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WUSTL Neuroscience Publications Archive - February 2014

Scopus weekly report:

February 1

February 14


February 14, 2014

Ching, S.a , Brown, E.N.b c
Modeling the dynamical effects of anesthesia on brain circuits
(2014) Current Opinion in Neurobiology, 25, pp. 116-122. 

a Department of Electrical and Systems Engineering, Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO 63130, United States
b Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114, United States
c Institute for Medical Engineering and Science, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, United States

General anesthesia has been used in the United States for more than 167 years. Now, using systems neuroscience paradigms how anesthetics act in the brain and central nervous system to create the states of general anesthesia is being understood. Propofol is one of the most widely used and the most widely studied anesthetics. When administered for general anesthesia or sedation, the electroencephalogram (EEG) under propofol shows highly structured, rhythmic activity that is strongly associated with changes in the patient's level of arousal. These highly structured oscillations lend themselves readily to mathematical descriptions using dynamical systems models. We review recent model descriptions of the commonly observed EEG patterns associated with propofol: paradoxical excitation, strong frontal alpha oscillations, anteriorization and burst suppression. Our analysis suggests that propofol's actions at GABAergic networks in the cortex, thalamus and brainstem induce profound brain dynamics that are one of the likely mechanisms through which this anesthetic induces altered arousal states from sedation to unconsciousness. Because these dynamical effects are readily observed in the EEG, the mathematical descriptions of how propofol's EEG signatures relate to its mechanisms of action in neural circuits provide anesthesiologists with a neurophysiologically based approach to monitoring the brain states of patients receiving anesthesia care. © 2014.

Document Type: Review
Source: Scopus

Arias, E.J.a , Derdeyn, C.P.a b c d , Dacey, R.G.a d , Zipfel, G.J.a b d
Advances and surgical considerations in the treatment of moyamoya disease
(2014) Neurosurgery, 74 (2 SUPPL.), pp. S116-S125. 

a Departments of Neurological Surgery, Washington University School of Medicine, Campus Box 8057, 660 S Euclid Ave, St. Louis, MO 63110, United States
b Departments of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Departments of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Stroke and Cerebrovascular Center, Washington University School of Medicine, St. Louis, MO, United States

Moyamoya is a rare disorder that involves steno-occlusive arterial changes of the anterior circulation, along with proliferative development of basal arterial collaterals. It is either idiopathic (called moyamoya disease) or the result of a specific underlying condition such as atherosclerosis, radiation therapy, or sickle cell disease (called moyamoya syndrome or phenomenon). In recent years, numerous insights into and advances in the understanding, evaluation, and management of moyamoya patients have occurred. This article briefly reviews the spectrum of moyamoya conditions and then provides a synopsis of numerous recent investigations that shed light on various aspects of the disease, including its clinical characteristics, natural history, underlying pathology, imaging, surgical techniques, and long-term patient outcome. Copyright © 2014 by the Congress of Neurological Surgeons.

Author Keywords
Cerebral revascularization;  Hemorrhagic stroke;  Ischemic stroke;  Moyamoya;  Natural history;  STAMCA bypass

Document Type: Article
Source: Scopus

Hashim, Y.M.a , Trinkaus, K.M.b , Linehan, D.C.a , Strasberg, S.S.a , Fields, R.C.a , Cao, D.c d , Hawkins, W.G.a
Regional lymphadenectomy is indicated in the surgical treatment of Pancreatic Neuroendocrine Tumors (PNETs)
(2014) Annals of Surgery, 259 (2), pp. 197-203. Cited 1 time.

a Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital, Washington University School of Medicine, 660 S. Euclid Ave, Saint Louis, MO, 63110, United States
b Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
c Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, United States
d Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Cancer Hospital, Beijing, China

OBJECTIVE:: To explore the prognostic importance and preoperative predictors of lymph node metastasis in an effort to guide surgical decision making in patients with pancreatic neuroendocrine tumors (PNETs). BACKGROUND:: PNETs are uncommon, and the natural history of the disease is not well described. As a result, there remains controversy regarding the optimal management of regional lymph nodes during resection of the primary tumor. METHODS:: A retrospective review of a prospectively maintained database of patients who underwent surgery for locoregional PNET between 1994 and 2012 was performed. Logistic regression was used to identify predictors of nodal metastasis. Overall survival and disease-free survival were calculated using Kaplan-Meier method. Results were expressed as P values and odds ratio estimates, with 95% confidence intervals. RESULTS:: One hundred thirty-six patients were identified, of whom 50 (38%) patients had nodal metastasis. The frequency of lymph node metastasis was higher for larger tumors [> 1.5 cm (odds ratio [OR] = 4.7)], tumors of the head as compared with body-tail of the pancreas (OR = 2.8), tumors with Ki-67 greater than 20% (OR = 6.7), and tumors with lymph vascular invasion (OR = 3.6) (P < 0.05). Median disease-free survival was lower for patients with nodal metastases (4.5 vs 14.6 years, P < 0.0001). CONCLUSIONS:: Lymph node metastasis is predictive of poor outcomes in patients with PNETs. Preoperative variables are not able to reliably predict patients where the probability of lymph node involvement was less than 12%. These data support inclusion of regional lymphadenectomy in patients undergoing pancreatic resections for PNET. © 2013 by Lippincott Williams and Wilkins.

Author Keywords
lymph node metastasis;  lymphadenectomy;  pancreatic neuroendocrine tumors

Document Type: Article
Source: Scopus

Owoso, A.a , Ndetei, D.M.b c , Mbwayo, A.W.b , Mutiso, V.N.b , Khasakhala, L.I.b , Mamah, D.a
Validation of a modified version of the PRIME screen for psychosis-risk symptoms in a non-clinical Kenyan youth sample
(2014) Comprehensive Psychiatry, 55 (2), pp. 380-387. 

a Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, United States
b Africa Mental Health Foundation, Nairobi, Kenya
c Department of Psychiatry, University of Nairobi, Kenya

