Department of Neurology, Washington UniversitySt. Louis, MO, United States

A growing body of evidence supports the application of the neurochemical dementia diagnostics (NDD) biomarkers for the diagnosis of dementing conditions. Biomarkers of Alzheimer's disease (AD) were recently classified as these reflecting amyloid β pathology (decreased CSF concentrations of Aβ42 and/or positive Aβ PET scan) and these reflecting neurodegeneration (increased CSF Tau concentrations, decreased uptake of FDG on FDG-PET, and cerebral atrophy on structural MRI). Particularly important seems the role of the biomarkers in the early diagnosis of AD, as the first pathophysiologic events observable in the CSF and amyloid β-PET occur years and perhaps decades before the onset of the earliest clinical symptoms. Therefore, the NDD tools enable the diagnosis of AD already in the early preclinical stage. This review summarizes pathophysiology underlying the CSF biomarkers, following a discussion of their role in the current guidelines for the diagnostic procedures. © 2014 Medical University of Bialystok. Published by Elsevier Urban &Partner Sp. z o.o. All rights reserved.

Author Keywords
Alzheimer's disease;  Amyloid β Tau;  Cerebrospinal fluid;  Clinical neurochemistry

Document Type: Review
Source: Scopus

Zipfel, G.J.
Editorial: Clipping of neurosurgical aneurysms: the dye is cast
(2015) Journal of neurosurgery, 122 (3), pp. 616-617. 

DOI: 10.3171/2014.8.JNS14957

Departments of Neurological Surgery and Neurology, Washington University School of Medicine, St. Louis, Missouri

Document Type: Editorial
Source: Scopus

Fagan, A.M.
What does it mean to be 'amyloid-positive'?
(2015) Brain : a journal of neurology, 138, pp. 514-516. 

DOI: 10.1093/brain/awu387

Department of Neurology, Knight Alzheimer's Disease Research Centre, Washington University School of Medicine, St. Louis, MO 63110

Document Type: Note
Source: Scopus

Haynos, A.F.a , Field, A.E.b , Wilfley, D.E.c , Tanofsky-Kraff, M.d
A novel classification paradigm for understanding the positive and negative outcomes associated with dieting
(2015) International Journal of Eating Disorders, 48 (4), pp. 362-366. 

DOI: 10.1002/eat.22355

a Department of Psychology, University of Nevada, Reno, Mail Stop 298Reno, NV, United States
b Department of Epidemiology, Harvard School of Public HealthBoston, MA, United States
c Department of Psychiatry, Washington University, School of MedicineSt. Louis, MO, United States
d Department of Medical and Clinical Psychology, Uniformed Services University of the Health SciencesBethesda, MD, United States

Document Type: Review
Source: Scopus

Munn-Chernoff, M.A.a b , Grant, J.D.a b , Agrawal, A.a b , Koren, R.c , Glowinski, A.L.a b , Bucholz, K.K.a b , Madden, P.A.F.a b , Heath, A.C.a b , Duncan, A.E.a b d
Are there common familial influences for major depressive disorder and an overeating-binge eating dimension in both European American and African American Female twins?
(2015) International Journal of Eating Disorders, 48 (4), pp. 375-382. 

DOI: 10.1002/eat.22280

a Department of Psychiatry, Washington University, School of Medicine, 660 South Euclid, Campus Box 8134St. Louis, MO, United States
b Midwest Alcoholism Research Center, Washington University, School of MedicineSt. Louis, MO, United States
c Genetic AllianceWashington, DC, United States
d George Warren Brown School of Social Work, Washington UniversitySt. Louis, DC, United States

Objective Although prior studies have demonstrated that depression is associated with an overeating-binge eating dimension (OE-BE) phenotypically, little research has investigated whether familial factors contribute to the co-occurrence of these phenotypes, especially in community samples with multiple racial/ethnic groups. We examined the extent to which familial (i.e., genetic and shared environmental) influences overlapped between Major Depressive Disorder (MDD) and OE-BE in a population-based sample and whether these influences were similar across racial/ethnic groups. Method Participants included 3,226 European American (EA) and 550 African American (AA) young adult women from the Missouri Adolescent Female Twin Study. An adaptation of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) was administered to assess lifetime DSM-IV MDD and OE-BE. Quantitative genetic modeling was used to estimate familial influences between both phenotypes; all models controlled for age. Results The best-fitting model, which combined racial/ethnic groups, found that additive genetic influences accounted for 44% (95% CI: 34%, 53%) of the MDD variance and 40% (25%, 54%) for OE-BE, with the remaining variances due to non-shared environmental influences. Genetic overlap was substantial (r<inf>g</inf> = .61 [.39,.85]); non-shared environmental influences on MDD and OE-BE overlapped weakly (r<inf>e</inf> = .26 [.09,.42]). Discussion Results suggest that common familial influences underlie MDD and OE-BE, and the magnitude of familial influences contributing to the comorbidity between MDD and OE-BE is similar between EA and AA women. If racial/ethnic differences truly exist, then larger sample sizes may be needed to fully elucidate familial risk for comorbid MDD and OE-BE across these groups. © 2014 Wiley Periodicals, Inc. (Int J Eat Disord 2015; 48:375-382) © 2014 Wiley Periodicals, Inc.

Author Keywords
African American;  binge eating;  major depression;  overeating;  race/ethnicity;  twins

Document Type: Article
Source: Scopus

Johnston, T.P.a , Tam-Williams, J.a , Schmandt, M.a , Patel, A.C.a , Cleveland, C.a , Coste, F.b , Kemp, J.S.a
Behavioral hyperventilation and central sleep apnea in two children
(2015) Journal of Clinical Sleep Medicine, 11 (4), pp. 487-489. 

DOI: 10.5664/jcsm.4612

a Washington University in St. Louis, Edward Mallinkrodt Department of PediatricsSt. Louis, MO, United States
b St. Louis Children's Hospital Pediatric Sleep CenterSt. Louis, MO, United States

Behavioral hyperventilation is a rarely recognized cause of central sleep apnea (CSA) among children. We report two pediatric patients who presented with prolonged central sleep apnea secondary to behavioral hyperventilation. One patient also had a prolonged corrected QT (QT<inf>C</inf>) interval resulting from hyperventilation. © 2015, American Academy of Sleep Medicine. All rights reserved.

Author Keywords
Anxiety;  Behavioral hyperventilation;  Central sleep apnea;  Prolonged qt<inf>c</inf> interval

Document Type: Article
Source: Scopus

Cho, S.K.a , Lenke, L.G.b , Bolon, S.M.c , Pahys, J.M.d , Cho, W.d , Kang, M.M.e , Zebala, L.P.b , Koester, L.A.b
Can intraoperative spinal cord monitoring reliably help prevent paraplegia during posterior vertebral column resection surgery?
(2015) Spine Deformity, 3 (1), pp. 73-81. 

DOI: 10.1016/j.jspd.2014.06.013

a Icahn School of Medicine at Mount Sinai, 1428 Madison AveNew York, NY, United States
b Washington University School of Medicine, Department of Orthopaedic Surgery, 660 S Euclid Ave,Campus Box 8233St. Louis, MO, United States
c Barnes-Jewish Hospital, 1 Barnes Jewish Hospital PlazaSt. Louis, MO, United States
d Albert Einstein Medical Center, 5501 Old York Road, Ste 1Philadelphia, PA, United States
e Regions Hospital, 640 Jackson St.St. Paul, MN, United States

Study Design: Retrospective case series. Objective: Analyze patients who underwent posterior vertebral column resection (PVCR) above the conus medullaris with intraoperative spinal cord monitoring (SCM) data loss. Summary of Background Data: PVCR is a powerful technique for treating severe spinal deformity but carries a high risk for major spinal cord deficits. Methods: We assessed clinical, radiographic, and electrophysiologic monitoring and operative records of 90 consecutive adult and pediatric patients (mean age, 24.8 years; range, 7.5 - 76.8) who underwent PVCR above the conus medullaris for severe spinal deformity performed from 2002 to 2010 by one surgeon at one institution. Results: Fifteen of 90 patients (16.7%) (10 male/5 female; mean age, 15 years) lost SCM (n = 13) or had data degradation meeting warning criteria (n = 2). Diagnoses were kyphoscoliosis (n = 8), angular kyphosis (n = 3), global kyphosis (n = 2), and severe scoliosis (n = 2). Seven were revisions. The average pre-/postoperative scolioses were 99° (range, 32° - 152°) and 43° (range, 6° - 76°), respectively. The average pre-/postoperative kyphoses were +100° (range, 60° - 170°) and +54° (range, 28° - 100°), respectively. SCM fluctuated during osteotomy on nine occasions, stabilizing with elevation of blood pressure in addition to anterior spinal cord decompression in four, correction of subluxation in one, and traction reduction in one. Seven patients had SCM changes during rod compression. Three required partial release of correction, two larger cage insertion, one subluxation correction, and one pedicle screw removal. One experienced changes during rod placement/removal, and another, as a result of hypothermia. Data returned in all after prompt intervention (mean, 10.1 minutes; range, 1e60) and all awoke with intact lower extremity function. Conclusion: The prevalence of SCM changes during PVCR above the conus medullaris was 16.7%, mostly during osteotomy and rod/ screw compression. Data returned with prompt intervention and all had intact lower extremity motor function postoperatively. These SCM "saves" strongly emphasize the importance of multimodality neurophysiologic monitoring during high-risk cases, minimizing postoperative complications. © 2015 Scoliosis Research Society.

Author Keywords
Paraplegia;  Spinal cord monitoring;  Spinal deformity;  Vertebral column resection

Document Type: Article
Source: Scopus

Coulthart, M.B.a , Ances, B.M.b
Creutzfeldt-Jakob disease
(2015) Neurology: Clinical Practice, 5 (2), pp. 99-101. 

DOI: 10.1212/CPJ.0000000000000103

a Canadian Creutzfeldt-Jakob Disease Surveillance System, Public Health Agency of CanadaOttawa, ON, Canada
b Department of Neurology, School of Medicine, Washington UniversitySt. Louis, MO, United States

Document Type: Editorial
Source: Scopus

Kung, N.H., Dhar, R., Keyrouz, S.G.
Diffuse leptomeningeal carcinomatosis mimicking brain death
(2015) Journal of the Neurological Sciences, . Article in Press. 

DOI: 10.1016/j.jns.2015.03.045

Department of Neurology, Washington University in St. Louis, MO, USA

Author Keywords
Brain death;  Coma;  Metastatic tumor

Document Type: Article in Press
Source: Scopus

Admon, R.a , Nickerson, L.D.b , Dillon, D.G.a , Holmes, A.J.c d , Bogdan, R.e , Kumar, P.a , Dougherty, D.D.d , Iosifescu, D.V.f , Mischoulon, D.d , Fava, M.d , Pizzagalli, D.A.a b
Dissociable cortico-striatal connectivity abnormalities in major depression in response to monetary gains and penalties
(2015) Psychological Medicine, 45 (1), pp. 121-131. 

DOI: 10.1017/S0033291714001123

a Center for Depression, Anxiety and Stress Research, McLean Hospital, Harvard Medical School Belmont, 115 Mill StreetBelmont, MA, United States
b McLean Imaging Center, McLean Hospital, Harvard Medical SchoolBelmont, MA, United States
c Department of Psychology, Harvard UniversityCambridge, MA, United States
d Department of Psychiatry, Massachusetts General Hospital, Harvard Medical SchoolBoston, MA, United States
e Department of Psychology, Washington University in St LouisSt Louis, MO, United States
f Mood and Anxiety Disorders Program, Mount Sinai School of MedicineNew York, NY, United States

Background. Individuals with major depressive disorder (MDD) are characterized by maladaptive responses to both positive and negative outcomes, which have been linked to localized abnormal activations in cortical and striatal brain regions. However, the exact neural circuitry implicated in such abnormalities remains largely unexplored. Method. In this study 26 unmedicated adults with MDD and 29 matched healthy controls (HCs) completed a monetary incentive delay task during functional magnetic resonance imaging (fMRI). Psychophysiological interaction (PPI) analyses probed group differences in connectivity separately in response to positive and negative outcomes (i.e. monetary gains and penalties). Results. Relative to HCs, MDD subjects displayed decreased connectivity between the caudate and dorsal anterior cingulate cortex (dACC) in response to monetary gains, yet increased connectivity between the caudate and a different, more rostral, dACC subregion in response to monetary penalties. Moreover, exploratory analyses of 14 MDD patients who completed a 12-week, double-blind, placebo-controlled clinical trial after the baseline fMRI scans indicated that a more normative pattern of cortico-striatal connectivity pre-treatment was associated with greater improvement in symptoms 12 weeks later. Conclusions. These results identify the caudate as a region with dissociable incentive-dependent dACC connectivity abnormalities in MDD, and provide initial evidence that cortico-striatal circuitry may play a role in MDD treatment response. Given the role of cortico-striatal circuitry in encoding action-outcome contingencies, such dysregulated connectivity may relate to the prominent disruptions in goal-directed behavior that characterize MDD. Copyright © 2014 Cambridge University Press.

Author Keywords
Caudate;  cingulate;  depression;  PPI;  reward;  treatment prediction

Document Type: Article
Source: Scopus

Musso, M.a aj aj , Westervelt, H.J.a b af , Long, J.D.c d , Morgan, E.e , Woods, S.P.e , Smith, M.M.c , Lu, W.c d , Paulsen, J.S.c , Cross, S.c , Ryan, P.c , Epping, E.A.c , Chiu, E.f , Preston, J.f , Goh, A.f , Antonopoulos, S.f , Loi, S.f , Chua, P.g , Komiti, A.g , Raymond, L.h , Decolongon, J.h , Fan, M.h , Coleman, A.h , Ross, C.A.i , Varvaris, M.i , Yoritomo, N.i , Mallonee, W.M.j , Suter, G.j , Samii, A.k , Macaraeg, A.k , Jones, R.l , Wood-Siverio, C.l , Factor, S.A.l , Barker, R.A.m , Mason, S.m , Guzman, N.V.m , McCusker, E.n , Griffith, J.n , Loy, C.n , Gunn, D.n , Orth, M.o , Süßmuth, S.o , Barth, K.o , Trautmann, S.o , Schwenk, D.o , Eschenbach, C.o , Quaid, K.p , Wesson, M.p , Wojcieszek, J.p , Guttman, M.q , Sheinberg, A.q , Karmalkar, I.q , Perlman, S.r , Clemente, B.r , Geschwind, M.D.s , Sha, S.s , Satris, G.s , Warner, T.t , Burrows, M.t , Rosser, A.u , Price, K.u , Hunt, S.u , Marshall, F.v , Chesire, A.v , Wodarski, M.v , Hickey, C.v , Panegyres, P.w , Lee, J.w , Tedesco, M.w , Maxwell, B.w , Perlmutter, J.x , Barton, S.x , Smith, S.x , Miedzybrodzka, Z.y , Rae, D.y , D'Alessandro, M.y , Craufurd, D.z , Bek, J.z , Howard, E.z , Mazzoni, P.aa , Marder, K.aa , Wasserman, P.aa , Kumar, R.ab , Erickson, D.ab , Nickels, B.ab , Wheelock, , Kjer, , Martin, , Farias, , Suchowersky, , Martin, , King, , Wieler, , Sran, , Ahmed, , Rao, , Reece, , Bura, , Mourany, , Montross, K.aj , Vonsattell, J.P.aa , Moskowitz, C.aa , Vik, S.c , Harrington, D.e , Hershey, T.x , Moser, D.J.c , Williams, J.c , Downing, N.c , Johnson, H.J.c , Aylward, , Magnotta, V.A.c , Kim, J.-I.c , Mills, J.A.c , Zhang, Y.c , Liu, D.c , Lourens, S.c , Erwin, C.ah , Nance, , Bockholt, H.J.c , Wyse, R.c
Intra-individual variability in prodromal Huntington disease and its relationship to genetic burden
(2015) Journal of the International Neuropsychological Society, 21 (1), pp. 8-21. 

DOI: 10.1017/S1355617714001076

a Department of Psychiatry and Human Behavior, Warren Alpert Medical, School of Brown UniversityProvidence, RI, United States
b Department of Psychiatry, Rhode Island HospitalProvidence, RI, United States
c Department of Psychiatry, University of Iowa, Carver College of MedicineIowa City, IA, United States
d Department of Biostatistics, University of Iowa, College of Public HealthIowa City, IA, United States
e Department of Psychiatry, University of California, San DiegoSan Diego, CA, United States
f St. Vincent's Hospital, University of MelbourneKew, VIC, Australia
g University of Melbourne, Royal Melbourne HospitalMelbourne, VIC, Australia
h University of British ColumbiaVancouver, BCC, Canada
i Johns Hopkins UniversityBaltimore, MD, United States
j Hereditary Neurological Disease CentreWichita, KS, United States
k University of Washington, VA Puget Sound Health Care SystemSeattle, WA, United States
l Emory University, School of MedicineAtlanta, GA, United States
m Cambridge Centre for Brain RepairCambridge, United Kingdom
n Westmead HospitalSydney, NSW, Australia
o University of UlmUlm, Germany
p Indiana University, School of MedicineIndianapolis, IN, United States
q Centre for Addiction and Mental Health, University of TorontoMarkham, ON, Canada
r UCLA, Medical CenterLos Angeles, CA, United States
s University of CaliforniaSan Francisco, CA, United States
t National Hospital for Neurology and NeurosurgeryLondon, United Kingdom
u Cardiff UniversityCardiff, United Kingdom
v University of RochesterRochester, NY, United States
w Neurosciences Unit, Graylands, Selby-Lemnos and Special Care Health ServicesPerth, WA, Australia
x Washington UniversitySt. Louis, MO, United States
y Clinical Genetics CentreAberdeen, United Kingdom
z University of ManchesterManchester, United Kingdom
aa Columbia University, Medical CenterNew York, NY, United States
ab Colorado Neurological InstituteEnglewood, CO, United States
ac University of California DavisSacramento, CA, United States
ad University of AlbertaEdmonton, AB, Canada
ae Cleveland Clinic FoundationCleveland, OH, United States
af Rhode Island Hospital, Alpert Medical School, Brown University, United States
ag Seattle Children's Research Institute, United States
ah Texas Tech University, Health Sciences Center, United States
ai University of Minnesota, United States

The current study sought to examine the utility of intra-individual variability (IIV) in distinguishing participants with prodromal Huntington disease (HD) from nongene-expanded controls. IIV across 15 neuropsychological tasks and within-task IIV using a self-paced timing task were compared as a single measure of processing speed (Symbol Digit Modalities Test [SDMT]) in 693 gene-expanded and 191 nongene-expanded participants from the PREDICT-HD study. After adjusting for depressive symptoms and motor functioning, individuals estimated to be closest to HD diagnosis displayed higher levels of across- and within-task variability when compared to controls and those prodromal HD participants far from disease onset (F<inf>ICV(3,877)</inf> = 11.25; p<.0001; F<inf>PacedTiming(3,877)</inf> = 22.89; p<.0001). When prodromal HD participants closest to HD diagnosis were compared to controls, Cohen's d effect sizes were larger in magnitude for the within-task variability measure, paced timing (-1.01), and the SDMT (-0.79) and paced tapping coefficient of variation (CV) (-0.79) compared to the measures of across-task variability [CV (0.55); intra-individual standard deviation (0.26)]. Across-task variability may be a sensitive marker of cognitive decline in individuals with prodromal HD approaching disease onset. However, individual neuropsychological tasks, including a measure of within-task variability, produced larger effect sizes than an index of across-task IIV in this sample. (JINS, 2015, 21, 8-21) © INS. The International Neuropsychological Society 2015.

Author Keywords
Adult;  Attention;  Cognition disorders/diagnosis;  Cognition disorders/genetics;  Executive function;  Huntington disease;  Intra-individual variability;  Neuropsychological tests;  Prodromal symptoms

Document Type: Article
Source: Scopus

Ong, C., Patel, K., Musiek, E., Van Stavern, G.
Mystery case: A young woman with isolated upbeating nystagmus
(2015) Neurology, 84 (4), pp. e17-e19. 

DOI: 10.1212/WNL.0000000000001178

Department of Neurology and Ophthalmology, Washington UniversitySt. Louis, MO, United States

Document Type: Short Survey
Source: Scopus

Waldron, M.a b , Doran, K.A.a , Bucholz, K.K.b , Duncan, A.E.b c , Lynskey, M.T.d , Madden, P.A.F.b , Sartor, C.E.b e , Heath, A.C.b
Parental separation, parental alcoholism, and timing of first sexual intercourse
(2015) Journal of Adolescent Health, 56 (5), pp. 550-556. 

DOI: 10.1016/j.jadohealth.2015.01.011

a Department of Counseling and Educational Psychology, School of Education, Indiana University, 201 N. Rose AvenueBloomington, IN, United States
b Midwest Alcoholism Research Center, Department of Psychiatry, Washington University School of MedicineSt. Louis, MO, United States
c George Warren Brown School of Social Work, Washington UniversitySt. Louis, MO, United States
d Addictions Department, Institute of Psychiatry, King's CollegeLondon, United Kingdom
e Department of Psychiatry, Yale University School of MedicineNew Haven, CT, United States

Purpose We examined timing of first voluntary sexual intercourse as a joint function of parental separation during childhood and parental history of alcoholism. Methods Data were drawn from a birth cohort of female like-sex twins (n = 569 African ancestry [AA]; n = 3,415 European or other ancestry [EA]). Cox proportional hazards regression was conducted predicting age at first sex from dummy variables coding for parental separation and parental alcoholism. Propensity score analysis was also employed to compare intact and separated families, stratified by predicted probability of separation. Results Earlier sex was reported by EA twins from separated and alcoholic families, compared to EA twins from intact nonalcoholic families, with effects most pronounced through the age of 14 years. Among AA twins, effects of parental separation and parental alcoholism were largely nonsignificant. Results of propensity score analyses confirmed unique risks from parental separation in EA families, where consistent effects of parental separation were observed across predicted probability of separation. For AA families, there was poor matching on risk factors presumed to predate separation, which limited interpretability of survival-analytic findings. Conclusions In European American families, parental separation during childhood is an important predictor of early-onset sex, beyond parental alcoholism and other correlated risk factors. To characterize risk for African Americans associated with parental separation, additional research is needed where matching on confounders can be achieved. © 2015 Society for Adolescent Health and Medicine.

Author Keywords
Parental alcoholism;  Parental separation or divorce;  Propensity score analysis;  Sexual intercourse;  Survival analysis

Document Type: Article
Source: Scopus

Sene, A.a , Chin-Yee, D.a , Apte, R.S.a b c
Seeing through VEGF: Innate and adaptive immunity in pathological angiogenesis in the eye
(2015) Trends in Molecular Medicine, 21 (1), pp. 43-51. 

DOI: 10.1016/j.molmed.2014.10.005

a Department of Ophthalmology, Washington University School of MedicineSt Louis, MO, United States
b Department of Developmental Biology, Washington University School of MedicineSt Louis, MO, United States
c Neuroscience Program, Washington University School of MedicineSt Louis, MO, United States

The central role of vascular endothelial growth factor (VEGF) signaling in regulating normal vascular development and pathological angiogenesis has been documented in multiple studies. Ocular anti-VEGF therapy is highly effective for treating a subset of patients with blinding eye disorders such as diabetic retinopathy and neovascular age-related macular degeneration (AMD). However, chronic VEGF suppression can lead to adverse effects associated with poor visual outcomes due to the loss of prosurvival and neurotrophic capacities of VEGF. In this review, we discuss emerging evidence for immune-related mechanisms that regulate ocular angiogenesis in a VEGF-independent manner. These novel molecular and cellular pathways may provide potential therapeutic avenues for a multitarget strategy, preserving the neuroprotective functions of VEGF in those patients whose disease is unresponsive to VEGF neutralization. © 2014 Elsevier Ltd.

Author Keywords
Age-related macular degeneration (AMD);  Angiogenesis;  Diabetic retinopathy;  Immune regulation;  Neovascularization;  Vascular endothelial growth factor (VEGF)

Document Type: Review
Source: Scopus

Fitzgerald, R.T.a , Radmanesh, A.b
Social media and research visibility
(2015) American Journal of Neuroradiology, 36 (4), p. 637. 

DOI: 10.3174/ajnr.A4054

a Department of Radiology, University of Arkansas for Medical Sciences, 4301 W Markham St.Little Rock, AR, United States
b Mallinckrodt Institute of Radiology, Washington University School of MedicineSt. Louis, MO, United States

Document Type: Note
Source: Scopus

Liu, Q.a , Liu, Q.b , Liu, Q.c , Dong, X.d , Dong, X.e
The role of the mrgpr receptor family in Itch
(2015) Handbook of Experimental Pharmacology, 226, pp. 71-88. 

DOI: 10.1007/978-3-662-44605-8_5

a The Center for the Study of Itch, Washington University Pain CenterSt. Louis, MO, United States
b Department of Anesthesiology, Washington University School of Medicine, 4940 Parkview PlaceSt. Louis, MO, United States
c Department of Anatomy and Neurobiology, Washington University School of Medicine, 4940 Parkview PlaceSt. Louis, MO, United States
d The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, 725 N Wolfe StreetBaltimore, MD, United States
e Howard Hughes Medical Institute, Johns Hopkins University School of MedicineBaltimore, MD, United States

Itch is a complex sensory modality that can be evoked by an extremely diverse set of stimuli and has multiple components of disease etiology. Thus, determining the basic molecular and cellular players is essential before we can tackle the more complex aspects of itch. The identification of novel itch receptors has been extremely fruitful and has uncovered novel signaling pathways and pruritogens. Mrgprs encode a family of G protein-coupled receptors, many of which are expressed specifically in sensory nerves and function as itch receptors in mediating histamine-independent itch. In this chapter, we will review the discovery of the receptor family, their specific expression, their roles as itch receptors, and the itch-inducing agonists. Furthermore, we will summarize the results indicating that Mrgpr-expressing sensory neurons are itch-sensing neurons. In the end we will discuss the role of Mrgprs and Mrgpr-positive neurons in chronic itch. © Springer-Verlag Berlin Heidelberg 2015.

