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WUSTL Neuroscience Publications Archive - November 2015

November 2015

November 27, 2015

Documents


Miner, J.J.a , Diamond, M.S.a b c d

Mechanisms of restriction of viral neuroinvasion at the blood-brain barrier
(2016) Current Opinion in Immunology, 38, pp. 18-23. 

DOI: 10.1016/j.coi.2015.10.008


a Department of Medicine, Washington University School of Medicine, St Louis, MO, United States
b Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, United States
c Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, United States
d Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis, MO, United States


Abstract
The blood-brain barrier (BBB) consists of highly specialized cells including brain microvascular endothelial cells, astrocytes, microglia, pericytes, and neurons, which act in concert to restrict the entry of pathogens, immune cells, and soluble molecules into the central nervous system (CNS). If pathogens manage to cross the BBB and establish infection within the CNS, the BBB can open in a regulated manner to allow leukocyte transmigration into the CNS so that microbes, infected cells, and debris can be cleared. This review highlights how different inflammatory cytokines or signaling pathways disrupt or enhance BBB integrity in a way that regulates entry of neurotropic viruses into the CNS. © 2015 Elsevier Ltd.


Document Type: Review
Source: Scopus



Shimony, J.S.a , Smyser, C.D.b , Wideman, G.c , Alexopoulos, D.b , Hill, J.d h , Harwell, J.e , Dierker, D.e , Van Essen, D.C.e , Inder, T.E.f i , Neil, J.J.g j
Comparison of cortical folding measures for evaluation of developing human brain
(2016) NeuroImage, 125, pp. 780-790. 

DOI: 10.1016/j.neuroimage.2015.11.001


a Mallinckrodt Institute of Radiology, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO, United States
b Department of Pediatric Neurology, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO, United States
c Boston Children's Hospital, Department of Neurology, 333 Longwood Ave., Boston, MA, United States
d Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO, United States
e Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO, United States
f Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO, United States
g Department of Pediatric Neurology, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO, United States
h Department of Emergency Medicine, New York-Presbyterian Hospital, 525 East 68th Street, New York, NY, United States
i Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, United States
j Boston Children's Hospital, Department of Neurology, 333 Longwood Ave, Boston, MA, United States


Abstract
We evaluated 22 measures of cortical folding, 20 derived from local curvature (curvature-based measures) and two based on other features (sulcal depth and gyrification index), for their capacity to distinguish between normal and aberrant cortical development. Cortical surfaces were reconstructed from 12 term-born control and 63 prematurely-born infants. Preterm infants underwent 2-4 MR imaging sessions between 27 and 42. weeks postmenstrual age (PMA). Term infants underwent a single MR imaging session during the first postnatal week. Preterm infants were divided into two groups. One group (38 infants) had no/minimal abnormalities on qualitative assessment of conventional MR images. The second group (25 infants) consisted of infants with injury on conventional MRI at term equivalent PMA. For both preterm infant groups, all folding measures increased or decreased monotonically with increasing PMA, but only sulcal depth and gyrification index differentiated preterm infants with brain injury from those without. We also compared scans obtained at term equivalent PMA (36-42. weeks) for all three groups. No curvature-based measured distinguished between the groups, whereas sulcal depth distinguished term control from injured preterm infants and gyrification index distinguished all three groups. When incorporating total cerebral volume into the statistical model, sulcal depth no longer distinguished between the groups, though gyrification index distinguished between all three groups and positive shape index distinguished between the term control and uninjured preterm groups. We also analyzed folding measures averaged over brain lobes separately. These results demonstrated similar patterns to those obtained from the whole brain analyses. Overall, though the curvature-based measures changed during this period of rapid cerebral development, they were not sensitive for detecting the differences in folding associated with brain injury and/or preterm birth. In contrast, gyrification index was effective in differentiating these groups. © 2015 Elsevier Inc.


Author Keywords
Brain injury;  Cortical curvature;  Cortical folding;  Premature infant


Document Type: Article
Source: Scopus



Butman, J.A.a b , Suga, N.a
Synaptic mechanisms shaping delay-tuned combination-sensitivity in the auditory thalamus of mustached bats
(2016) Hearing Research, 331, pp. 69-82. 

DOI: 10.1016/j.heares.2015.10.013


a Department of Biology, Washington University, One Brookings Drive, St. Louis, MO, United States
b MRI Section, Radiology and Imaging Sciences, Clinical Center of The National Institutes of Health, Bldg 10, 10 Center Drive, Bethesda, MD, United States


Abstract
For the processing of target-distance information, delay-tuned auditory neurons of the mustached bat show facilitative responses to a combination of signal elements of a biosonar pulse-echo pair with a specific echo delay. They are initially produced in the inferior colliculus by facilitative responses based on the coincidence of the rebound response following glycinergic inhibition to the first harmonic of the pulse and a short-latency response to the 2nd-4th harmonics of its echo. Here, we report that further facilitative responses to pulse-echo pairs of thalamic delay-tuned neurons are mediated by glutamate receptors (NMDA and non-NMDA receptors), and that GABAergic inhibition shortens the duration of facilitative responses mediated by NMDA-receptors, without changing the delay tuning of thalamic delay-tuned neurons. Different from collicular delay-tuned neurons, thalamic ones respond much more to pulse-echo pairs than individual signal elements. The neural mechanisms involved in shaping thalamic delay-tuning support a model of hierarchical signal processing in the auditory system. © 2015.


Author Keywords
Echolocation;  FM-FM neurons;  GABAergic inhibition;  Hierarchical processing;  NMDAergic facilitation;  Non-NMDA-Mediated facilitation


Document Type: Article
Source: Scopus



Chung, Y.S.a , Barch, D.b
Anhedonia is associated with reduced incentive cue related activation in the basal ganglia
(2015) Cognitive, Affective and Behavioral Neuroscience, 15 (4), pp. 749-767. 

DOI: 10.3758/s13415-015-0366-3


a Department of Psychology, Washington University, St. Louis, MO, United States
b Departments of Psychology, Psychiatry, and Radiology, Washington University, St. Louis, MO, United States


Abstract
Research has shown that reward incentives improve cognitive control in motivationally salient situations. Much previous work in this domain has focused on incentive cue-related activity in a number of brain regions, including the dorsolateral prefrontal cortex (DLPFC) and striatum. However, the more sustained changes in functional brain activity during task contexts with incentives have been relatively less explored. Here, we examined both the cue-related and sustained effects of rewards (i.e., monetary incentives) on cognitive control, with a particular focus on the roles of the DLPFC and striatum, using a mixed state–item design. We investigated whether variability in a reward-related trait (i.e., anhedonia) would modulate the sustained and/or the cue-related transient aspects of motivated cognitive control. Twenty-seven healthy individuals performed a modified response conflict task (Padmala & Pessoa, Journal of Cognitive Neuroscience, 23, 3419–3432, 2011) during scanning, in which participants were asked to categorize images as either houses or buildings with either congruent or incongruent overlaid words. Participants performed a baseline condition without knowledge of monetary incentives, followed by reward blocks with monetary incentives on some cued trials (reward cues) for fast and correct responses. We replicated previous work by showing increases in both sustained activity during reward versus baseline blocks and transient. cue-related activity in bilateral DLPFC and the basal ganglia. Importantly, healthy individuals with higher anhedonia showed less of an increase in trial-by-trial activity as a function of reward in the lateral globus pallidus. Together, our results suggest that reduced hedonic experience may be related to abnormality of reward cue-related activity in the basal ganglia. © 2015, Psychonomic Society, Inc.


Author Keywords
Cognitive control;  Emotion;  Mixed fMRI design;  Motivation;  Prefrontal cortex;  Reward


Document Type: Article
Source: Scopus



Miller, C.M.a , Pineda, J.b , Corry, M.c , Brophy, G.d , Smith, W.S.e
Emergency Neurologic Life Support (ENLS): Evolution of Management in the First Hour of a Neurological Emergency
(2015) Neurocritical Care, 23, pp. 1-4. 

DOI: 10.1007/s12028-015-0170-5


a Neurocritical Care and Cerebrovascular Diseases, OhioHealth, Columbus, OH, United States
b Departments of Pediatrics and Neurology, Washington University School of Medicine, St. Louis, MO, United States
c City College of San Francisco Paramedic Program, San Francisco, CA, United States
d Departments of Pharmacotherapy and Outcomes Science and Neurosurgery, Virginia Commonwealth University, Richmond, VA, United States
e Department of Neurology, University of California, San Francisco, CA, United States


Abstract
Emergency neurological life support (ENLS) is an educational program designed to provide users advisory instruction regarding management for the first few hours of a neurological emergency. The content of the course is divided into 14 modules, each addressing a distinct category of neurological injury. The course is appropriate for practitioners and providers from various backgrounds who work in environments of variable medical complexity. The focus of ENLS is centered on a standardized treatment algorithm, checklists to guide early patient care, and a structured format for communication of findings and concerns to other healthcare professionals. Certification and training in ENLS is hosted by the Neurocritical Care Society. This document introduces the concept of ENLS and describes the revisions that constitute this second version. © 2015, Springer Science+Business Media New York.


Author Keywords
Algorithm;  Critical care;  Emergency;  Neurocritical care;  Resuscitation


Document Type: Review
Source: Scopus



Stevens, R.D.a , Cadena, R.S.b , Pineda, J.c
Emergency Neurological Life Support: Approach to the Patient with Coma
(2015) Neurocritical Care, 23, pp. 69-75. 

DOI: 10.1007/s12028-015-0174-1


a Departments of Anesthesiology and Critical Care Medicine; Neurology; Neurosurgery; and Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
b Departments of Neurology, Neurosurgery, and Emergency Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, United States
c Department of Pediatrics, Division of Critical Care Medicine, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Coma is an acute failure of neuronal systems governing arousal and awareness and represents a medical emergency. When encountering a comatose patient, the clinician must have an organized approach to detect easily remediable causes, prevent ongoing neurologic injury, and determine a hierarchical plan for diagnostic tests, treatments, and neuromonitoring. Coma was chosen as an Emergency Neurological Life Support protocol because timely medical and surgical interventions can be life-saving, and the initial work-up of such patients is critical to establishing a correct diagnosis. © 2015, Springer Science+Business Media New York.


Author Keywords
Coma;  Consciousness;  Critical care;  Neurocritical care


Document Type: Review
Source: Scopus


Jauch, E.C.a , Pineda, J.A.b , Claude Hemphill, J.c

Emergency Neurological Life Support: Intracerebral Hemorrhage
(2015) Neurocritical Care, 23, pp. 83-93. 

DOI: 10.1007/s12028-015-0167-0


a Division of Emergency Medicine and Department of Neurosciences, Medical University of South Carolina, Charleston, United States
b Department of Pediatrics and Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, University of California, San Francisco, United States


Abstract
Intracerebral hemorrhage (ICH) is a subset of stroke due to bleeding within the parenchyma of the brain. It is potentially lethal, and survival depends on ensuring an adequate airway, reversal of coagulopathy, and proper diagnosis. ICH was chosen as an Emergency Neurological Life Support protocol because intervention within the first critical hour may improve outcome, and it is critical to have site-specific protocols to drive care quickly and efficiently. © 2015, Springer Science+Business Media New York.


Author Keywords
Coagulopathy;  ICH Score;  Intracerebral hemorrhage


Document Type: Review
Source: Scopus



Stevens, R.D.a , Shoykhet, M.b , Cadena, R.c
Emergency Neurological Life Support: Intracranial Hypertension and Herniation
(2015) Neurocritical Care, 23, pp. 76-82. 