Background The PRIME screen is a self-administered questionnaire designed to quickly assess individuals at risk for developing a psychotic disorder. It is shorter in both length and administration time compared to the Structured Interview for Psychosis-Risk Syndromes (SIPS) - a standard instrument for psychosis prodromal risk assessment. Validation of the PRIME against the SIPS has not been reported in large non-clinical populations. Methods A culturally modified version of the PRIME screen (mPRIME) was administered to Kenyan youth between the ages of 14 and 29. 182 completed both the SIPS and mPRIME. Validation measures (sensitivity, specificity, positive predictive value, negative predictive value) were calculated and the study sample was then broken down into true positives, false positives, and false negatives for comparison on different quantitative measures. Results Using previously suggested thresholds for a positive screen, the mPRIME had a sensitivity of 40% and a specificity of 64.8% for our entire sample. Positive predictive value (PPV) and negative predictive value (NPV) were 12.3% and 89.7%, respectively. Breaking the sample down by questionnaire outcome showed that true-positive individuals scored higher on average rate and intensity of endorsement of mPRIME items compared to false-positive and false-negatives, while false-negatives on average registered disagreement on all mPRIME questionnaire items. Conclusions The mPRIME does not appear to be an effective screener of at-risk individuals for psychosis in our non-clinical sample. Further validation efforts in other general populations are warranted. © 2014 Elsevier Inc.

Document Type: Article
Source: Scopus

Rachakonda, T.a , Jeffe, D.B.b , Shin, J.J.c , Mankarious, L.c , Fanning, R.J.d , Lesperance, M.M.e , Lieu, J.E.C.a
Validity, discriminative ability, and reliability of the hearing-related quality of life questionnaire for adolescents
(2014) Laryngoscope, 124 (2), pp. 570-578. 

a Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis MO, United States
b Department of Medicine-Health Behavior Research, Washington University School of Medicine, St. Louis MO, United States
c Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear Infirmary/Harvard Medical School, Cambridge MA, United States
d Department of Audiology, Phoenix Children's Hospital, Barrow Neurological Institute, Phoenix AZ, United States
e Division of Pediatric Otolaryngology, Department of Otolaryngology/Head and Neck Surgery, University of Michigan Health System, Ann Arbor MI, United States

Objectives/Hypothesis The prevalence of hearing loss (HL) in adolescents has grown over the past decade, but hearing-related quality of life (QOL) has not been well-measured. We sought to develop a reliable, valid measure of hearing-related QOL for adolescents and the Hearing Environments And Reflection on Quality of Life (HEAR-QL). Study Design Multisite observational study. Methods Adolescents with HL and siblings without HL were recruited from five centers. Participants completed the HEAR-QL and validated questionnaires measuring generic pediatric QOL (PedsQL), depression and anxiety (RCADS-25), and hearing-related QOL for adults (HHIA) to determine construct and discriminant validity. Participants completed the HEAR-QL 2 weeks later for test-retest reliability. We used exploratory principal components analysis to determine the HEAR-QL factor structure and measured reliability. Sensitivity and specificity of the HEAR-QL, PedsQL, HHIA, and RCADS-25 were assessed. We compared scores on all surveys between those with normal hearing, unilateral, and bilateral HL. Results A total of 233 adolescents (13-18 years old) participated: 179 with HL, 54 without HL. The original 45-item HEAR-QL was shortened to 28 items after determining factor structure. The resulting HEAR-QL-28 demonstrated excellent reliability (Cronbach's alpha = 0.95) and construct validity (HHIA: r =.845, PedsQL: r =.587; RCADS-25: r =.433). The HEAR-QL-28 displayed excellent discriminant validity, with higher area under the curve (0.932) than the PedsQL (0.597) or RCADS-25 (0.529). Teens with bilateral HL using hearing devices reported worse QOL on the HEAR-QL and HHIA than peers with HL not using devices. Conclusions The HEAR-QL is a sensitive, reliable, and valid measure of hearing-related QOL for adolescents. Level of Evidence 2b. Copyright © 2013 The American Laryngological, Rhinological and Otological Society, Inc.

Author Keywords
Adolescents;  hearing loss;  quality of life;  validation study

Document Type: Article
Source: Scopus

El Bitar, F.a b , Meunier, J.c , Villard, V.c , Alméras, M.c , Krishnan, K.d , Covey, D.F.d , Maurice, T.c , Akwa, Y.a
Neuroprotection by the synthetic neurosteroid enantiomers ent-PREGS and ent-DHEAS against Aβ25-35 peptide-induced toxicity in vitro and in vivo in mice
(2014) Psychopharmacology, pp. 1-20. Article in Press. 

a INSERM U788 and Université Paris SUD, Faculté de Médecine, UMR-S788, Le Kremlin-Bicêtre, 94276, France
b Department of Genetics, Research Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
c INSERM U710 and Université de Montpellier 2, Montpellier, 34095, France
d School of Medicine, Department of Developmental Biology, Washington University in St. Louis, St. Louis, 63110, United States

Rationale: Pregnenolone sulfate (PREGS) and dehydroepiandrosterone sulphate (DHEAS) are pro-amnesic, anti-amnesic and neuroprotective steroids in rodents. In Alzheimer's disease (AD) patient's brains, their low concentrations are correlated with high levels of Aβ and tau proteins. The unnatural enantiomer ent-PREGS enhanced memory in rodents. We investigated here whether ent-PREGS and ent-DHEAS could be neuroprotective in AD models. Objective: The effects of PREGS, ent-PREGS, DHEAS and ent-DHEAS against Aβ25-35 peptide-induced toxicity were examined in vitro on B104 neuroblastoma cells and in vivo in mice. Methods: B104 cells pretreated with the steroids before Aβ25-35 were analysed by flow cytometry measuring cell viability and death processes. Mice injected intracerebroventricularly with Aβ25-35 and the steroids were analysed for their memory abilities. Additionally, lipid peroxidation levels in the hippocampus were measured. Results: ent-PREGS and PREGS significantly attenuated the Aβ25-35-induced decrease in cell viability. Both steroids prevented the Aβ25-35-induced increase in late apoptotic cells. PREGS further attenuated the ratio of necrotic cells. ent-DHEAS and DHEAS significantly reduced the Aβ25-35-induced toxicity and prevented the cells from entering late apoptosis and necrosis. All steroids stimulated neurite outgrowth per se and prevented the Aβ25-35-induced decrease. In vivo, ent-PREGS and ent-DHEAS significantly attenuated the Aβ25-35-induced decrease in memory (spontaneous alternation and passive avoidance) and an increase in lipid peroxidation levels. In contrast to the natural steroids, both enantiomers prevented amnesia when injected 6 h before Aβ25-35 in contrast to the natural steroids. Conclusion: The unnatural steroids ent-PREGS and ent-DHEAS are potent neuroprotective agents and could be effective therapeutical tools in AD. © 2014 Springer-Verlag Berlin Heidelberg.