Author Keywords
BAM8-22;  Chloroquine;  DRG neurons;  G protein-coupled receptor;  GPCR;  Itch;  Knockout;  Labeled line;  Mouse;  Mrgprs;  Skin;  SLIGRL;  β-alanine

Document Type: Article
Source: Scopus

Tse, C.S.a , Chang, J.F.b , Fung, A.W.T.c , Lam, L.C.W.c , Hau, K.T.a , Leung, G.T.Y.c , Balota, D.A.d
The utility of a non-verbal prospective memory measure as a sensitive marker for early-stage Alzheimer's disease in Hong Kong
(2015) International Psychogeriatrics, 27 (2), pp. 231-242. 

DOI: 10.1017/S1041610214002038

a Department of Educational Psychology, Chinese University of Hong KongShatin,N.T., Hong Kong
b Department of Psychology, Guangdong University of Education, China
c Department of Psychiatry, Chinese University of Hong Kong, Hong Kong
d Department of Psychology and Neurology, Washington University in St. Louis, United States

Background: With the proportion of older adults in Hong Kong projected to double in size in the next 30 years, it is important to develop measures for detecting individuals in the earliest stage of Alzheimer's disease (AD, 0.5 in Clinical Dementia Rating, CDR). We tested the utility of a non-verbal prospective memory task (PM, ability to remember what one has to do when a specific event occurs in the future) as an early marker for AD in Hong Kong Chinese. Methods: A large community dwelling sample of older adults who are healthy controls (CDR 0, N = 125), in the earliest stage of AD (CDR 0.5, N = 125), or with mild AD (CDR 1, N = 30) participated in this study. Their reaction time/accuracy data were analyzed by mixed-factor analyses of variance to compare the performance of the three CDR groups. Logistic regression analyses were performed to test the discriminative power of these measures for CDR 0 versus 0.5 participants. Results: Prospective memory performance declined as a function of AD severity: CDR 0 > CDR 0.5 > CDR 1, suggesting the effects of early-stage AD and AD progression on PM. After partialling out the variance explained by psychometric measures (e.g., ADAS-Cog), reaction time/accuracy measures that reflected the PM still significantly discriminated between CDR 0 versus 0.5 participants in most of the cases. Conclusion: The effectiveness of PM measures in discriminating individuals in the earliest stage of AD from healthy older adults suggests that these measures should be further developed as tools for early-stage AD discrimination. Copyright © International Psychogeriatric Association 2014.

Author Keywords
Alzheimer's disease;  cognitive testing;  memory

Document Type: Article
Source: Scopus

Nguyen, K., McDaniel, M.A.
Using quizzing to assist student learning in the classroom: The good, the bad, and the ugly
(2015) Teaching of Psychology, 42 (1), pp. 87-92. 

DOI: 10.1177/0098628314562685

Washington UniversitySt. Louis, MO, United States

Recently, the testing effect has received a great deal of attention from researchers and educators who are intrigued by its potential to enhance student learning in the classroom. However, effective incorporation of testing (as a learning tool) merits a close examination of the conditions under which testing can enhance student learning in an authentic classroom setting, where a number of factors may deviate from the laboratory. Based on existing evidence, we highlight several studies that encompass a few of the complexities of using testing to enhance course performance, including situations in which quizzing is beneficial for summative test performance, contexts in which quizzing does not appear to be as beneficial, and instances in which quizzing may actually hamper final test performance. © The Author(s) 2014.

Author Keywords
Classroom;  Education;  Laboratory;  Testing effect


Document Type: Article
Source: Scopus



April 20, 2015

Razafsky, D., Hodzic, D.
A variant of Nesprin1 giant devoid of KASH domain underlies the molecular etiology of autosomal recessive cerebellar ataxia type I
(2015) Neurobiology of Disease, 78, pp. 57-67. 

DOI: 10.1016/j.nbd.2015.03.027

Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 S. EuclidSt Louis, MO, United States

Nonsense mutations across the whole coding sequence of Syne1/. Nesprin1 have been linked to autosomal recessive cerebellar ataxia Type I (ARCA1). However, nothing is known about the molecular etiology of this late-onset debilitating pathology. In this work, we report that Nesprin1 giant is specifically expressed in CNS tissues. We also identified a CNS-specific splicing event that leads to the abundant expression of a KASH-LESS variant of Nesprin1 giant (KLNes1g) in the cerebellum. KLNes1g displayed a noncanonical localization at glomeruli of cerebellar mossy fibers whereas Nesprin2 exclusively decorated the nuclear envelope of all cerebellar neurons. In immunogold electron microscopy, KLNes1g colocalized both with synaptic vesicles within mossy fibers and with dendritic membranes of cerebellar granule neurons. We further identified vesicle- and membrane-associated proteins in KLNes1g immunoprecipitates. Together, our results suggest that the loss of function of KLNes1g resulting from Nesprin1 nonsense mutations underlies the molecular etiology of ARCA1. © 2015 Elsevier Inc.

Author Keywords
ARCA1;  Autosomal recessive cerebellar ataxia Type I;  Cerebellar granule neuron;  Cerebellar mossy fiber;  Cerebellum;  KASH;  KLNes1g;  Nesprin;  Spinocerebellar ataxia

Document Type: Article
Source: Scopus

Ciao, A.C.a b , Accurso, E.C.b , Fitzsimmons-Craft, E.E.c , Le Grange, D.d
Predictors and moderators of psychological changes during the treatment of adolescent bulimia nervosa
(2015) Behaviour Research and Therapy, 69, pp. 48-53. 

DOI: 10.1016/j.brat.2015.04.002

a Western Washington University, Department of PsychologyBellingham, WA, United States
b The University of Chicago, Department of Psychiatry and Behavioral NeuroscienceChicago, IL, United States
c Washington University School of Medicine, Department of PsychiatrySt. Louis, MO, United States
d University of California, Departments of Psychiatry and PediatricsSan Francisco, CA, United States

This study examined predictors of psychological change among 80 adolescents with bulimia nervosa (BN) participating in a randomized-controlled trial comparing family-based treatment (FBT) to supportive psychotherapy (SPT). Psychological outcomes (cognitive eating disorder pathology, depression, and self-esteem) were explored at baseline, post-treatment, and 6-month follow-up. Multi-level growth models examined predictors of rate of change in psychological outcomes and moderators of treatment effects. All psychological outcomes improved through 6-month follow-up (moderate to large effect sizes) across both treatments. Overall, few significant predictors were identified. Older adolescents had faster change in self-esteem relative to younger adolescents (p=0.03). Adolescents taking psychotropic medication at baseline had faster change in eating concerns relative to adolescents not taking medication (p=0.02). Age (p=0.02) and baseline purging severity (p=0.03) moderated the relationship between treatment condition and change in eating concerns, where younger adolescents and individuals with high baseline purging had greater change when treated with FBT relative to SPT. Age and purging did not significantly moderate change in other psychological outcomes. Bulimic symptom improvement did not predict change in psychological symptoms. Generally, FBT and SPT were equally efficacious with respect to psychological improvement, although FBT may be more efficacious in younger adolescents and those with more frequent purging. © 2015 Elsevier Ltd.

Author Keywords
Adolescents;  Bulimia nervosa;  Family-based treatment;  Supportive psychotherapy

Document Type: Article
Source: Scopus

Frontera, J.a , Ziai, W.b , O’Phelan, K.c , Leroux, P.D.d , Kirkpatrick, P.J.e , Diringer, M.N.f , Suarez, J.I.g , The Second Neurocritical Care Research Conference Investigatorsh
Regional Brain Monitoring in the Neurocritical Care Unit
(2015) Neurocritical Care, 12 p. Article in Press. 

DOI: 10.1007/s12028-015-0133-x

a Cerebrovascular Center, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland Clinic Mail Code S80Cleveland, OH, United States
b Department of Neurology, Neurological Surgery, Anesthesiology and Critical Care Medicine, Johns Hopkins UniversityBaltimore, MD, United States
c Department of Neurology, Miller School of Medicine, University of MiamiMiami, FL, United States
d Main Line Health Brain and Spine CenterWynnewood, PA, United States
e Division of Neurosurgery, University of CambridgeCambridge, United Kingdom
f Section Neurological Critical Care, Department of Neurology, Neurosurgery, and Anesthesiology, Washington University, St LouisMO, United States
g Division of Vascular Neurology and Neurocritical Care, Department of Neurology, Baylor College of MedicineHouston, TX, United States

Regional multimodality monitoring has evolved over the last several years as a tool to understand the mechanisms of brain injury and brain function at the cellular level. Multimodality monitoring offers an important augmentation to the clinical exam and is especially useful in comatose neurocritical care patients. Cerebral microdialysis, brain tissue oxygen monitoring, and cerebral blood flow monitoring all offer insight into permutations in brain chemistry and function that occur in the context of brain injury. These tools may allow for development of individual therapeutic strategies that are mechanistically driven and goal-directed. We present a summary of the discussions that took place during the Second Neurocritical Care Research Conference regarding regional brain monitoring. © 2015 Springer Science+Business Media New York

Author Keywords
Brain tissue oxygenation;  Cerebral blood flow;  Microdialysis;  Neurocritical care;  Neuromonitoring

Document Type: Article in Press
Source: Scopus

Wang, D.L.a , Li, H.b c , Liang, R.b , Bao, J.b c
Identification of multiple metabolic enzymes from mice cochleae tissue using a novel functional proteomics technology
(2015) PLoS ONE, 10 (3), art. no. e0121826, . 

DOI: 10.1371/journal.pone.0121826

a Department of Biology, Vanderbilt UniversityNashville, TN, United States
b Department of Otolaryngology, School of Medicine, Washington UniversitySt. Louis, MO, United States
c Translational Research Center, Department of Anatomy and Neurobiology, Northeast Ohio Medical UniversityRootstown, OH, United States

A new type of technology in proteomics was developed in order to separate a complex protein mixture and analyze protein functions systematically. The technology combines the ability of two-dimensional gel electrophoresis (2-DE) to separate proteins with a protein elution plate (PEP) to recover active proteins for functional analysis and mass spectrometry (MS)-based identification. In order to demonstrate the feasibility of this functional proteomics approach, NADH and NADPH-dependent oxidases, major redox enzyme families, were identified from mice cochlear tissue after a specific drug treatment. By comparing the enzymatic activity between mice that were treated with a drug and a control group significant changes were observed. Using MS, five NADH-dependent oxidases were identified that showed highly altered enzymatic activities due to the drug treatment. In essence, the PEP technology allows for a systematic analysis of a large enzyme family from a complex proteome, providing insights in understanding the mechanism of drug treatment. © 2015 Wang et al.

Document Type: Article
Source: Scopus

Zipfel, G.J.
Ultra-early surgery for aneurysmal subarachnoid hemorrhage
(2015) Journal of neurosurgery, 122 (2), pp. 381-382. 

DOI: 10.3171/2014.8.JNS141613

Departments of Neurological Surgery and Neurology, Washington University School of Medicine, St. Louis, Missouri

Document Type: Editorial
Source: Scopus

Stewart, S.B.a b , Koller, J.M.b , Campbell, M.C.a c , Perlmutter, J.S.a c d e f , Black, K.J.a b c d e
Additive global cerebral blood flow normalization in arterial spin labeling perfusion imaging
(2015) PeerJ, 2015 (3), art. no. e834, . 

DOI: 10.7717/peerj.834

a Department of Neurology, Washington University School of MedicineSt Louis, MO, United States
b Department of Psychiatry, Washington University School of MedicineSt Louis, MO, United States
c Department of Radiology, Washington University School of MedicineSt Louis, MO, United States
d Departments of Anatomy and Neurobiology, Washington University School of MedicineSt Louis, MO, United States
e Division of Biology and Biomedical Sciences, Washington University School of MedicineSt Louis, MO, United States
f Programs in Physical Therapy and Occupational Therapy, Washington University School of MedicineSt Louis, MO, United States

To determine how different methods of normalizing for global cerebral blood flow (gCBF) affect image quality and sensitivity to cortical activation, pulsed arterial spin labeling (pASL) scans obtained during a visual task were normalized by either additive or multiplicative normalization of modal gCBF. Normalization by either method increased the statistical significance of cortical activation by a visual stimulus. However, image quality was superior with additive normalization, whether judged by intensity histograms or by reduced variability within gray and white matter. © 2015 Stewart et al.

Author Keywords
Arterial spin labeling;  ASL;  Cerebral blood flow;  Cerebral blood flow measurement;  FMRI;  Functional magnetic resonance imaging;  Parkinson's disease

Document Type: Article
Source: Scopus

Agrawal, A.a , Lynskey, M.T.b , Kapoor, M.a , Bucholz, K.K.a , Edenberg, H.J.c , Schuckit, M.d , Brooks, A.e , Hesselbrock, V.f , Kramer, J.g , Saccone, N.h , Tischfield, J.d , Bierut, L.J.a
Are genetic variants for tobacco smoking associated with cannabis involvement?
(2015) Drug and Alcohol Dependence, 150, pp. 183-187. 

DOI: 10.1016/j.drugalcdep.2015.02.029

a Washington University School of Medicine, Department of PsychiatrySt. Louis, MO, United States
b Institute of Psychiatry, Addictions DepartmentLondon, United Kingdom
c Indiana University School of MedicineIndianapolis, IN, United States
d University of CaliforniaSan Diego, CA, United States
e Rutgers University, Department of GeneticsPiscataway, NJ, United States
f University of Connecticut Health Center, Department of PsychiatryFarmington, CT, United States
g University of Iowa Carver College of MedicineIowa City, IA, United States
h Washington University School of Medicine, Department of GeneticsSt. Louis, MO, United States

Background: Cannabis users are highly likely to also be tobacco cigarette smokers and a proportion of this comorbidity is attributable to shared genetic influences. Three large meta-analyses of genomewide association studies (GWAS) of tobacco smoking have identified multiple genomewide significant (p&lt;5×10-8) single nucleotide polymorphisms (SNPs). We examine whether these SNPs are associated with tobacco smoking and with cannabis involvement in an independent sample. Method: Eleven SNPs associated with cigarettes per day (CPD), ever versus never smoking and current smoking/smoking cessation at p&lt;5×10-8 were selected from three published meta-analyses. Association analyses were conducted with similar tobacco smoking measures in 2716 European-American subjects from the Study of Addictions Genes and Environment (SAGE) and with lifetime and current cannabis use and DSM-IV cannabis abuse/dependence. Results: Cannabis use and tobacco smoking correlated at 0.54. Rs16969968 in CHRNA5 (and its proxy, rs1051730 in CHRNA3) and rs1451240, a proxy for rs13280604 in CHRNB3, were associated with CPD after Bonferroni correction (p&lt;. 0.006). rs1451240 was also associated with DSM-IV cannabis abuse/dependence. Rs6265 in BDNF was associated with smoking initiation, as in the original meta-analysis and also with lifetime cannabis use. Associations with cannabis involvement were no longer significant upon adjustment for the tobacco smoking measures. Conclusions: The modest associations between cannabis involvement and SNPs for tobacco smoking were not independent of the comorbidity between tobacco and cannabis involvement. Larger samples of individuals might be required to articulate the specific genetic architecture of cannabis involvement. © 2015 Elsevier Ireland Ltd.

Author Keywords
Cannabis;  Chrna5;  Tobacco

Document Type: Article
Source: Scopus

Fleisher, A.S.a b c d , Chen, K.c d e , Quiroz, Y.T.f g , Jakimovich, L.J.d , Gutierrez Gomez, M.g , Langois, C.M.d , Langbaum, J.B.S.c d , Roontiva, A.c d , Thiyyagura, P.c d , Lee, W.c d , Ayutyanont, N.c d , Lopez, L.g , Moreno, S.g , Muñoz, C.g , Tirado, V.g , Acosta-Baena, N.g , Fagan, A.M.h , Giraldo, M.g , Garcia, G.g , Huentelman, M.J.c f , Tariot, P.N.c d i , Lopera, F.g , Reiman, E.M.c d i j
Associations between biomarkers and age in the presenilin 1 E280A autosomal dominant Alzheimer disease kindred: A cross-sectional study
(2015) JAMA Neurology, 72 (3), pp. 316-324. 

DOI: 10.1001/jamaneurol.2014.3314

a Eli Lilly and CompanyIndianapolis, IN, United States
b Department of Neurosciences, University of CaliforniaSan Diego, United States
c Banner Alzheimer's Institute, 901 E Willetta StPhoenix, AZ, United States
d Banner Alzheimer's InstitutePhoenix, AZ, United States
e Department of Mathematics and Statistics, Arizona State UniversityTempe, United States
f Department of Neurology, Massachusetts General Hospital, Harvard Medical SchoolBoston, United States
g Grupo de Neurociencias, Universidad de AntioquiaMedellín, Colombia
h Department of Neurology, Washington University School of MedicineSt Louis, MO, United States
i Department of Psychiatry, University of ArizonaPhoenix, United States
j Division of Neurogenomics, Translational Genomics Research InstitutePhoenix, AZ, United States

IMPORTANCE: Age-associated changes in brain imaging and fluid biomarkers are characterized and compared in presenilin 1 (PSEN1) E280A mutation carriers and noncarriers from the world's largest known autosomal dominant Alzheimer disease (AD) kindred. OBJECTIVE: To characterize and compare age-associated changes in brain imaging and fluid biomarkers in PSEN1 E280A mutation carriers and noncarriers. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional measures of 18F-florbetapir positron emission tomography, 18F-fludeoxyglucose positron emission tomography, structural magnetic resonance imaging, cerebrospinal fluid (CSF), and plasma biomarkers of AD were assessed from 54 PSEN1 E280A kindred members (age range, 20-59 years). MAIN OUTCOMES AND MEASURES: We used brain mapping algorithms to compare regional cerebral metabolic rates for glucose and gray matter volumes in cognitively unimpaired mutation carriers and noncarriers. We used regression analyses to characterize associations between age and the mean cortical to pontine 18F-florbetapir standard uptake value ratios, precuneus cerebral metabolic rates for glucose, hippocampal gray matter volume, CSF Aβ1-42, total tau and phosphorylated tau181, and plasma Aβ measurements. Age at onset of progressive biomarker changes that distinguish carriers from noncarriers was estimated using best-fitting regression models. RESULTS: Compared with noncarriers, cognitively unimpaired mutation carriers had significantly lower precuneus cerebral metabolic rates for glucose, smaller hippocampal volume, lower CSF Aβ1-42, higher CSF total tau and phosphorylated tau181, and higher plasma Aβ1-42 measurements. Sequential changes in biomarkers were seen at age 20 years (95%CI, 14-24 years) for CSF Aβ1-42, age 16 years (95%CI, 11-24 years) for the mean cortical 18F-florbetapir standard uptake value ratio, age 15 years (95%CI, 10-24 years) for precuneus cerebral metabolic rate for glucose, age 15 years (95%CI, 7-20 years) for CSF total tau, age 13 years (95%CI, 8-19 years) for phosphorylated tau181, and age 6 years (95%CI, 1-10 years) for hippocampal volume, with cognitive decline up to 6 years before the kindred's estimated median age of 44 years (95%CI, 43-45 years) at mild cognitive impairment diagnosis. No age-associated findings were seen in plasma Aβ1-42 or Aβ1-40. CONCLUSIONS AND RELEVANCE: This cross-sectional study provides additional information about the course of different AD biomarkers in the preclinical and clinical stages of autosomal dominant AD. Copyright 2015 American Medical Association. All rights reserved.

Document Type: Article
Source: Scopus

Yang, H.a b , Zhang, G.c , Cui, J.c d e
BK channels: Multiple sensors, one activation gate
(2015) Frontiers in Physiology, 6 (FEB), art. no. 00029, . 

DOI: 10.3389/fphys.2015.00029

a Ion Channel Research Unit, Duke University Medical CenterDurham, NC, United States
b Department of Biochemistry, Duke University Medical CenterDurham, NC, United States
c Department of Biomedical Engineering, Washington University in Saint LouisSt. Louis, MO, United States
d Cardiac Bioelectricity and Arrhythmia Center, Washington University in Saint LouisSt. Louis, MO, United States
e Center for The Investigation of Membrane Excitability Disorders, Washington University in Saint LouisSt. Louis, MO, United States

Ion transport across cell membranes is essential to cell communication and signaling. Passive ion transport is mediated by ion channels, membrane proteins that create ion conducting pores across cell membrane to allow ion flux down electrochemical gradient. Under physiological conditions, majority of ion channel pores are not constitutively open. Instead, structural region(s) within these pores breaks the continuity of the aqueous ion pathway, thereby serves as activation gate(s) to control ions flow in and out. To achieve spatially and temporally regulated ion flux in cells, many ion channels have evolved sensors to detect various environmental stimuli or the metabolic states of the cell and trigger global conformational changes, thereby dynamically operate the opening and closing of their activation gate. The sensors of ion channels can be broadly categorized as chemical sensors and physical sensors to respond to chemical (such as neural transmitters, nucleotides and ions) and physical (such as voltage, mechanical force and temperature) signals, respectively. With the rapidly growing structural and functional information of different types of ion channels, it is now critical to understand how ion channel sensors dynamically control their gates at molecular and atomic level. The voltage and Ca2+ activated BK channels, a K+ channel with an electrical sensor and multiple chemical sensors, provide a unique model system for us to understand how physical and chemical energy synergistically operate its activation gate. © 2015 Yang, Zhang and Cui.

Author Keywords
Allosteric gating;  BK channels;  Calcium binding proteins;  Ion channel gating;  Ion permeation;  Magnesium binding;  Modular organization;  Voltage sensor domain

Document Type: Review
Source: Scopus

Fasano, R.M.a b , Meier, E.R.a b , Hulbert, M.L.c
Cerebral vasculopathy in children with sickle cell anemia
(2015) Blood Cells, Molecules, and Diseases, 54 (1), pp. 17-25. 

DOI: 10.1016/j.bcmd.2014.08.007

a Center for Cancer and Blood Disorders, Children's National Health SystemWashington, DC, United States
b Department of Pediatrics, The George Washington University School of Medicine and Health SciencesWashington, DC, United States
c Department of Pediatrics, Washington University School of MedicineSt. Louis, MO, United States

Sickle cell anemia (SCA)-associated cerebral vasculopathy and moyamoya is a unique entity reflecting the abnormal interactions between sickled red blood cells (RBCs) and the cerebral arterial endothelium. Endothelial injury, coagulation activation, and the inflammatory response generated by sickled RBCs are implicated in the development of cerebral vasculopathy, but the pathophysiology remains incompletely understood. SCA-specific screening and treatment guidelines have successfully reduced the incidence of overt strokes in this high-risk population. However, despite aggressive hematological management, many children with cerebral vasculopathy due to SCA have progressive vasculopathy and recurrent strokes; therefore, more effective therapies, such as revascularization surgery and curative hematopoietic stem cell transplant, are urgently needed. © 2014 Elsevier Inc.

Author Keywords
Cerebral vasculopathy;  Moyamoya;  Sickle cell anemia;  Stroke

Document Type: Review
Source: Scopus

Musiek, E.S.
Circadian clock disruption in neurodegenerative diseases: Cause and effect?
(2015) Frontiers in Pharmacology, 6 (FEB), art. no. 29, . 

DOI: 10.3389/fphar.2015.00029

Hope Center for Neurological Disorders, Department of Neurology, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. LouisSaint Louis, MO, United States

Disturbance of the circadian system, manifested as disrupted daily rhythms of physiologic parameters such as sleep, activity, and hormone secretion, has long been observed as a symptom of several neurodegenerative diseases, including Alzheimer disease. Circadian abnormalities have generally been considered consequences of the neurodegeneration. Recent evidence suggests, however, that circadian disruption might actually contribute to the neurodegenerative process, and thus might be a modifiable cause of neural injury. Herein we will review the evidence implicating circadian rhythms disturbances and clock gene dysfunction in neurodegeneration, with an emphasis on future research directions and potential therapeutic implications for neurodegenerative diseases. © 2015 Musiek.

Author Keywords
Alzheimer disease;  Bmal1;  Circadian clock;  Huntington disease;  Neurodegeneration;  Per2

Document Type: Article
Source: Scopus

MacKillop, J.a b c , Few, L.R.d , Stojek, M.K.e , Murphy, C.M.e , Malutinok, S.F.e , Johnson, F.T.e , Hofmann, S.G.f , McGeary, J.E.c g h , Swift, R.M.c f , Monti, P.M.c
D-cycloserine to enhance extinction of cue-elicited craving for alcohol: A translational approach
(2015) Translational Psychiatry, 5, p. e544. 