DOI: 10.1007/s12028-015-0168-z


a Departments of Anesthesiology and Critical Care Medicine, Neurology, Neurosurgery, and Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
b Pediatric Critical Care Medicine, Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
c Departments of Neurology, Neurosurgery, and Emergency Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, United States


Abstract
Sustained intracranial hypertension and acute brain herniation are “brain codes,” signifying catastrophic neurological events that require immediate recognition and treatment to prevent irreversible injury and death. As in cardiac arrest, a brain code mandates the organized implementation of a stepwise management algorithm. The goal of this emergency neurological life support protocol is to implement an evidence-based, standardized approach to the evaluation and management of patients with intracranial hypertension and/or herniation. © 2015, Springer Science+Business Media New York.


Author Keywords
Brain edema;  Herniation;  Hyperventilation;  Osmotherapy


Document Type: Review
Source: Scopus


Brophy, G.M.a , Human, T.b , Shutter, L.c
Emergency Neurological Life Support: Pharmacotherapy
(2015) Neurocritical Care, 23, pp. 48-68. 

DOI: 10.1007/s12028-015-0158-1


a Departments of Pharmacotherapy & Outcomes Science and Neurosurgery, Virginia Commonwealth University, Richmond, VA, United States
b Department of Clinical Pharmacy, Barnes-Jewish Hospital, Washington University in St. Louis, St. Louis, MO, United States
c Departments of Critical Care Medicine, Neurology & Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States


Abstract
The appropriate use of medications during Emergency Neurological Life Support (ENLS) is essential to optimize patient care. Important considerations when choosing the appropriate agent include the patient’s organ function and medication allergies, potential adverse drug effects, drug interactions, and critical illness and aging pathophysiologic changes. Critical medications used during ENLS include hyperosmolar therapy, anticonvulsants, antithrombotics, anticoagulant reversal and hemostatic agents, anti-shivering agents, neuromuscular blockers, antihypertensive agents, sedatives, vasopressors and inotropes, and antimicrobials. This article focuses on the important pharmacokinetic and pharmacodynamics characteristics, advantages and disadvantages, and clinical pearls of these therapies, providing practitioners with essential drug information to optimize pharmacotherapy in acutely ill neurocritical care patients. © 2015, Springer Science+Business Media New York.


Author Keywords
Adverse drug event;  Drug interaction;  ENLS;  Medication;  Pharmacotherapy


Document Type: Review
Source: Scopus



Rittenberger, J.C.a , Friess, S.b , Polderman, K.H.c
Emergency Neurological Life Support: Resuscitation Following Cardiac Arrest
(2015) Neurocritical Care, 23, pp. 119-128. 

DOI: 10.1007/s12028-015-0171-4


a Department of Emergency Medicine, University of Pittsburgh, Pittsburgh, PA, United States
b Department of Pediatrics, Washington University School of Medicine, St. Louis, St. Louis, MO, United States
c Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States


Abstract
Cardiac arrest is the most common cause of death in North America. Neurocritical care interventions, including targeted temperature management (TTM), have significantly improved neurological outcomes in patients successfully resuscitated from cardiac arrest. Therefore, resuscitation following cardiac arrest was chosen as an emergency neurological life support protocol. Patients remaining comatose following resuscitation from cardiac arrest should be considered for TTM. This protocol will review induction, maintenance, and re-warming phases of TTM, along with management of TTM side effects. Aggressive shivering suppression is necessary with this treatment to ensure the maintenance of a target temperature. Ancillary testing, including electrocardiography, computed tomography and/or magnetic resonance imaging of the brain, continuous electroencephalography monitoring, and correction of electrolyte, blood gas, and hematocrit changes, are also necessary to optimize outcomes. © 2015, Springer Science+Business Media New York.


Author Keywords
Brain cooling;  Cardiac arrest;  Hypothermia;  Myocardial infarction;  Sudden death;  Temperature management


Document Type: Review
Source: Scopus


Garvin, R.a , Venkatasubramanian, C.b , Lumba-Brown, A.c , Miller, C.M.d

Emergency Neurological Life Support: Traumatic Brain Injury
(2015) Neurocritical Care, 23, pp. 143-154. 

DOI: 10.1007/s12028-015-0176-z


a University of Texas Science Health Science Center, San Antonio, TX, United States
b Stanford University, Stanford, CA, United States
c Pediatric Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
d OhioHealth, Columbus, OH, United States


Abstract
Traumatic Brain Injury (TBI) was chosen as an Emergency Neurological Life Support topic due to its frequency, the impact of early intervention on outcomes for patients with TBI, and the need for an organized approach to the care of such patients within the emergency setting. This protocol was designed to enumerate the practice steps that should be considered within the first critical hour of neurological injury. © 2015, Springer Science+Business Media New York.


Author Keywords
Emergency;  Neurocritical care;  Trauma;  Traumatic brain injury


Document Type: Review
Source: Scopus


Stein, D.M.a , Pineda, J.A.b , Roddy, V.c , Knight, W.A., IVd

Emergency Neurological Life Support: Traumatic Spine Injury
(2015) Neurocritical Care, 23, pp. 155-164. 

DOI: 10.1007/s12028-015-0169-y


a R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, University of Maryland School of Medicine, Baltimore, United States
b Department of Pediatrics and Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Emergency Medicine, Broward Health Medical Center, Fort Lauderdale, FL, United States
d Departments of Emergency Medicine and Neurosurgery, University of Cincinnati, Cincinnati, OH, United States


Abstract
Traumatic spine injuries (TSIs) carry significantly high risks of morbidity, mortality, and exorbitant health care costs from associated medical needs following injury. For these reasons, TSI was chosen as an ENLS protocol. This article offers a comprehensive review on the management of spinal column injuries using the best available evidence. Alhough the review focuses primarily on cervical spinal column injuries, thoracolumbar injuries are briefly discussed as well. The initial emergency department clinical evaluation of possible spinal fractures and cord injuries, along with the definitive early management of confirmed injuries, is also covered. © 2015, Springer Science+Business Media New York.


Author Keywords
Neurotrauma;  Spine fracture;  Traumatic myelopathy


Document Type: Review
Source: Scopus



McKinney, R.M., Vernier, C., Ben-Shahar, Y.
The neural basis for insect pheromonal communication
(2015) Current Opinion in Insect Science, 12, pp. 86-92. 

DOI: 10.1016/j.cois.2015.09.010


Department of Biology, Washington University, St. Louis, MO, United States


Abstract
Insects rely on chemosensory signals to drive a multitude of behavioral decisions. From conspecific and mate recognition to aggression, the proper detection and processing of these chemical signals - termed pheromones - is crucial for insects fitness. Although the identities and physiological impacts of diverse insect pheromones have been known for many years, how these important molecules are perceived and processed by the nervous system to produce evolutionarily beneficial behaviors is still mostly unknown. Here we present an overview of the current state of research into the peripheral and central nervous system mechanisms that process and drive behavioral responses to diverse pheromonal cues. © 2015 Elsevier Inc. All rights reserved.


Document Type: Article
Source: Scopus



Yarboi, J.a , Compas, B.E.a , Brody, G.H.b , White, D.c , Rees Patterson, J.c , Ziara, K.c , King, A.c
Association of social-environmental factors with cognitive function in children with sickle cell disease
(2015) Child Neuropsychology, 18 p. Article in Press. 

DOI: 10.1080/09297049.2015.1111318


a Department of Psychology & Human Development, Vanderbilt University, Nashville, TN, USA
b Department of Child & Family Development and Center for Family Research, University of Georgia, Athens, GA, USA
c Department of Pediatric Hematology & Oncology, Washington University School of Medicine, St. Louis, MO, USA


Abstract
The aim of this study was to examine the relationship between cognitive function in pediatric sickle cell disease (SCD) patients and mothers’ reports of social-environmental stress, depressive symptoms, and parenting. A total of 65 children with SCD completed comprehensive neuropsychological testing to assess several domains of cognitive functioning, including general intellectual ability, academic achievement, and executive function. Mothers reported on demographics, social-environmental stress, depressive symptoms, and parenting. As predicted, children with SCD significantly underperformed relative to normative data on measures of cognitive function. Associations between maternal social-environmental stress, maternal depressive symptoms, and parenting were mixed. The results show partial support for the hypothesis that greater stress and depressive symptoms and less positive parenting are associated with poorer cognitive function in children with SCD. Linear regression analyses showed that maternal financial stress was the strongest predictor across all domains of cognitive function. The findings replicate and extend past research, reaffirming that children with SCD are at risk for cognitive impairment across multiple domains. Additionally, social-environmental stress, particularly financial strain, is linked to mothers’ depressive symptoms and parenting behaviors as well as children’s cognitive function. Future studies using direct observations of parenting behaviors are needed. These findings, along with recent research on parenting interventions, may inform the development of concrete, teachable parenting and coping skills to improve cognitive functioning in children with SCD. © 2015 Taylor & Francis


Author Keywords
cognitive function;  parenting;  poverty;  Sickle cell disease;  stress


Document Type: Article in Press
Source: Scopus

Kurth, C.

Anxiety, normative uncertainty, and social regulation
(2015) Biology and Philosophy, 21 p. Article in Press. 

DOI: 10.1007/s10539-015-9508-9


Washington University in Saint Louis, St Louis, MO, United States


Abstract
Emotion plays an important role in securing social stability. But while emotions like fear, anger, and guilt have received much attention in this context, little work has been done to understand the role that anxiety plays. That’s unfortunate. I argue that a particular form of anxiety—what I call ‘practical anxiety’—plays an important, but as of yet unrecognized, role in norm-based social regulation. More specifically, it provides a valuable form of metacognition, one that contributes to social stability by helping individuals negotiate the challenges that come from having to act in the face of unclear norms. © 2015 Springer Science+Business Media Dordrecht


Author Keywords
Anxiety;  Cooperation;  Emotion;  Fear;  Social regulation;  Uncertainty


Document Type: Article in Press
Source: Scopus



Xu, H.a , Iyer, N.a , Huettner, J.E.b , Sakiyama-Elbert, S.E.a
A puromycin selectable cell line for the enrichment of mouse embryonic stem cell-derived V3 interneurons
(2015) Stem Cell Research and Therapy, 6 (1), art. no. 213, . 

DOI: 10.1186/s13287-015-0213-z


a Department of Biomedical Engineering, Washington University in St. Louis, 1 Brookings Drive, Box 1097, St. Louis, MO, United States
b Department of Cell Biology and Physiology, Washington University, School of Medicine, St. Louis, MO, United States


Abstract
Introduction: Spinal V3 interneurons (INs) are a commissural, glutamatergic, propriospinal neuron population that holds great potential for understanding locomotion circuitry and local rewiring after spinal cord injury. Embryonic stem cells hold promise as a cell source. However, the inevitable heterogeneity resulting from differentiation protocols makes studying post-mitotic stem cell-derived neuron populations difficult because proliferative glia quickly overtake a culture. Previously, an induction protocol for V3 INs was established. However, because of the heterogeneous population resulting from the induction protocol, functional characterization of the induced cells was not possible. Methods: A selectable murine transgenic embryonic stem cell (ESC) line (Sim1-Puro) was generated by recombineering. The expression of the puromycin resistance enzyme, puromycin N-acetyl-transferase (PAC), was knocked into the locus of a post-mitotic V3 IN marker (Sim1), allowing Sim1 gene regulatory elements to control PAC expression. The resulting cell line was characterized for Sim1 expression by in situ hybridization, for glutamatergic marker expression by immunocytochemistry and quantitative real time polymerase chain reaction (qRT-PCR), and for functional maturation by electrophysiology. Results: Puromycin selection significantly enriched the population for V3 INs, allowing long-term characterization. The selected population expressed the neuronal marker β-III tubulin and the glutamatergic neuron marker VGluT2. The selected V3 INs also exhibited appropriate functional maturation, as assessed by electrophysiology, and remained glutamatergic for 2 weeks. Conclusion: The Sim1-Puro cell line provides a simple, high throughput method for generating large numbers of V3 INs from mouse ESCs for future in vitro and cell transplantation studies. © 2015 Xu et al.