Author Keywords
β-amyloid toxicity;  Alzheimer's disease;  Dehydroepiandrosterone sulphate;  Enantiomer;  Learning and memory;  Memory;  Neuroprotection;  Neurosteroid;  Oxidative stress;  Pregnenolone sulphate

Document Type: Article in Press
Source: Scopus

Long, C.J.a b , Holden, T.A.c , McClelland, G.H.b , Parkinson, W.S.a , Shelton, C.d , Kelsall, D.C.e , Smith, Z.M.a
Examining the Electro-Neural Interface of Cochlear Implant Users Using Psychophysics, CT Scans, and Speech Understanding
(2014) JARO - Journal of the Association for Research in Otolaryngology, pp. 1-12. Article in Press. 

a Research and Technology Labs, Cochlear Ltd., 13059 E. Peakview Avenue, Centennial, 80111, United States
b University of Colorado, Campus Box 345, Boulder, 80309, United States
c Department of Otolaryngology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, 63110, United States
d Otolaryngology Head and Neck Surgery, University of Utah, 50 N Medical Drive, 3C120 SOM, Salt Lake City, 84132, United States
e Rocky Mountain Ear Center, 601 E. Hampden Avenue #430, Englewood, 80113, United States

This study examines the relationship between focused-stimulation thresholds, electrode positions, and speech understanding in deaf subjects treated with a cochlear implant (CI). Focused stimulation is more selective than monopolar stimulation, which excites broad regions of the cochlea, so may be more sensitive as a probe of neural survival patterns. Focused thresholds are on average higher and more variable across electrodes than monopolar thresholds. We presume that relatively high focused thresholds are the result of larger distances between the electrodes and the neurons. Two factors are likely to contribute to this distance: (1) the physical position of electrodes relative to the modiolus, where the excitable auditory neurons are normally located, and (2) the pattern of neural survival along the length of the cochlea, since local holes in the neural population will increase the distance between an electrode and the nearest neurons. Electrode-to-modiolus distance was measured from high-resolution CT scans of the cochleae of CI users whose focused-stimulation thresholds were also measured. A hierarchical set of linear models of electrode-to-modiolus distance versus threshold showed a significant increase in threshold with electrode-to-modiolus distance (average slope = 11 dB/mm). The residual of these models was hypothesized to reflect neural survival in each subject. Consonant-Nucleus-Consonant (CNC) word scores were significantly correlated with the within-subject variance of threshold (r2 = 0.82), but not with within-subject variance of electrode distance (r2 = 0.03). Speech understanding also significantly correlated with how well distance explained each subject's threshold data (r2 = 0.63). That is, subjects with focused thresholds that were well described by electrode position had better speech scores. Our results suggest that speech understanding is highly impacted by individual patterns of neural survival and that these patterns manifest themselves in how well (or poorly) electrode position predicts focused thresholds. © 2014 Association for Research in Otolaryngology.

Author Keywords
cochlear implants;  electrode configuration;  neural survival;  psychophysics;  speech reception;  spiral ganglion cell

Document Type: Article in Press
Source: Scopus

Van Snellenberg, J.X.a , Barch, D.M.b
Introduction to the special issue in honor of Edward E. Smith
(2014) Cognitive, Affective and Behavioral Neuroscience, pp. 1-2. Article in Press. 

a Division of Cognitive Neuroscience, New York State Psychiatric Institute, New York, United States
b Departments of Psychology, Psychiatry and Radiology, Washington University in St. Louis, St Louis, United States

Document Type: Article in Press
Source: Scopus

Pepino, M.Y.a , Mennella, J.A.b
Cigarette smoking and obesity are associated with decreased fat perception in women
(2014) Obesity, . Article in Press. 

a Department of Medicine, Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine Washington University School of Medicine St. Louis, Missouri USA
b Monell Chemical Senses Center Philadelphia, Pennsylvania USA

Objective: Smoking and obesity are independently associated with high consumption of high-fat foods in women. We tested whether the co-occurrence of smoking and obesity associates with reduced oral fat perception. Design and Methods: Four groups of women (14 obese smokers, 11 obese never-smokers, 10 normal-weight smokers, 12 normal-weight never-smokers) rated vanilla puddings that varied in fat content for perceived intensity of creaminess and sweetness, using the general Labeled Magnitude Scale (gLMS), and degree of pleasantness, using the hedonic gLMS. To determine the role of retronasal smell, subjects rated puddings with and without noseclips. Results: For all groups, perception of creaminess grew with increasing fat concentrations; puddings with any amount of fat were perceived as sweeter than fat-free pudding, and sweetness was enhanced when tasted without noseclips. Overall, obese smokers perceived less creaminess, sweetness, and pleasure while tasting the puddings than did the other three groups (all P values<0.02). Conclusion: The ability to perceive fat and sweetness in and derive pleasure from foods is particularly compromised in obese women who smoke, which could contribute to excess calorie intake in this population already at high risk for cardiovascular and metabolic disease. Retronasal olfaction appears not to contribute to blunted flavor perception observed in obese smokers. © 2014 The Obesity Society.

Document Type: Article in Press
Source: Scopus

Conway, C.R.a b , Chibnall, J.T.b , Cumming, P.c , Mintun, M.A.d e , Gebara, M.A.I.a , Perantie, D.C.a , Price, J.L.f , Cornell, M.E.a , McConathy, J.E.g , Gangwani, S.a , Sheline, Y.I.h
Antidepressant response to aripiprazole augmentation associated with enhanced FDOPA utilization in striatum: A preliminary PET study
(2014) Psychiatry Research - Neuroimaging, . Article in Press. 