DOI: 10.1038/tp.2015.41

a Department of Psychiatry and Behavioural Neurosciences, McMaster University, St. Joseph's Healthcare Hamilton, 100 West 5th StreetHamilton, ON, Canada
b Homewood Research Institute, Homewood Health CentreGuelph, ON, Canada
c Center for Alcohol and Addiction Studies, Brown UniversityProvidence, RI, United States
d Department of Psychiatry, Washington UniversitySt. Louis, MO, United States
e Department of Psychology, University of GeorgiaAthens, GA, United States
f Department of Psychological and Brain Sciences, Boston UniversityBoston, MA, United States
g Providence Veterans Affairs Medical CenterProvidence, RI, United States
h Division of Behavioral Genetics, Department of Psychiatry, Rhode Island HospitalProvidence, RI, United States

Cue-elicited craving for alcohol is well established but extinction-based treatment to extinguish this response has generated only modest positive outcomes in clinical trials. Basic and clinical research suggests that D-cycloserine (DCS) enhances extinction to fear cues under certain conditions. However, it remains unclear whether DCS would also accelerate extinction of cue-elicited craving for alcohol. The goal of the current study was to examine whether, compared with placebo (PBO), DCS enhanced extinction of cue-elicited craving among treatment-seeking individuals with alcohol use disorders (AUDs). Participants were administered DCS (50 mg) or PBO 1 h before an alcohol extinction paradigm in a simulated bar environment on two occasions. The extinction procedures occurred 1 week apart and were fully integrated into outpatient treatment. Subjective craving for alcohol was the primary variable of interest. Follow-up cue reactivity sessions were conducted 1 week and 3 weeks later to ascertain persisting DCS effects. Drinking outcomes and tolerability were also examined. DCS was associated with augmented reductions in alcohol craving to alcohol cues during the first extinction session and these effects persisted through all subsequent sessions, suggesting facilitation of extinction. Participants in the DCS condition reported significant short-term reductions in drinking, although these did not persist to follow-up, and found the medication highly tolerable. These findings provide evidence that DCS enhances extinction of cue-elicited craving for alcohol in individuals with AUDs in the context of outpatient treatment. The potential clinical utility of DCS is discussed, including methodological considerations and context-dependent learning. © 2015 Translational Psychiatry.

Document Type: Article
Source: Scopus

Hansen, J.a , Snow, C.b , Tuttle, E.a , Ghoneim, D.H.a , Yang, C.-S.b , Spencer, A.b , Gunter, S.A.c , Smyser, C.D.d , Gurnett, C.A.d , Shinawi, M.e , Dobyns, W.B.f g , Wheless, J.h , Halterman, M.W.a i , Jansen, L.A.c , Paschal, B.M.b j , Paciorkowski, A.R.a i k
De novo mutations in SIK1 cause a spectrum of developmental epilepsies
(2015) American Journal of Human Genetics, 96 (4), pp. 682-690. 

DOI: 10.1016/j.ajhg.2015.02.013

a Center for Neural Development and Disease, University of Rochester Medical CenterRochester, NY, United States
b Center for Cell Signaling, University of VirginiaCharlottesville, VA, United States
c Department of Neurology, University of VirginiaCharlottesville, VA, United States
d Department of Neurology, Washington UniversitySt. Louis, MO, United States
e Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington UniversitySt. Louis, MO, United States
f Department of Neurology, Division of Genetic Medicine, University of WashingtonSeattle, WA, United States
g Center for Integrative Brain Research, Seattle Research InstituteSeattle, WA, United States
h LeBonheur Children's Hospital, University of TennesseeMemphis, TN, United States
i Department of Neurology, University of Rochester Medical CenterRochester, NY, United States
j Departments of Biochemistry and Molecular Genetics, University of VirginiaCharlottesville, VA, United States
k Departments of Pediatrics and Biomedical Genetics, University of Rochester Medical CenterRochester, NY, United States

Developmental epilepsies are age-dependent seizure disorders for which genetic causes have been increasingly identified. Here we report six unrelated individuals with mutations in salt-inducible kinase 1 (SIK1) in a series of 101 persons with early myoclonic encephalopathy, Ohtahara syndrome, and infantile spasms. Individuals with SIK1 mutations had short survival in cases with neonatal epilepsy onset, and an autism plus developmental syndrome after infantile spasms in others. All six mutations occurred outside the kinase domain of SIK1 and each of the mutants displayed autophosphorylation and kinase activity toward HDAC5. Three mutations generated truncated forms of SIK1 that were resistant to degradation and also showed changes in sub-cellular localization compared to wild-type SIK1. We also report the human neuropathologic examination of SIK1-related developmental epilepsy, with normal neuronal morphology and lamination but abnormal SIK1 protein cellular localization. Therefore, these results expand the genetic etiologies of developmental epilepsies by demonstrating SIK1 mutations as a cause of severe developmental epilepsy. © 2015 The American Society of Human Genetics.

Document Type: Article
Source: Scopus

Tuttle, K.R.a , McGill, J.B.b , Bastyr, E.J.c , Poi, K.K.c , Shahri, N.d , Anderson, P.W.c
Effect of ruboxistaurin on albuminuria and estimated GFR in people with diabetic peripheral neuropathy: Results from a randomized trial
(2015) American Journal of Kidney Diseases, 65 (4), pp. 634-636. 

DOI: 10.1053/j.ajkd.2014.11.024

a Providence Health Care and University of Washington, School of MedicineSpokane, WA, United States
b Washington UniversitySt Louis, MI, United States
c Eli Lilly and CoIndianapolis, IN, United States
d Inventiv Health ClinicalSan Diego, CA, United States

Document Type: Letter
Source: Scopus

Rosell, D.R.a b , Zaluda, L.C.a c , McClure, M.M.a c , Perez-Rodriguez, M.M.a c , Strike, K.S.a c , Barch, D.M.d , Harvey, P.D.e f , Girgis, R.R.g h , Hazlett, E.A.a c , Mailman, R.B.i , Abi-Dargham, A.g h , Lieberman, J.A.g h , Siever, L.J.a c
Effects of the D1 dopamine receptor agonist dihydrexidine (DAR-0100A) on working memory in schizotypal personality disorder
(2015) Neuropsychopharmacology, 40 (2), pp. 446-453. 

DOI: 10.1038/npp.2014.192

a Department of Psychiatry, Icahn School of Medicine at Mount SinaiNew York, NY, United States
b Department of Outpatient Psychiatry, James J. Peters VA Medical CenterBronx, NY, United States
c Mental Illness Research, Education, and Clinical Center (MIRECC VISN 3), James J. Peters Department of Veterans Affairs Medical Center, 130 West Kingsbridge RoadBronx, NY, United States
d Department of Psychology, Washington University in St LouisSt Louis, MO, United States
e Department of Psychiatry, University of Miami Miller School of MedicineMiami, FL, United States
f Research Service, Bruce W. Carter VA Medical CenterMiami, FL, United States
g New York State Psychiatric InstituteNew York, NY, United States
h Department of Psychiatry, Columbia University Medical CenterNew York, NY, United States
i Department of Pharmacology, Penn State University College of MedicineHershey, PA, United States

Pharmacological enhancement of prefrontal D1 dopamine receptor function remains a promising therapeutic approach to ameliorate schizophrenia-spectrum working memory deficits, but has yet to be rigorously evaluated clinically. This proof-of-principle study sought to determine whether the active enantiomer of the selective and full D1 receptor agonist dihydrexidine (DAR-0100A) could attenuate working memory impairments in unmedicated patients with schizotypal personality disorder (SPD). We performed a randomized, double-blind, placebo-controlled trial of DAR-0100A (15 mg/150 ml of normal saline administered intravenously over 30 min) in medication-free patients with SPD (n=16) who met the criteria for cognitive impairment (ie, scoring below the 25th percentile on tests of working memory). We employed two measures of verbal working memory that are salient to schizophrenia-spectrum cognitive deficits, and that clinical data implicate as being associated with prefrontal D1 availability: (1) the Paced Auditory Serial Addition Test (PASAT); and (2) the N-back test (ratio of 2-back:0-back scores). Study procedures occurred over four consecutive days, with working memory testing on Days 1 and 4, and DAR-0100A/placebo administration on Days 2-4. Treatment with DAR-0100A was associated with significantly improved PASAT performance relative to placebo, with a very large effect size (Cohen's d=1.14). Performance on the N-back ratio was also significantly improved; however, this effect rested on both a non-significant enhancement and diminution of 2-back and 0-back performance, respectively; therefore interpretation of this finding is more complicated. DAR-0100A was generally well tolerated, with no serious medical or psychiatric adverse events; common side effects were mild to moderate and transient, consisting mainly of sedation, lightheadedness, tachycardia, and hypotension; however, we were able to minimize these effects, without altering the dose, with supportive measures, eg, co-administered normal saline. Although preliminary, these findings lend further clinical support to the potential of D 1 receptor agonists to treat schizophrenia-spectrum working memory impairments. These data suggest a need for further studies with larger group sizes, serum DAR-0100A levels, and a more comprehensive neuropsychological battery. © 2015 American College of Neuropsychopharmacology. All rights reserved.

Document Type: Article
Source: Scopus

Valtcheva, M.V.a b , Samineni, V.K.a , Golden, J.P.a , Gereau, R.W., IVa , Davidson, S.a
Enhanced nonpeptidergic intraepidermal fiber density and an expanded subset of chloroquine-responsive trigeminal neurons in a mouse model of dry skin itch
(2015) Journal of Pain, 16 (4), pp. 346-356. 

DOI: 10.1016/j.jpain.2015.01.005

a Washington University Pain Center, Department of Anesthesiology, Washington University in St. LouisSt. Louis, MO, United States
b Medical Scientist Training Program, Washington University in St. LouisSt. Louis, MO, United States

Chronic pruritic conditions are often associated with dry skin and loss of epidermal barrier integrity. In this study, repeated application of acetone and ether followed by water (AEW) to the cheek skin of mice produced persistent scratching behavior with no increase in pain-related forelimb wiping, indicating the generation of itch without pain. Cheek skin immunohistochemistry showed a 64.5% increase in total epidermal innervation in AEW-treated mice compared to water-treated controls. This increase was independent of scratching, because mice prevented from scratching by Elizabethan collars showed similar hyperinnervation. To determine the effects of dry skin treatment on specific subsets of peripheral fibers, we examined Ret-positive, calcitonin gene-related peptide (CGRP)-positive, and glial cell line-derived neurotrophic factor family receptor α3 (GFRα3)-positive intraepidermal fiber density. AEW treatment increased Ret-positive fibers but not CGRP-positive or GFRα3-positive fibers, suggesting that a specific subset of nonpeptidergic fibers could contribute to dry skin itch. To test whether trigeminal ganglion neurons innervating the cheek exhibited altered excitability after AEW treatment, primary cultures of retrogradely labeled neurons were examined using whole-cell patch clamp electrophysiology. AEW treatment produced no differences in measures of excitability compared to water-treated controls. In contrast, a significantly higher proportion of trigeminal ganglion neurons was responsive to the nonhistaminergic pruritogen chloroquine after AEW treatment. We conclude that nonpeptidergic, Ret-positive fibers and chloroquine-sensitive neurons may contribute to dry skin pruritus. Perspective This study examines the underlying neurobiological mechanisms of persistent dry skin itch. Our results indicate that nonpeptidergic epidermal hyperinnervation and nonhistaminergic pruritic receptors are potential targets for chronic pruritus. © 2015 American Pain Society.

Author Keywords
epidermis;  GDNF family receptor α3 (GFRa3);  glial cellderived neurotrophic factor (GDNF);  hyperinnervation;  Pruritus;  Ret;  xerosis

Document Type: Article
Source: Scopus

Thimgan, M.S.a b , Toedebusch, C.c , McLeland, J.c , Duntley, S.P.c d , Shaw, P.J.a
Excessive daytime sleepiness is associated with changes in salivary inflammatory genes transcripts
(2015) Mediators of Inflammation, 2015, art. no. 539627, . 

DOI: 10.1155/2015/539627

a Department of Anatomy and Physiology, Washington University, School of MedicineSt. Louis, MO, United States
b Department of Biological Sciences, Missouri University of Science and Technology, 400 W. 11th StreetRolla, MO, United States
c Department of Neurology, Washington University, School of MedicineSt. Louis, MO, United States
d Critical Care, Pulmonary and Sleep Associates, 274 Union BoulevardLakewood, CO, United States

Excessive daytime sleepiness (EDS) is a ubiquitous problem that affects public health and safety. A test that can reliably identify individuals that suffer from EDS is needed. In contrast to other methods, salivary biomarkers are an objective, inexpensive, and noninvasive method to identify individuals with inadequate sleep. Although we have previously shown that inflammatory genes are elevated in saliva samples taken from sleep deprived individuals, it is unclear if inflammatory genes will be elevated in clinical populations with EDS. In this study, salivary samples from individuals with sleep apnea were evaluated using the Taqman low density inflammation array. Transcript levels for 3 genes, including prostaglandin-endoperoxide synthase 2 (PTGS2), were elevated in patients with sleep apnea. Interestingly, PTGS2 was also elevated in patients with EDS but who did not have sleep apnea. These data demonstrate the feasibility of using salivary transcript levels to identify individuals that self-report excessive daytime sleepiness. © 2015 Matthew S. Thimgan et al.

Document Type: Article
Source: Scopus

Gidday, J.M.a b c
Extending injury- and disease-resistant CNS phenotypes by repetitive epigenetic conditioning
(2015) Frontiers in Neurology, 6 (MAR), art. no. 42, . 

DOI: 10.3389/fneur.2015.00042

a Department of Neurosurgery, Washington University School of MedicineSt Louis, MO, United States
b Department of Ophthalmology and Visual Sciences, Washington University School of MedicineSt Louis, MO, United States
c Department of Cell Biology and Physiology, Washington University School of MedicineSt Louis, MO, United States

Significant reductions in the extent of acute injury in the CNS can be achieved by exposure to different preconditioning stimuli, but the duration of the induced protective phenotype is typically short-lasting, and thus is deemed as limiting its clinical applicability. Extending the period over which such adaptive epigenetic changes persist - in effect, expanding conditioning's "therapeutic window" - would significantly broaden the potential applications of such a treatment approach in patients. The frequency of the conditioning stimulus may hold the key. While transient (1-3 days) protection against CNS ischemic injury is well established preclinically following a single preconditioning stimulus, repetitively presenting preconditioning stimuli extends the duration of ischemic tolerance by many weeks. Moreover, repetitive intermittent postconditioning enhances post-ischemic recovery metrics and improves long-term survival. Intermittent conditioning is also efficacious for preventing or delaying injury in preclinical models of chronic neurodegenerative disease, and for promoting long-lasting functional improvements in a number of other pathologies as well. Although the detailed mechanisms underlying these protracted kinds of neuroplasticity remain largely unstudied, accumulating empirical evidence supports the contention that all of these adaptive phenotypes are epigenetically mediated. Going forward, additional preclinical demonstrations of the ability to induce sustained beneficial phenotypes that reduce the burden of acute and chronic neurodegeneration, and experimental interrogations of the regulatory constructs responsible for these epigenetic responses, will accelerate the identification of not only efficacious but also practical, adaptive epigenetics-based treatments for individuals with neurological disease. © 2015 Gidday.

Author Keywords
Epigenetics;  Neuroprotection;  Postconditioning;  Preconditioning;  Retina;  Stroke

Document Type: Article
Source: Scopus

Monserrate, A.E.a b , Ryman, D.C.c d , Ma, S.c , Xiong, C.e , Noble, J.M.f , Ringman, J.M.g , Morris, J.C.c e , Danek, A.h , Müller-Sarnowski, F.h , Clifford, D.B.c , McDade, E.M.i , Brooks, W.S.j , Darby, D.G.k , Masters, C.L.k , Weston, P.S.J.l , Farlow, M.R.m , Graff-Radford, N.R.n , Salloway, S.P.o , Fagan, A.M.c , Oliver, A.c e , Bateman, R.J.c , Dominantly Inherited Alzheimer Networkp
Factors associated with the onset and persistence of post-lumbar puncture headache
(2015) JAMA Neurology, 72 (3), pp. 325-332. 

DOI: 10.1001/jamaneurol.2014.3974

a University of Puerto Rico School of MedicineSan Juan, Puerto Rico
b Institute of Clinical and Translational Sciences, Washington University School of MedicineSt Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8111St Louis, MO, United States
d Dominantly Inherited Alzheimer Network Clinical Core, Washington University School of MedicineSt Louis, MO, United States
e Division of Biostatistics, Washington University School of MedicineSt Louis, MO, United States
f Department of Neurology, Columbia University Medical CenterNew York, NY, United States
g Mary S. Easton Center for Alzheimer's Disease Research, University of CaliforniaLos Angeles, United States
h Department of Neurology, Ludwig-Maximilians Universität MunichMunich, Germany
i Department of Neurology, University of PittsburghPittsburgh, PA, United States
j Neuroscience Research Australia, University of New South WalesSydney, Australia
k Florey Institute for Neuroscience and Mental Health, University of MelbourneMelbourne, Australia
l School of Life and Medical Sciences, University College LondonLondon, United Kingdom
m Indiana Alzheimer Disease Center, Indiana UniversityIndianapolis, United States
n Department of Radiology, Mayo ClinicJacksonville, FL, United States
o Memory and Aging Program, Butler Hospital, Brown Medical SchoolProvidence, RI, United States

IMPORTANCE: This study assesses factors associated with the most common adverse event following lumbar puncture. OBJECTIVE: To identify factors associated with the risk, onset, and persistence of post-dural puncture headache (PDPH). DESIGN, SETTING, AND PARTICIPANTS: We performed univariate and multivariable analyses of 338 lumbar punctures in the Dominantly Inherited Alzheimer Network observational study using linear mixed models, adjusting for participant-level and family-level random effects. MAIN OUTCOMES AND MEASURES: We directly evaluated associations of 3 post-lumbar puncture outcomes (immediate postprocedural headache, PDPH at 24-hour follow-up, and PDPH receiving a therapeutic blood patch) with participant age and sex, positioning, collection method, needle size, needle insertion site, and cerebrospinal fluid (CSF) volume collected. RESULTS: The incidence of adverse events included 73 immediate postprocedural headaches (21.6%), 59 PDPHs at 24-hour follow-up (17.5%), and 15 PDPHs receiving a therapeutic blood patch (4.4%). Greater volume of CSF collected was associated with increased risk of immediate postprocedural headache, largely owing to a nonlinear increase in risk on collection of volumes above 30 mL (odds ratio, 3.73 for >30 mL and 0.98 for <17 mL). In contrast, collection of higher volumes showed a protective effect in decreasing rates of PDPH at 24-hour follow-up and rates of PDPH receiving a therapeutic blood patch (odds ratio, 0.35 per 10 mL). Although differences in needle size did not reach statistical significance, no participant in the 24G needle group received a therapeutic blood patch compared to 8 of 253 for the larger 22G needles. CONCLUSIONS AND RELEVANCE: Factors that acutely lower CSF pressure (eg, seated positioning or extracting very high volumes of CSF) may be associated with transient post-lumbar puncture headache, without increasing rates of persistent PDPH or therapeutic blood patch. Collection of up to 30 mL of CSF appears to be well tolerated and safe. Copyright 2015 American Medical Association. All rights reserved.

Document Type: Article
Source: Scopus

Ito, H.a , Shiwaku, H.a , Yoshida, C.a , Homma, H.a , Luo, H.a , Chen, X.a , Fujita, K.a , Musante, L.b , Fischer, U.b , Frints, S.G.M.c d , Romano, C.e , Ikeuchi, Y.f g , Shimamura, T.h , Imoto, S.h , Miyano, S.h , Muramatsu, S.-I.i , Kawauchi, T.j , Hoshino, M.k , Sudol, M.l , Arumughan, A.m , Wanker, E.E.m , Rich, T.n , Schwartz, C.o , Matsuzaki, F.p , Bonni, A.f g , Kalscheuer, V.M.b , Okazawa, H.a
In utero gene therapy rescues microcephaly caused by Pqbp1-hypofunction in neural stem progenitor cells
(2015) Molecular Psychiatry, 20 (4), pp. 459-471. 

DOI: 10.1038/mp.2014.69

a Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45, YushimaBunkyo-ku, Tokyo, Japan
b Department of Human Molecular Genetics, Max-Planck Institute for Molecular GeneticsBerlin-Dahlem, Germany
c Department of Clinical Genetics, University Hospital AzM MaastrichtMaastricht, Netherlands
d School for Oncology and Developmental Biology, GROW, Maastricht UniversityMaastricht, Netherlands
e Unità Operativa Complessa di Pediatria e Genetica Medica, IRCCS Associazione Oasi Maria SantissimaTroina (Enna), Italy
f Department of Anatomy and Neurobiology, Washington University School of MedicineSt Louis, MO, United States
g Department of Neurobiology, Harvard Medical SchoolBoston, MA, United States
h Human Genome Center, Institute of Medical Science, University of TokyoTokyo, Japan
i Department of Neurology, Jichi Medical UniversityTochigi, Japan
j Department of Anatomy, Keio University School of MedicineTokyo, Japan
k Department of Biochemistry and Cellular Biology, National Center for Neurology and PsychiatryTokyo, Japan
l Laboratory of Signal Transduction and Proteomic Profiling, Weis Center for Research, Geisinger ClinicDanville, PA, United States
m Department of Neurogenetics, Max-Delbrück Center for Molecular MedicineBerlin-Buch, Germany
n Institute of Infection, Immunity and Inflammation, University of GlasgowGlasgow, United Kingdom
o JC Self Research Institute of Human Genetics, Greenwood Genetic CenterGreenwood, SC, United States
p Laboratory for Cell Asymmetry, Center for Developmental Biology, RIKENChuo-ku, Kobe, Japan

Human mutations in PQBP1, a molecule involved in transcription and splicing, result in a reduced but architecturally normal brain. Examination of a conditional Pqbp1-knockout (cKO) mouse with microcephaly failed to reveal either abnormal centrosomes or mitotic spindles, increased neurogenesis from the neural stem progenitor cell (NSPC) pool or increased cell death in vivo. Instead, we observed an increase in the length of the cell cycle, particularly for the M phase in NSPCs. Corresponding to the developmental expression of Pqbp1, the stem cell pool in vivo was decreased at E10 and remained at a low level during neurogenesis (E15) in Pqbp1-cKO mice. The expression profiles of NSPCs derived from the cKO mouse revealed significant changes in gene groups that control the M phase, including anaphase-promoting complex genes, via aberrant transcription and RNA splicing. Exogenous Apc4, a hub protein in the network of affected genes, recovered the cell cycle, proliferation, and cell phenotypes of NSPCs caused by Pqbp1-cKO. These data reveal a mechanism of brain size control based on the simple reduction of the NSPC pool by cell cycle time elongation. Finally, we demonstrated that in utero gene therapy for Pqbp1-cKO mice by intraperitoneal injection of the PQBP1-AAV vector at E10 successfully rescued microcephaly with preserved cortical structures and improved behavioral abnormalities in Pqbp1-cKO mice, opening a new strategy for treating this intractable developmental disorder. © 2015 Macmillan Publishers Limited All rights reserved.

Document Type: Article
Source: Scopus

Elfenbein, H.A.
Individual Differences in Negotiation: A Nearly Abandoned Pursuit Revived
(2015) Current Directions in Psychological Science, 24 (2), pp. 131-136. 

DOI: 10.1177/0963721414558114

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

The commonsense notion that personal characteristics influence how effectively we negotiate has presented researchers with a mystery: Throughout the decades, scholars have concluded that there are few reliable findings to support it. In this article, I review existing research as well as new research in which my colleagues and I join a growing minority revisiting this nearly abandoned topic. The categories of individual differences previously studied include background characteristics, abilities, personality traits, motivations, and expectations and beliefs. Reviewing this work presents an optimistic conclusion: The strongest and most reliable predictors of negotiation performance are also the most open to personal change. Namely, positive expectations and comfort with negotiation consistently predict better performance. Another consistent finding is that abilities such as cognitive intelligence and creativity help for win-win agreements. Results suggest promise for a topic that is important to researchers, educators, organizations, and the public alike. © The Author(s) 2015

Author Keywords
abilities;  bargaining;  individual differences;  negotiation;  personality;  traits

Document Type: Article
Source: Scopus

Olsen, C.S.a , Kuppermann, N.b , Jaffe, D.M.c , Brown, K.d , Babcock, L.e , Mahajan, P.V.f , Leonard, J.C.c g
Interobserver agreement in retrospective chart reviews for factors associated with cervical spine injuries in children
(2015) Academic Emergency Medicine, 22 (4), pp. 487-491. 

DOI: 10.1111/acem.12630

a Division of Critical Care, Department of Pediatrics, University of Utah School of MedicineSalt Lake City, UT, United States
b University of California, School of MedicineDavis, CA, United States
c Department of Pediatrics, Washington University, St. Louis Children's HospitalSt. Louis, MO, United States
d Division of Emergency Medicine, Department of Pediatrics, George Washington University School of MedicineWashington, DC, United States
e Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical CenterCincinnati, OH, United States
f Children's Hospital of Michigan, Department of Pediatrics, Wayne State University School of MedicineDetroit, MI, United States
g Nationwide Children's Hospital, Ohio State UniversityColumbus, OH, United States

Objectives The objective was to describe the interobserver agreement between trained chart reviewers and physician reviewers in a multicenter retrospective chart review study of children with cervical spine injuries (CSIs). Methods Medical records of children younger than 16 years old with cervical spine radiography from 17 Pediatric Emergency Care Applied Research Network (PECARN) hospitals from years 2000 through 2004 were abstracted by trained reviewers for a study aimed to identify predictors of CSIs in children. Independent physician-reviewers abstracted patient history and clinical findings from a random sample of study patient medical records at each hospital. Interobserver agreement was assessed using percent agreement and the weighted kappa (κ) statistic, with lower 95% confidence intervals. Results Moderate or better agreement (κ > 0.4) was achieved for most candidate CSI predictors, including altered mental status (κ = 0.87); focal neurologic findings (κ = 0.74); posterior midline neck tenderness (κ = 0.74); any neck tenderness (κ = 0.89); torticollis (κ = 0.79); complaint of neck pain (κ = 0.83); history of loss of consciousness (κ = 0.89); nonambulatory status (κ = 0.74); and substantial injuries to the head (κ = 0.50), torso/trunk (κ = 0.48), and extremities (κ = 0.59). High-risk mechanisms showed near-perfect agreement (diving, κ = 1.0; struck by car, κ = 0.93; other motorized vehicle crash, κ = 0.93; fall, κ = 0.92; high-risk motor vehicle collision, κ = 0.89; hanging, κ = 0.80). Fair agreement was found for clotheslining mechanisms (κ = 0.36) and substantial face injuries (κ = 0.40). Conclusions Most retrospectively assessed variables thought to be predictive of CSIs in blunt trauma-injured children had at least moderate interobserver agreement, suggesting that these data are sufficiently valid for use in identifying potential predictors of CSI. © 2015 by the Society for Academic Emergency Medicine.