Author Keywords
Electrophysiology;  Functional neuronal maturation;  Neural differentiation;  Recombineering;  Sim1;  Spinal interneuron


Document Type: Article
Source: Scopus

Hayward, K.S.a b , Eng, J.J.a c , Boyd, L.A.a , Lakhani, B.a , Bernhardt, J.b d , Lang, C.E.e

Exploring the Role of Accelerometers in the Measurement of Real World Upper-Limb Use After Stroke
(2015) Brain Impairment, 18 p. Article in Press. 

DOI: 10.1017/BrImp.2015.21


a Department of Physical Therapy, University of British Columbia, Vancouver, British Columbia, Canada
b Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia
c Rehabilitation Research Program, Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada
d College of Science Health and Engineering, Latrobe University, Melbourne, Victoria, Australia
e Program in Physical Therapy, Program in Occupational Therapy, Department of Neurology, Washington University School of Medicine, St Louis, Missouri, USA


Abstract
The ultimate goal of upper-limb rehabilitation after stroke is to promote real-world use, that is, use of the paretic upper-limb in everyday activities outside the clinic or laboratory. Although real-world use can be collected through self-report questionnaires, an objective indicator is preferred. Accelerometers are a promising tool. The current paper aims to explore the feasibility of accelerometers to measure upper-limb use after stroke and discuss the translation of this measurement tool into clinical practice. Accelerometers are non-invasive, wearable sensors that measure movement in arbitrary units called activity counts. Research to date indicates that activity counts are a reliable and valid index of upper-limb use. While most accelerometers are unable to distinguish between the type and quality of movements performed, recent advancements have used accelerometry data to produce clinically meaningful information for clinicians, patients, family and care givers. Despite this, widespread uptake in research and clinical environments remains limited. If uptake was enhanced, we could build a deeper understanding of how people with stroke use their arm in real-world environments. In order to facilitate greater uptake, however, there is a need for greater consistency in protocol development, accelerometer application and data interpretation. Copyright © Australasian Society for the Study of Brain Impairment 2015


Author Keywords
accelerometry;  arm;  paresis;  recovery;  stroke;  wearable sensors


Document Type: Article in Press
Source: Scopus


Jung, M.E., WippoldII, F.J., Goebel, J.A.

Can High-Resolution Computed Tomography Detect a Therapeutic Response to Medical Treatment in a Patient With Otosclerosis?
(2015) Otology and Neurotology, . Article in Press. 

DOI: 10.1097/MAO.0000000000000863


*Department of Otolaryngology Head and Neck Surgery †Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, U.S.A.


Document Type: Article in Press
Source: Scopus




Eaton, M.M.a , Cao, L.Q.a , Chen, Z.a b , Franks, N.P.c , Evers, A.S.a b , Akk, G.a b
Mutational analysis of the putative high-affinity propofol binding site in human β3 Homomeric GABAA Receptors
(2015) Molecular Pharmacology, 88 (4), pp. 736-745. 

DOI: 10.1124/mol.115.100347


a Department of Anesthesiology, School of Medicine, Washington University, 660 South Euclid Avenue, St. Louis, MO, United States
b Taylor Family Institute for Innovative Psychiatric Research, School of Medicine, Washington University, 660 South Euclid Avenue, St. Louis, MO, United States
c Department of Life Sciences, Imperial College London, South Kensington, United Kingdom


Abstract
Propofol is a sedative and anesthetic agent that can both activate GABAA receptors and potentiate receptor activation elicited by submaximal concentrations of the transmitter. A recent modeling study of the β3 homomeric GABAA receptor postulated a high-affinity propofol binding site in a hydrophobic pocket in the middle of a triangular cleft lined by the M1 and M2 membrane-spanning domains of one subunit and the M2 domain of the neighboring subunit. The goal of the present study was to gain functional evidence for the involvement of this pocket in the actions of propofol. Human b3 and a1b3 receptors were expressed in Xenopus oocytes, and the effects of substitutions of selected residues were probed on channel activation by propofol and pentobarbital. The data demonstrate the vital role of the β 3(Y143), β 3(F221), β 3(Q224), and β 3(T266) residues in the actions of propofol but not pentobarbital in β 3 receptors. The effects of β 3(Y143W) and β 3(Q224W) on activation by propofol are likely steric because propofol analogs with less bulky ortho substituents activated both wild-type and mutant receptors. The T266W mutation removed activation by propofol in β 3 homomeric receptors; however, this mutation alone or in combination with a homologous mutation (I271W) in the α1 subunit had almost no effect on activation properties in a1b3 heteromeric receptors. We hypothesize that heteromeric α1β3 receptors can be activated by propofol interactions with β 3- β 3, α1- β 3, and β 3- α 1 interfaces, but the exact locations of the binding site and/ or nature of interactions vary in different classes of interfaces. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.


Document Type: Article
Source: Scopus




Pourzanjani, A.a , Herzog, E.D.b , Petzold, L.R.a
On the inference of functional circadian networks using Granger Causality
(2015) PLoS ONE, 10 (9), art. no. e0137540, . 

DOI: 10.1371/journal.pone.0137540


a Department of Computer Science, University of California, Santa Barbara, Santa Barbara, CA, United States
b Department of Biology, Washington University, St. Louis, MO, United States


Abstract
Being able to infer one way direct connections in an oscillatory network such as the suprachiastmatic nucleus (SCN) of the mammalian brain using time series data is difficult but crucial to understanding network dynamics. Although techniques have been developed for inferring networks from time series data, there have been no attempts to adapt these techniques to infer directional connections in oscillatory time series, while accurately distinguishing between direct and indirect connections. In this paper an adaptation of Granger Causality is proposed that allows for inference of circadian networks and oscillatory networks in general called Adaptive Frequency Granger Causality (AFGC). Additionally, an extension of this method is proposed to infer networks with large numbers of cells called LASSO AFGC. The method was validated using simulated data from several different networks. For the smaller networks the method was able to identify all one way direct connections without identifying connections that were not present. For larger networks of up to twenty cells the method shows excellent performance in identifying true and false connections; this is quantified by an area-under-the-curve (AUC) 96.88%. We note that this method like other Granger Causality-based methods, is based on the detection of high frequency signals propagating between cell traces. Thus it requires a relatively high sampling rate and a network that can propagate high frequency signals. © 2015 Pourzanjani et al.


Document Type: Article
Source: Scopus




Mamdani, M.a , Williamson, V.a , McMichael, G.O.a , Blevins, T.b , Aliev, F.a c , Adkins, A.a , Hack, L.a , Bigdeli, T.a , Van Der Vaart, A.D.e , Web, B.T.a , Bacanu, S.-A.a , Kalsi, G.h , Kendler, K.S.a c d , Miles, M.F.a e , Dick, D.a c d f , Riley, B.P.a c d , Dumur, C.b , Vladimirov, V.I.a c g i , Hesselbrock, V.j , Edenberg, H.J.k , Nurnberger, J., Jr.k , Foroud, T.k , Kuperman, S.l , Kramer, J.l , Porjesz, B.m , Bierut, L.n , Goate, A.n , Rice, J.n , Bucholz, K.n , Schuckit, M.o , Tischfield, J.p , Almasy, L.q , Taylor, R.r , Dick, D.s , Bauer, L.j , Koller, D.k , O'Connor, S.k , Wetherill, L.k , Xuei, X.k , Chan, G.l , Kang, S.m , Manz, N.m , Rangaswamy, M.m , Rohrbaugh, J.n , Wang, J.-C.n , Brooks, A.p , Aliev, F.s , Parsian, A.t , Reilly, M.t
Integrating mRNA and miRNA weighted gene co-expression networks with eQTLs in the nucleus accumbens of subjects with alcohol dependence
(2015) PLoS ONE, 10 (9), art. no. e0137671, . 

DOI: 10.1371/journal.pone.0137671


a Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States
b Department of Pathology, Virginia Commonwealth University, Richmond, VA, United States
c Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States
d Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States
e Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
f Department of Psychology, Virginia Commonwealth University, Richmond, VA, United States
g Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, Richmond, VA, United States
h Department of Social, Genetic and Developmental Psychiatry, Institute of Psychiatry, London, United Kingdom
i Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, MD, United States
j University of Connecticut, United States
k Indiana University, United States
l University of Iowa, United States
m SUNY Downstate, United States
n Washington University in St. Louis, United States
o University of California at San Diego, United States
p Rutgers University, United States
q Texas Biomedical Research Institute, United States
r Howard University, United States
s Virginia Commonwealth University, United States


Abstract
Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-typespecific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05). In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001). Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively) in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA). In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD. © 2015 Mamdani et al.


Document Type: Article
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, 36 (9), pp. 7027-7034. 

DOI: 10.1007/s13277-015-3388-0


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


Abstract
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
Source: Scopus




Schnepp, R.W.a , Khurana, P.a , Attiyeh, E.F.a b , Raman, P.a c , Chodosh, S.E.a , Oldridge, D.A.a , Gagliardi, M.E.a , Conkrite, K.L.a , Asgharzadeh, S.d , Seeger, R.C.d , Madison, B.B.e , Rustgi, A.K.f g h i , Maris, J.M.a b j , Diskin, S.J.a b j
A LIN28B-RAN-AURKA Signaling Network Promotes Neuroblastoma Tumorigenesis
(2015) Cancer Cell, 28 (5), pp. 599-609. 

DOI: 10.1016/j.ccell.2015.09.012


a Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, United States
b Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
c Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
d Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, United States
e Division of Gastroenterology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
f Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
g Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
h Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
i Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
j Abramson Family Cancer Research Institute, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, United States


Abstract
A more complete understanding of aberrant oncogenic signaling in neuroblastoma, a malignancy of the developing sympathetic nervous system, is paramount to improving patient outcomes. Recently, we identified LIN28B as an oncogenic driver in high-risk neuroblastoma. Here, we identify the oncogene RAN as a LIN28B target and show regional gain of chromosome 12q24 as an additional somatic alteration resulting in increased RAN expression. We show that LIN28B influences RAN expression by promoting RAN Binding Protein 2 expression and by directly binding RAN mRNA. Further, we demonstrate a convergence of LIN28B and RAN signaling on Aurora kinase A activity. Collectively, these findings demonstrate that LIN28B-RAN-AURKA signaling drives neuroblastoma oncogenesis, suggesting that this pathway may be amenable to therapeutic targeting. © 2015 Elsevier Inc.


Document Type: Article
Source: Scopus


Hassenstab, J.a b , Ruvolo, D.a , Jasielec, M.c , Xiong, C.c , Grant, E.c , Morris, J.C.a d

Absence of practice effects in preclinical Alzheimer's disease
(2015) Neuropsychology, 29 (6), pp. 940-948. 

DOI: 10.1037/neu0000208


a Charles F. and Joanne Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychology, Washington University School of Medicine, St. Louis, MO, United States
c Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pathology and Immunology, Department of Physical Therapy, Department of Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Objective: To describe how practice effects influence cognitive trajectories and determine if a reduction in practice effects is a potential marker of Stage-III preclinical Alzheimer's disease (AD). Method: Participants included 263 older adults who were cognitively normal at baseline (i.e., had a Clinical Dementia Rating [CDR] of 0; Morris, 1993) and returned for an average of 9.5 annual visits. Participants completed standard tests of episodic memory, visuospatial ability, semantic memory, and executive function. Progressors (n = 66) converted to CDR > 0 with a diagnosis of symptomatic AD after a minimum of 3 visits and stable participants (n = 197) never progressed to CDR > 0. Practice effects, defined as the slope of performance across Visits 1-3, were compared between groups and used within subjects to predict risk of conversion. Change-point models that accounted for retest were contrasted with linear models that ignored retest. Results: The stable group showed practice effects on episodic-memory measures (β = 0.14, SE = .02, p < .0001) but the progressor group did not (β = 0.03, SE = .03, p = .343). Across all participants, practice effects on episodic-memory tests were associated with a decreased risk of progression to AD as indicated by the subdistribution hazards model (SHR; Fine & Gray, 1999); SHR = .110, 95% CI [.032, .384], p = .001). Finally, use of change-point models dramatically altered rate-of-change estimates compared with models that ignored practice. Conclusion: Our results indicate that preclinical AD is marked by a reduction in practice effects in episodic memory and that the magnitude of gain from retesting is inversely related to progression risk. Assessment of practice effects may be a face-valid indicator of Stage-III preclinical AD.