a Washington University School of Medicine, Department of Psychiatry, 660 South Euclid, Campus Box 8134, St. Louis, MO 63110, USA
b Saint Louis University School of Medicine, Department of Neurology and Psychiatry, 1438 South Grand Boulevard, St. Louis, MO 63104, USA
c Department of Nuclear Medicine, Friedrich-Alexander University, Erlangen/Nuremberg, Germany
d Washington University School of Medicine, Departments of Radiology and Psychiatry, St. Louis, MO 63110, USA
e Avid Radiopharmaceuticals, Philadelphia, PA 19104, USA
f Washington University School of Medicine, Department of Anatomy and Neurobiology, St. Louis, MO 63110, USA
g Washington University School of Medicine, Department of Radiology, Division of Nuclear Medicine, St. Louis, MO 63110, USA
h Washington University School of Medicine, Departments of Psychiatry, Neurology, and Radiology, St. Louis, MO 63110, USA

Several double blind, prospective trials have demonstrated an antidepressant augmentation efficacy of aripiprazole in depressed patients unresponsive to standard antidepressant therapy. Although aripiprazole is now widely used for this indication, and much is known about its receptor-binding properties, the mechanism of its antidepressant augmentation remains ill-defined. In vivo animal studies and in vitro human studies using cloned dopamine dopamine D2 receptors suggest aripiprazole is a partial dopamine agonist; in this preliminary neuroimaging trial, we hypothesized that aripiprazole's antidepressant augmentation efficacy arises from dopamine partial agonist activity. To test this, we assessed the effects of aripiprazole augmentation on the cerebral utilization of 6-[18F]-fluoro-3,4-dihydroxy-l-phenylalanine (FDOPA) using positron emission tomography (PET). Fourteen depressed patients, who had failed 8 weeks of antidepressant therapy with selective serotonin reuptake inhibitors, underwent FDOPA PET scans before and after aripiprazole augmentation; 11 responded to augmentation. Whole brain, voxel-wise comparisons of pre- and post-aripiprazole scans revealed increased FDOPA trapping in the right medial caudate of augmentation responders. An exploratory analysis of depressive symptoms revealed that responders experienced large improvements only in putatively dopaminergic symptoms of lassitude and inability to feel. These preliminary findings suggest that augmentation of antidepressant response by aripiprazole may be associated with potentiation of dopaminergic activity. © 2014 Elsevier Ireland Ltd. All rights reserved.

Author Keywords
Aripiprazole;  Caudate;  Dopamine;  Positron emission tomography;  Treatment-resistant depression

Document Type: Article in Press
Source: Scopus

Xu, X.a , Wells, A.B.b c , O'Brien, D.R.b c , Nehorai, A.a , Dougherty, J.D.b c
Cell type-specific expression analysis to identify putative cellular mechanisms for neurogenetic disorders
(2014) Journal of Neuroscience, 34 (4), pp. 1420-1431. 

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

Recent advances have substantially increased the number of genes that are statistically associated with complex genetic disorders of the CNS such as autism and schizophrenia. It is now clear that there will likely be hundreds of distinct loci contributing to these disorders, underscoring a remarkable genetic heterogeneity. It is unclear whether this genetic heterogeneity indicates an equal heterogeneity of cellular mechanisms for these diseases. The commonality of symptoms across patients suggests there could be a functional convergence downstream of these loci upon a limited number of cell types or circuits that mediate the affected behaviors. One possible mechanism for this convergence would be the selective expression of at least a subset of these genes in the cell types that comprise these circuits. Using profiling data from mice and humans, we have developed and validated an approach, cell type-specific expression analysis, for identifying candidate cell populations likely to be disrupted across sets of patients with distinct genetic lesions. Using human genetics data and postmortem gene expression data, our approach can correctly identify the cell types for disorders of known cellular etiology, including narcolepsy and retinopathies. Applying this approach to autism, a disease where the cellular mechanism is unclear, indicates there may be multiple cellular routes to this disorder. Our approach may be useful for identifying common cellular mechanisms arising from distinct genetic lesions. © 2014 the authors.

Document Type: Article
Source: Scopus

Kring, A.M.a , Barch, D.M.b
The motivation and pleasure dimension of negative symptoms: Neural substrates and behavioral outputs
(2014) European Neuropsychopharmacology, . Article in Press. 

a Department of Psychology, University of California, Berkley, CA, USA
b Departments of Psychology, Psychiatry and Radiology, Washington University, St. Louis, MO, USA

A range of emotional and motivation impairments have long been clinically documented in people with schizophrenia, and there has been a resurgence of interest in understanding the psychological and neural mechanisms of the so-called "negative symptoms" in schizophrenia, given their lack of treatment responsiveness and their role in constraining function and life satisfaction in this illness. Negative symptoms comprise two domains, with the first covering diminished motivation and pleasure across a range of life domains and the second covering diminished verbal and non-verbal expression and communicative output. In this review, we focus on four aspects of the motivation/pleasure domain, providing a brief review of the behavioral and neural underpinnings of this domain. First, we cover liking or in-the-moment pleasure: immediate responses to pleasurable stimuli. Second, we cover anticipatory pleasure or wanting, which involves prediction of a forthcoming enjoyable outcome (reward) and feeling pleasure in anticipation of that outcome. Third, we address motivation, which comprises effort computation, which involves figuring out how much effort is needed to achieve a desired outcome, planning, and behavioral response. Finally, we cover the maintenance emotional states and behavioral responses. Throughout, we consider the behavioral manifestations and brain representations of these four aspects of motivation/pleasure deficits in schizophrenia. We conclude with directions for future research as well as implications for treatment. © 2013 Elsevier B.V. and ECNP.

Author Keywords
Anticipation;  Effort;  Motivation;  Neural substrates;  Pleasure;  Schizophrenia

Document Type: Article in Press
Source: Scopus

Solga, A.C., Gianino, S.M., Gutmann, D.H.
NG2-cells are not the cell of origin for murine neurofibromatosis-1 (Nf1) optic glioma
(2014) Oncogene, 33 (3), pp. 289-299. 