Document Type: Conference Paper
Source: Scopus

Shinawi, M.a , Coorg, R.b , Shimony, J.S.c , Grange, D.K.a , Al-Kateb, H.d
Intragenic CAMTA1 deletions are associated with a spectrum of neurobehavioral phenotypes
(2015) Clinical Genetics, 87 (5), pp. 478-482. 

DOI: 10.1111/cge.12407

a Department of Pediatrics Division of Genetics and Genomic Medicine, 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 Radiology, Washington University School of MedicineSt. Louis, MO, United States
d Department of Pathology and Immunology, Washington University School of MedicineSt. Louis, MO, United States

Intragenic copy number variations involving the CAMTA1 (calmodulin-binding transcription activator 1) gene have recently been reported in four unrelated families with intellectual disability (ID), ataxia, behavioral- and cerebellar-abnormalities. We report a detailed phenotypic and molecular characterization of three individuals with novel intragenic CAMTA1 deletions from two unrelated families and compare the findings to those of previously reported patients. Our patients had deletions of exons 6-11 and presented with ID, developmental delay (DD), attention deficit hyperactivity disorder (ADHD) and constipation. Two individuals from one family had also unsteady gait. Consistent phenotypes associated with CAMTA1 intragenic rearrangements include ID, speech problems and some dysmorphic features whereas neurobehavioral abnormalities are variable. We did not observe obvious phenotypic differences between patients with in-frame and those with frameshift rearrangements. There is an increased evidence that CAMTA1 has a role in brain and cerebellar function. CAMTA1 should be added to the growing list of genes associated with ID/DD, especially when behavioral problems, cerebellar signs, and/or dysmorphism are also present. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Author Keywords
CAMTA1;  Chromosomal;  Clinical genetics;  Deletions;  Microarray;  Neurobehavioral abnormalities

Document Type: Article
Source: Scopus

Krauss, M.J.a , Cavazos-Rehg, P.A.a , Agrawal, A.b , Bierut, L.J.a , Grucza, R.A.a
Long-term effects of minimum legal drinking age laws on marijuana and other illicit drug use in adulthood
(2015) Drug and Alcohol Dependence, 149, pp. 173-179. 

DOI: 10.1016/j.drugalcdep.2015.01.043

a Department of Psychiatry, Washington University School of Medicine, 660 South Euclid AvenueSt. Louis, MO, United States
b Department of Psychology, Washington University School of Medicine, 660 South Euclid AvenueSt. Louis, MO, United States

Background: Exposure to permissive minimum legal drinking age (MLDA) laws (ability to purchase alcohol <21 years) during adolescence can have long-term effects, including heavy alcohol use or alcohol use disorders as adults. We examined whether exposure to permissive MLDA laws during adolescence has long-term effects on illicit drug use and disorders in adulthood. Methods: Participants from the 2004-2012 National Survey of Drug Use and Health (NSDUH) were linked with historical state MLDA laws. Participants born in 1949-1972 (age 31-63 years at observation, n= 110,300) were analyzed because they came of legal age for alcohol purchase when changes occurred in state MLDA laws. Logistic regression was used to model drug use measures as a function of exposure to permissive MLDA during adolescence, adjusting for state and birth-year fixed effects, demographics, and salient state characteristics. Results: Rates of past month use, past year use, and abuse/dependence of marijuana were 4.7%, 7.8%, and 1.2%, respectively. Rates of past month use, past year use, and abuse/dependence of illicit drugs other than marijuana were 2.9%, 6.2%, and 0.7%, respectively. Among the full sample, exposure to permissive MLDA laws was not significantly associated with drug use or abuse/dependence in adulthood. Men exposed to permissive MLDA laws were at 20% increased odds of past year illicit drug use (aOR 1.20, 95% CI 1.09-1.32). Conclusions: Restricting alcohol access during adolescence did not increase long-term drug use. Allowing the purchase of alcohol among those less than 21 years of age could increase the risk of drug use later in life. © 2015 Elsevier Ireland Ltd.

Author Keywords
Alcohol policy;  Illicit drugs;  Marijuana;  Minimum legal drinking age

Document Type: Article
Source: Scopus

Abernathy, D.G.a b , Yoo, A.S.a
MicroRNA-dependent genetic networks during neural development
(2015) Cell and Tissue Research, 359 (1), pp. 179-185. 

DOI: 10.1007/s00441-014-1899-4

a Department of Developmental Biology, Washington University School of MedicineSt. Louis, MO, United States
b Washington University School of MedicineSt. Louis, MO, United States

The development of the structurally and functionally diverse mammalian nervous system requires the integration of numerous levels of gene regulation. Accumulating evidence suggests that microRNAs are key mediators of genetic networks during neural development. Importantly, microRNAs are found to regulate both feedback and feedforward loops during neural development leading to large changes in gene expression. These repressive interactions provide an additional mechanism that facilitates the establishment of complexity within the nervous system. Here, we review studies that have enabled the identification of microRNAs enriched in the brain and discuss the way that genetic networks in neural development depend on microRNAs. © Springer-Verlag Berlin Heidelberg 2014.

Author Keywords
Brain;  Direct reprogramming;  Epigenetics;  Genetic networks;  MicroRNAs;  Neural development

Document Type: Review
Source: Scopus

Moreira, P.A.S.a , Robert Cloninger, C.b , Dinis, L.a , Sá, L.a , Oliveira, J.T.a , Dias, A.a , Oliveira, J.a
Personality and well-being in adolescents
(2015) Frontiers in Psychology, 6 (JAN), art. no. 494, . 

DOI: 10.3389/fpsyg.2015.00494

a Instituto de Psicologia e de Ciências da Educação, Universidade Lusíada do PortoPorto, Portugal
b Center for Well-being, School of Medicine, Washington UniversitySt. Louis, MO, United States

Different profiles of the character dimensions of self-directedness, cooperativeness and self-transcendence result in different levels of wellbeing among adults. However, the influence of the multidimensional character profiles on adolescents' composite wellbeing remains unexplored. This study builds on previous studies with adults, and examines the linear and non-linear associations between the dimensions of the psychobiological model of personality and well-being in adolescents. Participated in this study 1540 adolescents (M = 15.44, SD = 1.731). Personality was assessed using the Temperament and Character Inventory (TCI). Well-being was evaluated in a composite perspective: satisfaction with social support, health-related quality of life, satisfaction with life and affect. Variable-centered and individual-centered analyses were performed. Self-directedness was strongly associated with all dimensions of affective and cognitive well-being regardless of the other two character traits. Cooperativeness was associated with non-affective well-being and with positive affect, but only when associated to elevation of Self-directedness and Self-transcendence. Self-Directedness and Cooperativeness explained 15.5% of the non-affective well-being variance. Self-Directedness and Self-Transcendence explained 10.4% of the variance in affective well-being. This study confirms the tendencies found in previous studies with adults from other societies, where each character dimension gives an independent contribution to well-being depending on the interactions with other Character dimensions. Also, this study highlights the importance of considering the non-linear influences of the character dimensions in understanding of adolescents' wellbeing. These results have strong implications for youth positive mental health promotion, including for school-based policies and practices. © 2015 Moreira, Cloninger, Dinis, Sá, Oliveira, Dias and Oliveira.

Author Keywords
Adolescents;  Character;  Happiness;  Health;  Personality;  Psychobiological model of personality;  Wellbeing;  Wellness

Document Type: Article
Source: Scopus

Yang, S.a , Sung, J.a b , Kim, J.-H.c , Song, Y.-M.d , Lee, K.e , Kim, H.-N.f , Kim, H.-L.f , Cloninger, C.R.g
Some personality traits converge gradually by long-term partnership through the lifecourse - Genetic and environmental structure of Cloninger's temperament and character dimensions
(2015) Journal of Psychiatric Research, 63, pp. 43-49. 

DOI: 10.1016/j.jpsychires.2015.01.020

a Complex Disease and Genome Epidemiology Branch, Department of Epidemiology, School of Public Health, Seoul National University, South Korea
b Institute of Environment and Health, Seoul National University, South Korea
c Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, South Korea
d Department of Family Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, South Korea
e Department of Family Medicine, Busan Paik Hospital, Inje University College of Medicine, South Korea
f Department of Biochemistry, School of Medicine, Ewha Womans University, South Korea
g Departments of Psychiatry, Genetics, and Psychology, Washington UniversitySt. Louis, MO, United States

Temperament and Character Inventory (TCI) is a comprehensive personality inventory that is widely used in behavioral genetics. The original theory suggested that temperament traits were under genetic influences, whereas character traits were gradually built by an interaction between temperaments and environment until early adulthood. This study attempted to evaluate TCI by examining the genetic and environmental contributions to personality with particular attention to spousal effects. From 687 families, a total of 3459 Korean adult individuals completed the survey. Among them, there were 542 Monozygotic (MZ) twin pairs and 122 Dizygotic twin pairs. Intraclass correlation coefficients (ICCs) and heritability were calculated to examine the genetic and shared environmental contributions to personality. Moderate genetic contributions (0.17-0.43) were found for all TCI traits along with the evidence of shared environment (0.11-0.31) for harm avoidance (HA) and all characters. The ICCs of TCI in MZ pairs ranged 0.36-0.46. Spouses' had little resemblance for temperament, whereas for character dimensions, spouses (0.27-0.38) were more similar than first degree relatives (0.10-0.29). Resemblance between spouses increased with duration of marriage for most characters and HA. When the growing similarities between spouses were compared with their MZ cotwins' for subgroup of 81 trios, self-directedness (SD) of character showed even more similarities toward their spouses than cotwins as partnership duration increased (r=0.32). Our findings with regard to change in SD into late adulthood support the psychobiological theory of temperament and character, which suggests that both personality domains have distinct developmental trajectories despite equally large genetic influences. © 2015 Elsevier Ltd.

Author Keywords
Heritability;  Personality;  Temperament and character inventory;  Twin-family study

Document Type: Article
Source: Scopus

Gilbert, D.G.a , Pergadia, M.L.b c
The psychology of the smoker
(2015) Progress in Respiratory Research, 42, pp. 58-71. 

DOI: 10.1159/000369325

a Southern Illinois University, Department of Psychology, LSII, 1125 Lincoln DriveCarbondale, IL, United States
b Charles E. Schmidt College of Medicine, Florida Atlantic UniversityBoca Raton, FL, United States
c Washington University, School of MedicineSt. Louis, MO, United States

Vulnerability to becoming a smoker, the likelihood of smoking in a given situation and individual differences in smoking patterns are influenced by complex interactions of nicotine with genetically influenced differences in brain functioning, psychological traits, learning and responses to contextual states. This review addresses these interactions using the recently developed Research Domain Criteria (RDoC) of the National Institute of Mental Health (NIMH) that provide new ways of classifying neuropsychiatric disorders based on basic dimensions across multiple units of analysis, from genes to neural circuits to behavior, that cut across disorders as traditionally defined. NIMH expects that the RDoC approach will lead to new and better-focused treatments. The RDoC research domains/constructs are: (1) negative valence systems (fear, anxiety and loss); (2) positive valence systems (reward learning and reward valuation); (3) cognitive systems (attention, perception, working memory and cognitive control); (4) systems for social processes (attachment formation, social communication, perception of self and perception of others), and (5) arousal/modulatory systems (arousal, circadian rhythm and sleep wakefulness). The smoker status and the acute effects of smoking/nicotine and smoking abstinence have well-established and significant effects on all of these systems, though the nuances of the subcategories articulated in the RDoC have only recently received attention in studies of smokers. © 2015 S. Karger AG, Basel.

Document Type: Review
Source: Scopus

Delforterie, M.J.a , Lynskey, M.T.b , Huizink, A.C.a , Creemers, H.E.c , Grant, J.D.d , Few, L.R.d , Glowinski, A.L.d , Statham, D.J.e , Trull, T.J.f , Bucholz, K.K.d , Madden, P.A.F.d , Martin, N.G.g , Heath, A.C.d , Agrawal, A.d
The relationship between cannabis involvement and suicidal thoughts and behaviors
(2015) Drug and Alcohol Dependence, 150, pp. 98-104. 

DOI: 10.1016/j.drugalcdep.2015.02.019

a VU University, Department of Developmental Psychology and EMGO, Institute for Health and Care ResearchAmsterdam, Netherlands
b Addictions Department, Institute of Psychiatry, King's College London, United Kingdom
c Research Institute of Child Development and Education, University of AmsterdamAmsterdam, Netherlands
d Department of Psychiatry, Washington University School of MedicineSt. Louis, MO, United States
e School of Social Sciences, University of the Sunshine CoastQLD, Australia
f University of Missouri, Department of Psychological SciencesColumbia, MO, United States
g QIMR Berghofer Medical Research InstituteBrisbane, QLD, Australia

Background: In the present study, we examined the relationship between cannabis involvement and suicidal ideation (SI), plan and attempt, differentiating the latter into planned and unplanned attempt, taking into account other substance involvement and psychopathology. Methods: We used two community-based twin samples from the Australian Twin Registry, including 9583 individuals (58.5% female, aged between 27 and 40). The Semi-Structured Assessment of the Genetics of Alcoholism (SSAGA) was used to assess cannabis involvement which was categorized into: (0) no cannabis use (reference category); (1) cannabis use only; (2) 1-2 cannabis use disorder symptoms; (3) 3 or more symptoms. Separate multinomial logistic regression analyses were conducted for SI and suicide attempt with or without a plan. Twin analyses examined the genetic overlap between cannabis involvement and SI. Results: All levels of cannabis involvement were related to SI, regardless of duration (odds ratios [ORs]. = 1.28-2.00, p<. 0.01). Cannabis use and endorsing ≥3 symptoms were associated with unplanned (SANP; ORs. = 1.95 and 2.51 respectively, p<. 0.05), but not planned suicide attempts (p>. 0.10). Associations persisted even after controlling for other psychiatric disorders and substance involvement. Overlapping genetic (rG= 0.45) and environmental (rE= 0.21) factors were responsible for the covariance between cannabis involvement and SI. Conclusions: Cannabis involvement is associated, albeit modestly, with SI and unplanned suicide attempts. Such attempts are difficult to prevent and their association with cannabis use and cannabis use disorder symptoms requires further study, including in different samples and with additional attention to confounders. © 2015 .

Author Keywords
Cannabis use;  Cannabis use disorder symptoms;  Suicidal thoughts and behaviors

Document Type: Article
Source: Scopus

Raichle, M.E.
The restless brain: How intrinsic activity organizes brain function
(2015) Philosophical Transactions of the Royal Society B: Biological Sciences, 370 (1668), art. no. 20140172, 11 p. Cited 1 time.

DOI: 10.1098/rstb.2014.0172

Mallinckrodt Institute of Radiology, Washington University School of Medicine, 4525 Scott AvenueSt Louis, MO, United States

Traditionally studies of brain function have focused on task-evoked responses. By their very nature such experiments tacitly encourage a reflexive view of brain function. While such an approach has been remarkably productive at all levels of neuroscience, it ignores the alternative possibility that brain functions are mainly intrinsic and ongoing, involving information processing for interpreting, responding to and predicting environmental demands. I suggest that the latter view best captures the essence of brain function, a position that accords well with the allocation of the brain’s energy resources, its limited access to sensory information and a dynamic, intrinsic functional organization. The nature of this intrinsic activity, which exhibits a surprising level of organization with dimensions of both space and time, is revealed in the ongoing activity of the brain and its metabolism. As we look to the future, understanding the nature of this intrinsic activity will require integrating knowledge from cognitive and systems neuroscience with cellular and molecular neuroscience where ion channels, receptors, components of signal transduction and metabolic pathways are all in a constant state of flux. The reward for doing so will be a much better understanding of human behaviour in health and disease. ã 2015 The Authors.

Author Keywords
Aerobic glycolysis;  Functional connectivity;  Local field potentials;  Neoteny;  Resting state;  Slow cortical potentials

Document Type: Review
Source: Scopus

Corley, M., Kroll, K.L.
The roles and regulation of Polycomb complexes in neural development
(2015) Cell and Tissue Research, 359 (1), pp. 65-85. 

DOI: 10.1007/s00441-014-2011-9

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

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. © Springer-Verlag Berlin Heidelberg 2014.

Author Keywords
Chromatin;  Epigenetic;  Gliogenesis;  Neurogenesis;  Polycomb

Document Type: Review
Source: Scopus

Haroutounian, S.a , Nikolajsen, L.b c , Finnerup, N.B.b , Jensen, T.S.b d
Topical Capsaicin Response as a Phenotypic Measure in Patients with Pain
(2015) Pain Medicine (United States), 16 (4), pp. 823-825. 

DOI: 10.1111/pme.12657

a Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of MedicineSt Louis, MO, United States
b Danish Pain Research Center, Aarhus University HospitalAarhus, Denmark
c Department of Anesthesiology, Aarhus University HospitalAarhus, Denmark
d Department of Neurology, Aarhus University HospitalAarhus, Denmark

Document Type: Letter
Source: Scopus

Rucker, J.J.H.a e , Tansey, K.E.a c , Rivera, M.a p , Pinto, D.b q , Cohen-Woods, S.a , Uher, R.a h , Aitchison, K.J.a n , Craddock, N.c , Owen, M.J.c , Jones, L.o , Jones, I.c , Korszun, A.f , Barnes, M.R.d , Preisig, M.g , Mors, O.m , Maier, W.i , Rice, J.j , Rietschel, M.k , Holsboer, F.l , Farmer, A.E.a e , Craig, I.W.a , Scherer, S.W.b r , McGuffin, P.a e , Breen, G.a e
Phenotypic Association Analyses with Copy Number Variation in Recurrent Depressive Disorder
(2015) Biological Psychiatry, . Article in Press. 

DOI: 10.1016/j.biopsych.2015.02.025

a Medical Research Council Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, United Kingdom
b The Centre for Applied Genomics and Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
c Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, Wales, United Kingdom
d GlaxoSmithKline, Verona, Italy, and Greenford
e National Institute for Health Research Biomedical Research Centre, South London and Maudsley National Health Service Foundation Trust and Institute of Psychiatry, King's College London
f Barts and The London School of Medicine and Denistry, Queen Mary University of London, London, United Kingdom
g Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland
h Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada
i Department of Psychiatry, University of Bonn, Bonn, Germany
j Department of Psychiatry, Washington University, St Louis, Missouri
k Central Institute of Mental Health, Mannheim
l Max Planck Institute of Psychiatry (FH), Munich, Germany
m Centre of Psychiatric Research, Aarhus University Hospital, Risskov, Denmark
n Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada
o Department of Psychiatry, University of Birmingham, Birmingham, United Kingdom
p Section of Psychiatry, Institute of Neurosciences, Biomedical Research Centre, CIBERSAM, University of Granada, Granada, Spain
q Departments of Psychiatry and Genetics and Genomic Sciences, Seaver Autism Center, The Mindich Child Health and Development Institute, Mount Sinai School of Medicine, New York, New York
r McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada

Background: Defining the molecular genomic basis of the likelihood of developing depressive disorder is a considerable challenge. We previously associated rare, exonic deletion copy number variants (CNV) with recurrent depressive disorder (RDD). Sex chromosome abnormalities also have been observed to co-occur with RDD. Methods: In this reanalysis of our RDD dataset(N = 3106 cases; 459 screened control samples and 2699 population control samples), we further investigated the role of larger CNVs and chromosomal abnormalities in RDD and performed association analyses with clinical data derived from this dataset. Results: We found an enrichment of Turner's syndrome among cases of depression compared with the frequency observed in a large population sample(N = 34,910) of live-born infants collected in Denmark (two-sided p = .023, odds ratio = 7.76 [95% confidence interval = 1.79-33.6]), a case of diploid/triploid mosaicism, and several cases of uniparental isodisomy. In contrast to our previous analysis, large deletion CNVs were no more frequent in cases than control samples, although deletion CNVs in cases contained more genes than control samples (two-sided p = .0002). Conclusions: After statistical correction for multiple comparisons, our data do not support a substantial role for CNVs in RDD, although (as has been observed in similar samples) occasional cases may harbor large variants with etiological significance. Genetic pleiotropy and sample heterogeneity suggest that very large sample sizes are required to study conclusively the role of genetic variation in mood disorders. © 2015 Society of Biological Psychiatry.

Author Keywords
Affective Disorders;  Copy Number Variation;  Depression;  Genetics;  Phenotypes

Document Type: Article in Press
Source: Scopus

Heath, A.C., Waldron, M.C., Martin, N.G., Nelson, E.C., Bucholz, K.K., Madden, P.A.
Human mate selection and addiction: a conceptual critique
(2014) Behavior genetics, 44 (5), pp. 419-426. 

DOI: 10.1007/s10519-014-9669-3

Department of Psychiatry 8134, Washington University School of Medicine, Midwest Alcoholism Research Center, 4560 Clayton Avenue, Suite 1000, St Louis, MO, 63110, USA, AHeath@WUSTL.EDU

The authors review past work on modeling human mate selection, and suggest, using illustrations from existing literature on the impact of alcoholism on relationship formation and dissolution and reproduction, that the challenges of adequately characterizing human mate selection have not yet been overcome. Some paths forwards are suggested.

Document Type: Review
Source: Scopus

April 15, 2015

Suga, N.
Neural processing of auditory signals in the time domain: Delay-tuned coincidence detectors in the mustached bat
(2015) Hearing Research, 324, pp. 19-36. 

DOI: 10.1016/j.heares.2015.02.008

Department of Biology, Washington University, One Brookings DriveSt. Louis, MO, United States

The central auditory system produces combination-sensitive neurons tuned to a specific combination of multiple signal elements. Some of these neurons act as coincidence detectors with delay lines for the extraction of spectro-temporal information from sounds. "Delay-tuned" neurons of mustached bats are tuned to a combination of up to four signal elements with a specific delay between them and form a delay map. They are produced in the inferior colliculus by the coincidence of the rebound response following glycinergic inhibition to the first harmonic of a biosonar pulse with the short-latency response to the 2nd-4th harmonics of its echo. Compared with collicular delay-tuned neurons, thalamic and cortical ones respond more to pulse-echo pairs than individual sounds. Cortical delay-tuned neurons are clustered in the three separate areas. They interact with each other through a circuit mediating positive feedback and lateral inhibition for adjustment and improvement of the delay tuning of cortical and subcortical neurons. The current article reviews the mechanisms for delay tuning and the response properties of collicular, thalamic and cortical delay-tuned neurons in relation to hierarchical signal processing. © 2015 Elsevier B.V.

Document Type: Review
Source: Scopus

Farlow, J.L.a , Lin, H.a , Sauerbeck, L.b , Lai, D.a , Koller, D.L.a , Pugh, E.c , Hetrick, K.c , Ling, H.c , Kleinloog, R.d , Van Der Vlies, P.e , Deelen, P.e f , Swertz, M.A.e f , Verweij, B.H.d , Regli, L.d g , Rinkel, G.J.E.d , Ruigrok, Y.M.d , Doheny, K.c , Liu, Y.a , Foroud, T.a i , Broderick, J.b h , Woo, D.h , Kissela, B.h , Kleindorfer, D.h , Schneider, A.h , Zuccarello, M.h , Ringer, A.h , Deka, R.h , Brown, R.D., Jr.j , Huston, J., IIIj , Mesissner, I.j , Wiebers, D.j , Qureshi, A.I.k , Rasmussen, P.A.l , Connolly, E.S., Jr.m , Sacco, R.L.m , Malkaff, M.n , Payner, T.D.o , Ferguson, G.G.p , Aldrich, E.F.q , Rouleau, G.r , Anderson, C.S.s , Mee, E.W.t , Hankey, G.J.u , Knuckey, N.v , Reilly, P.L.w , Laidlaw, J.D.x , D'Urso, P.y , Rosenfeld, J.V.y , Morgan, M.K.z , Dorsch, N.aa , Besser, M.ab , Batjer, , Richard, , Kassam, , Steinberg, , Johnston, , Ko, , Giannotta, S.L.ah , Kassell, , Worrall, , Lui, , Dumont, , Tirschell, D.L.aj , Kaufmann, A.M.ak , Fisher, W.S., IIIal , Aziz, , Day, , Du, , Ogilvy, , Lewis, S.B.ap , Murphy, , Radvany, , Gandhi, , Lisabeth, , Pandey, , Morgenstern, , Derdeyn, , Langefeld, , Bailey-Wilson,
Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm
(2015) PLoS ONE, 10 (3), art. no. e0121104, . 