Author Keywords
Alzheimer's disease;  Dementia;  Memory;  Practice effects;  Retest


Document Type: Article
Source: Scopus




Ghani, M.a , Reitz, C.b c d , Cheng, R.b , Vardarajan, B.N.c , Jun, G.e f g , Sato, C.a , Naj, A.h , Rajbhandary, R.h , Wang, L.-S.i , Valladares, O.i , Lin, C.-F.i , Larson, E.B.j k , Graff-Radford, N.R.l m , Evans, D.n , De Jager, P.L.o p q , Crane, P.K.j , Buxbaum, J.D.r s t u , Murrell, J.R.v , Raj, T.p , Ertekin-Taner, N.l m , Logue, M.e , Baldwin, C.T.e , Green, R.C.p w x , Barnes, L.L.y z , Cantwell, L.B.i , Fallin, M.D.aa , Go, R.C.P.ab , Griffith, P.A.ac , Obisesan, T.O.ad , Manly, J.J.b d , Lunetta, K.L.a f , Kamboh, M.I.ae af , Lopez, O.L.af , Bennett, D.A.y ag , Hendrie, H.ah ai aj , Hall, K.S.ai , Goate, A.M.ak , Byrd, G.S.al , Kukull, W.A.am , Foroud, T.M.z , Haines, J.L.an , Farrer, L.A.e f g ao ap , Pericak-Vance, M.A.h , Lee, J.H.b c aq , Schellenberg, G.D.i , St. George-Hyslop, P.a , Mayeux, R.b c d af ar , Rogaeva, E.a , Albert, M.S.as , Albin, R.L.at , Apostolova, L.G.au , Arnold, S.E.av , Barber, R.aw , Barmada, M.M.ae , Beach, T.G.ax , Beecham, G.W.ay , Beekly, D.az , Bigio, E.H.ba , Bird, T.D.bb , Blacker, D.bc , Boeve, B.F.m , Bowen, J.D.bd , Boxer, A.au , Burke, J.R.be , Cai, G.bf , Cairns, N.J.bg , Cao, C.bh , Carlson, C.S.bi , Carney, R.M.bj , Carroll, S.L.bk , Chui, H.C.bl , Clark, D.G.bm , Cribbs, D.H.au , Crocco, E.A.bj , Cruchaga, C.bn , DeCarli, C.au , DeKosky, S.T.bo , Demirci, F.Y.ae , Dick, M.bp , Faber, K.M.v , Fallon, K.B.bq , Ferris, S.br , Frosch, M.P.bs , Galasko, D.R.bt , Ganguli, M.bu , Gearing, M.bv , Geschwind, D.H.bw , Ghetti, B.bx , Gilbert, J.R.ay , Gilman, S.at , Glass, J.D.by , Growdon, J.H.bz , Hakonarson, H.ca , Hamilton, R.L.cb , Hamilton-Nelson, K.L.cc , Haroutunian, V.cd , Harrell, L.E.ce , Honig, L.S.cf , Hulette, C.M.cg , Hyman, B.T.bz , Jarvik, G.P.ch , Jicha, G.A.ci , Jin, L.-W.cj , Karydas, A.au , Kauwe, J.S.K.ck , Kaye, J.A.cl , Kim, R.ck , Koo, E.H.bs , Kowall, N.W.cm , Kramer, J.H.cn , Kramer, P.co , LaFerla, F.M.cp , Lah, J.J.by , Lang-Walker, R.cq , Leverenz, J.B.cr , Levey, A.I.by , Li, G.cs , Lieberman, A.P.ct , Lyketsos, C.G.cu , Mack, W.J.cv , Marson, D.C.ay , Martiniuk, F.cw , Mash, D.C.cx , Masliah, E.cy , McCormick, W.C.j , McCurry, S.M.cz , McDavid, A.N.bi , McKee, A.C.da , Mesulam, M.db , Miller, B.L.au , Miller, C.A.dc , Miller, J.W.ck , Montine, T.J.dd , Morris, J.C.de , Olichney, J.M.au , Parisi, J.E.df , Peskind, E.ct , Petersen, R.C.dg , Pierce, A.au , Poon, W.W.dh , Potter, H.di , Quinn, J.F.cm , Raj, A.bh , Raskind, M.ct , Reiman, E.M.dj , Reisberg, B.dk , Ringman, J.M.au , Roberson, E.D.dl , Sano, M.r , Saykin, A.J.dm , Schneider, J.A.dn , Schneider, L.S.do , Seeley, W.W.au , Smith, A.G.bh , Sonnen, J.A.dd , Spina, S.by , Stern, R.A.ao , Tanzi, R.E.bz , Trojanowski, J.Q.i , Troncoso, J.C.dp , Tsuang, D.W.dq , Van Deerlin, V.M.i , Van Eldik, L.J.dr , Vinters, H.V.ds , Vonsattel, J.P.dt , Weintraub, S.du , Welsh-Bohmer, K.A.dv , Williamson, J.ce , Woltjer, R.L.dw , Wright, C.B.dx , Younkin, S.G.l , Yu, C.-E.cy , Yu, L.dy
Association of long runs of homozygosity with Alzheimer disease among African American individuals
(2015) JAMA Neurology, 72 (11), pp. 1313-1323. 

DOI: 10.1001/jamaneurol.2015.1700z


a Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Tower, 60 Leonard Ave, Toronto, ON, Canada
b Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, United States
c Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, United States
d Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, United States
e Department of Medicine (Biomedical Genetics), Boston University, Boston, MA, United States
f Department of Biostatistics, Boston University, Boston, MA, United States
g Department of Ophthalmology, Boston University, Boston, MA, United States
h John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, United States
i Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States
j Department of Medicine, University of Washington, Seattle, United States
k Group Health Research Institute, Group Health, Seattle, WA, United States
l Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
m Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
n Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University, Medical Center, Chicago, IL, United States
o Program in Translational Neuropsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA, United States
p Harvard Medical School, Boston, MA, United States
q Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, United States
r Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, United States
s Department of Genetics and Genomics Sciences, Mount Sinai School of Medicine, New York, NY, United States
t Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, United States
u Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY, United States
v Department of Medical and Molecular Genetics, Indiana University, Indianapolis, United States
w Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States
x Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital, Boston, MA, United States
y Department of Neurological Sciences, Rush University, Medical Center, Chicago, IL, United States
z Department of Behavioral Sciences, Rush University, Medical Center, Chicago, IL, United States
aa Department of Epidemiology, Johns Hopkins University, School of Public Health, Baltimore, MD, United States
ab School of Public Health, University of Alabama at Birmingham, United States
ac SABA University, School of Medicine, SABA, Dutch Caribbean, United States
ad Division of Geriatrics, Howard University Hospital, Washington, DC, United States
ae Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, United States
af Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, PA, United States
ag Rush Alzheimer's Disease Center, Rush University, Medical Center, Chicago, IL, United States
ah Indiana University, Center for Aging Research, Indianapolis, United States
ai Department of Psychiatry, Indiana University, School of Medicine, Indianapolis, United States
aj Regenstrief Institute Inc., Indianapolis, IN, United States
ak Hope Center Program on Protein Aggregation and Neurodegeneration, Department of Psychiatry, Washington University, School of Medicine, St Louis, MO, United States
al Department of Biology, North Carolina A and T University, Greensboro, United States
am National Alzheimer's Coordinating Center, Department of Epidemiology, University of Washington, Seattle, United States
an Vanderbilt Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, United States
ao Department of Neurology, Boston University, Boston, MA, United States
ap Department of Epidemiology, Boston University, Boston, MA, United States
aq Department of Epidemiology, College of Physicians and Surgeons, Columbia University, New York, NY, United States
ar Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, United States
as Department of Neurology, Johns Hopkins University, Baltimore, MD, United States
at Department of Neurology, University of Michigan, Ann Arbor Healthcare System, Michigan Alzheimer Disease Center, Ann Arbor, VA, United States
au Department of Neurology, University of California, Los Angeles, United States
av Department of Psychiatry, University of Pennsylvania, Perelman School of Medicine, United States
aw Department of Pharmacology and Neuroscience, University of North Texas, Health Science Center, FortWorth, United States
ax Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Phoenix, AZ, United States
ay John P. Hussman Institute for Human Genomics, John T. MacDonald Foundation, Department of Human Genetics, University of Miami, Miami, FL, United States
az National Alzheimer's Coordinating Center, University of Washington, Seattle, United States
ba Department of Pathology and Cognitive Neurology, Alzheimer's Disease Center, Northwestern University, Feinberg School of Medicine, United States
bb Department of Neurology, University of Washington, VA Puget Sound Health Care System/GRECC, Seattle, United States
bc Department of Epidemiology, Harvard School of Public Health, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, United States
bd Swedish Medical Center, Seattle, WA, United States
be Department of Medicine, Duke University, Durham, NC, United States
bf Departments of Psychiatry and Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, United States
bg Department of Pathology and Immunology, Washington University, St Louis, MO, United States
bh USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, United States
bi Fred Hutchinson Cancer Research Center, Seattle, WA, United States
bj Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, United States
bk Department of Pathology, University of Alabama at Birmingham, United States
bl Department of Neurology, University of Southern California, Los Angeles, United States
bm Department of Neurology, University of Alabama at Birmingham, United States
bn Department of Psychiatry, Hope Center Program on Protein Aggregation and Neurodegeneration, Washington Univ., School of Medicine, St Louis, MO, United States
bo University of Virginia, School of Medicine, Charlottesville, United States
bp Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, United States
bq Department of Neurology, Indiana University, Indianapolis, United States
br Department of Psychiatry, New York University, New York, United States
bs C. S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charlestown, United States
bt Department of Neurosciences, University of California, San Diego, United States
bu Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
bv Department of Pathology, Laboratory Medicine, Emory Alzheimer's Disease Center, Emory University, Atlanta, GA, United States
bw Neurogenetics Program, University of California, Los Angeles, United States
bx Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, United States
by Department of Neurology, Emory University, Atlanta, GA, United States
bz Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States
ca Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
cb Department of Pathology (Neuropathology), University of Pittsburgh, Pittsburgh, PA, United States
cc John P. Hussman Institute for Human Genetics, University of Miami, Miami, FL, United States
cd Departments of Psychiatry and Genetics and Genomics Sciences, Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY, United States
ce Sanders-Brown Center on Aging, Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, United States
cf Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, NY, United States
cg Department of Pathology, Duke University, Durham, NC, United States
ch Departments of Genome Sciences and Medicine, Medical Genetics, University of Washington, Seattle, United States
ci Sanders-Brown Center on Aging, Department of Neurology, University of Kentucky, Lexington, United States
cj Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, United States
ck Department of Biology, Brigham-Young University, Provo, UT, United States
cl Department of Neurology, Oregon Health and Science University, Portland Veterans Affairs Medical Center, Portland, United States
cm Department of Neurology and Pathology, Boston University, Boston, MA, United States
cn Department of Neuropsychology, University of California, San Francisco, United States
co Departments of Neurology and Molecular and Medical Genetics, Oregon Health and Science University, Portland, United States
cp Department of Neurobiology and Behavior, University of California, Irvine, United States
cq Department of Biology, North Carolina A and T State University, Greensboro, United States
cr Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH, United States
cs Department of Psychiatry and Behavioral Sciences, University of Washington, School of Medicine, VA Puget Sound Health Care System/GRECC, Seattle, United States
ct Department of Pathology, University of Michigan, Ann Arbor, United States
cu Department of Psychiatry, Johns Hopkins University, Baltimore, MD, United States
cv Department of Preventive Medicine, University of Southern California, Los Angeles, United States
cw Department of Medicine-Pulmonary, New York University, New York, United States
cx Department of Neurology, University of Miami, Miami, FL, United States
cy Departments of Neurosciences and Pathology, University of California, San Diego, San Diego, United States
cz School of Nursing Northwest Research Group on Aging, University of Washington, Seattle, United States
da Departments of Neurology and Pathology, Boston University, Boston, MA, United States
db Cognitive Neurology and Alzheimer's Disease Center, Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL, United States
dc Department of Pathology, University of Southern California, Los Angeles, United States
dd Department of Pathology, University of Washington, Seattle, United States
de Departments of Pathology and Immunology and Neurology, Washington University, St Louis, MO, United States
df Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
dg Department of Neurology, Mayo Clinic, Rochester, MN, United States
dh Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, United States
di Department of Neurology, University of Colorado, School of Medicine, Aurora, United States
dj Neurogenomics Division, Translational Genomics Research Institute, Arizona Alzheimer's Consortium, Department of Psychiatry, University of Arizona, Banner Alzheimer's Institute, Phoenix, United States
dk Department of Psychiatry, Alzheimer's Disease Center, New York University, New York, United States
dl Department of Neurology, University of Texas Southwestern, Dallas, United States
dm Departments of Medical and Molecular Genetics and Radiology and Imaging Sciences, Indiana University, Indianapolis, United States
dn Department of Neurological Sciences, Rush Alzheimer's Disease Center, Department of Pathology (Neuropathology), Rush University, Medical Center, Chicago, IL, United States
do Departments of Neurology and Psychiatry, University of Southern California, Los Angeles, United States
dp Department of Pathology, Johns Hopkins University, Baltimore, MD, United States
dq VA Puget Sound Health Care System, GRECC, Department of Psychiatry and Behavioral Sciences, University of Washington, School of Medicine, Seattle, United States
dr Sanders-Brown Center on Aging, Department of Anatomy and Neurobiology, University of Kentucky, Lexington, United States
ds Departments of Neurology and Pathology and Laboratory Medicine, University of California, Los Angeles, United States
dt Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Pathology, Columbia University, United States
du Cognitive Neurology and Alzheimer's Disease Center, Department of Psychiatry, Northwestern University, Feinberg School of Medicine, United States
dv Departments of Medicine and Psychiatry and Behavioral Sciences, Duke University, Durham, NC, United States
dw Department of Pathology, Oregon Health and Science University, Portland, OR, United States
dx Evelyn F. McKnight Brain Institute, Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, United States
dy Department of Neurological Sciences, Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, United States