Department of Neurology, Washington University School of Medicine, Box 8111 660 South Euclid Avenue, St Louis, MO 63110, United States

Low-grade glial neoplasms (astrocytomas) represent one of the most common brain tumors in the pediatric population. These tumors frequently form in the optic pathway (optic pathway gliomas, OPGs), especially in children with the neurofibromatosis type 1 (NF1)-inherited tumor predisposition syndrome. To model these tumors in mice, we have previously developed several Nf1 genetically-engineered mouse strains that form optic gliomas. However, there are three distinct macroglial cell populations in the optic nerve (astrocytes, NG2+ (nerve/glial antigen 2) cells and oligodendrocytes). The presence of NG2+ cells in the optic nerve raises the intriguing possibility that these cells could be the tumor-initiating cells, as has been suggested for adult glioma. In this report, we used a combination of complementary in vitro and novel genetically-engineered mouse strains in vivo to determine whether NG2+ cells could give rise to Nf1 optic glioma. First, we show that Nf1 inactivation results in a cell-autonomous increase in glial fibrillary acidic protein+ (GFAP+), but not in NG2+, cell proliferation in vitro. Second, similar to the GFAP-Cre transgenic strain that drives Nf1 optic gliomagenesis, NG2-expressing cells also give rise to all three macroglial lineages in vivo. Third, in contrast to the GFAP-Cre strain, Nf1 gene inactivation in NG2+ cells is not sufficient for optic gliomagenesis in vivo. Collectively, these data demonstrate that NG2+ cells are not the cell of origin for mouse optic glioma, and support a model in which gliomagenesis requires Nf1 loss in specific neuroglial progenitors during embryogenesis. © 2014 Macmillan Publishers Limited.

Author Keywords
genetically-engineered mice;  neurofibromatosis type 1;  NG2+;  optic glioma

Document Type: Article
Source: Scopus

Cruchaga, C.a b , Karch, C.M.a b , Jin, S.C.a , Benitez, B.A.a , Cai, Y.a , Guerreiro, R.c d , Harari, O.a , Norton, J.a , Budde, J.a , Bertelsen, S.a , Jeng, A.T.a , Cooper, B.a , Skorupa, T.a , Carrell, D.a , Levitch, D.a , Hsu, S.a , Choi, J.a , Ryten, M.c , Hardy, J.c , Trabzuni, D.c , Weale, , Ramasamy, , Smith, , Sassi, C.c d , Bras, J.c , Gibbs, J.R.c d , Hernandez, D.G.c d , Lupton, M.K.e f , Powell, J.e , Forabosco, P.g , Ridge, P.G.h , Corcoran, C.D.i j , Tschanz, J.T.j k , Norton, M.C.j k l , Munger, R.G.l m , Schmutz, C.h , Leary, M.h , Demirci, F.Y.n , Bamne, M.N.n , Wang, X.n , Lopez, O.L.o p , Ganguli, M.q , Medway, C.r , Turton, J.r , Lord, J.r , Braae, A.r , Barber, I.r , Brown, K.r , Passmore, , Craig, , Johnston, , McGuinness, , Todd, , Heun, , Kölsch, H.ah , Kehoe, , Hooper, N.M.aj , Vardy, E.R.L.C.ak , Mann, , Pickering-Brown, , Kalsheker, N.r , Lowe, J.r , Morgan, K.r , David Smith, , Wilcock, , Warden, , Holmes, , Pastor, P.s t u , Lorenzo-Betancor, O.s , Brkanac, Z.v , Scott, E.w ao , Topol, E.w ao , Rogaeva, E.x , Singleton, A.B.d , Kamboh, M.I.n o p , St George-Hyslop, P.x y , Cairns, N.b z , Morris, J.C.z aa ab , Kauwe, J.S.K.h , Goate, A.M.a b aa ab ac
Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease
(2014) Nature, 505 (7484), pp. 550-554. 

a Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, MO 63110, United States
b Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University, 425 South Euclid Avenue, St. Louis, MO 63110, United States
c Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom
d Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD 20892, United States
e Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom
f Neuroimaging Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, Australia
g Istituto di Genetica Delle Popolazioni - CNR, Trav. La Crucca, 3-Reg. Baldinca, 07100 Li Punti, Sassari, Italy
h Department of Biology, Brigham Young University, Provo, UT 84602, United States
i Department of Mathematics and Statistics, Utah State University, Logan, UT 84322, United States
j Center for Epidemiologic Studies, Utah State University, Logan, UT 84322, United States
k Department of Psychology, Utah State University, Logan, UT 84322, United States
l Department of Family Consumer and Human Development, Utah State University, Logan, UT 84322, United States
m Department of Nutrition, Dietetics, and Food Sciences, Utah State University, Logan, UT 84322, United States
n Department of Human Genetics, University of Pittsburgh, 130 Desoto Street, Pittsburgh, PA 15261, United States
o Alzheimer's Disease Research Center, University of Pittsburgh, 130 Desoto Street, Pittsburgh, PA 15261, United States
p Department of Neurology, University of Pittsburgh, 130 Desoto Street, Pittsburgh, PA 15261, United States
q Department of Psychiatry, University of Pittsburgh, 130 Desoto Street, Pittsburgh, PA 15261, United States
r Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham NG7 2UH, United Kingdom
s Neurogenetics Laboratory, Division of Neurosciences, University of Navarra, Avenida Pío XII, 55, 31008 Pamplona, Navarra, Spain
t Department of Neurology, Clínica Universidad de Navarra, School of Medicine, University of Navarra Avenida Pío XII, 36, 31008 Pamplona, Spain
u CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain
v University of Washington, 325 Ninth Avenue, Seattle, WA 98104-2499, United States
w Scripps Research Institute, San Diego, CA 3344, United States
x Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Avenue, Toronto, ON M5T 2S8, Canada
y Cambridge Institute for Medical Research, Department of Clinical Neurosciences, University of Cambridge, Hills Road, Cambridge CB2 0XY, United Kingdom
z Pathology and Immunology, Washington University, 425 South Euclid Avenue, St. Louis, MO 63110, United States
aa Department of Neurology, Washington University, 425 South Euclid Avenue, St. Louis, MO 63110, United States
ab Knight ADRC, Washington University, 425 South Euclid Avenue, St. Louis, MO 63110, United States
ac Department of Genetics, Washington University, 425 South Euclid Avenue, St. Louis, MO(63110, United States
ad Department of Medical and Molecular Genetics, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom
ae MRC Sudden Death Brain Bank Project, University of Edinburgh, South Bridge, Edinburgh EH8 9YL, United Kingdom
af Queen's University Belfast, University Road, Belfast BT7 1NN, United Kingdom
ag Royal Derby Hospital, Uttoxeter Road, Derby, DE22 3NE, United Kingdom
ah University of Bonn, Regina-Pacis-Weg 3, 53113 Bonn, Germany
ai University of Bristol, Tyndall Avenue, Bristol, City of Bristol BS8 1TH, United Kingdom
aj University of Leeds, Woodhouse Lane, Leeds, West Yorkshire LS2 9JT, United Kingdom
ak University of Newcastle, Newcastle-upon-Tyne, Tyne and Wear NE1 7RU, United Kingdom
al University of Manchester, Oxford Road, Manchester, Greater Manchester M13 9PL, United Kingdom
am University of Oxford (OPTIMA), Wellington Square, Oxford OX1 2JD, United Kingdom
an University of Southampton, University Road, Southampton SO17 1BJ, United Kingdom
ao Scripps Research Institute, North Torrey Pines Court, San Diego, CA 92037, United States

Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD). These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case-control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer's disease in seven independent case-control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimer's disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer's disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer's disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-β precursor protein (APP) and extracellular Aβ42 and Aβ40 (the 42-and 40-residue isoforms of the amyloid-β peptide), and knockdown of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex traits. © 2014 Macmillan Publishers Limited. All rights reserved.


Document Type: Article
Source: Scopus


February 1, 2014


Ferentinos, P.a , Rivera, M.a b , Ising, M.c , Spain, S.L.d , Cohen-Woods, S.e , Butler, A.W.a f , Craddock, N.g , Owen, M.J.g , Korszun, A.h , Jones, L.i , Jones, I.g , Gill, M.j , Rice, J.P.k , Maier, W.l , Mors, O.m , Rietschel, M.n , Lucae, S.c , Binder, E.B.c , Preisig, M.o , Tozzi, F.p , Muglia, P.q , Breen, G.a r , Craig, I.W.a , Farmer, A.E.a , Müller-Myhsok, B.c , McGuffin, P.a , Lewis, C.M.a d

Investigating the genetic variation underlying episodicity in major depressive disorder: Suggestive evidence for a bipolar contribution
(2014) Journal of Affective Disorders, 155 (1), pp. 81-89. 

a MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom
b Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, University of Granada, Spain
c Max Planck Institute of Psychiatry, Germany Max Planck Institute of Psychiatry, Munich, Germany
d Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, United Kingdom
e Department of Psychiatry, University of Adelaide, Adelaide, Australia
f Department of Psychiatry, University of Hong Kong, Hong Kong, Hong Kong
g MRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom
h Barts and the London Medical School, Queen Mary University of London, London, United Kingdom
i Department of Psychiatry, Neuropharmacology and Neurobiology Section, University of Birmingham, Birmingham, United Kingdom
j Department of Psychiatry, Trinity Centre for Health Science, Dublin, Ireland
k Department of Psychiatry, Washington University, St. Louis, MO, United States
l Department of Psychiatry, University of Bonn, Bonn, Germany
m Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark
n Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany
o University Hospital Center, University of Lausanne, Lausanne, Switzerland
p Aptuit Center for Drug Discovery and Development, Verona, Italy
q Department of Psychiatry, University of Toronto, Toronto, Canada
r NIHR Biomedical Research Centre for Mental Health, South London and Maudsley NHS Foundation Trust, King's College London, London, United Kingdom

Background Highly recurrent major depressive disorder (MDD) has reportedly increased risk of shifting to bipolar disorder; high recurrence frequency has, therefore, featured as evidence of 'soft bipolarity'. We aimed to investigate the genetic underpinnings of total depressive episode count in recurrent MDD. Methods Our primary sample included 1966 MDD cases with negative family history of bipolar disorder from the RADIANT studies. Total episode count was adjusted for gender, age, MDD duration, study and center before being tested for association with genotype in two separate genome-wide analyses (GWAS), in the full set and in a subset of 1364 cases with positive family history of MDD (FH+). We also calculated polygenic scores from the Psychiatric Genomics Consortium MDD and bipolar disorder studies. Results Episodicity (especially intermediate episode counts) was an independent index of MDD familial aggregation, replicating previous reports. The GWAS produced no genome-wide significant findings. The strongest signals were detected in the full set at MAGI1 (p=5.1×10-7), previously associated with bipolar disorder, and in the FH+ subset at STIM1 (p=3.9×10-6 after imputation), a calcium channel signaling gene. However, these findings failed to replicate in an independent Munich cohort. In the full set polygenic profile analyses, MDD polygenes predicted episodicity better than bipolar polygenes; however, in the FH+ subset, both polygenic scores performed similarly. Limitations Episode count was self-reported and, therefore, subject to recall bias. Conclusions Our findings lend preliminary support to the hypothesis that highly recurrent MDD with FH+ is part of a 'soft bipolar spectrum' but await replication in larger cohorts. © 2013 Elsevier B.V.

Author Keywords
Bipolar spectrum;  Episode count;  Family history;  Genome-wide association study;  Major depression;  Polygenic

Document Type: Article
Source: Scopus

Vulin, A.a , Wein, N.a , Strandjord, D.M.b , Johnson, E.K.a , Findlay, A.R.a , Maiti, B.c , Howard, M.T.d , Kaminoh, Y.J.a , Taylor, L.E.a , Simmons, T.R.a , Ray, W.C.e , Montanaro, F.a , Ervasti, J.M.b , Flanigan, K.M.a f
The ZZ domain of dystrophin in DMD: Making sense of missense mutations
(2014) Human Mutation, 35 (2), pp. 257-264. 

a The Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States
b Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, United States
c The Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d The Department of Human Genetics, The University of Utah, Salt Lake City, UT, United States
e The Department of Mathematical Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States
f The Departments of Pediatrics and Neurology, The Ohio State University, Columbus, OH, United States

Duchenne muscular dystrophy (DMD) is associated with the loss of dystrophin, which plays an important role in myofiber integrity via interactions with β-dystroglycan and other members of the transmembrane dystrophin-associated protein complex. The ZZ domain, a cysteine-rich zinc-finger domain near the dystrophin C-terminus, is implicated in forming a stable interaction between dystrophin and β-dystroglycan, but the mechanism of pathogenesis of ZZ missense mutations has remained unclear because not all such mutations have been shown to alter β-dystroglycan binding in previous experimental systems. We engineered three ZZ mutations (p.Cys3313Phe, p.Asp3335His, and p.Cys3340Tyr) into a short construct similar to the Dp71 dystrophin isoform for in vitro and in vivo studies and delineated their effect on protein expression, folding properties, and binding partners. Our results demonstrate two distinct pathogenic mechanisms for ZZ missense mutations. The cysteine mutations result in diminished or absent subsarcolemmal expression because of protein instability, likely due to misfolding. In contrast, the aspartic acid mutation disrupts binding with β-dystroglycan despite an almost normal expression at the membrane, confirming a role for the ZZ domain in β-dystroglycan binding but surprisingly demonstrating that such binding is not required for subsarcolemmal localization of dystrophin, even in the absence of actin binding domains. © 2013 WILEY PERIODICALS, INC.