DOI: 10.1371/journal.pone.0121104

a Department of Medical and Molecular Genetics, Indiana University, School of MedicineIndianapolis, IN, United States
b Department of Neurology and Rehabilitation Medicine, University of Cincinnati, School of MedicineCincinnati, OH, United States
c Center for Inherited Disease Research, Johns Hopkins UniversityBaltimore, MD, United States
d Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center UtrechtUtrecht, Netherlands
e Department of Genetics, University Medical Center Groningen, University of GroningenGroningen, Netherlands
f Genomics Coordination Center, University Medical Center Groningen, University of GroningenGroningen, Netherlands
g Department of Neurosurgery, University Hospital ZurichZurich, Switzerland
h University of Cincinnati, United States
i Indiana University, United States
j Mayo ClinicRochester, United States
k University of Medicine and Dentistry of New Jersey, United States
l Cleveland Clinic Foundation, United States
m Columbia University, United States
n University of TexasHouston, United States
o Indianapolis Neurosurgical Group, Inc, Goodman Campbell Brain and Spine, United States
p University of Western OntarioLondon, United Kingdom
q University of MarylandBaltimore, United States
r McGill University, University of Montreal, Notre Dame Hospital, Canada
s Auckland UniServices, George InstituteSydney, United States
t Auckland Uniservices, New Zealand
u Royal Perth Hospital, Australia
v Sir Charles Gairdner Hospital, Australia
w Royal Adlaide Hospital, Australia
x Royal Melbourne Hospital, Australia
y Alfred Hospital, Australia
z Royal North Shore Hospital, Australia
aa Westmead Hospital, Australia
ab Royal Prince Alfred Hospital, Australia
ac Northwestern University, United States
ad University of Ottawa, Canada
ae University of Pittsburgh, United States
af Stanford University, United States
ag University of CaliforniaSan Francisco, United States
ah University of Southern California, United States
ai University of Virginia, United States
aj University of WashingtonSeattle, United States
ak University of ManitobaWinnipeg, Canada
al University of AlabamaBirmingham, United States
am Allegheny General Hospital, United States
an Brigham and Women's HospitalBoston, United States
ao Massachusetts General HospitalBoston, United States
ap University of FloridaGainesville, United States
aq Johns Hopkins University, United States
ar University of MichiganAnn Arbor, United States
as Washington UniversitySt. Louis, United States
at Wake Forest School of Medicine, United States

Genetic risk factors for intracranial aneurysm (IA) are not yet fully understood. Genomewide association studies have been successful at identifying common variants; however, the role of rare variation in IA susceptibility has not been fully explored. In this study, we report the use of whole exome sequencing (WES) in seven densely-affected families (45 individuals) recruited as part of the Familial Intracranial Aneurysm study. WES variants were prioritized by functional prediction, frequency, predicted pathogenicity, and segregation within families. Using these criteria, 68 variants in 68 genes were prioritized across the seven families. Of the genes that were expressed in IA tissue, one gene (TMEM132B) was differentially expressed in aneurysmal samples (n=44) as compared to control samples (n=16) (false discovery rate adjusted p-value=0.023). We demonstrate that sequencing of densely affected families permits exploration of the role of rare variants in a relatively common disease such as IA, although there are important study design considerations for applying sequencing to complex disorders. In this study, we explore methods of WES variant prioritization, including the incorporation of unaffected individuals, multipoint linkage analysis, biological pathway information, and transcriptome profiling. Further studies are needed to validate and characterize the set of variants and genes identified in this study. © 2015 Farlow et al.

Document Type: Article
Source: Scopus

Sahlholm, K.a , Liao, F.b , Holtzman, D.M.b , Xu, J.a , Mach, R.H.a c
Sigma-2 receptor binding is decreased in female, but not male, APP/PS1 mice
(2015) Biochemical and Biophysical Research Communications, . Article in Press. 

DOI: 10.1016/j.bbrc.2015.03.052

a Department of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd., St. Louis, MO 63110, USA
b Department of Neurology, Washington University School of Medicine, 510 S. Kingshighway Blvd., St. Louis, MO 63110, USA
c University of Pennsylvania, Department of Radiology, 231 S. 34th St, Philadelphia, PA 19104, USA

The sigma-2 receptor is a steroid-binding membrane-associated receptor which has been implicated in cell survival. Sigma-2 has recently been shown to bind amyloid-β (Aβ) oligomers in Alzheimer's disease (AD) brain. Furthermore, blocking this interaction was shown to prevent or reverse the effects of Aβ to cause cognitive impairment in mouse models and synaptic loss in neuronal cultures. In the present work, the density of sigma-2 receptors was measured in a double transgenic mouse model of amyloid-β deposition (APP/PS1). Comparisons were made between males and females and between transgenic and wt animals.Sigma-2 receptor density was assessed by quantitative autoradiography performed on coronal brain slices using [3H]N-[4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)butyl]-2-methoxy-5-methyl-benzamide ([3H]RHM-1), which has a 300-fold selectivity for the sigma-2 receptor over the sigma-1 receptor. The translocator protein of 18kDa (TSPO) is expressed on activated microglia and is a marker for neuroinflammation. TSPO has been found to be upregulated in neurodegenerative disorders, including AD. Therefore, in parallel with the sigma-2 autoradiography experiments, we measured TSPO expression using the selective radioligand, [3H]PBR28. We also quantified Aβ plaque burden in the same animals using a monoclonal antibody raised against aggregated Aβ.Sigma-2 receptor density was significantly decreased in piriform and motor cortices as well as striata of 16-month old female, but not male, APP/PS1 mice as compared to their wt counterparts. [3H]PBR28 binding and immunostaining for Aβ plaques were significantly increased in piriform and motor cortices of both male and female transgenic mice. In striatum however, significant increases were observed only in females. © 2015 Elsevier Inc.

Author Keywords
Alzheimer's disease;  Peripheral benzodiazepine receptor;  PGRMC1;  Sigma-2 receptor;  Transgenic mice

Document Type: Article in Press
Source: Scopus

Goyal, M.S.a , Gottumukkala, R.a , Bhalla, S.a , Kates, A.b , Zipfel, G.J.c , Derdeyn, C.P.a c
Bicuspid aortic valves and thoracic aortic aneurysms in patients with intracranial aneurysms
(2015) Neurology, 84 (1), pp. 46-49. 

DOI: 10.1212/WNL.0000000000001104

a Mallinckrodt Institute of Radiology, Washington University School of MedicineSt. Louis, MO, United States
b Cardiovascular Division, Department of Internal Medicine, Washington University School of MedicineSt. Louis, MO, United States
c Departments of Neurology and Neurosurgery, Washington University School of MedicineSt. Louis, MO, United States

Objective: The purpose of this study was to determine the prevalence of bicuspid aortic valves (BAVs) and thoracic ascending aortic aneurysms (TAAs) in a retrospective cohort of patients treated for intracranial aneurysms (IAs). Methods: Patients treated for IA at our institution between 2002 and 2011 were identified and their clinical records reviewed. Those without an echocardiogram of sufficient quality to assess the aortic valve were excluded. The prevalence of BAVs and TAAs in this remaining cohort was determined based on echocardiography reports, medical records, and cross-sectional chest imaging. Results: Of 1,047 patients, 317 had adequate echocardiography for assessment of BAV. Of these, 82 also had cross-sectional chest imaging. Of the 317 patients, 2 had BAV and 15 had TAA. The prevalence of BAVs (0.6%, 95% confidence interval 0.2%-2.2%) was similar to population prevalence estimates for this condition; however, the prevalence of TAAs (4.7%, 95% confidence interval 2.9%-7.6%) was larger than expected in a normal age- and sex-matched population. Conclusions: Our data demonstrate an association between IA and TAA, but not independently for BAV. © 2014 American Academy of Neurology.

Document Type: Article
Source: Scopus

Søvik, E.a , Perry, C.J.b , Barron, A.B.c
Insect reward systems: Comparing flies and bees
(2015) Advances in Insect Physiology, 48, pp. 189-226. 

DOI: 10.1016/bs.aiip.2014.12.006

a Department of Biology, Washington University in St. LouisSt. Louis, MO, United States
b School of Chemical and Biological Sciences, Queen Mary UniversityLondon, United Kingdom
c Department of Biological Sciences, Macquarie UniversitySydney, NSW, Australia

Many elements of animal behaviour are organised by an innate reward-seeking drive stemming from neurobiological reward systems. The behavioural concept of reward and its neurobiological substrates was initially developed in mammalian systems, and there it has become clear that several novel social behaviours evolved through the co-option of reward pathways. Only more recently has reward been explored in insects. In this review, we consider current knowledge about reward pathways in the two predominant insect models: Drosophila melanogaster and the honey bee Apis mellifera. These two models are phylogenetically distantly related and have vastly different ecologies: fruit flies are mostly solitary while honey bees live in complex societies involving social foraging and brood care. Initially, it was assumed the reward system was essentially similar between these two organisms, but more recent studies have appeared to highlight quite significant differences. Here, we critically evaluate apparent differences in the neurobiology of the reward system between these organisms. We discuss which differences may be real and which may be reflective of the very different modes of analysis applied in these two models. Finally, we discuss how modification of reward systems might have contributed to social evolution in insects. © 2015 Elsevier Ltd.

Author Keywords
Dopamine;  Drosophila;  Honey bee;  Invertebrate neurobiology;  OA-VUMa2;  Octopamine;  Reward seeking;  Social evolution;  Social reward;  VUMmx1

Document Type: Article
Source: Scopus

Surratt, H.L.a , Kurtz, S.P.a , Levi-Minzi, M.A.a , Cicero, T.J.b , Tsuyuki, K.a , O'Grady, C.L.a
Pain treatment and antiretroviral medication adherence among vulnerable HIV-positive patients
(2015) AIDS Patient Care and STDs, 29 (4), pp. 186-192. 

DOI: 10.1089/apc.2014.0104

a Center for Applied Research on Substance Use and Health Disparities, Nova Southeastern University, 2 NE 40th StreetMiami, FL, United States
b Department of Psychiatry, Washington University, School of MedicineSt. Louis, MO, United States

Pain represents a significant source of morbidity, function loss, and decreased quality of life among people living with HIV. The present study examined the associations among pain, pain treatment, and ARV adherence among indigent, HIV-positive substance abusers. Participants were recruited via targeted sampling strategies, and completed a one-time computer-assisted personal interview. ANOVA and chi-square tests were used to analyze differences in demographics, health and psychological status, health behaviors, by pain and pain treatment status; a multivariate logistic regression model was constructed to examine the contribution of pain/treatment status to recent ARV adherence. Results indicated that those with untreated pain had lower odds of achieving gold-standard 95% ARV adherence as compared to the pain-free and treated pain groups; higher substance dependence symptoms were also associated with significantly lower odds of 95% ARV adherence. Findings suggest that pain management is critical to the health of people living with HIV, specifically those with high levels of co-morbid health and psychological problems. The prevalence of untreated pain was elevated among this group, and contributed to reduced ARV adherence. Providers of clinical care to disadvantaged HIV-positive patients should emphasize routine assessment and appropriate treatment of pain in order to provide comprehensive HIV care. © Copyright 2015, Mary Ann Liebert, Inc. 2015.

Document Type: Article
Source: Scopus

Kubanek, J.a b , Snyder, L.H.a b
Reward-based decision signals in parietal cortex are partially embodied
(2015) Journal of Neuroscience, 35 (12), pp. 4869-4881. 

DOI: 10.1523/JNEUROSCI.4618-14.2015

a Department of Anatomy and Neurobiology, Washington University School of MedicineSt Louis, MO, United States
b Department of Biomedical Engineering, Washington University in St LouisSt Louis, MO, United States

Recordings in the lateral intraparietal area (LIP) reveal that parietal cortex encodes variables related to spatial decision-making, the selection of desirable targets in space. It has been unclear whether parietal cortex is involved in spatial decision-making in general, or whether specific parietal compartments subserve decisions made using specific actions. To test this, we engaged monkeys (Macaca mulatta) in a reward-based decision task in which they selected a target based on its desirability. The animals’ choice behavior in this task followed the molar matching law, and in each trial was governed by the desirability of the choice targets. Critically, animals were instructed to make the choice using one of two actions: eye movements (saccades) and arm movements (reaches). We recorded the discharge activity of neurons in area LIP and the parietal reach region (PRR) of the parietal cortex. In line with previous studies, we found that both LIP and PRR encode a reward-based decision variable, the target desirability. Crucially, the target desirability was encoded in LIP at least twice as strongly when choices were made using saccades compared with reaches. In contrast, PRR encoded target desirability only for reaches and not for saccades. These data suggest that decisions can evolve in dedicated parietal circuits in the context of specific actions. This finding supports the hypothesis of an intentional representation of developing decisions in parietal cortex. Furthermore, the close link between the cognitive (decision-related) and bodily (action-related) processes presents a neural contribution to the theories of embodied cognition. © 2015 the authors.

Author Keywords
Decision making;  Eye (saccade);  Hand (reach);  Lip;  Matching law;  Parietal reach region

Document Type: Article
Source: Scopus

Massaro, A.N.a , Murthy, K.b , Zaniletti, I.c , Cook, N.d , Digeronimo, R.e , Dizon, M.b , Hamrick, S.E.G.f , Mckay, V.J.g , Natarajan, G.h , Rao, R.i , Smith, D.j , Telesco, R.k , Wadhawan, R.l , Asselin, J.M.m , Durand, D.J.m , Evans, J.R.d , Dykes, F.f , Reber, K.M.n , Padula, M.A.d , Pallotto, E.K.o , Short, B.L.a , Mathur, A.M.j
Short-term outcomes after perinatal hypoxic ischemic encephalopathy: A report from the Children's Hospitals Neonatal Consortium HIE focus group
(2015) Journal of Perinatology, 35 (4), pp. 290-296. 

DOI: 10.1038/jp.2014.190

a Department of Pediatrics, Children's National Medical Center, George Washington University, 111 Michigan Avenue NWWashington, DC, United States
b Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University ChicagoIL, United States
c Children's Hospitals AssociationOverland Park, KS, United States
d Department of Pediatrics, Children's Hospital of Philadelphia, University of PennsylvaniaPhiladelphia, PA, United States
e Department of Pediatrics, University of Utah, Primary Children's Medical CenterSalt Lake City, UT, United States
f Emory University, Department of Pediatrics, Children's Healthcare of Atlanta at EglestonAtlanta, GA, United States
g All Children's HospitalSt Petersburg, FL, United States
h Department of Pediatrics, Wayne State University, Children's Hospital of MichiganDetroit, MI, United States
i Department of Pediatrics, Washington University, St Louis Children's HospitalSt Loius, MO, United States
j Department of Pediatrics, Children's Hospital Colorado, University of ColoradoAurora, CO, United States
k Children's Hospital of Pittsburgh of UPMCPittsburgh, PA, United States
l Florida Hospital for ChildrenOrlando, FL, United States
m Children's Hospital Oakland and Research Center, Neonatal/Pediatric ResearchOakland, CA, United States
n Nationwide Children's Hospital, Department of Pediatrics, Ohio State UniversityColumbus, OH, United States
o Children's Hospitals Mercy and Clinics, Department of Pediatrics, University of MissouriKansas City, MO, United States

Objective:To characterize infants affected with perinatal hypoxic ischemic encephalopathy (HIE) who were referred to regional neonatal intensive care units (NICUs) and their related short-term outcomes.Study Design:This is a descriptive study evaluating the data collected prospectively in the Children's Hospital Neonatal Database, comprised of 27 regional NICUs within their associated children's hospitals. A consecutive sample of 945 referred infants born ≥36 weeks' gestation with perinatal HIE in the first 3 days of life over approximately 3 years (2010-July 2013) were included. Maternal and infant characteristics are described. Short-term outcomes were evaluated including medical comorbidities, mortality and status of survivors at discharge.Result:High relative frequencies of maternal predisposing conditions, cesarean and operative vaginal deliveries were observed. Low Apgar scores, profound metabolic acidosis, extensive resuscitation in the delivery room, clinical and electroencephalographic (EEG) seizures, abnormal EEG background and brain imaging directly correlated with the severity of HIE. Therapeutic hypothermia was provided to 85% of infants, 15% of whom were classified as having mild HIE. Electrographic seizures were observed in 26% of the infants. Rates of complications and morbidities were similar to those reported in prior clinical trials and overall mortality was 15%.Conclusion:Within this large contemporary cohort of newborns with perinatal HIE, the application of therapeutic hypothermia and associated neurodiagnostic studies appear to have expanded relative to reported clinical trials. Although seizure incidence and mortality were lower compared with those reported in the trials, it is unclear whether this represented improved outcomes or therapeutic drift with the treatment of milder disease. © 2015 Nature America, Inc.

Document Type: Article
Source: Scopus

Li, P.a , Bracamontes, J.R.a , Manion, B.D.a , Mennerick, S.b c , Steinbach, J.H.a c , Evers, A.S.a c , Akk, G.a c
The neurosteroid 5β-pregnan-3α-ol-20-one enhances actions of etomidate as a positive allosteric modulator of α1β2γ2L GABAA receptors
(2014) British Journal of Pharmacology, 171 (23), pp. 5446-5457. 

DOI: 10.1111/bph.12861

a Department of Anesthesiology, Washington University School of MedicineSt Louis, MO, United States
b Department of Psychiatry, Washington University School of MedicineSt Louis, MO, United States
c Department of Taylor Family, Institute for Innovative Psychiatric Research, Washington University School of MedicineSt Louis, MO, United States

Background and Purpose Neurosteroids potentiate responses of the GABAA receptor to the endogenous agonist GABA. Here, we examined the ability of neurosteroids to potentiate responses to the allosteric activators etomidate, pentobarbital and propofol. Experimental Approach Electrophysiological assays were conducted on rat α1β2γ2L GABAA receptors expressed in HEK 293 cells. The sedative activity of etomidate was studied in Xenopus tadpoles and mice. Effects of neurosteroids on etomidate-elicited inhibition of cortisol synthesis were determined in human adrenocortical cells. Key Results The neurosteroid 5β-pregnan-3α-ol-20-one (3α5βP) potentiated activation of GABAA receptors by GABA and allosteric activators. Co-application of 1 μM 3α5βP induced a leftward shift (almost 100-fold) of the whole-cell macroscopic concentration-response relationship for gating by etomidate. Co-application of 100 nM 3α5βP reduced the EC50 for potentiation by etomidate of currents elicited by 0.5 μM GABA by about three-fold. In vivo, 3α5βP (1mg kg-1) reduced the dose of etomidate required to produce loss of righting in mice (ED50) by almost 10-fold. In tadpoles, the presence of 50 or 100 nM 3α5βP shifted the EC50 for loss of righting about three- or ten-fold respectively. Exposure to 3α5βP did not influence inhibition of cortisol synthesis by etomidate. Conclusions and Implications Potentiating neurosteroids act similarly on orthosterically and allosterically activated GABAA receptors. Co-application of neurosteroids with etomidate can significantly reduce dosage requirements for the anaesthetic, and is a potentially beneficial combination to reduce undesired side effects. © 2014 The British Pharmacological Society.

Document Type: Article
Source: Scopus


April 5, 2015

Kubanek, J.a , Snyder, L.H.a , Abrams, R.A.b
Reward and punishment act as distinct factors in guiding behavior
(2015) Cognition, 139, pp. 154-167. 

DOI: 10.1016/j.cognition.2015.03.005

a Department of Anatomy and Neurobiology, Washington University School of MedicineSt. Louis, MO, United States
b Department of Psychology, Washington University in St. LouisSt. Louis, MO, United States

Behavior rests on the experience of reinforcement and punishment. It has been unclear whether reinforcement and punishment act as oppositely valenced components of a single behavioral factor, or whether these two kinds of outcomes play fundamentally distinct behavioral roles. To this end, we varied the magnitude of a reward or a penalty experienced following a choice using monetary tokens. The outcome of each trial was independent of the outcome of the previous trial, which enabled us to isolate and study the effect on behavior of each outcome magnitude in single trials. We found that a reward led to a repetition of the previous choice, whereas a penalty led to an avoidance of the previous choice. Surprisingly, the effects of the reward magnitude and the penalty magnitude revealed a pronounced asymmetry. The choice repetition effect of a reward scaled with the magnitude of the reward. In a marked contrast, the avoidance effect of a penalty was flat, not influenced by the magnitude of the penalty. These effects were mechanistically described using a reinforcement learning model after the model was updated to account for the penalty-based asymmetry. The asymmetry in the effects of the reward magnitude and the punishment magnitude was so striking that it is difficult to conceive that one factor is just a weighted or transformed form of the other factor. Instead, the data suggest that rewards and penalties are fundamentally distinct factors in governing behavior. © 2015 Elsevier B.V.

Author Keywords
Gain;  Instrumental (operant) behavior;  Law of effect;  Loss;  Penalty;  Reinforcement


Document Type: Article
Source: Scopus
Salt, A.N., Gill, R.M., Hartsock, J.J.

Perilymph Kinetics of FITC-Dextran Reveals Homeostasis Dominated by the Cochlear Aqueduct and Cerebrospinal Fluid
(2015) JARO - Journal of the Association for Research in Otolaryngology, 15 p. Article in Press. 

DOI: 10.1007/s10162-015-0512-1

Department of Otolaryngology, Washington University School of Medicine, 660, South Euclid Avenue, Box 8115St. Louis, MO, United States

Understanding how drugs are distributed in perilymph following local applications is important as local drug therapies are increasingly used to treat disorders of the inner ear. The potential contribution of cerebrospinal fluid (CSF) entry to perilymph homeostasis has been controversial for over half a century, largely due to artifactual contamination of collected perilymph samples with CSF. Measures of perilymph flow and of drug distribution following round window niche applications have both suggested a slow, apically directed flow occurs along scala tympani (ST) in the normal, sealed cochlea. In the present study, we have used fluorescein isothiocyanate-dextran as a marker to study perilymph kinetics in guinea pigs. Dextran is lost from perilymph more slowly than other substances so far quantified. Dextran solutions were injected from pipettes sealed into the lateral semicircular canal (SCC), the cochlear apex, or the basal turn of ST. After varying delays, sequential perilymph samples were taken from the cochlear apex or lateral SCC, allowing dextran distribution along the perilymphatic spaces to be quantified. Variability was low and findings were consistent with the injection procedure driving volume flow towards the cochlear aqueduct, and with volume flow during perilymph sampling driven by CSF entry at the aqueduct. The decline of dextran with time in the period between injection and sampling was consistent with both a slow volume influx of CSF (
30 nL/min) entering the basal turn of ST at the cochlear aqueduct and a CSF-perilymph exchange driven by pressure-driven fluid oscillation across the cochlear aqueduct. Sample data also allowed contributions of other processes, such as communications with adjacent compartments, to be quantified. The study demonstrates that drug kinetics in the basal turn of ST is complex and is influenced by a considerable number of interacting processes. © 2015 Association for Research in Otolaryngology

Author Keywords
blood-labyrinth barrier;  cochlea;  perilymph pharmacokinetics;  round window

Document Type: Article in Press
Source: Scopus


Maschi, D.a b , Klyachko, V.A.a b
A nanoscale resolution view on synaptic vesicle dynamics
(2015) Synapse, 69 (5), pp. 256-267. 

DOI: 10.1002/syn.21795

a Department of Cell Biology and Physiology, Center for Investigations of Membrane Excitability Diseases, Washington University School of MedicineSt. Louis, MO, United States
b Department of Biomedical Engineering, Washington UniversitySt. Louis, MO, United States

The ability of synapses to sustain neurotransmitter release during continuous activity critically relies on an efficient vesicle recycling program. Despite extensive research on synaptic function, the basic mechanisms of vesicle recycling remain poorly understood due to the relative inaccessibility of central synapses to conventional recording techniques. The extremely small size of synaptic vesicles, nearly five times below the diffraction-limited resolution of conventional light microscopy, has hampered efforts to define the mechanisms controlling their cycling. The complex sequence of dynamic processes that occur within the nerve terminals and link vesicle endocytosis and the subsequent round of release has been particularly difficult to study. The recent development of nanoscale-resolution imaging techniques has provided an opportunity to overcome these limitations and begin to reveal the mechanisms controlling vesicle recycling within individual nerve terminals. Here we summarize the recent advances in the implementation of super-resolution imaging and single-particle tracking approaches to study the dynamic steps of the vesicle recycling process within presynaptic terminals. © 2014 Wiley Periodicals, Inc.

Author Keywords
Single particle tracking;  Vesicle recycling


Document Type: Article
Source: Scopus

Kinch, M.S.a , Patridge, E.b
An analysis of FDA-approved drugs for psychiatric disorders
(2015) Drug Discovery Today, 20 (3), pp. 292-295. 

DOI: 10.1016/j.drudis.2014.08.013

a Washington University in St LouisSt Louis, MO, United States
b Yale Center for Molecular DiscoveryWest Haven, CT, United States


Document Type: Editorial
Source: Scopus

Findlay, A.R.a , Wein, N.a , Kaminoh, Y.a , Taylor, L.E.a , Dunn, D.M.b , Mendell, J.R.a c d , King, W.M.d , Pestronk, A.e , Florence, J.M.e , Mathews, K.D.f , Finkel, R.S.g , Swoboda, K.J.h , Howard, M.T.b , Day, J.W.i , McDonald, C.e j m , Nicolas, A.k l , Le Rumeur, E.k l , Weiss, R.B.b , Flanigan, K.M.a c d
Clinical phenotypes as predictors of the outcome of skipping around DMD exon 45
(2015) Annals of Neurology, 77 (4), pp. 668-674. 