Abstract
IMPORTANCE: Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3%of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-basedROHmeasurementswere analyzed using rawor imputed genotype data.We studied the rawgenotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals).We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES: The ROHs larger than 1Mb, 2Mb, or 3Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS: The African American cohort had a lowdegree of inbreeding (F × 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2Mb (P =.004) or greater than 3Mb (P =.02), aswell as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 =.04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 =.02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 =.03; ROHs >3 Mb). Atotal of 43 of 49 nominally significant genescommonfor both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1Mb in cases vs 12.11 in controls; 2.986Mb average size of ROHs >2Mb in cases vs 2.889Mb in controls; and 22%of cases with ROHs >3Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 =.006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 =.01; ROHs >1 Mb), encoding a protein from the Claudin family, members of whichwere previously suggested as ADbiomarkers. CONCLUSIONS AND RELEVANCE: To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals. Copyright 2015 American Medical Association. All rights reserved.


Document Type: Article
Source: Scopus




Xu, H., Sakiyama-Elbert, S.E.
Directed Differentiation of V3 Interneurons from Mouse Embryonic Stem Cells
(2015) Stem Cells and Development, 24 (22), pp. 2723-2732. Cited 1 time.

DOI: 10.1089/scd.2015.0122


Department of Biomedical Engineering, Center of Regenerative Medicine, Washington University in St. Louis., 1 Brookings Drive Box 1097, St. Louis, MO, United States


Abstract
Excitatory commissural V3 interneurons (INs) of the ventral spinal cord have been shown to balance locomotor rhythm regularity and robustness in vivo. Unfortunately, due to the scarcity of these cells in the spinal cord, in vitro studies of dissociated V3 INs have yet to be reported. In this study, we developed an induction protocol for V3 INs from mouse embryonic stem cells. The effect of the concentration of a strong sonic hedgehog (Shh) agonist (smoothened agonist [SAG]) and retinoic acid (RA) on expression of progenitor p3 and postmitotic V3 IN transcription factor markers (ie, Nkx2.2 and Sim1) was examined. Cells were differentiated toward a more ventral fate by increasing the duration of SAG exposure from 4 days in a previously established motoneuron induction protocol to 6 days. At the end of the induction period, transcription factor expression was assessed using quantitative real-time polymerase chain reaction, immunocytochemistry, in situ hybridization, and flow cytometry. Lower concentrations of RA and a longer duration of SAG exposure led to increased levels of p3 and V3 marker expression. This novel induction protocol reveals the importance of Shh signaling duration in the dorsal-ventral patterning of the neural tube, and it provides a method to obtain V3 INs for future studies to allow better understanding their role in rewiring and regeneration after spinal cord injury. © Mary Ann Liebert, Inc. 2015.


Document Type: Article
Source: Scopus


Werner, K.B.a , Few, L.R.b , Bucholz, K.K.b

Epidemiology, comorbidity, and behavioral genetics of antisocial personality disorder and psychopathy
(2015) Psychiatric Annals, 45 (4), pp. 195-199. 

DOI: 10.3928/00485713-20150401-08


a George Warren Brown School of Social Work, Washington University, United States
b Department of Psychiatry, Washington University School of Medicine, United States


Abstract
Psychopathy is theorized as a disorder of personality and affective deficits, and an Antisocial Personality Disorder (ASPD) diagnosis is primarily behaviorally based. Although ASPD and psychopathy are similar and are highly comorbid with each other, they are not synonymous. ASPD has been well studied in community samples with estimates of its lifetime prevalence ranging from 1% to 4% of the general population. In contrast, psychopathy is almost exclusively investigated within criminal populations so that its prevalence in the general population has been inferred by psychopathic traits rather than a disorder (1%). Differences in etiology and comorbidity with each other and other psychiatric disorders are also evident. This article briefly reviews the epidemiology, etiology, and comorbidity of ASPD and psychopathy, focusing predominately on research completed in community and clinical populations. The authors aim to highlight ASPD and psychopathy as related, but distinct disorders. © SLACK Incorporated.


Document Type: Article
Source: Scopus




Schlaepfer, C.H., Wessel, R.
Excitable membranes and action potentials in paramecia: An analysis of the electrophysiology of ciliates
(2015) Journal of Undergraduate Neuroscience Education, 14 (1), pp. A82-A86. 


Physics Department, Washington University, St. Louis, MO, United States


Abstract
The ciliate Paramecium caudatum possesses an excitable cell membrane whose action potentials (APs) modulate the trajectory of the cell swimming through its freshwater environment. While many stimuli affect the membrane potential and trajectory, students can use current injection and extracellular ionic concentration changes to explore how APs cause reversal of the cell's motion. Students examine these stimuli through intracellular recordings, also gaining insight into the practices of electrophysiology. Paramecium's large size of around 150 μm, simple care, and relative ease to penetrate make them ideal model organisms for undergraduate students' laboratory study. The direct link between behavior and excitable membranes has thought provoking evolutionary implications for the study of paramecia. Recording from the cell, students note a small resting potential around -30 mV, differing from animal resting potentials. By manipulating ion concentrations, APs of the relatively long length of 20-30 ms up to several minutes with depolarizations maxing over 0 mV are observed. Through comparative analysis of membrane potentials and the APs induced by either calcium or barium, students can deduce the causative ions for the APs as well as the mechanisms of paramecium APs. Current injection allows students to calculate quantitative electric characteristics of the membrane. Analysis will follow the literature's conclusion in a V-Gated Ca++ influx and depolarization resulting in feedback from intracellular Ca++ that inactivates V-Gated Ca++ channels and activates Ca-Dependent K+ channels through a secondary messenger cascade that results in the K+ efflux and repolarization. © 2015 Faculty for Undergraduate Neuroscience.


Author Keywords
Action potential;  Ciliates;  Excitability;  Ionic conductances;  Paramecium;  Paramecium caudatum


Document Type: Article
Source: Scopus




Kaur, T.a , Zamani, D.a c e , Tong, L.d , Rube, E.W.b d , Ohlemiller, K.K.a , Hirose, K.a , Warchol, M.E.a
Fractalkine signaling regulates macrophage recruitment into the cochlea and promotes the survival of spiral ganglion neurons after selective hair cell lesion
(2015) Journal of Neuroscience, 35 (45), pp. 15050-15061. 

DOI: 10.1523/JNEUROSCI.2325-15.2015


a Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Otolaryngology, University of Washington School of Medicine, Seattle, WA, United States
c Department of Communication Sciences and Disorders, University of South Florida, Tampa, FL, United States
d Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, WA, United States
e Department of Communication Sciences and Disorders, University of Florida, Tampa, FL, United States


Abstract
Macrophages are recruited into the cochlea in response to injury caused by acoustic trauma or ototoxicity, but the nature of the interaction between macrophages and the sensory structures of the inner ear remains unclear. The present study examined the role of fractalkine signaling in regulating the injury-evoked behavior of macrophages following the selective ablation of cochlear hair cells.Weused a novel transgenic mouse model in which the human diphtheria toxin receptor (huDTR) is selectively expressed under the control of Pou4f3, a hair cell-specific transcription factor. Administration of diphtheria toxin (DT) to these mice resulted in nearly complete ablation of cochlear hair cells, with no evident pathology among supporting cells, spiral ganglion neurons, or cells of the cochlear lateral wall. Hair cell death led to an increase in macrophages associated with the sensory epithelium of the cochlea. Their numbers peaked at 14 days after DT and then declined at later survival times. Increased macrophages were also observed within the spiral ganglion, but their numbers remained elevated for (at least) 56 d after DT. To investigate the role of fractalkine signaling in macrophage recruitment, we crossed huDTR mice to a mouse line that lacks expression of the fractalkine receptor (CX3CR1). Disruption of fractalkine signaling reduced macrophage recruitment into both the sensory epithelium and spiral ganglion and also resulted in diminished survival of spiral ganglion neurons after hair cell death. Our results suggest a fractalkine-mediated interaction between macrophages and the neurons of the cochlea. © 2015 the authors.