Author Keywords
Duchenne muscular dystrophy;  Dystrophin;  Missense mutation;  ZZ domain

Document Type: Article
Source: Scopus

Nasiriavanaki, M.a , Xia, J.a , Wan, H.a , Bauer, A.Q.b , Culver, J.P.b , Wang, L.V.a
High-resolution photoacoustic tomography of resting-state functional connectivity in the mouse brain
(2014) Proceedings of the National Academy of Sciences of the United States of America, 111 (1), pp. 21-26. 

a Optical Imaging Laboratory, Department of Biomedical Engineering, United States
b Department of Radiology, Washington University in St. Louis, St. Louis, MO 63130, United States

The increasing use of mouse models for human brain disease studies presents an emerging need for a new functional imaging modality. Using optical excitation and acoustic detection, we developed a functional connectivity photoacoustic tomography system, which allows noninvasive imaging of resting-state functional connectivity in the mouse brain, with a large field of view and a high spatial resolution. Bilateral correlations were observed in eight functional regions, including the olfactory bulb, limbic, parietal, somatosensory, retrosplenial, visual, motor, and temporal regions, as well as in several subregions. The borders and locations of these regions agreed well with the Paxinos mouse brain atlas. By subjecting the mouse to alternating hyperoxic and hypoxic conditions, strong and weak functional connectivities were observed, respectively. In addition to connectivity images, vascular images were simultaneously acquired. These studies show that functional connectivity photoacoustic tomography is a promising, noninvasive technique for functional imaging of the mouse brain.

Author Keywords
FcPAT;  Hyperoxia;  Hypoxia;  Mouse brain functional imaging;  RSFC

Document Type: Article
Source: Scopus

Jensen, J.L.a , McDaniel, M.A.b , Woodard, S.M.a , Kummer, T.A.a
Teaching to the Test...or Testing to Teach: Exams Requiring Higher Order Thinking Skills Encourage Greater Conceptual Understanding
(2014) Educational Psychology Review, pp. 1-23. Article in Press. 

a Department of Biology, Brigham Young University, 401 WIDB, Provo, 84602, United States
b Department of Psychology, Washington University, Campus Box 1125, One Brookings Drive, St. Louis, 63130, United States

In order to test the effect of exam-question level on fostering student conceptual understanding, low-level and high-level quizzes and exams were administered in two sections of an introductory biology course. Each section was taught in a high-level inquiry based style but was assigned either low-level questions (memory oriented) on the quizzes and exams, or high-level questions (application, evaluation, and analysis) on the quizzes and exams for the entirety of the semester. A final exam consisting of 20 low-level and 21 high-level questions was given to both sections. We considered several theoretical perspectives based on testing effect, test expectancy, and transfer-appropriate processing literature as well as the theoretical underpinnings of Bloom's taxonomy. Reasoning from these theoretical perspectives, we predicted that high-level exams would encourage not only deeper processing of the information by students in preparation for the exam but also better memory for the core information (learned in the service of preparing for high-level questions). Results confirmed this prediction, with students in the high-level exam condition demonstrating higher performance on both the low-level final-exam items and the high-level final exam items. This pattern suggests that students who are tested throughout the semester with high-level questions acquire deep conceptual understanding of the material and better memory for the course information, and lends support to the proposed hierarchical nature of Bloom's taxonomy. © 2014 Springer Science+Business Media New York.

Author Keywords
Assessment;  Biology;  Bloom's taxonomy;  Test expectancy;  Testing effect

Document Type: Article in Press
Source: Scopus

Goyal, M.S.a , Hawrylycz, M.b , Miller, J.A.b , Snyder, A.Z.a , Raichle, M.E.a
Aerobic glycolysis in the human brain is associated with development and neotenous gene expression
(2014) Cell Metabolism, 19 (1), pp. 49-57. Cited 1 time.

a Neuroimaging Laboratories, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 4525 Scott Avenue, St. Louis, MO 63110, United States
b Allen Institute for Brain Science, 551 North 34th Street, Seattle, WA 98103, United States

Aerobic glycolysis (AG; i.e., nonoxidative metabolism of glucose despite the presence of abundant oxygen) accounts for 10%-12% of glucose used by the adult human brain. AG varies regionally in the resting state. Brain AG may support synaptic growth and remodeling; however, data supporting this hypothesis are sparse. Here, we report on investigations on the role of AG in the human brain. Meta-analysis of prior brain glucose and oxygen metabolism studies demonstrates that AG increases during childhood, precisely when synaptic growth rates are highest. In resting adult humans, AG correlates with the persistence of gene expression typical of infancy (transcriptional neoteny). In brain regions with the highest AG, we find increased gene expression related to synapse formation and growth. In contrast, regions high in oxidative glucose metabolism express genes related to mitochondria and synaptic transmission. Our results suggest that brain AG supports developmental processes, particularly those required for synapse formation and growth. © 2014 Elsevier Inc.