DOI: 10.1002/ana.24365

a Center for Gene Therapy, Research Institute, Nationwide Children's Hospital, 700 Children's DriveColumbus, OH, United States
b Department of Human Genetics, University of Utah, School of MedicineSalt Lake City, UT, United States
c Departments of Pediatrics, Ohio State UniversityColumbus, OH, United States
d Departments of Neurology, Ohio State UniversityColumbus, OH, United States
e Department of Neurology, Washington University at St LouisSt Louis, MO, United States
f Department of Pediatrics and Neurology, University of Iowa Carver, College of MedicineIowa City, IA, United States
g Division of Neurology, Nemours Children's HospitalOrlando, FL, United States
h Department of Neurology, University of Utah, School of MedicineSalt Lake City, UT, United States
i Department of Neurology, University of MinnesotaMinneapolis, MN, United States
j Department of Physical Medicine and Rehabilitation, University of California DavisSacramento, CA, United States
k University of RennesRennes, France
l Rennes Institute of Genetics and Development, National Center for Scientific ResearchRennes, France
m Departments of Neurology, Pediatrics, and Pathology, Stanford University, School of MedicineStanford, CA, United States

Objective Exon-skipping therapies aim to convert Duchenne muscular dystrophy (DMD) into less severe Becker muscular dystrophy (BMD) by altering pre-mRNA splicing to restore an open reading frame, allowing translation of an internally deleted and partially functional dystrophin protein. The most common single exon deletion - exon 45 (Δ45) - may theoretically be treated by skipping of either flanking exon (44 or 46). We sought to predict the impact of these by assessing the clinical severity in dystrophinopathy patients. Methods Phenotypic data including clinical diagnosis, age at wheelchair use, age at loss of ambulation, and presence of cardiomyopathy were analyzed from 41 dystrophinopathy patients containing equivalent in-frame deletions. Results As expected, deletions of either exons 45 to 47 (Δ45-47) or exons 45 to 48 (Δ45-48) result in BMD in 97% (36 of 37) of subjects. Unexpectedly, deletion of exons 45 to 46 (Δ45-46) is associated with the more severe DMD phenotype in 4 of 4 subjects despite an in-frame transcript. Notably, no patients with a deletion of exons 44 to 45 (Δ44-45) were found within the United Dystrophinopathy Project database, and this mutation has only been reported twice before, which suggests an ascertainment bias attributable to a very mild phenotype. Interpretation The observation that Δ45-46 patients have typical DMD suggests that the conformation of the resultant protein may result in protein instability or altered binding of critical partners. We conclude that in DMD patients with Δ45, skipping of exon 44 and multiexon skipping of exons 46 and 47 (or exons 46-48) are better potential therapies than skipping of exon 46 alone. Ann Neurol 2015 Ann Neurol 2015;77:668-674 © 2015 American Neurological Association.


Document Type: Article
Source: Scopus


Dale, A.M.a , Agboola, F.a b , Yun, A.b c , Zeringue, A.a b , Al-Lozi, M.T.a , Evanoff, B.a
Comparison of Automated Versus Traditional Nerve Conduction Study Methods for Median Nerve Testing in a General Worker Population
(2015) PM and R, 7 (3), pp. 276-282. 

DOI: 10.1016/j.pmrj.2014.10.003

a Divisions of General Medical Sciences and Neurology, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8005St. Louis, MO, United States
b Saint Louis University School of Public HealthSt Louis, MO, United States
c Washington State Hospital AssociationSeattle, WA, United States

Objective: To investigate the validity of automated nerve conduction studies compared to traditional electrodiagnostic studies (EDS) for testing median nerve abnormalities in a working population. Design: Agreement study and sensitivity investigation from 2 devices. Setting: Field research testing laboratory. Participants: Active workers from several industries participating in a longitudinal study of carpal tunnel syndrome. Methods: Sixty-two subjects received bilateral median and ulnar nerve conduction testing across the wrist with a traditional device and the NC-stat automated device. We compared the intermethod agreement of analogous measurements. Main outcome measurement: Nerve conduction study parameters. Results: Median motor and sensory latency comparisons showed excellent agreement (intraclass correlation coefficients 0.85 and 0.80, respectively). Areas under the receiver operating characteristic curves were 0.97 and 0.96, respectively, using the optimal thresholds of 4.4-millisecond median motor latency (sensitivity 100%, specificity 86%) and 3.9-millisecond median sensory latency (sensitivity 100%, specificity 87%). Ulnar nerve testing results were less favorable. Conclusion: The automated NC-stat device showed excellent agreement with traditional EDS for detecting median nerve conduction abnormalities in a general population of workers, suggesting that this automated nerve conduction device can be used to ascertain research case definitions of carpal tunnel syndrome in population health studies. Further study is needed to determine optimal thresholds for defining median conduction abnormalities in populations that are not seeking clinical care. © 2015 American Academy of Physical Medicine and Rehabilitation.


Document Type: Article
Source: Scopus


Ellingson, B.M.a b c d , Kim, E.e , Woodworth, D.C.b c , Marques, H.e , Boxerman, J.L.f , Safriel, Y.g , McKinstry, R.C.h , Bokstein, F.i , Jain, R.j o , Chi, T.L.k , Sorensen, A.G.l p , Gilbert, M.R.m , Barboriak, D.P.n
Diffusion MRI quality control and functional diffusion map results in ACRIN 6677/RTOG 0625: A multicenter, randomized, phase II trial of bevacizumab and chemotherapy in recurrent glioblastoma
(2015) International Journal of Oncology, 46 (5), pp. 1883-1892. 

DOI: 10.3892/ijo.2015.2891

a UCLA Neuro-Oncology Program, David Geffen School of Medicine, University of California Los AngelesLos Angeles, CA, United States
b Department of Radiological Sciences, David Geffen School of Medicine, University of California, 924 Westwood Boulevard, Suite 615Los Angeles, CA, United States
c Department of Biomedical Physics, David Geffen School of Medicine, University of California Los AngelesLos Angeles, CA, United States
d Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, University of California Los AngelesLos Angeles, CA, United States
e Center for Statistical Sciences, Brown UniversityProvidence, RI, United States
f Department of Diagnostic Imaging, Rhode Island Hospital, Alpert Medical School of Brown UniversityProvidence, RI, United States
g Radiology Associates of Clearwater, University of South FloridaClearwater, FL, United States
h Mallinckrodt Institute of Radiology, Washington University in St. LouisSt. Louis, MO, United States
i Neuro-Oncology Service, Tel Aviv Sourasky Medical Center, Israel
j Departments of Radiology and Neurosurgery, Henry Ford HospitalDetroit, MI, United States
k Department of Diagnostic Radiology, University of Texas MD Anderson Cancer CenterHouston, TX, United States
l A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical SchoolCharlestown, MA, United States
m Department of Neuro-Oncology, University of Texas MD Anderson Cancer CenterHouston, TX, United States
n Department of Radiology, Duke University Medical CenterDurham, NC, United States
o Department of Diagnostic Radiology, Langone Medical Center, New York UniversityNew York, NY, United States
p Siemens HealthcareMalvern, PA, United States

Functional diffusion mapping (fDM) is a cancer imaging technique that quantifies voxelwise changes in apparent diffusion coefficient (ADC). Previous studies have shown value of fDMs in bevacizumab therapy for recurrent glioblastoma multiforme (GBM). The aim of the present study was to implement explicit criteria for diffusion MRI quality control and independently evaluate fDM performance in a multicenter clinical trial (RTOG 0625/ACRIN 6677). A total of 123 patients were enrolled in the current multicenter trial and signed institutional review board-approved informed consent at their respective institutions. MRI was acquired prior to and 8 weeks following therapy. A 5-point QC scoring system was used to evaluate DWI quality. fDM performance was evaluated according to the correlation of these metrics with PFS and OS at the first follow-up time-point. Results showed ADC variability of 7.3% in NAWM and 10.5% in CSF. A total of 68% of patients had usable DWI data and 47% of patients had high quality DWI data when also excluding patients that progressed before the first follow-up. fDM performance was improved by using only the highest quality DWI. High pre-treatment contrast enhancing tumor volume was associated with shorter PFS and OS. A high volume fraction of increasing ADC after therapy was associated with shorter PFS, while a high volume fraction of decreasing ADC was associated with shorter OS. In summary, DWI in multicenter trials are currently of limited value due to image quality. Improvements in consistency of image quality in multicenter trials are necessary for further advancement of DWI biomarkers. © 2015, Spandidos Publications. All rights reserved.

Author Keywords
Bevacizumab;  Diffusion MRI;  Functional diffusion mapping;  Functional diffusion maps;  Glioblastoma;  Magnetic resonance imaging


Document Type: Article
Source: Scopus


Liao, F.a , Jiang, H.a , Srivatsan, S.b , Xiao, Q.c , Lefton, K.B.d , Yamada, K.e , Mahan, T.E.d , Lee, J.-M.c , Shaw, A.S.b , Holtzman, D.M.a
Effects of CD2-associated protein deficiency on amyloid-β in neuroblastoma cells and in an APP transgenic mouse model
(2015) Molecular Neurodegeneration, 10 (1), art. no. 12, . 

DOI: 10.1186/s13024-015-0006-y

a Department of Neurology, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of MedicineSt. Louis, MO, United States
b Department of Pathology and Immunology, Washington University School of MedicineSt. Louis, MO, United States
c Department of Neurology, Hope Center for Neurological Disorders, Washington University School of MedicineSt. Louis, MO, United States
d Department of Neurology, Washington University School of MedicineSt. Louis, MO, United States
e Department of Neuropathology, Graduate School of Medicine, University of TokyoTokyo, Japan

Background: CD2-associated protein (CD2AP) is an SH3-containing scaffold adaptor protein which regulates the actin cytoskeleton. Recently, CD2AP was identified as a genetic risk factor for Alzheimer's disease (AD) by several genome-wide association studies. One of the hallmarks of AD is the accumulation of aggregated forms of Amyloid-β (Aβ) in the brain. In humans, CD2AP AD susceptibility locus (rs9349407) is associated with an increased plaque burden. Aβ production is highly regulated by endocytosis and is influenced by lysosomal function. Lysosomal trafficking is influenced by CD2AP. In this study, we decreased CD2AP levels in N2a neuroblastoma cultures and PS1APP mice and analyzed Aβ levels and plaque burden. Results: Our data show that suppressing CD2AP expression using shRNA in N2a-APP695 cells results in decreased cell membrane amyloid precursor protein, decreased Aβ release and a lower Aβ42/Aβ40 ratio. CD2AP protein is expressed in the brain as detected by western blot, and the expression level is dependent on gene dosage. In 1-month old PS1APP mice, complete loss of CD2AP in brain resulted in a decreased Aβ42/Aβ40 ratio in brain tissue lysates while there was no effect on Aβ deposition or accumulation in PS1APP mice expressing one copy of CD2AP. Conclusion: CD2-Associated Protein affects Aβ levels and Aβ42/Aβ40 ratio in vitro. The effect of CD2-Associated Protein on Aβ metabolism is subtle in vivo. © 2015 Liao et al.; licensee BioMed Central.

Author Keywords
Alzheimer's disease;  Amyloid-β;  CD2AP


Document Type: Article
Source: Scopus

McElroy, S.L.a b , Hudson, J.I.c , Mitchell, J.E.d e , Wilfley, D.f , Ferreira-Cornwell, M.C.g , Gao, J.g , Wang, J.g h , Whitaker, T.g , JonasMD, J.g i , Gasior, M.g
Efficacy and safety of lisdexamfetamine for treatment of adults with moderate to severe binge-eating disorder: A randomized clinical trial
(2015) JAMA Psychiatry, 72 (3), pp. 235-246. 

DOI: 10.1001/jamapsychiatry.2014.2162

a Research Institute, Lindner Center of HOPE, 4075 Old Western Row RdMason, OH, United States
b Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of MedicineCincinnati, OH, United States
c Department of Psychiatry, McLean Hospital, Harvard Medical SchoolBelmont, MA, United States
d Neuropsychiatric Research InstituteFargo, ND, United States
e Department of Neuroscience, University of North Dakota School of MedicineFargo, United States
f Department of Psychology, Washington University School of MedicineSt Louis, MO, United States
g ShireWayne, PA, United States
h CSL BehringKing of Prussia, PA, United States
i Sage TherapeuticsCambridge, MA, United States

IMPORTANCE: Binge-eating disorder (BED), a public health problem associated with psychopathological symptoms and obesity and possibly with metabolic syndrome, lacks approved pharmacotherapies. OBJECTIVE: To examine the efficacy and safety of lisdexamfetamine dimesylate, a dextroamphetamine prodrug, to treat moderate to severe BED. DESIGN, SETTING, AND PARTICIPANTS: We performed a randomized, double-blind, parallel-group, forced dose titration, placebo-controlled clinical trial at 30 sites from May 10, 2011, through January 30, 2012. Safety and intention-to-treat analyses included 259 and 255 adults with BED, respectively. INTERVENTIONS: Lisdexamfetamine dimesylate at dosages of 30, 50, or 70mg/d or placebo were provided to study participants (1:1:1:1). Dosages were titrated across 3weeks and maintained for 8weeks.We followed up participants for a mean (SD) of 7 (2) days after the last dose. MAIN OUTCOMES AND MEASURES: We assessed the change in binge-eating (BE) behaviors measured as days per week (baseline to week 11) with a mixed-effects model using transformed log (BE days per week) + 1. Secondary measures included BE cessation for 4 weeks. Safety assessments included treatment-emergent adverse events, vital signs, and change in weight. RESULTS At week 11, log-transformed BE days per week decreased with the 50-mg/d (least squares [LS] mean [SE] change, -1.49 [0.066]; P = .008) and 70-mg/d (LS mean [SE] change, -1.57 [0.067]; P < .001) treatment groups but not the 30-mg/d treatment group (LS mean [SE] change, -1.24 [0.067]; P = .88) compared with the placebo group. Nontransformed mean (SD) days per week decreased for placebo and the 30-, 50-, and 70-mg/d treatment groups by -3.3 (2.04), -3.5 (1.95), -4.1 (1.52), and -4.1 (1.57), respectively. The percentage of participants achieving 4-week BE cessation was lower with the placebo group (21.3%) compared with the 50-mg/d (42.2%[P = .01]) and 70-mg/d (50.0%[P < .001]) treatment groups. The incidence of any treatment-emergent adverse events was 58.7% for the placebo group and 84.7%for the combined treatment group. In the treatment groups, 1.5% of participants had serious treatment-emergent adverse effects. Events with a frequency of at least 5% and changes in heart rate were generally consistent with the known safety profile. The mean (SD) change in body weight was -0.1 (3.09), -3.1 (3.64), -4.9 (4.43), -4.9 (3.93), and -4.3 (4.09) kg for the placebo group, the 30-, 50-, and 70-mg/d treatment groups, and the combined treatment groups, respectively (P < .001 for each dose vs placebo group comparison in post hoc analysis). CONCLUSIONS AND RELEVANCE: The 50- and 70-mg/d treatment groups demonstrated efficacy compared with the placebo group in decreased BE days, BE cessation, and global improvement. The safety profile was generally consistent with previous findings in adults with attention deficit/hyperactivity disorder. Further investigation of lisdexamfetamine in BED is ongoing. Copyright 2015 American Medical Association. All rights reserved.


Document Type: Article
Source: Scopus

Chimowitz, M.I.a , Derdeyn, C.P.b c d
Endovascular therapy for atherosclerotic intracranial arterial stenosis: Back to the drawing board
(2015) JAMA - Journal of the American Medical Association, 313 (12), pp. 1219-1220. 

a Department of Neurosciences, Medical University of South CarolinaCharleston, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S Kingshighway BlvdSt Louis, MO, United States
c Department of Neurology, Washington University School of MedicineSt Louis, MO, United States
d Department of Neurological Surgery, Washington University School of MedicineSt Louis, MO, United States


Document Type: Editorial
Source: Scopus

Heinemann, A.W.a b , Magasi, S.c , Hammel, J.c d , Carlozzi, N.E.e , Garcia, S.F.f g , Hahn, E.A.g , Lai, J.-S.g , Tulsky, D.h i , Gray, D.B.j , Hollingsworth, H.j , Jerousek, S.a
Environmental factors item development for persons with stroke, traumatic brain injury, and spinal cord injury
(2015) Archives of Physical Medicine and Rehabilitation, 96 (4), pp. 589-595. Cited 4 times.

DOI: 10.1016/j.apmr.2013.11.024

a Center for Rehabilitation Outcomes Research, Rehabilitation Institute of Chicago, 345 E Superior StChicago, IL, United States
b Department of Physical Medicine and Rehabilitation, Feinberg School of Medicine, Northwestern UniversityChicago, IL, United States
c Department of Occupational Therapy, University of Illinois at ChicagoChicago, IL, United States
d Department of Disability and Human Development, University of Illinois at ChicagoChicago, IL, United States
e Department of Physical Medicine and Rehabilitation, University of MichiganAnn Arbor, MI, United States
f Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern UniversityChicago, IL, United States
g Department of Medical Social Sciences, Feinberg School of Medicine, Northwestern UniversityChicago, IL, United States
h Departments of Rehabilitation Medicine, Orthopedic Surgery and General Medicine, Langone Medical Center Ambulatory Care Center, New York UniversityNew York, NY, United States
i Kessler FoundationWest Orange, NJ, United States
j Program in Occupational Therapy, Washington UniversitySt Louis, MO, United States

Objectives To describe methods used in operationalizing environmental factors; to describe the results of a research project to develop measures of environmental factors that affect participation; and to define an initial item set of facilitators and barriers to participation after stroke, traumatic brain injury, and spinal cord injury. Design Instrument development included an extensive literature review, item classification and selection, item writing, and cognitive testing following the approach of the Patient-Reported Outcomes Measurement Information System. Setting Community. Participants Content area and outcome measurement experts (n=10) contributed to instrument development; individuals (n=200) with the target conditions participated in focus groups and in cognitive testing (n=15). Interventions None. Main Outcome Measures Environmental factor items were categorized in 6 domains: assistive technology; built and natural environment; social environment; services, systems, and policies; access to information and technology; and economic quality of life. Results We binned 2273 items across the 6 domains, winnowed this pool to 291 items for cognitive testing, and recommended 274 items for pilot data collection. Conclusions Five of the 6 domains correspond closely to the International Classification of Functioning, Disability and Health taxonomy of environmental factors; the sixth domain, economic quality of life, reflects an important construct that reflects financial resources that affect participation. Testing with a new and larger sample is underway to evaluate reliability, validity, and sensitivity. © 2015 American Congress of Rehabilitation Medicine.

Author Keywords
Environment;  Qualitative research;  Questionnaires;  Rehabilitation


Document Type: Article
Source: Scopus

Hadžic, T.a d , Park, D.a , Abruzzi, K.C.b , Yang, L.c , Trigg, J.S.a , Rohs, R.c , Rosbash, M.b , Taghert, P.H.a
Genome-wide features of neuroendocrine regulation in Drosophila by the basic helix-loop-helix transcription factor DIMMED
(2015) Nucleic Acids Research, 43 (4), pp. 2199-2215. 

DOI: 10.1093/nar/gku1377

a Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 South Euclid AvenueSt. Louis, MO, United States
b Howard Hughes Medical Institute, Department of Biology, Brandeis UniversityWaltham, MA, United States
c Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern CaliforniaLos Angeles, CA, United States
d Department of Psychiatry, Washington University Medical School, 660 South Euclid AvenueSt. Louis, MO, United States

Neuroendocrine (NE) cells use large dense core vesicles (LDCVs) to traffic, process, store and secrete neuropeptide hormones through the regulated secretory pathway. The dimmed (DIMM) basic helix-loop-helix transcription factor of Drosophila controls the level of regulated secretory activity in NE cells. To pursue its mechanisms, we have performed two independent genome-wide analyses of DIMM's activities: (i) in vivo chromatin immunoprecipitation (ChIP) to define genomic sites of DIMM occupancy and (ii) deep sequencing of purified DIMM neurons to characterize their transcriptional profile. By this combined approach, we showed that DIMM binds to conserved E-boxes in enhancers of 212 genes whose expression is enriched in DIMM-expressing NE cells. DIMM binds preferentially to certain E-boxes within first introns of specific gene isoforms. Statistical machine learning revealed that flanking regions of putative DIMM binding sites contribute to its DNA binding specificity. DIMM's transcriptional repertoire features at least 20 LDCV constituents. In addition, DIMM notably targets the pro-secretory transcription factor, creb-A, but significantly, DIMM does not target any neuropeptide genes. DIMM therefore prescribes the scale of secretory activity in NE neurons, by a systematic control of both proximal and distal points in the regulated secretory pathway. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.


Document Type: Article
Source: Scopus


Brossier, N.M.a , Gutmann, D.H.b
Improving outcomes for neurofibromatosis 1-associated brain tumors
(2015) Expert Review of Anticancer Therapy, 15 (4), pp. 415-423. 

DOI: 10.1586/14737140.2015.1009043

a Department of Pediatrics, St. Louis Children's HospitalSt. Louis, MO, United States
b Department of Neurology, Washington University, School of Medicine, 660 South Euclid AvenueSt. Louis, MO, United States

Children and adults with neurofibromatosis type 1 (NF1) are predisposed to developing CNS tumors, including optic pathway gliomas (OPGs), brainstem gliomas (BSGs) and high-grade gliomas. Although current first-line treatments for low-grade gliomas (OPGs and BSGs) may prevent further tumor growth, they rarely result in restoration of the associated visual or neurological deficits. The availability of accurate small-animal models of NF1-associated brain tumors has established tractable experimental platforms for the discovery and evaluation of promising therapeutic agents. On the basis of these preclinical studies, biologically targeted agents are now being evaluated in children with NF1-associated low-grade brain tumors. Collectively, these models have also begun to reveal potential neuroprotective and risk assessment strategies for this brain tumor-prone population. © 2015 Informa UK Ltd.

Author Keywords
brainstem glioma;  cyclic AMP;  genetically-engineered mice;  microglia;  mTOR;  neurofibromatosis type 1;  optic pathway glioma;  preclinical;  RAS


Document Type: Review
Source: Scopus

Searles Nielsen, S.a b , Checkoway, H.c , Criswell, S.R.d , Farin, F.M.b , Stapleton, P.L.b , Sheppard, L.b e , Racette, B.A.d f
Inducible nitric oxide synthase gene methylation and parkinsonism in manganese-exposed welders
(2015) Parkinsonism and Related Disorders, 21 (4), pp. 355-360. 

DOI: 10.1016/j.parkreldis.2015.01.007

a University of Washington, Department of NeurologySeattle, WA, United States
b University of Washington, Department of Environmental and Occupational Health SciencesSeattle, WA, United States
c University of California San Diego, Department of Family and Preventive MedicineLa Jolla, CA, United States
d Washington University, Department of NeurologySt. Louis, MO, United States
e University of Washington, Department of BiostatisticsSeattle, WA, United States
f University of the Witwatersrand, School of Public HealthParktown, South Africa

Introduction: Neurologist-assessed parkinsonism signs are prevalent among workers exposed to manganese (Mn)-containing welding fume. Neuroinflammation may possibly play a role. Inducible nitric oxide synthase, coded by NOS2, is involved in inflammation, and particulate exposure increases the gene's expression through methylation of CpG sites in the 5' region. Methods: We assessed DNA methylation at three CpG sites in the NOS2 exon 1 from blood from 201 welders. All were non-Hispanic Caucasian men 25-65 years old who were examined by a neurologist specializing in movement disorders. We categorized the workers according to their Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3) scores as parkinsonism cases (UPDRS3≥15; n=49), controls (UPDRS3<6; n=103), or intermediate (UPDRS3 ≥6 to < 15; n=49). Results: While accounting for age, examiner and experimental plate, parkinsonism cases had lower mean NOS2 methylation than controls (p-value for trend=0.04), specifically at CpG site 8329 located in an exonic splicing enhancer of NOS2 (p-value for trend=0.07). These associations were not observed for the intermediate UPDRS3 group (both p-value for trend≥0.59). Conclusions: Inflammation mediated by inducible nitric oxide synthase may possibly contribute to the association between welding fume and parkinsonism, but requires verification in a longitudinal study. © 2015 Elsevier Ltd.

Author Keywords
DNA methylation;  Manganese;  Nitric oxide synthase type II;  Occupational exposure;  Parkinsonian disorders;  Welding


Document Type: Article
Source: Scopus

Chen, Y.-H.a , McGowan, L.a , Cimino, P.J.b , Dahiya, S.b , Leonard, J.R.c , Lee, D.a , Gutmann, D.H.a
Mouse low-grade gliomas contain cancer stem cells with unique molecular and functional properties
(2015) Cell Reports, 10 (11), pp. 1899-1912. 