Author Keywords
Cochlea;  Fractalkine;  Hair cells;  Macrophages;  Neuroprotection;  Spiral ganglion neurons


Document Type: Article
Source: Scopus




Ment, L.R.a al bc , Ådén, U.b bc r bc , Bauer, C.R.c aw , Bada, H.S.d ax , Carlo, W.A.e v at , Kaiser, J.R.f w , Lin, A.g al , Cotten, C.M.h , Murray, J.i , Page, G.j ar , Hallman, M.k , Lifton, R.P.l , Zhang, H.m al , Bryant, C.n , Cassady, C.n , Garcia, C.n , Johnson, Y.R.n , Karpen, H.E.n , Munden, M.M.n , Shores, G.n , Cassese, J.o , Hensman, A.M.o , Vieira, E.o , Vohr, B.o , Wallach, M.o , Cummings, J.J.p , MacGilvray, S.S.p , Moseley, S.p , Trapanotto, V.p , Poindexter, B.q , Wilson, L.D.q , Wright-Coltart, S.q , Bartocci, M.r , Printz, G.r , Hopper, A.s , Smith, L.s , Wood, B.P.s , Young, L.s , Allan, W.C.t , Alfsson, J.u , Sävman, K.u , Royal, S.A.v , Young, D.W.v , Cosby, S.v , Helms, C.v , Angtuaco, T.w , Carol Sikes, N.w , Mason, M.J.w , Whit Hall, R.w , Bada, H.x , Challa, H.R.x , Grider, D.x , Kriss, V.x , Whitehead, V.x , Abdenour, G.y , Bauer, C.y , Danton, G.y , Montesinos, D.y , Gaurav, S.y , Philias, W.y , Teomete, U.y , Barks, J.z , Christensen, M.z , Sanchez, R.z , Sieg, M.z , Wiggins, S.z , Fuller, J.aa , Hartenberger, C.aa , Montman, R.aa , Williams, J.B.aa , Williamson, S.aa , Bose, C.ab , Clark, C.L.ab , Laughon, M.ab , Abbasi, S.ac , Cook, N.M.ac , Mancini, T.ac , Chaudhary, A.ad , DeMauro, C.ad , Schmidt, B.ad , Dean, E.ae , Eyal, F.ae , Maertens, P.ae , Boulden, T.F.af , Cohen, H.L.af , Dempsey, S.af , LeNoue, P.af , Pourcyrous, M.af , Bird, K.ag , Faix, R.G.ag , Hedlund, G.ag , Moore, K.ag , Osborne, K.ag , Weaver-Lewis, K.ag , Yoder, B.A.ag , Mayock, D.E.ah , Dighe, M.ah , Brown, P.L.ai , Michael O'Shea, T.ai , Peters, N.ai , Inder, T.aj , Lukas, K.aj , Mathur, A.aj , McKinstry, R.aj , Shimony, J.aj , Joshi, A.ak , Ann Nelson, J.ak , Shankaran, S.ak ba , Woldt, E.H.ak , Baker, K.al , Bizzarro, M.J.al , Choi, M.al , Ehrenkranz, R.al , Farhi, A.al , Goodman, T.R.al , Katz, K.al , Konstantino, M.al , Liu, Z.al , Maller-Kesselman, J.al , Nelson-Williams, C.al , Min, X.al , Walsh, M.C.am , Fanaroff, A.A.am , Newman, N.S.am , Siner, B.S.am , Schibler, K.an , Donovan, E.F.an , Narendran, V.an , Alexander, B.an , Grisby, C.an , Hessling, J.an , Mersmann, M.W.an , Mincey, H.L.an , Michael Cotten, C.ao , Goldberg, R.N.ao , Auten, K.J.ao , Stoll, B.J.ap , Hale, E.C.ap , Higgins, R.D.aq , Wright, L.L.aq , Yaffe, S.J.aq , McClure, E.M.aq , Archer, S.W.aq , Das, A.ar , McDonald, S.A.ar , Poole, W.K.ar , Hastings, B.K.ar , O'Donnell Auman, J.ar , Zaterka-Baxter, K.M.ar , Van Meurs, K.P.as , Stevenson, D.K.as , Ball, M.B.as , Ambalavanan, N.at , Collins, M.V.at , Cosby, S.S.at , Finer, N.N.au , Rasmussen, M.R.au , Kaegi, D.au , Arnell, K.au , Demetrio, C.au , Rich, W.au , Bell, E.F.av , Johnson, K.J.av , Murray, J.C.av , Duara, S.aw , Everett-Thomas, R.aw , Korones, S.B.ax , Hudson, T.ax , Sánchez, P.J.ay , Laptook, A.R.ay , Salhab, W.A.ay , Madison, S.ay , Miller, N.A.ay , Hensley, G.ay , Guzman, A.ay , Kennedy, K.A.az , Tyson, J.E.az , Akpa, E.G.az , Cluff, P.A.az , Franco, C.I.az , Lis, A.E.az , McDavid, G.E.az , Tate, P.P.az , Sood, B.G.ba , Ganesh Konduri, G.ba , Bara, R.ba , Muran, G.ba , Jobe, A.H.bb
Genes and environment in neonatal intraventricular hemorrhage
(2015) Seminars in Perinatology, 39 (8), pp. 592-603. 

DOI: 10.1053/j.semperi.2015.09.006


a Department of Pediatrics and Neurology, Yale University School of Medicine, 333 Cedar St, P.O. Box 208064, New Haven, CT, United States
b Department of Women and Child health, Karolinska Institutet, Stockholm, Sweden
c Department of Pediatrics, University of Miami-Leonard M. Miller School of Medicine, Miami, FL, United States
d University of Kentucky, Lexington, KY, United States
e Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, United States
f Department of Pediatrics, University of Arkansas, Little Rock, AR, United States
g Department of Pediatrics, Yale University School of Medicine, New Haven, CT, United States
h Department of Pediatrics, Duke University, Durham, NC, United States
i Department of Pediatrics, Anatomy and Cell Biology, Biology, Epidemiology, Preventive Medicine, University of Iowa, Iowa City, IA, United States
j RTI International, Atlanta, GA, United States
k Department of Pediatrics and Biocenter, University of Oulu and Oulu University Hospital, Oulu, Finland
l Department of Genetics, Yale University School of Medicine, New Haven, CT, United States
m Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT, United States
n Baylor College of Medicine, Texas Children's Hospital and Ben Taub General Hospital, United States
o Brown University and Women and Infants Hospital, United States
p East Carolina University, Brody School of Medicine, United States
q Indiana University School of Medicine and Riley Hospital for Children, United States
r Karolinska Institutet, Karolinska University Hospital, United States
s Loma Linda University School of Medicine, United States
t Maine Medical Center, United States
u Sahlgrenska Academy at the University of Gothenburg, Queen Silvia Children's Hospital, United States
v University of Alabama at Birmingham, Women's and Infants' Center, United States
w University of Arkansas for Medical Sciences, United States
x University of Kentucky, United States
y University of Miami-Leonard M. Miller School of Medicine, Holtz Children's Hospital, United States
z University of Michigan, United States
aa University of New Mexico Health Science Center, United States
ab University of North Carolina at Chapel Hill, University of North Carolina Children's Hospital, United States
ac University of Pennsylvania, Pennsylvania Hospital, United States
ad University of Pennsylvania, Children's Hospital of Philadelphia, Hospital of the University of Pennsylvania, United States
ae University of South Alabama, Children's and Women's Hospital, United States
af University of Tennessee Health Sciences Center, Regional Medical Center Hospital, United States
ag University of Utah and Intermountain Healthcare, United States
ah University of Washington, United States
ai Wake Forest School of Medicine, Forsyth Medical Center, Brenner Children's Hospital, United States
aj Washington University in St. Louis, St. Louis Children's Hospital, United States
ak Wayne State University, Children's Hospital of Michigan, Hutzel Women's Hospital, United States
al Yale University School of Medicine, United States
am Case Western Reserve University, Rainbow Babies and Children's Hospital, United States
an Cincinnati Children's Hospital Medical Center, University Hospital, and Good Samaritan Hospital, United States
ao Duke University School of Medicine University Hospital, Alamance Regional Medical Center, Durham Regional Hospital, United States
ap Emory University, Children's Healthcare of Atlanta, Grady Memorial Hospital, Emory Crawford Long Hospital, United States
aq Eunice Kennedy Shriver National Instituteof Child Healthand Human Development, United States
ar RTI International, United States
as Stanford University, Lucile Packard Children's Hospital, United States
at University of Alabamaat Birmingham Health System and Children's Hospital of Alabama, United States
au University of California-San Diego Medical Centerand Sharp Mary Birch Hospital for Women, United States
av University of Iowa, United States
aw University of Miami Holtz Children's Hospital, United States
ax University of Tennessee, United States
ay University of Texas Southwestern Medical Centerat Dallas, Parkland Health and Hospital System, Children's Medical Center Dallas, United States
az University of Texas Health Science Centerat Houston Medical School, Children's Memorial Hermann Hospital, Lyndon B. Johnson General Hospital, United States
ba Wayne State University, Hutzel Women's Hospital, Children's Hospital of Michigan, United States
bb University of Cincinnati, United States


Abstract
Emerging data suggest intraventricular hemorrhage (IVH) of the preterm neonate is a complex disorder with contributions from both the environment and the genome. Environmental analyses suggest factors mediating both cerebral blood flow and angiogenesis contribute to IVH, while candidate gene studies report variants in angiogenesis, inflammation, and vascular pathways. Gene-by-environment interactions demonstrate the interaction between the environment and the genome, and a non-replicated genome-wide association study suggests that both environmental and genetic factors contribute to the risk for severe IVH in very low-birth weight preterm neonates. © 2015 Elsevier Inc.


Author Keywords
Genes;  GWAS;  Intraventricular hemorrhage;  Neonate;  Preterm


Document Type: Review
Source: Scopus



Papadimitriou, D.T.a i , Manolakos, E.f g , Bothou, C.h , Zoupanos, G.b , Papoulidis, I.f , Orru, S.g , Skarmoutsos, F.d , Delides, A.e , Bakoula, C.c , Papadimitriou, A.i , Urano, F.j
Maternal uniparental disomy of chromosome 4 and homozygous novel mutation in the WFS1 gene in a paediatric patient with Wolfram syndrome
(2015) Diabetes and Metabolism, 41 (5), pp. 433-435. 

DOI: 10.1016/j.diabet.2015.06.003


a Department of Pediatric Endocrinology and Diabetes, Athens Medical Center, 58, av. Kifissias, Maroussi, Athens, Greece
b Department of Pediatric Urology, Athens Medical Center, Athens, Greece
c Department of Pediatrics, Athens Medical Center, Athens, Greece
d Department of Pediatric Opthalmology, Athens Medical center, Athens, Greece
e Department of Pediatric Otorhinolaryngology, Athens Medical center, Athens, Greece
f Access to Genome, Athens-Thessaloniki, Greece
g Department of Medical Genetics, University of Cagliari, Binaghi hospital, Cagliari, Italy
h Medical School, Athens University, Athens, Greece
i Pediatric Endocrine Unit, Attikon University Hospital, Athens, Greece
j Washington University School of Medicine, Saint-Louis, MO, United States


Document Type: Letter
Source: Scopus




Kopp, N.a b , Climer, S.c , Dougherty, J.D.a b
Moving from capstones toward cornerstones: Successes and challenges in applying systems biology to identify mechanisms of autism spectrum disorders
(2015) Frontiers in Genetics, 6 (OCT), art. no. 301, . 

DOI: 10.3389/fgene.2015.00301


a Department of Genetics, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
b Department of Psychiatry, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
c Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, MO, United States


Abstract
The substantial progress in the last few years toward uncovering genetic causes and risk factors for autism spectrum disorders (ASDs) has opened new experimental avenues for identifying the underlying neurobiological mechanism of the condition. The bounty of genetic findings has led to a variety of data-driven exploratory analyses aimed at deriving new insights about the shared features of these genes. These approaches leverage data from a variety of different sources such as co-expression in transcriptomic studies, protein-protein interaction networks, gene ontologies (GOs) annotations, or multi-level combinations of all of these. Here, we review the recurrent themes emerging from these analyses and highlight some of the challenges going forward. Themes include findings that ASD associated genes discovered by a variety of methods have been shown to contain disproportionate amounts of neurite outgrowth/cytoskeletal, synaptic, and more recently Wnt-related and chromatin modifying genes. Expression studies have highlighted a disproportionate expression of ASD gene sets during mid fetal cortical development, particularly for rare variants, with multiple analyses highlighting the striatum and cortical projection and interneurons as well. While these explorations have highlighted potentially interesting relationships among these ASD-related genes, there are challenges in how to best transition these insights into empirically testable hypotheses. Nonetheless, defining shared molecular or cellular pathology downstream of the diverse genes associated with ASDs could provide the cornerstones needed to build toward broadly applicable therapeutic approaches. © 2015 Kopp, Climer and Dougherty.