Document Type: Article
Source: Scopus

Sharma, A.a b c , Viets, R.a , Parsons, M.S.a b c , Reis, M.d , Chrisinger, J.e , Wippold II, F.J.a b c f
A two-tiered approach to MRI for hearing loss: Incremental cost of a comprehensive MRI over high-resolution T2-weighted imaging
(2014) American Journal of Roentgenology, 202 (1), pp. 136-144. 

a Mallinckrodt Institute of Radiology, Washington University School of Medicine, Campus Box 8131, 510 S Kingshighway Blvd, St. Louis, MO 63110, United States
b Department of Radiology, Barnes-Jewish Hospital South, St. Louis, MO, United States
c Department of Radiology, St. Louis Children's Hospital, St. Louis, MO, United States
d Department of Radiology, St. Louis University School of Medicine, St. Louis, MO, United States
e Department of Pathology, Washington University School of Medicine, St. Louis, MO, United States
f Department of Radiology/Nuclear Medicine, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, United States

OBJECTIVE. The objective of our study was to compare the cost-effectiveness of two approaches to using MRI for the evaluation of patients with hearing loss. MATERIALS AND METHODS. We developed a decision tree to compare the cost-effectiveness of conventional MRI with that of a proposed two-tiered model in which an initial 3D T2-weighted imaging examination was used to determine the need for comprehensive MR scanning. Three radiologists independently and blindly reviewed the 3D T2-weighted images acquired as part of the comprehensive MR examinations of 256 patients with hearing loss to assess the diagnostic efficacy of the two-tiered approach. Costs were defined in terms of both the scanner utilization time for the imaging facility and the dollar amount for payers. Effectiveness was defined in terms of the ability to correctly detect the presence or absence of disease. RESULTS. The conventional approach was less cost-effective, with a baseline incremental cost-effectiveness ratio (ICER) of 27,299 minutes of scanner utilization per unit increase in effectiveness. Assuming a 50% reduction in the reimbursement of the technical component from the current level by the Centers for Medicare & Medicaid Services, this result reflected an ICER of $258,664 per unit increase in effectiveness. The results of a sensitivity analysis showed the robustness of the cost-effectiveness of the two-tiered imaging approach in a variety of scenarios that reflect differences in scanning practices and possible differences in recall rates. The conventional imaging approach was absolutely dominated by the two-tiered approach in the scenarios created to reflect the expected range of prevalence of disease. CONCLUSION. A two-tiered approach to MRI provides a more cost-effective alternative to the current approach of using a comprehensive MRI examination without and with contrast material to evaluate patients with hearing loss. © American Roentgen Ray Society.

Author Keywords
Cost-effectiveness;  MRI;  Sensorineural hearing loss;  Vestibular schwannoma

Document Type: Article
Source: Scopus

Reynolds, M.R.a , Derdeyn, C.P.a b c , Grubb, R.L.a b , Powers, W.J.d , Zipfel, G.J.a b c
Extracranial-intracranial bypass for ischemic cerebrovascular disease: What have we learned from the Carotid Occlusion Surgery Study?
(2014) Neurosurgical Focus, 36 (1), art. no. E9, . 

a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC, United States

Extracranial-intracranial (EC-IC) arterial bypass has been used in the treatment of various neurosurgical pathologies including skull base tumors requiring sacrifice of a large intracranial artery; complex intracranial aneurysms requiring trapping; and distal revascularization, moyamoya disease, and symptomatic cerebrovascular stenoocclusive disease. The latter indication has been the subject of intense investigations in several large randomized controlled trials, most recently the Carotid Occlusion Surgery Study (COSS). In the present literature review and synthesis, the authors examine the current evidence available for EC-IC arterial bypass for the treatment of ischemic cerebrovascular disease including both extracranial carotid artery occlusive disease and intracranial atherosclerotic disease. They focus particular attention on EC-IC arterial bypass for the treatment of symptomatic hemodynamic cerebral ischemia and how lessons learned from the COSS might guide future investigations into the treatment of this disease. © AANS, 2014.

Author Keywords
Carotid artery occlusion;  Carotid occlusion surgery study;  Extracranial-intracranial arterial bypass;  Ischemic stroke;  Transient ischemic attack

Document Type: Article
Source: Scopus

Queller, D.C., Strassmann, J.E.
The veil of ignorance can favour biological cooperation
(2013) Biology Letters, 9 (6), art. no. 20130365, . Cited 1 time.

Department of Biology CB1137, Washington University in St Louis, One Brookings Drive, St Louis, MO 63130, United States

Lack of information is a constraint but ignorance can sometimes assist the evolution of cooperation by constraining selfishness. We discuss examples involving both ignorance of role or pay-off and ignorance of relatedness. Ignorance can favour cooperative traits like grouping and warning coloration and reduce conflicts from meiotic drive, imprinting, greenbeards and various forms of nepotism. © 2013 The Author(s) Published by the Royal Society. All rights reserved.

Author Keywords
Conflict;  Cooperation;  Meiosis;  Nepotism;  Relatedness;  Veil of ignorance

Document Type: Article
Source: Scopus

Cain, M.D.a , Vo, B.Q.b , Kolesnikov, A.V.b , Kefalov, V.J.b , Culican, S.M.b , Kerschensteiner, D.b , Blumer, K.J.a
An allosteric regulator of R7-RGS proteins influences light-evoked activity and glutamatergic waves in the inner retina
(2013) PLoS ONE, 8 (12), art. no. e82276, . 

a Department of Cell Biology and Physiology, Washington University, School of Medicine, St. Louis, MO, United States
b Department of Ophthalmology and Visual Sciences, Washington University, School of Medicine, St. Louis, MO, United States

In the outer retina, G protein-coupled receptor (GPCR) signaling mediates phototransduction and synaptic transmission between photoreceptors and ON bipolar cells. In contrast, the functions of modulatory GPCR signaling networks in the inner retina are less well understood. We addressed this question by determining the consequences of augmenting modulatory Gi/o signaling driven by endogenous transmitters. This was done by analyzing the effects of genetically ablating the R7 RGSbinding protein (R7BP), a membrane-targeting protein and positive allosteric modulator of R7-RGS (regulator of the G protein signaling 7) family that deactivates Gi/oa subunits. We found that R7BP is expressed highly in starburst amacrine cells and retinal ganglion cells (RGCs). As indicated by electroretinography and multielectrode array recordings of adult retina, ablation of R7BP preserved outer retina function, but altered the firing rate and latency of ON RGCs driven by rods and cones but not rods alone. In developing retina, R7BP ablation increased the burst duration of glutamatergic waves whereas cholinergic waves were unaffected. This effect on glutamatergic waves did not result in impaired segregation of RGC projections to eye-specific domains of the dorsal lateral geniculate nucleus. R7BP knockout mice exhibited normal spatial contrast sensitivity and visual acuity as assessed by optomotor reflexes. Taken together these findings indicate that R7BP-dependent regulation of R7-RGS proteins shapes specific aspects of light-evoked and spontaneous activity of RGCs in mature and developing retina. Copyright: © 2013 Cain et al.

Document Type: Article
Source: Scopus