DOI: 10.1016/j.celrep.2015.02.041

a Department of Neurology, Washington University School of MedicineSt. Louis, MO, United States
b Department of Pathology, Washington University School of MedicineSt. Louis, MO, United States
c Department of Neurosurgery, Washington University School of MedicineSt. Louis, MO, United States

The availability of adult malignant glioma stem cells (GSCs) has provided unprecedented opportunities to identify the mechanisms underlying treatment resistance. Unfortunately, there is a lack of comparable reagents for the study of pediatric low-grade glioma (LGG). Leveraging a neurofibromatosis 1 (Nf1) genetically engineered mouse LGG model, we report the isolation of CD133+ multi-potent low-grade glioma stem cells (LG-GSCs), which generate glioma-like lesions histologically similar to the parent tumor following injection into immunocompetent hosts. Inaddition, we demonstrate that these LG-GSCs harbor selective resistance to currently employed conventional and biologically targeted anti-cancer agents, which reflect the acquisition of new targetable signaling pathway abnormalities. Using transcriptomic analysis to identify additional molecular properties, we discovered that mouse and human LG-GSCs harbor high levels of Abcg1 expression critical for protecting against ER-stress-induced mouse LG-GSC apoptosis. Collectively, these findings establish that LGG cancer stem cells have unique molecular and functional properties relevant to brain cancer treatment. © 2015 The Authors.


Document Type: Article
Source: Scopus


Dori, A., Lopate, G., Keeling, R., Pestronk, A.
Myovascular innervation: Axon loss in small-fiber neuropathies
(2015) Muscle and Nerve, 51 (4), pp. 514-521. 

DOI: 10.1002/mus.24356

Department of Neurology, Washington University School of Medicine in St. Louis, 660 South Euclid Avenue, Box 8111St. Louis, MO, United States

Introduction: Vascular denervation occurs in some neuropathies, but measurement of small perivascular axons has been difficult. Methods: We evaluated 31 consecutive patients who had both muscle and skin biopsies. We quantitated myovascular innervation by staining unmyelinated axons with peripherin and non-myelinating Schwann cells with neural cell adhesion molecule and comparing their areas. Results: Perivascular unmyelinated axon-Schwann (UAS) ratios correlated with axon density in skin (r=0.679; P<0.0001). Low UAS ratios (≤0.25) had a sensitivity of 90% and specificity of 91% for a clinical diagnosis of small-fiber neuropathy (P<0.0001). Autonomic features were more common in patients with low perivascular UAS ratios (P=0.002). A patient subgroup with myovascular, but not skin, denervation commonly had muscle discomfort and autonomic features. Conclusions: UAS ratio measurements, comparing axons and associated non-myelinating Schwann cells, can quantitate perivascular innervation. Small-fiber neuropathies are often associated with myovascular denervation. Some patients with muscle discomfort have selective myovascular denervation. © 2014 Wiley Periodicals, Inc..

Author Keywords
Autonomic symptoms;  Muscle biopsy;  Muscle pain;  Small-fiber neuropathy;  Vascular innervation


Document Type: Article
Source: Scopus

Gu, X.a b c , Cantle, J.P.a b c , Greiner, E.R.a d , Lee, C.Y.D.a b c , Barth, A.M.e , Gao, F.a b , Park, C.S.a b c , Zhang, Z.f g , Sandoval-Miller, S.a b c , Zhang, R.L.a b c , Diamond, M.f g , Mody, I.e , Coppola, G.a b c e , Yang, X.W.a b c
N17 Modifies Mutant Huntingtin Nuclear Pathogenesis and Severity of Disease in HD BAC Transgenic Mice
(2015) Neuron, 85 (4), pp. 726-741. 

DOI: 10.1016/j.neuron.2015.01.008

a Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los AngelesLos Angeles, CA, United States
b Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los AngelesLos Angeles, CA, United States
c Brain Research Institute, David Geffen School of Medicine, University of California, Los AngelesLos Angeles, CA, United States
d Department of Chemistry and Biochemistry, University of California, Los AngelesLos Angeles, CA, United States
e Department of Neurology, David Geffen School of Medicine, University of California, Los AngelesLos Angeles, CA, United States
f Department of Neurology, Washington University School of MedicineSt. Louis, MO, United States
g Department of Neurology and Neurotherapeutics, University of Texas, Southwestern Medical CenterDallas, TX, United States

The nucleus is a critical subcellular compartment forthe pathogenesis of polyglutamine disorders, including Huntington's disease (HD). Recent studies suggest the first 17-amino-acid domain (N17) of mutant huntingtin (mHTT) mediates its nuclear exclusion in cultured cells. Here, we test whether N17 could be a molecular determinant of nuclear mHTT pathogenesis invivo. BAC transgenic mice expressing mHTT lacking the N17 domain (BACHD-δN17) show dramatically accelerated mHTT pathology exclusively in the nucleus, which is associatedwith HD-like transcriptionopathy. Interestingly, BACHD-δN17 mice manifest more overt disease-like phenotypes than the original BACHD mice, including body weight loss, movement deficits, robust striatal neuron loss, and neuroinflammation. Mechanistically, N17 is necessary for nuclear exclusion of small mHTT fragments that are part of nuclear pathology in HD. Together, our study suggests that N17 modifies nuclear pathogenesis and disease severity in HD mice by regulating subcellularlocalization of known nuclear pathogenic mHTT species. © 2015 Elsevier Inc.


Document Type: Article
Source: Scopus

Vadivelu, S.a , Stewart, T.J.b , Qu, Y.a , Horn, K.c , Liu, S.a , Li, Q.a , Silver, J.c , McDonald, J.W.a , McDonald, J.W.d
Ng2+progenitors derived from embryonic stem cells penetrate glial scar and promote axonal outgrowth into white matter after spinal cord injury
(2015) Stem Cells Translational Medicine, 4 (4), pp. 401-411. 


a The International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at the Kennedy Krieger InstituteBaltimore, MD, United States
b Department of Neurosurgery, Washington University School of MedicineSt. Louis, MO, United States
c Department of Neurosciences, Case Western Reserve University School of MedicineCleveland, OH, United States
d Department of Neurology and Neuroscience, Johns Hopkins University School of MedicineBaltimore, MD, United States

The glial scar resulting from spinal cord injury is rich in chondroitin sulfate proteoglycan (CSPG), a formidable barrier to axonal regeneration. We explored the possibility of breaching that barrier by first examining the scar in a functional in vitro model. We found that embryonic stem cell-derived neural lineage cells (ESNLCs) with prominent expression of nerve glial antigen 2 (NG2) survived, passed through an increasingly inhibitory gradient of CSPG, and expressed matrix metalloproteinase 9 (MMP-9) at the appropriate stage of their development. Outgrowth of axons from ESNLCs followed because the migrating cells sculpted pathways in which CSPG was degraded. The degradative mechanism involved MMP-9 but not MMP-2. To confirm these results in vivo, we transplanted ESNLCs directly into the cavity of a contused spinal cord 9 days after injury. A week later, ESNLCs survived and were expressing both NG2 and MMP-9. Their axons had grown through long distances (>10 mm), although they preferred to traverse white rather than gray matter. These data are consistent with the concept that expression of inhibitory CSPG within the injury scar is an important impediment to regeneration but that NG2+ progenitors derived from ESNLCs can modify the microenvironment to allow axons to grow through the barrier. This beneficial action may be partly due to developmental expression of MMP-9. We conclude that it might eventually be possible to encourage axonal regeneration in the human spinal cord by transplanting ESNLCs or other cells that express NG2. © AlphaMed Press.

Author Keywords
Axonal regeneration;  Central nervous;  Differentiation;  Glia;  Glial scar;  Matrix metalloproteinase;  Neural progenitor;  Plasticity;  Spinal cord injury


Document Type: Article
Source: Scopus

Connolly, A.M.a b , Malkus, E.C.a , Mendell, J.R.c , Flanigan, K.M.c , Miller, J.P.d , Schierbecker, J.R.a , Siener, C.A.a , Golumbek, P.T.a b , Zaidman, C.M.a b , Mcdonald, C.M.e , Johnson, L.e , Nicorici, A.e , Karachunski, P.I.f , Day, J.W.g , Kelecic, J.M.g , Lowes, L.P.c , Alfano, L.N.c , Darras, B.T.h , Kang, P.B.i , Quigley, J.h , Pasternak, A.E.h , Florence, J.M.a , Anand, P.j , Wulf, C.O.j , Goude, E.j , Dalton, J.C.k , Viollet-Callendret, L.l , Buser, K.K.m , Shriber, E.n o , Parad, R.n o
Outcome reliability in non-Ambulatory Boys/Men with duchenne muscular dystrophy
(2015) Muscle and Nerve, 51 (4), pp. 522-532. 

DOI: 10.1002/mus.24346

a Department of Neurology, Washington University School of Medicine in Saint LouisSt. Louis, MO, United States
b Department of Pediatrics, Washington University School of Medicine in Saint LouisSt. Louis, MO, United States
c Department of Pediatrics, The Ohio State University and Center for Gene Therapy, Nationwide Children's HospitalColumbus, OH, United States
d Division of Biostatistics, Washington University School of Medicine in Saint LouisSt. Louis, MO, United States
e Department Physical Medicine and Rehabilitation, University of California, Davis Medical CenterSacramento, CA, United States
f Department of Neurology, University of MinnesotaMinneapolis, MI, United States
g Department of Neurology, Stanford UniversityStanford, CA, United States
h Department of Neurology, Harvard University, Boston Children's HospitalBoston, MA, United States
i Department of Neurology, University of Florida College of MedicineGainesville, FL, United States
j Department of Neurology, Washington University School of Medicine in Saint LouisSt. Louis, MO, United States
k Department of Neurology, University of MinnesotaMinneapolis, MN, United States
l Department of Pediatrics, The Ohio State University and Center for Gene Therapy, Nationwide Children's HospitalColumbus, OH, United States
m Department of Neurology, University of MinnesotaMinneapolis, MN, United States
n Department of Neurology, Harvard UniversityBoston, MA, United States
o Boston Children's HospitalBoston, MA, United States

Introduction: Therapeutic trials in Duchenne muscular dystrophy (DMD) often exclude non-ambulatory individuals. Here we establish optimal and reliable assessments in a multicenter trial. Methods: Non-ambulatory boys/men with DMD (N=91; 16.7±4.5 years of age) were assessed by trained clinical evaluators. Feasibility (percentage completing task) and reliability [intraclass correlation coefficients (ICCs) between morning and afternoon tests] were measured. Results: Forced vital capacity (FVC), assessed in all subjects, showed a mean of 47.8±22% predicted (ICC 0.98). Brooke Upper Extremity Functional Rating (Brooke) and Egen Klassifikation (EK) scales in 100% of subjects showed ICCs ranging from 0.93 to 0.99. Manual muscle testing, range of motion, 9-hole peg test, and Jebsen-Taylor Hand Function Test (JHFT) demonstrated varied feasibility (99% to 70%), with ICCs ranging from 0.99 to 0.64. We found beneficial effects of different forms of corticosteroids for the Brooke scale, percent predicted FVC, and hand and finger strength. Conclusions: Reliable assessment of non-ambulatory boys/men with DMD is possible. Clinical trials will have to consider corticosteroid use. © 2014 Wiley Periodicals, Inc..

Author Keywords
Corticosteroids;  Duchenne muscular dystrophy;  Non-ambulatory;  Pulmonary function;  Quality of life;  Strength


Document Type: Article
Source: Scopus

Avidan, M.S.a b
Power of negative thinking
(2015) British journal of anaesthesia, 114 (1), pp. 3-5. 

DOI: 10.1093/bja/aeu263

a Department of Anesthesiology, Washington University School of Medicine, Campus Box 8054, 660 S Euclid Ave, St Louis, MO 63110, USA
b Department of Anesthesiology, Washington University School of Medicine, Campus Box 8054, 660 S Euclid Ave, St Louis, MO 63110, USA


Document Type: Editorial
Source: Scopus

Musiek, E.S.
Preventing an unholy alliance
(2015) Science Translational Medicine, 7 (280), art. no. 280ec51, . 

DOI: 10.1126/scitranslmed.aaa9875

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


Document Type: Note
Source: Scopus

Rutherford, M.A.a b
Resolving the structure of inner ear ribbon synapses with STED microscopy
(2015) Synapse, 69 (5), pp. 242-255. 

DOI: 10.1002/syn.21812

a Department of Otolaryngology, Central Institute for the Deaf, Washington University School of Medicine, Washington University School of MedicineSt. Louis, MO, United States
b Inner Ear Lab, Department of Otolaryngology, University of Göttingen Medical CenterGöttingen, Germany

Synapses are diverse in form and function; however, the mechanisms underlying this diversity are poorly understood. To illuminate structure/function relationships, robust analysis of molecular composition and morphology is needed. The molecular-anatomical components of synapses-vesicles, clusters of voltage-gated ion channels in presynaptic densities, arrays of transmitter receptors in postsynaptic densities-are only tens to hundreds of nanometers in size. Measuring the topographies of synaptic proteins requires nanoscale resolution of their molecularly specific labels. Super-resolution light microscopy has emerged to meet this need. Achieving 50 nm resolution in thick tissue, we employed stimulated emission depletion (STED) microscopy to image the functionally and molecularly unique ribbon-type synapses in the inner ear that connect mechano-sensory inner hair cells to cochlear nerve fibers. Synaptic ribbons, bassoon protein, voltage-gated Ca2+ channels, and glutamate receptors are inhomogeneous in their spatial distributions within synapses; the protein clusters assume variations of shapes typical for each protein specifically at cochlear afferent synapses. Heterogeneity of substructure among these synapses may contribute to functional differences among auditory nerve fibers. The morphology of synaptic voltage-gated Ca2+ channels matures over development in a way that depends upon bassoon protein, which aggregates in similar form. Functional properties of synaptic transmission appear to depend on voltage-gated Ca2+ channel cluster morphology and position relative to synaptic vesicles. Super-resolution light microscopy is a group of techniques that complement electron microscopy and conventional light microscopy. Although technical hurdles remain, we are beginning to resolve the details of molecular nanoanatomy that relate mechanistically to synaptic function. © 2015 Wiley Periodicals, Inc.

Author Keywords
AMPA receptor;  Bassoon;  CaV1.3;  Cochlea;  CtBP2/Ribeye;  Hair cell;  Spiral ganglion neuron;  Stimulated emission depletion;  Stimulus-secretion coupling;  Super-resolution light microscopy


Document Type: Article
Source: Scopus

Saini, A.a , Emke, A.R.a , Silva, M.C.a , Perlman, S.J.b
Response to eculizumab in Escherichia coli O157: H7-induced hemolytic uremic syndrome with severe neurological manifestations
(2015) Clinical Pediatrics, 54 (4), pp. 387-389. 

DOI: 10.1177/0009922814534520

a Division of Critical Care Medicine, Department of Pediatrics, Washington University School of MedicineSt Louis, MO, United States
b Division of Neurology and Behavioural Pediatrics, Department of Pediatrics, University of Iowa Carver College of MedicineIowa City, IA, United States


Document Type: Article
Source: Scopus

Wang, L.a , Benzinger, T.L.b d e , Hassenstab, J.a c e , Blazey, T.a , Owen, C.b , Liu, J.g , Fagan, A.M.a e f , Morris, J.C.a e f , Ances, B.M.a b e f
Spatially distinct atrophy is linked to β-amyloid and tau in preclinical Alzheimer disease
(2015) Neurology, 84 (12), pp. 1254-1260. 

DOI: 10.1212/WNL.0000000000001401

a Departments of Neurology, Washington UniversitySaint Louis, MO, United States
b Departments of Radiology, Washington UniversitySaint Louis, MO, United States
c Departments of Psychology, Washington UniversitySaint Louis, MO, United States
d Departments of Neurosurgery, Washington UniversitySaint Louis, MO, United States
e Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington UniversitySaint Louis, MO, United States
f Hope Center for Neurological Disorders, Washington UniversitySaint Louis, MO, United States
g Division of Biostatistics, Washington UniversitySaint Louis, MO, United States

Objectives: To determine whether an MRI-based Alzheimer disease (AD) signature biomarker can detect tau-related neurodegeneration in preclinical AD, and to assess whether AD signature cortical thinning is associated with cognitive changes in cognitively normal (CN) older individuals. Methods: In a large cohort of CN individuals (n 188), we measured the hippocampal volume and cortical thickness within independently defined AD signature regions. We cross-sectionally assessed the associations between AD signature cortical thinning or hippocampal atrophy with CSF biomarkers of tau (increased tau) and β-amyloid (Aβ) (decreased Aβ42). We also examined the impact of AD signature cortical thinning or other biomarker changes (i.e., hippocampal atrophy, reduced CSF Aβ42, or increased CSF tau) on cognitive performance in CN individuals. Results: Elevated CSF tau was associated with AD signature cortical thinning but not hippocampal atrophy. In contrast, decreased CSF Aβ42 was associated with hippocampal loss but not AD signature cortical thinning. In addition, AD signature cortical thinning was associated with lower visuospatial performance. Reduced CSF Aβ42 was related to poorer performance on episodic memory. Conclusions: Spatially distinct neurodegeneration is associated with Aβ and tau pathology in preclinical AD. Aβ deposition and AD signature cortical atrophy independently affect cognition in CN older individuals. © © 2015 American Academy of Neurology.


Document Type: Article
Source: Scopus

Petersen, S.C.a , Luo, R.b , Liebscher, I.c , Giera, S.b , Jeong, S.-J.b , Mogha, A.a , Ghidinelli, M.d , Feltri, M.L.d , Schöneberg, T.c , Piao, X.b , Monk, K.R.a e
The Adhesion GPCR GPR126 Has Distinct, Domain-Dependent Functions in Schwann Cell Development Mediated by Interaction with Laminin-211
(2015) Neuron, 85 (4), pp. 755-769. 

DOI: 10.1016/j.neuron.2014.12.057

a Department of Developmental Biology, Washington University School of MedicineSt. Louis, MO, United States
b Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital and Harvard Medical SchoolBoston, MA, United States
c Institute of Biochemistry, Medical Faculty, University of LeipzigLeipzig, Germany
d Department of Biochemistry, University of Buffalo, The State University of New YorkBuffalo, NY, United States
e Hope Center for Neurological Disorders, Washington University School of MedicineSt. Louis, MO, United States

Myelin ensheathes axons to allow rapid propagation of action potentials and proper nervous system function. In the peripheral nervous system, Schwann cells(SCs) radially sort axons into a 1:1 relationship before wrapping an axonal segment to form myelin. SC myelination requires the adhesion G protein-coupled receptor GPR126, which undergoes autoproteolytic cleavage into an N-terminal fragment (NTF) and a seven-transmembrane-containing C-terminal fragment (CTF). Here we show that GPR126 has domain-specific functions in SC development whereby the NTF is necessary and sufficient for axon sorting, whereas the CTF promotes wrapping through cAMP elevation. These biphasic roles of GPR126 are governed by interactions with Laminin-211, which we define as a novel ligand for GPR126 that modulates receptor signaling via a tethered agonist. Our work suggests a model in which Laminin-211 mediates GPR126-induced cAMP levels to control early and late stages of SC development. © 2015 Elsevier Inc.


Document Type: Article
Source: Scopus

Levinson, C.A., Byrne, M.
The fear of food measure: A novel measure for use in exposure therapy for eating disorders
(2015) International Journal of Eating Disorders, 48 (3), pp. 271-283. 

DOI: 10.1002/eat.22344

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

Objective: Exposure therapy for mealtime anxiety has preliminarily been effective at increasing food intake and decreasing anxiety in individuals with anorexia nervosa (AN). To enhance our knowledge of exposure therapy for AN researchers and clinicians need a comprehensive measure that assesses outcomes relevant to exposure therapy for AN. Method: In the current four studies we developed Fear of Food Measure (FOFM) that assesses three cognitive and behavioral outcomes: trait anxiety about eating, food avoidance behaviors, and feared concerns related to eating. Results: In a community (N = 399) and undergraduate female sample (N = 203) the FOFM exhibited a good three-factor structure and convergent and divergent validity. In a sample of women (N = 72) we showed that the anxiety about eating subscale significantly predicted in vivo food intake over and above other established predictors of eating (e.g., restraint). In a clinical sample diagnosed with an eating disorder (N = 41) we showed that anxiety about eating was associated with food intake and anxiety during an exposure meal and that all subscales of the FOFM significantly decreased over the course of a four-session exposure intervention. Finally, we found that participants diagnosed with an eating disorder had higher levels of fear of food than did matched controls (N = 23). Discussion: The FOFM is a psychometrically valid measure that can assess if patients are improving while undergoing exposure therapy and could be used to pinpoint problematic behaviors that can be addressed in exposure therapy. © 2014 Wiley Periodicals, Inc.

Author Keywords
anorexia nervosa;  anxiety about eating;  eating disorders;  exposure therapy;  food avoidance


Document Type: Article
Source: Scopus

North, C.S.a b , Pollio, D.E.c , Hong, B.A.d , Pandya, A.e , Smith, R.P.f , Pfefferbaum, B.g
The postdisaster prevalence of major depression relative to PTSD in survivors of the 9/11 attacks on the world trade center selected from affected workplaces
(2015) Comprehensive Psychiatry, . Article in Press. 

DOI: 10.1016/j.comppsych.2015.02.009

a Program in Trauma and Disaster and Staff Psychiatrist, VA North Texas Health Care System, Dallas, TX, USA
b Departments of Psychiatry and Emergency Medicine, The University of Texas Southwestern Medical Center, 6363 Forest Park Rd., Dallas, TX 75390-8828, USA
c The University of Alabama at Birmingham, Department of Social Work, College of Arts and Sciences, Birmingham, AL, USA
d Washington University School of Medicine, Department of Psychiatry, St. Louis, MO, USA
e Keck School of Medicine, Department of Psychiatry and Behavioral Sciences, University of California, Los Angeles, CA, USA
f Ichan School of Medicine at Mt. Sinai and The New York Harbor Health Care System - Manhattan VA, New York, NY, USA
g The University of Oklahoma College of Medicine, Department of Psychiatry and Behavioral Sciences, College of Medicine, Oklahoma City, OK, USA

Background: Studies of survivors of the September 11, 2001 attacks on the World Trade Center in New York City suggest that postdisaster depressive disorders may be at least as prevalent, or even more prevalent, than posttraumatic stress disorder (PTSD), unlike findings from most other disaster studies. The relative prevalence and incidence of major depressive disorder (MDD) and PTSD were examined after the 9/11 attacks relative to trauma exposures. Methods: This study used full diagnostic assessment methods and careful categorization of exposure groups based on DSM-IV-TR criteria for PTSD to examine 373 employees of 9/11-affected New York City workplaces. Results: Postdisaster new MDD episode (26%) in the entire sample was significantly more prevalent (p. <. .001) than 9/11-related PTSD (14%). Limiting the comparison to participants with 9/11 trauma exposures, the prevalence of postdisaster new MDD episode and 9/11-related PTSD did not differ (p = .446). The only 9/11 trauma exposure group with a significant difference in relative prevalence of MDD and PTSD were those with a 9/11 trauma-exposed close associate, for whom postdisaster new MDD episode (45%) was more prevalent (p = .046) than 9/11-related PTSD (31%). Conclusions: Because of the conditional definition of PTSD requiring trauma exposure that is not part of MDD criteria, prevalence comparisons of these two disorders must be limited to groups with qualifying trauma exposures to be meaningful. Findings from this study suggest distinct mechanisms underlying these two disorders that differentially relate to direct exposure to trauma vs. the magnitude of the disaster and personal connectedness to disaster and community-wide effects. © 2015.


Document Type: Article in Press
Source: Scopus

Zhang, A.a , Fisher, A.J.b , Bailey, J.O.a , Kass, A.E.c , Wilfley, D.E.c d , Taylor, C.B.a
The self-rating of the effects of alcohol questionnaire predicts heavy episodic drinking in a high-risk eating disorder population
(2015) International Journal of Eating Disorders, 48 (3), pp. 333-336. 

DOI: 10.1002/eat.22365

a Department of Psychiatry, Stanford University Medical CenterStanford, CA, United States
b Department of Psychology, University of California, BerkeleyBerkeley, CA, United States
c Department of Psychology, Washington University in St. LouisSt. Louis, MO, United States
d Department of Psychiatry, Washington University, School of Medicine in St. LouisSt. Louis, MO, United States

Objective: Heavy episodic drinking (HED) is a serious problem among college women at high-risk for developing eating disorders (EDs). The main objectives of this study are to determine the relationship of the self-rating of the effects of alcohol (SRE) questionnaire and HED over time, and to determine the effects of relationship breakups on HED among college-aged women at high-risk for EDs. Method: Data collected from 163 participants in a randomized controlled trial evaluating the effectiveness of an ED prevention program were used in the analyses. Measures included the SRE, obtained at baseline, and self-reports of the number of HED episodes and relationship breakups each month for the past 12 months. Results: Generalized linear mixed-effect regression models with Poisson distribution were conducted to test the effects of several variables on reported HED episodes over 12 months. Analyses demonstrated that SRE scores and the presence of a breakup predicted increased HED over time. Discussion: The SRE may be useful in identifying individuals at risk of or with EDs who are at increased risk of HED. Furthermore, relationship breakups predict HED. Findings from the current study could be used to inform clinical interventions for this population. © 2014 Wiley Periodicals, Inc.

Author Keywords
alcohol;  college women;  heavy episodic drinking;  high-risk;  SRE


Document Type: Article
Source: Scopus

Elfenbein, H.A.a , Barsade, S.G.b , Eisenkraft, N.c
The social perception of emotional abilities: Expanding what we know about observer ratings of emotional intelligence
(2015) Emotion, 15 (1), pp. 17-34. 