Author Keywords
ASD;  Autism;  CSEA;  Network analysis;  Review;  Systems biology;  WGCNA


Document Type: Review
Source: Scopus


Angres, D.a , Dupont, R.b , Gold, M.S.c

Perspectives on the opioid crisis
(2015) Psychiatric Annals, 45 (10), pp. 522-526. 

DOI: 10.3928/00485713-20151001-08


a Northwestern University, Feinberg School of Medicine, United States
b DuPont and Associates, Institute for Behavior and Health, United States
c Scientific Advisory Boards, River Mend Health The Keck School of Medicine at USC, Washington University School of Medicine, United States


Abstract
Health care providers, addiction specialists, and legislators are in agreement that novel and more effective means of reducing opioid and other addicting substance misuse and abuse are critical at this time in our country. The statistics are dismal and increasingly alarming, with more and more individuals at risk. The widespread availability and use of the antiopiate pharmaceutical, naloxone, to reverse life-threatening overdoses is a beginning and a step in the right direction, but can only be considered an initial intervention. What should follow naloxone? We know the answer if the patient is an anesthesiologist resuscitated in the hospital. For everyone who is not a licensed health provider, it is less clear. Substance abuse treatment in the United States is predominantly outpatient, short term, and with few objective checks on the effectiveness of treatment. Substance abuse treatment of health professions is radically different in that it is not a treatment program but is a program of active care management. This management includes residential treatment and sustained monitoring of abstinence. Few addicted patients receive anything that approximates evidence-based care. © SLACK Incorporated.


Document Type: Article
Source: Scopus




Brangwynne, C.P.a , Tompa, P.b c , Pappu, R.V.d
Polymer physics of intracellular phase transitions
(2015) Nature Physics, 11 (11), pp. 899-904. 

DOI: 10.1038/nphys3532


a Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, United States
b VIB Structural Biology Research Center (SBRC), Vrije Universiteit Brussel, Brussels, Belgium
c Institute of Enzymology, Research Centre for Natural Sciences of the Hungarian Academy of Sciences, Budapest, Hungary
d Department of Biomedical Engineering, Center for Biological Systems Engineering, Washington University in St Louis, St Louis, MO, United States


Abstract
Intracellular organelles are either membrane-bound vesicles or membrane-less compartments that are made up of proteins and RNA. These organelles play key biological roles, by compartmentalizing the cell to enable spatiotemporal control of biological reactions. Recent studies suggest that membrane-less intracellular compartments are multicomponent viscous liquid droplets that form via phase separation. Proteins that have an intrinsic tendency for being conformationally heterogeneous seem to be the main drivers of liquid-liquid phase separation in the cell. These findings highlight the relevance of classical concepts from the physics of polymeric phase transitions for understanding the assembly of intracellular membrane-less compartments. However, applying these concepts is challenging, given the heteropolymeric nature of protein sequences, the complex intracellular environment, and non-equilibrium features intrinsic to cells. This provides new opportunities for adapting established theories and for the emergence of new physics. © 2015 Macmillan Publishers Limited. All rights reserved.


Document Type: Article
Source: Scopus




Miller, N.S.a , Gold, M.S.b
Prescription opioids and addiction
(2015) Psychiatric Annals, 45 (10), pp. 516-521. 

DOI: 10.3928/00485713-20151001-07


a Bear River Health at Walloon Lake, United States
b Scientific Advisory Boards, River Mend Health, The Keck School of Medicine at USC, Washington University School of Medicine, United States


Abstract
Why are opioid medications prescribed in large quantities and high frequency when there is little or no proven efficacy for their therapeutic value? Why are opioids the most commonly prescribed medication in the United States when their adverse consequences continue to grow? Why does the medical profession continue to prescribe opioid medications that result in increased pain and increased disability? This article summarizes the inherent addictive pharmacologic properties that are the impetus and basis for America’s current opioid epidemic. © SLACK Incorporated.


Document Type: Article
Source: Scopus




Brown, G.a , Baer, M.b
Protecting the turf: The effect of territorial marking on others' creativity
(2015) Journal of Applied Psychology, 100 (6), pp. 1785-1797. 

DOI: 10.1037/a0039254


a Gustavson School of Business, University of Victoria, Canada
b Olin Business School, Washington University, St. Louis, MO, United States


Abstract
Territorial marking allows people to communicate that a territory has been claimed. Across 2 studies, we examine the impact of territorial marking of one's ideas on others' invited creativity when asked to provide feedback. Integrating research on territoriality and self-construal, we examine the effect of control-oriented marking on invited creativity (Study 1), and the extent to which an independent versus interdependent self-construal moderates this effect (Study 2). Results of Study 1 demonstrate that the use of control-oriented marking to communicate a territorial claim over one's ideas inhibits invited creativity, and this effect is mediated by intrinsic motivation. Also consistent with our hypotheses, the results of Study 2 show that self-construal moderates the effect of control-oriented marking on others' intrinsic motivation and creativity. Marking diminishes invited creativity among people with an independent self-construal but serves to enhance the creativity of those with an interdependent self-construal. Consistent with Study 1, intrinsic motivation mediates this moderated effect. Our results highlight the important but heretofore understudied role of territoriality in affecting others' creativity as well as the role of independent versus interdependent self-construal in shaping this effect.


Author Keywords
Cognitive evaluation theory;  Creativity;  Individualismcollectivism;  Self-construal;  Territoriality


Document Type: Article
Source: Scopus




Palmer, R.H.C.a b , Mcgeary, J.E.a b c , Heath, A.C.d , Keller, M.C.e , Brick, L.A.a , Knopik, V.S.a b
Shared additive genetic influences on DSM-IV criteria for alcohol dependence in subjects of European ancestry
(2015) Addiction, 110 (12), pp. 1922-1931. 

DOI: 10.1111/add.13070


a Division of Behavioral Genetics, Department of Psychiatry, Rhode Island Hospital, Providence, RI, United States
b Department of Psychiatry and Human Behavior, Brown University, Providence, RI, United States
c Providence Veterans Affairs Medical Center, Providence, RI, United States
d Midwest Alcoholism Research Center, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
e Department of Psychology and Neuroscience, Institute for Behavioral Genetics, University of Colorado at Boulder, Boulder, CO, United States


Abstract
Background and Aims: Genetic studies of alcohol dependence (AD) have identified several candidate loci and genes, but most observed effects are small and difficult to reproduce. A plausible explanation for inconsistent findings may be a violation of the assumption that genetic factors contributing to each of the seven DSM-IV criteria point to a single underlying dimension of risk. Given that recent twin studies suggest that the genetic architecture of AD is complex and probably involves multiple discrete genetic factors, the current study employed common single nucleotide polymorphisms in two multivariate genetic models to examine the assumption that the genetic risk underlying DSM-IV AD is unitary. Design, Setting, Participants, Measurements: AD symptoms and genome-wide single nucleotide polymorphism (SNP) data from 2596 individuals of European descent from the Study of Addiction: Genetics and Environment were analyzed using genomic-relatedness-matrix restricted maximum likelihood. DSM-IV AD symptom covariance was described using two multivariate genetic factor models. Findings: Common SNPs explained 30% (standard error = 0.136, P = 0.012) of the variance in AD diagnosis. Additive genetic effects varied across AD symptoms. The common pathway model approach suggested that symptoms could be described by a single latent variable that had a SNP heritability of 31% (0.130, P = 0.008). Similarly, the exploratory genetic factor model approach suggested that the genetic variance/covariance across symptoms could be represented by a single genetic factor that accounted for at least 60% of the genetic variance in any one symptom. Conclusion: Additive genetic effects on DSM-IV alcohol dependence criteria overlap. The assumption of common genetic effects across alcohol dependence symptoms appears to be a valid assumption. © 2015 John Wiley & Sons, Ltd.


Author Keywords
Alcohol dependence;  Alcoholism;  Diagnostic criteria;  DSM-IV;  GCTA;  Genetics


Document Type: Article
Source: Scopus




Thotala, D.a d , Karvas, R.M.a , Engelbach, J.A.c , Garbow, J.R.b c d , Hallahan, A.N.a , DeWees, T.A.a , Laszlo, A.a , Hallahan, D.E.a c d e
Valproic acid enhances the efficacy of radiation therapy by protecting normal hippocampal neurons and sensitizing malignant glioblastoma cells
(2015) Oncotarget, 6 (33), pp. 35004-35022. 

DOI: 10.18632/oncotarget.5253


a Department of Radiation Oncology, Washington University, St. Louis, MO, United States
b School of Medicine, Washington University, St. Louis, MO, United States
c Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, United States
d Siteman Cancer Center, Washington University, St. Louis, MO, United States
e Hope Center, Washington University, St. Louis, MO, United States


Abstract
Neurocognitive deficits are serious sequelae that follow cranial irradiation used to treat patients with medulloblastoma and other brain neoplasms. Cranial irradiation causes apoptosis in the subgranular zone of the hippocampus leading to cognitive deficits. Valproic acid (VPA) treatment protected hippocampal neurons from radiation-induced damage in both cell culture and animal models. Radioprotection was observed in VPA-treated neuronal cells compared to cells treated with radiation alone. This protection is specific to normal neuronal cells and did not extend to cancer cells. In fact, VPA acted as a radiosensitizer in brain cancer cells. VPA treatment induced cell cycle arrest in cancer cells but not in normal neuronal cells. The level of anti-apoptotic protein Bcl-2 was increased and the pro-apoptotic protein Bax was reduced in VPA treated normal cells. VPA inhibited the activities of histone deacetylase (HDAC) and glycogen synthase kinase-3ß (GSK3ß), the latter of which is only inhibited in normal cells. The combination of VPA and radiation was most effective in inhibiting tumor growth in heterotopic brain tumor models. An intracranial orthotopic glioma tumor model was used to evaluate tumor growth by using dynamic contrast-enhanced magnetic resonance (DCE MRI) and mouse survival following treatment with VPA and radiation. VPA, in combination with radiation, significantly delayed tumor growth and improved mouse survival. Overall, VPA protects normal hippocampal neurons and not cancer cells from radiation-induced cytotoxicity both in vitro and in vivo. VPA treatment has the potential for attenuating neurocognitive deficits associated with cranial irradiation while enhancing the efficiency of glioma radiotherapy.


Author Keywords
Cancer therapy;  Histone deacetylase (HDAC);  Neuroprotection;  Radioprotection;  Valproic acid (VPA)

 


Document Type: Article
Source: Scopus

 

 

November 20, 2015

Clifford, D.B.
Progressive multifocal leukoencephalopathy therapy
(2015) Journal of NeuroVirology, 21 (6), pp. 632-636. 