DOI: 10.1037/a0038436

a Olin School of Business, Washington UniversitySt. Louis, United States
b Wharton School, University of Pennsylvania, United States
c Kenan-Flagler Business School, University of North CarolinaChapel Hill, United States

We examine the social perception of emotional intelligence (EI) through the use of observer ratings. Individuals frequently judge others' emotional abilities in real-world settings, yet we know little about the properties of such ratings. This article examines the social perception of EI and expands the evidence to evaluate its reliability and cross-judge agreement, as well as its convergent, divergent, and predictive validity. Three studies use real-world colleagues as observers and data from 2,521 participants. Results indicate significant consensus across observers about targets' EI, moderate but significant self-observer agreement, and modest but relatively consistent discriminant validity across the components of EI. Observer ratings significantly predicted interdependent task performance, even after controlling for numerous factors. Notably, predictive validity was greater for observer-rated than for self-rated or ability-tested EI. We discuss the minimal associations of observer ratings with ability-tested EI, study limitations, future directions, and practical implications. © 2015 American Psychological Association.

Author Keywords
Ability tests;  Emotional intelligence;  Observer ratings;  Self-ratings;  Social perception;  Social relations model


Document Type: Article
Source: Scopus

Ong, C.J.
Tipping point: Head computed tomography and its impact on neurology training
(2015) Annals of Neurology, 77 (4), pp. 556-559. 

DOI: 10.1002/ana.24363

Department of Neurology, Washington University, School of Medicine, 660 South EuclidSt. Louis, MO, United States


Document Type: Article
Source: Scopus

Zygourakis, C.C.a , Vasudeva, V.b , Lai, P.M.R.b , Kim, A.H.c , Wang, H.d , Du, R.b
Transient pupillary dilation following local papaverine application in intracranial aneurysm surgery
(2015) Journal of Clinical Neuroscience, 22 (4), pp. 676-679. 

DOI: 10.1016/j.jocn.2014.10.016

a Department of Neurosurgery, University of California San FranciscoSan Francisco, CA, United States
b Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis StreetBoston, MA, United States
c Department of Neurosurgery, Washington University in St. LouisSt. Louis, MO, United States
d Department of Neurosurgery, Carle Foundation Hospital, University of Illinois College of Medicine at Urbana-ChampaignUrbana, IL, United States

Isolated cases of transient pupillary changes after local intracisternal papaverine administration during aneurysm surgery have been reported. This study aimed to determine the prevalence and factors associated with this phenomenon. We assessed a total of 103 consecutive patients who underwent craniotomy for cerebral aneurysm clipping for the presence of postoperative pupillary dilation (mydriasis) after intracisternal papaverine administration. Univariate and multivariate logistic regression were conducted to evaluate the association of mydriasis with patient age, sex, duration of surgery, and aneurysm location. We observed either ipsilateral or bilateral pupillary dilation in the immediate postoperative period in nine out of 103 patients (8.7%). This phenomenon was not associated with patient age or sex. There was a trend towards positive correlation with aneurysms located at the anterior communicating artery (odds ratio 3.76, p = 0.10), and a negative correlation with the duration of surgery (odds ratio 0.57, p = 0.08). All pupillary dilation resolved within several hours, and the onset and resolution were consistent with the half-life of papaverine. To our knowledge, this represents the largest study of posteropative pupillary changes due to papaverine. The current findings are consistent with the small number of prior case reports of transient pupillary changes after papaverine administration and appear to reflect the local anesthetic action of papaverine on the oculomotor nerve. © 2014 Elsevier Ltd. All rights reserved.

Author Keywords
Drug effects;  Intracranial aneurysm;  Mydriasis;  Papaverine;  Pupil dilation


Document Type: Article
Source: Scopus


Adler, J.M.a , Turner, A.F.b , Brookshier, K.M.c , Monahan, C.c , Walder-Biesanz, I.c , Harmeling, L.H.d , Albaugh, M.e , McAdams, D.P.f , Oltmanns, T.F.g
Variation in narrative identity is associated with trajectories of mental health over several years
(2015) Journal of Personality and Social Psychology, 108 (3), pp. 476-496. 

DOI: 10.1037/a0038601

a Olin College of Engineering; Ariana F.Turner, United States
b Department of Psychology, Scripps College, United States
c Franklin W. Olin College of Engineering, United States
d Department of Psychology, Bates College, United States
e Department of Human Development and Social Policy, Northwestern University, United States
f Department of Psychology and Department of Human Development and Social Policy, Northwestern University, United States
g Department of Psychology and Department of Psychiatry, Washington University in St. Louis, United States

This article presents 2 longitudinal studies designed to assess the relationship between variability in narrative identity and trajectories of mental health over several years. In Study 1, core scenes from 89 late-mid-life adults' life stories were assessed for several narrative themes. Participants' mental health and physical health were assessed concurrently with the narratives and annually for the subsequent 4 years. Concurrent analyses indicated that the themes of agency, redemption, and contamination were significantly associated with mental health. Longitudinal analyses indicated that these same 3 themes were significantly associated with participants' trajectories of mental health over the course of 4 years. Exploratory analyses indicated that narratives of challenging experiences may be central to this pattern of results. In Study 2, similar longitudinal analyses were conducted on a sample of 27 late-mid-life adults who received a major physical illness diagnosis between the baseline assessment and 6 months later and a matched sample of 27 control participants who remained healthy throughout the study. Participants' mental health and physical health were assessed every 6 months for 2 years. In this study, the themes of agency, communion, redemption, and contamination in participants' life narratives collected at baseline (before any participant became sick) were significantly associated with mental health in the group of participants who went on to receive a medical diagnosis, but not in the control group. Taken together, the results of these 2 studies indicate that the way an individual constructs personal narratives may impact his or her trajectory of mental health over time. © 2015 American Psychological Association.

Author Keywords
Agency;  Communion;  Contamination;  Health;  Narrative identity;  Redemption


Document Type: Article
Source: Scopus

Zhu, C.a , Herrmann, U.S.a , Li, B.a , Abakumova, I.a , Moos, R.a , Schwarz, P.a , Rushing, E.J.a , Colonna, M.b , Aguzzi, A.a
Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains
(2015) Neurobiology of Aging, . Article in Press. 

DOI: 10.1016/j.neurobiolaging.2015.02.019

a Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA

Dysfunctional variants of the innate immune cell surface receptor TREM2 (triggering receptor expressed on myeloid cells-2) were identified as major genetic risk factors for Alzheimer's disease and other neurodegenerative conditions. Here we assessed a possible involvement of TREM2 in prion disease. We report that TREM2 expression by microglia is significantly up-regulated upon prion infection. However, depletion of TREM2 did not affect disease incubation time and survival after intracerebral prion infection. Interestingly, markers of microglial activation were attenuated in prion-infected TREM2-/- mice, suggesting an involvement of TREM2 in prion-induced microglial activation. Further phenotype profiling of microglia revealed that TREM2 deficiency did not change microglial phenotypes. We conclude that TREM2 is involved in prion-induced microglial activation but does not noticeably modulate the pathogenesis of experimental prion infections. © 2015 Elsevier Inc.

Author Keywords
Microglial activation;  Neuroinflammation;  Pathogenesis;  Prion disease;  TREM2


Document Type: Article in Press
Source: Scopus

Hershey, L.A.a b
Smoking and Parkinson disease: where there is smoke there may not be fire
(2014) Neurology, 83 (16), pp. 1392-1393. 

DOI: 10.1212/WNL.0000000000000896

a From the Department of Neurology (L.A.H.), University of Oklahoma Health Sciences Center, Oklahoma City; and Departments of Neurology, Radiology, and Neurobiology, and Programs of Physical Therapy and Occupational Therapy (J.S.P.), Washington University, St. Louis, MO.
b From the Department of Neurology (L.A.H.), University of Oklahoma Health Sciences Center, Oklahoma City; and Departments of Neurology, Radiology, and Neurobiology, and Programs of Physical Therapy and Occupational Therapy (J.S.P.), Washington University, St. Louis, MO


Document Type: Editorial
Source: Scopus

Harpole, J.K.a , Woods, C.M.a , Rodebaugh, T.L.b , Levinson, C.A.b , Lenze, E.J.c
How bandwidth selection algorithms impact exploratory data analysis using kernel density estimation
(2014) Psychological Methods, 19 (3), pp. 428-434. 

DOI: 10.1037/a0036850

a Department of Psychology, University of Kansas, United States
b Department of Psychology, Washington UniversitySt. Louis, United States
c Department of Psychiatry, Washington University, St. Louis School of Medicine, United States

Exploratory data analysis (EDA) can reveal important features of underlying distributions, and these features often have an impact on inferences and conclusions drawn from data. Graphical analysis is central to EDA, and graphical representations of distributions often benefit from smoothing. A viable method of estimating and graphing the underlying density in EDA is kernel density estimation (KDE). This article provides an introduction to KDE and examines alternative methods for specifying the smoothing bandwidth in terms of their ability to recover the true density. We also illustrate the comparison and use of KDE methods with 2 empirical examples. Simulations were carried out in which we compared 8 bandwidth selection methods (Sheather-Jones plug-in [SJDP], normal rule of thumb, Silverman's rule of thumb, least squares cross-validation, biased cross-validation, and 3 adaptive kernel estimators) using 5 true density shapes (standard normal, positively skewed, bimodal, skewed bimodal, and standard lognormal) and 9 sample sizes (15, 25, 50, 75, 100, 250, 500, 1,000, 2,000). Results indicate that, overall, SJDP outperformed all methods. However, for smaller sample sizes (25 to 100) either biased cross-validation or Silverman's rule of thumb was recommended, and for larger sample sizes the adaptive kernel estimator with SJDP was recommended. Information is provided about implementing the recommendations in the R computing language. © 2014 American Psychological Association.

Author Keywords
Adaptive kernel density estimation;  Bandwidth selection;  Exploratory data analysis;  Graphical analysis;  Kernel density estimation


Document Type: Article
Source: Scopus

Johnson, E.O.a b c , Hancock, D.B.a b c , Gaddis, N.C.a b c , Levy, J.L.a b c , Page, G.a b c , Novak, S.P.a b c , Glasheen, C.a b c , Saccone, N.L.d , Rice, J.P.d , Moreau, M.P.e , Doheny, K.F.f , Romm, J.M.f , Brooks, A.I.e , Aouizerat, B.E.g h , Bierut, L.J.d , Kral, A.H.a b c
Novel genetic locus implicated for HIV-1 acquisition with putative regulatory links to HIV replication and infectivity: A genome-wide association study
(2015) PLoS ONE, 10 (3), art. no. e0118149, . 

DOI: 10.1371/journal.pone.0118149

a RTI InternationalResearch Triangle Park, NC, United States
b RTI InternationalAtlanta, GA, United States
c RTI InternationalSan Francisco, CA, United States
d Washington University School of MedicineSt. Louis, MO, United States
e Rutgers University Cell and DNA Repository (RUCDR)Piscataway, NJ, United States
f Center for Inherited Disease Research (CIDR), Johns Hopkins UniversityBaltimore, MD, United States
g School of Nursing, University of California San FranciscoSan Francisco, CA, United States
h Institute for Human Genetics, University of California San FranciscoSan Francisco, CA, United States

Fifty percent of variability in HIV-1 susceptibility is attributable to host genetics. Thus identifying genetic associations is essential to understanding pathogenesis of HIV-1 and important for targeting drug development. To date, however, CCR5 remains the only gene conclusively associated with HIV acquisition. To identify novel host genetic determinants of HIV-1 acquisition, we conducted a genome-wide association study among a high-risk sample of 3,136 injection drug users (IDUs) from the Urban Health Study (UHS). In addition to being IDUs, HIV- controls were frequency-matched to cases on environmental exposures to enhance detection of genetic effects. We tested independent replication in the Women's Interagency HIV Study (N=2,533). We also examined publicly available gene expression data to link SNPs associated with HIV acquisition to known mechanisms affecting HIV replication/infectivity. Analysis of the UHS nominated eight genetic regions for replication testing. SNP rs4878712 in FRMPD1 met multiple testing correction for independent replication (P=1.38×10-4), although the UHS-WIHS meta-analysis p-value did not reach genome-wide significance (P=4.47×10-7 vs. P&lt;5.0×10-8) Gene expression analyses provided promising biological support for the protective G allele at rs4878712 lowering risk of HIV: (1) the G allele was associated with reduced expression of FBXO10 (r=-0.49, P=6.9×10-5); (2) FBXO10 is a component of the Skp1-Cul1-F-box protein E3 ubiquitin ligase complex that targets Bcl-2 protein for degradation; (3) lower FBXO10 expression was associated with higher BCL2 expression (r=-0.49, P=8×10-5); (4) higher basal levels of Bcl-2 are known to reduce HIV replication and infectivity in human and animal in vitro studies. These results suggest new potential biological pathways by which host genetics affect susceptibility to HIV upon exposure for follow-up in subsequent studies. © 2015 Johnson et al.

Document Type: Article
Source: Scopus

Huang, J.a , Liu, Y.a , Oltean, A.c , Beebe, D.C.a b
Bmp4 from the optic vesicle specifies murine retina formation
(2015) Developmental Biology, . Article in Press. 

DOI: 10.1016/j.ydbio.2015.03.006

a Department of Ophthalmology and Visual Science, USA
b Department of Cell Biology and Physiology, Washington University School of Medicine, USA
c Department of Biomedical Engineering, Washington University, Saint Louis, MO, USA

Previous studies of mouse embryos concluded that after the optic vesicle evaginates from the ventral forebrain and contacts the surface ectoderm, signals from the ectoderm specify the distal region of the optic vesicle to become retina and signals from the optic vesicle induce the lens. Germline deletion of Bmp4 resulted in failure of lens formation. We performed conditional deletion of Bmp4 from the optic vesicle to test the function of Bmp4 in murine eye development. The optic vesicle evaginated normally and contacted the surface ectoderm. Lens induction did not occur. The optic cup failed to form and the expression of retina-specific genes decreased markedly in the distal optic vesicle. Instead, cells in the prospective retina expressed genes characteristic of the retinal pigmented epithelium. We conclude that Bmp4 is required for retina specification in mice. In the absence of Bmp4, formation of the retinal pigmented epithelium is the default differentiation pathway of the optic vesicle. Differences in the signaling pathways required for specification of the retina and retinal pigmented epithelium in chicken and mouse embryos suggest major changes in signaling during the evolution of the vertebrate eye. © 2015 Elsevier Inc.

Author Keywords
Bmp4;  Evolution;  Optic cup;  Retina;  Retinal pigmented epithelium

Document Type: Article in Press
Source: Scopus

Voelker, C.C.J.a , Lucisano, A.b , Kallogjeri, D.a , Sinks, B.C.a , Goebel, J.A.a
Comparison of the gaze stabilization test and the dynamic visual acuity test in unilateral vestibular loss patients and controls
(2015) Otology and Neurotology, 36 (4), pp. 746-754. 

DOI: 10.1097/MAO.0000000000000689

a Dizziness and Balance Center, Department of Otolaryngology - Head and Neck Surgery, Washington University School of MedicineSt. Louis, MO, United States
b Washington University School of MedicineSt. Louis, MO, United States

Objective: Compare the dynamic visual acuity test (DVAT) and gaze stabilization test (GST) in patients with unilateral vestibular loss (UVL) and healthy control subjects using a novel computerized testing system prototype. Study Design: Cross-sectional study. Setting: Tertiary academic referral laboratory. Patients: Seventeen UVL patients (median age 62 yr) with bithermal caloric asymmetry (≥49%) or ablative surgery and 17 control subjects (median age 57 yr). Intervention(s): Diagnostic. Main Outcome Measure(s): Comparison of DVAT and GST results during self-generated sinusoidal head movements using transient unpredictable target presentations less than 95 milliseconds in duration. Results: UVL patients had significantly higher DVAT scores toward the lesioned side compared with controls (p = 0.001) and the non-lesioned side (p = 0.003), but the non-lesioned side was not significantly different from controls (p = 0.157). When comparing GST scores, UVL patients required a slower head velocity to maintain visual acuity with movement toward the lesioned side compared with controls (p < 0.001) and the non-lesioned side (p = 0.004). In addition, UVL patients had significantly lower scores toward the non-lesioned side (p = 0.002) compared to controls. ROC curve analysis identified optimal thresholds for abnormal test results to discriminate the lesioned side from controls. A DVAT score greater than or equal to 0.3 ΔlogMAR provided 65% sensitivity and 88% specificity while a GST score less than or equal to 95 degrees/s provided 71% sensitivity and 100% specificity. When GST results were normal, adding DVAT increased overall sensitivity to 88% with 88% specificity. Conclusions: Both GST and DVAT demonstrated reduced gaze stabilization toward the lesioned side in the patient group compared with normal controls. Performing GST first and utilizing DVAT when GST was normal provides optimal identification of patients with vestibular dysfunction. © 2014, Otology & Neurotology, Inc.

Author Keywords
Dynamic visual acuity test;  Gaze stabilization test;  Vestibular testing

Document Type: Article
Source: Scopus

Kaphingst, K.A.a c , Stafford, J.D.a , McGowan, L.D.a , Seo, J.a , Lachance, C.R.b , Goodman, M.S.a
Effects of racial and ethnic group and health literacy on responses to genomic risk information in a medically underserved population
(2015) Health Psychology, 34 (2), pp. 101-110. Cited 1 time.

DOI: 10.1037/hea0000177

a Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, United States
b Social and Behavioral Research Branch, National Human Genome Research Institute, National Institutes of HealthBethesda, MD, United States
c Huntsman Cancer Institute, Department of Communication, University of Utah, United States

Objective: Few studies have examined how individuals respond to genomic risk information for common, chronic diseases. This randomized study examined differences in responses by type of genomic information (genetic test/family history) and disease condition (diabetes/heart disease), and by race/ethnicity in a medically underserved population. Methods: 1,057 English-speaking adults completed a survey containing 1 of 4 vignettes (2-by-2 randomized design). Differences in dependent variables (i.e., interest in receiving genomic assessment, discussing with doctor or family, changing health habits) by experimental condition and race/ethnicity were examined using chi-squared tests and multivariable regression analysis. Results: No significant differences were found in dependent variables by type of genomic information or disease condition. In multivariable models, Hispanics were more interested in receiving a genomic assessment than Whites (OR = 1.93; p < .0001); respondents with marginal (OR = 1.54; p = .005) or limited (OR = 1.85; p = .009) health literacy had greater interest than those with adequate health literacy. Blacks (OR = 1.78; p = .001) and Hispanics (OR = 1.85; p =.001) had greater interest in discussing information with family than Whites. Non-Hispanic Blacks (OR = 1.45; p = .04) had greater interest in discussing genomic information with a doctor than Whites. Blacks (β = -0.41; p < .001) and Hispanics (β = -0.25; p = 033) intended to change fewer health habits than Whites; health literacy was negatively associated with number of health habits participants intended to change. Conclusions: Findings suggest that race/ethnicity may affect responses to genomic risk information. Additional research could examine how cognitive representations of this information differ across racial/ethnic groups. Health literacy is also critical to consider in developing approaches to communicating genomic information. © 2015 American Psychological Association.

Author Keywords
Cultural competence;  Family history;  Genetic communication;  Genetic susceptibility testing;  Health literacy

Document Type: Article
Source: Scopus

Bieser, S.a , Reis, M.a , Guzman, M.a , Gauvain, K.b , Elbabaa, S.a , Braddock, S.R.a , Abdel-Baki, M.S.a
Grade II pilocytic astrocytoma in a 3-month-old patient with encephalocraniocutaneous lipomatosis (ECCL): Case report and literature review of low grade gliomas in ECCL
(2015) American Journal of Medical Genetics, Part A, 167 (4), pp. 878-881. 

DOI: 10.1002/ajmg.a.37017

a Saint Louis University School of MedicineSt. Louis, MO, United States
b Washington University School of MedicineSt. Louis, MO, United States

Encephalocraniocutaneous lipomatosis (ECCL) is a rare congenital syndrome with an unknown etiology. Since 1970, around 60 cases have been reported in English literature. ECCL is usually classified by cutaneous lesions and non-progressive intracranial or spinal lipomas; however three cases of ECCL associated with low grade glioma (LGG) have been described. We report on the fourth case of LGG in a patient with ECCL; a grade II pilocytic astrocytoma with pilomyxoid features in a 3-month-old male, the youngest in literature. © 2015 Wiley Periodicals, Inc.

Author Keywords
Encephalocraniocutaneous;  Glioma;  Lipomatosis

Document Type: Article
Source: Scopus

Aschenbrenner, A.J., Balota, D.A.
Interactive effects of working memory and trial history on stroop interference in cognitively healthy aging
(2015) Psychology and Aging, 30 (1), pp. 1-8. 

DOI: 10.1037/pag0000012

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

Past studies have suggested that Stroop interference increases with age; however the robustness of this effect after controlling for processing speed has been questioned. Both working memory (WM) and the congruency of the immediately preceding trial have also been shown to moderate the magnitude of Stroop interference. Specifically, interference is smaller both for individuals with higher working memory capacity and following an incongruent trial. At present, it is unclear whether and how these 3 variables (age, WM and previous congruency) interact to predict interference effects in the standard Stroop color-naming task. We present analyses of Stroop interference in a large database of Stroop color-naming trials from a lifespan sample of well-screened, cognitively healthy, older adults. Our results indicated age-related increases in interference (after controlling for processing speed) that were exaggerated for individuals with low WM. This relationship between age and WM occurred primarily when the immediately preceding trial was congruent. Following an incongruent trial, interference increased consistently with age, regardless of WM. Taken together, these results support previous accounts of multiple mechanisms underlying control in the Stroop task and provide insight into how each component is jointly affected by age, WM, and trial history. © 2015 American Psychological Association.

Author Keywords
Aging;  Attention;  Congruency-sequence effect;  Working memory

Document Type: Article
Source: Scopus

Emery, C.R.a c , Wu, S.b c , Raghavan, R.d e
The hutong effect: Informal social control and community psychology in Beijing
(2015) Injury Prevention, 21 (2), pp. 121-125. 

DOI: 10.1136/injuryprev-2013-041117

a Yonsei UniversitySeoul, South Korea
b School of Management, Kyung Hee UniversitySeoul, South Korea
c Tsinghua UniversityBeijing, China
d Brown School, Washington University in St. LouisSt Louis, MO, United States
e Department of Psychiatry, Washington University School of MedicineSt Louis, MO, United States

Background Nearly 2.4 million Beijing residents experience intimate partner violence (IPV) annually. Of these 2.4 million, over 800 000 are injured by IPV; more than 300 000 are injured badly enough to require medical attention. Informal social control exerted by neighbours in communities with high levels of family-community integration (like those made up of residents of traditional courtyard house-and-alley Beijing neighbourhoods called ‘Hutongs’) may protect against IPV injury compared with apartment dwellers. Methods We tested the protective effects of informal social control and Hutong residence in a randomly selected, three-stage cluster sample of Beijing families reporting IPV. Informal social control of IPV (ISC_IPV) was measured using two 7-question Likert scales developed by the first author. Interviewers were given detailed instructions on how to classify neighbourhoods as Hutong-style or not. We used a Sobel test to examine whether the Hutong effect was mediated by informal social control. The initial sample was of 506 families. Analyses were carried out on 113 families who reported any IPV in the last year. Results Random effects regression models showed that both acts of informal social control and Hutong residence were associated with less IPV injury. However, the protective finding for Hutong residence was not explained by informal social control, collective efficacy, characteristics of the IPV or demographic characteristics of respondents and households. Conclusions The unique protective association with Hutong residence suggests that the benefits of community life remain insufficiently theorised and understood. © 2015, BMJ Publishing Group. All rights reserved.

Document Type: Article
Source: Scopus

Zhou, Y.a b , Holland, M.J.c , Makalo, P.d , Joof, H.d , Roberts, C.c , Mabey, D.C.W.c , Bailey, R.L.c , Burton, M.J.c , Weinstock, G.M.a e , Burr, S.E.c d
The conjunctival microbiome in health and trachomatous disease: A case control study
(2014) Genome Medicine, 6, art. no. 99, pp. 1-10. 

DOI: 10.1186/s13073-014-0099-x

a The Genome Institute, Washington UniversitySt Louis, MO, United States
b Department of Pediatrics, Washington University School of MedicineSt Louis, MO, United States
c Department of Clinical Research, London School of Hygiene and Tropical MedicineLondon, United Kingdom
d Disease Control and Elimination Theme, Medical Research Council UnitFajara, Gambia
e The Jackson Laboratory for Genomic MedicineFarmington, CT, United States

Background: Trachoma, caused by Chlamydia trachomatis, remains the world's leading infectious cause of blindness. Repeated ocular infection during childhood leads to scarring of the conjunctiva, in-turning of the eyelashes (trichiasis) and corneal opacity in later life. There is a growing body of evidence to suggest non-chlamydial bacteria are associated with clinical signs of trachoma, independent of C. trachomatis infection. Methods: We used deep sequencing of the V1-V3 region of the bacterial 16S rRNA gene to characterize the microbiome of the conjunctiva of 220 residents of The Gambia, 105 with healthy conjunctivae and 115 with clinical signs of trachoma in the absence of detectable C. trachomatis infection. Deep sequencing was carried out using the Roche-454 platform. Sequence data were processed and analyzed through a pipeline developed by the Human Microbiome Project. Results: The microbiome of healthy participants was influenced by age and season of sample collection with increased richness and diversity seen in younger participants and in samples collected during the dry season. Decreased diversity and an increased abundance of Corynebacterium and Streptococcus were seen in participants with conjunctival scarring compared to normal controls. Abundance of Corynebacterium was higher still in adults with scarring and trichiasis compared to adults with scarring only. Conclusions: Our results indicate that changes in the conjunctival microbiome occur in trachomatous disease; whether these are a cause or a consequence is yet unknown. © 2014 Zhou et al.; licensee BioMed Central Ltd.


Document Type: Article
Source: Scopus