DOI: 10.1007/s13365-014-0289-8


Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, Saint Louis, MO, United States


Abstract
Progressive multifocal leukoencephalopathy (PML) is caused by the JC virus in the setting of chronic immune deficiency. Developing therapy has been challenged by the rarity of the disease as well as the complexity of patients in whom it develops. Several small trials directed at presumptive antiviral therapies have failed to show convincing clinical efficacy. However, the prognosis of PML has evolved from an almost uniformly fatal encephalitis to a disease where a majority of patients survive. This improvement in outlook has been driven by effective immune reconstitution strategies for the underlying disease, most prominently the improved therapy for human immunodeficiency virus and ability to reverse the effects of natalizumab. While a rapid acting and effective antiviral therapy remains a sought for goal, optimal immune reconstitution to control JC virus without causing brain-damaging immune reconstitution inflammatory syndrome (IRIS) currently is the most practical approach to treat PML. © 2014, Journal of NeuroVirology, Inc.


Author Keywords
Immune reconstitution inflammatory syndrome;  IRIS;  JC virus;  Natalizumab;  PML;  Progressive multifocal leukoencephalopathy


Document Type: Article
Source: Scopus




Mattsson, N.a , Carrillo, M.C.b , Dean, R.A.c , Devous, M.D.d , Nikolcheva, T.e , Pesini, P.f , Salter, H.g h , Potter, W.Z.i , Sperling, R.S.j , Bateman, R.J.k , Bain, L.J.l , Liu, E.m
Revolutionizing Alzheimer's disease and clinical trials through biomarkers
(2015) Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring, 1 (4), pp. 412-419. 

DOI: 10.1016/j.dadm.2015.09.001


a Clinical Memory Research Unit, Lund University, Sweden
b Alzheimer's Association, Chicago, IL, United States
c Eli Lilly and Co Inc., Indianapolis, IN, United States
d Avid Radiopharmaceuticals, Philadelphia, PA, United States
e F. Hoffmann-La Roche, Basel, Switzerland
f Araclon Grifols, Zaragoza, Spain
g AztraZeneca, Stockholm, Sweden
h Department of Clinical Neuroscience, Karolinska Institutet, Sweden
i Foundation for the NIH, Bethesda, MD, United States
j Brigham and Women's Hospital, Boston, MA, United States
k Washington University School of Medicine, St. Louis, MO, United States
l Elverson, PA, United States
m Janssen Research and Development, LLC., San Diego, CA, United States


Abstract
The Alzheimer's Association's Research Roundtable met in May 2014 to explore recent progress in developing biomarkers to improve understanding of disease pathogenesis and expedite drug development. Although existing biomarkers have proved extremely useful for enrichment of subjects in clinical trials, there is a clear need to develop novel biomarkers that are minimally invasive and that more broadly characterize underlying pathogenic mechanisms, including neurodegeneration, neuroinflammation, and synaptic dysfunction. These may include blood-based assays and new neuropsychological testing protocols, as well as novel ligands for positron emission tomography imaging, and advanced magnetic resonance imaging methodologies. In addition, there is a need for biomarkers that can serve as theragnostic markers of response to treatment. Standardization remains a challenge, although international consortia have made substantial progress in this area and provide lessons for future standardization efforts. © 2015 The Authors.


Author Keywords
Alzheimer's disease;  Amyloid;  Biomarkers;  Blood biomarkers;  Cerebrospinal fluid;  Clinical trials;  CSF;  Imaging;  MRI;  PET;  Tau


Document Type: Review
Source: Scopus




McCollum, M.a b , LaVesser, P.a c , Berg, C.a
Participation in Daily Activities of Young Adults with High Functioning Autism Spectrum Disorder
(2015) Journal of Autism and Developmental Disorders, 11 p. Article in Press. 

DOI: 10.1007/s10803-015-2642-z


a Washington University School of Medicine, St. Louis, MO, United States
b St. John’s Children’s Hospital, 800 E Carpenter St, Springfield, IL, United States
c University of Colorado Denver, Denver, CO, United States


Abstract
Young adults with an autism spectrum disorder (ASD) struggle to assume adult roles. This research assessed the feasibility of using the Adolescent and Young Adult Activity Card Sort (AYA-ACS) with emerging adults with high functioning ASD. Two phases were utilized during this research: (1) comparing the activity participation reported by emerging adults with an ASD and that reported by their caring adult; (2) examining the barriers to participation reported. Preliminary results demonstrate that the AYA-ACS appears to be a reliable and valid method of identifying emerging adults’ participation strengths as well as personal and environmental challenges in a variety of age-appropriate activities. The AYA-ACS could assist service providers by providing an understanding of the challenges to participation faced by this population and aid in developing client centered interventions. © 2015 Springer Science+Business Media New York


Author Keywords
Activity card sort;  Activity involvement;  Autism spectrum disorder;  Emerging adults;  Engagement;  Participation;  Transition age;  Young adults


Document Type: Article in Press
Source: Scopus




Jacobs, J.V.a b , Earhart, G.M.c d e , McNeely, M.E.c d
Can postural instability tests improve the prediction of future falls in people with Parkinson’s disease beyond knowing existing fall history?
(2015) Journal of Neurology, 7 p. Article in Press. 

DOI: 10.1007/s00415-015-7950-x


a Liberty Mutual Research Institute for Safety, 71 Frankland Rd, Hopkinton, MA, United States
b Department of Rehabilitation and Movement Science, University of Vermont, 305 Rowell Building, 106 Carrigan Drive, Burlington, VT, United States
c Program in Physical Therapy, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
d Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
e Department of Anatomy and Neurobiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States


Abstract
This study sought to determine whether the backward-stepping Push and Release (P&R) Test and the Pull Test, or comprehensive batteries of postural instability (the Mini-BESTest and Brief-BESTest), significantly improve the prediction of future falls beyond knowing a person’s baseline fall history. Complete data were available for 43 of 80 participants with PD. At baseline, participants completed the BESTest (which was scored for all versions and includes the P&R Test), the Unified PD Rating Scale (UPDRS) motor section (which includes the Pull Test), and the participants’ reported falls experienced in the previous 6 months. Participants were classified as recurrent fallers if they reported more than one fall in the 12 months subsequent to baseline. Stepwise logistic regressions determined whether the P&R Test, Pull Test, Brief-BESTest, Mini-BESTest, or UPDRS motor score improved predictions of recurrent fallers independent of baseline fall-group status. Independently, all assessments significantly predicted future recurrent fallers, but only the Mini-BESTest and Brief-BESTest significantly improved predictions of future recurrent fallers independent of baseline fall-group status. The results suggest that, although single tests of reactive postural control do not offer significant predictive benefit, predictions of future recurrent fallers with PD do benefit from a balance examination in addition to knowing whether an individual has a recent history of falls. © 2015 Springer-Verlag Berlin Heidelberg


Author Keywords
BESTest;  Falls;  Parkinson’s disease;  Pull Test;  Push and Release Test


Document Type: Article in Press
Source: Scopus




Ong, C.J., Yarbrough, C.K., Derdeyn, C.P.
Response to Letter Regarding Article, “Endovascular Thrombectomy for Anterior Circulation Stroke: Systematic Review and Meta-Analysis”
(2015) Stroke, . Article in Press. 

DOI: 10.1161/STROKEAHA.115.011727


Department of Neurology, Washington University School of Medicine, St. Louis, MO Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO


Document Type: Article in Press
Source: Scopus




Fouke, S.J.a , Benzinger, T.b , Gibson, D.c , Ryken, T.C.d , Kalkanis, S.N.e , Olson, J.J.f
The role of imaging in the management of adults with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline
(2015) Journal of Neuro-Oncology, 23 p. Article in Press. 

DOI: 10.1007/s11060-015-1908-9


a Swedish Neuroscience Institute, 751 Northeast Blakely Drive, Suite 4020, Seattle, WA, United States
b Washington University School of Medicine, St. Louis, MO, United States
c Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
d Department of Neurosurgery, Kansas University Medical Center, Kansas City, KS, United States
e Department of Neurosurgery, Henry Ford Health System, Detroit, MI, United States
f Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, United States


Abstract
Question: What is the optimal imaging technique to be used in the diagnosis of a suspected low grade glioma, specifically: which anatomic imaging sequences are critical for most accurately identifying or diagnosing a low grade glioma (LGG) and do non-anatomic imaging methods and/or sequences add to the diagnostic specificity of suspected low grade gliomas? Target population: These recommendations apply to adults with a newly diagnosed lesion with a suspected or histopathologically proven LGG. Level II: In patients with a suspected brain tumor, the minimum magnetic resonance imaging (MRI) exam should be an anatomic exam with both T2 weighted and pre- and post-gadolinium contrast enhanced T1 weighted imaging. Level II: In patients with a suspected brain tumor, anatomic imaging sequences should include T1 and T2 weighted and Fluid Attenuation Inversion Recovery (FLAIR) MR sequences and will include T1 weighted imaging after the administration of gadolinium based contrast. Computed tomography (CT) can provide additional information regarding calcification or hemorrhage, which may narrow the differential diagnosis. At a minimum, these anatomic sequences can help identify a lesion as well as its location, and potential for surgical intervention. Level II: Class II evidence from multiple studies and a significant number of Class III series support the addition of diffusion and perfusion weighted MR imaging in the assessment of suspected LGGs, for the purposes of discriminating the potential for tumor subtypes and identification of suspicion of higher grade diagnoses. Level III: Multiple series offer Class III evidence to support the potential for magnetic resonance spectroscopy (MRS) and nuclear medicine methods including positron emission tomography and single-photon emission computed tomography imaging to offer additional diagnostic specificity although these are less well defined and their roles in clinical practice are still being defined. Question: Which imaging sequences or parameters best predict the biological behavior or prognosis for patients with LGG? Target population: These recommendations apply to adults with a newly diagnosed lesion with a suspected or histopathologically proven LGG. Recommendation: Anatomic and advanced imaging methods and prognostic stratification Level III: Multiple series suggest a role for anatomic and advanced sequences to suggest prognostic stratification among low grade gliomas. Perfusion weighted imaging, particularly when obtained as a part of diagnostic evaluation (as recommended above) can play a role in consideration of prognosis. Other imaging sequences remain investigational in terms of their role in consideration of tumor prognosis as there is insufficient evidence to support more formal recommendations as to their use at this time. Question: What is the optimal imaging technique to be used in the follow-up of a suspected (or biopsy proven) LGG? Target population: This recommendation applies to adults with a newly diagnosed low grade glioma. Level II: In patients with a diagnosis of LGG, anatomic imaging sequences should include T2/FLAIR MR sequences and T1 weighted imaging before and after the administration of gadolinium based contrast. Serial imaging should be performed to identify new areas of contrast enhancement or significant change in tumor size, which may signify transformation to a higher grade. Level III: Advanced imaging utility may depend on tumor subtype. Multicenter clinical trials with larger cohorts are needed. For astrocytic tumors, baseline and longitudinal elevations in tumor perfusion as assessed by dynamic susceptibility contrast perfusion MRI are associated with shorter time to tumor progression, but can be difficult to standardize in clinical practice. For oligodendrogliomas and mixed gliomas, MRS may be helpful for identification of progression. © 2015 Springer Science+Business Media New York


Author Keywords
Diagnostic specificity;  Guidelines;  Low grade glioma;  Magnetic resonance imaging;  Prognosis


Document Type: Article in Press
Source: Scopus




Kharasch, E.D., Eisenach, J.C.
Wherefore Gabapentinoids?: Was There Rush Too Soon to Judgment?
(2015) Anesthesiology, . Article in Press. 

DOI: 10.1097/ALN.0000000000000914


From the Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri (E.D.K.); Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St. Louis, Missouri (E.D.K.); the Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University in St. Louis, St. Louis, Missouri (E.D.K.); and Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, North Carolina ( J.C.E.).


Document Type: Article in Press
Source: Scopus




Andó, B.a , Álmos, P.Z.a , Németh, V.L.a , Kovács, I.a b , Fehér-Csókás, A.a , Demeter, I.a , Rózsa, S.c , Urbán, R.d , Kurgyis, E.a , Szikszay, P.e , Janka, Z.a , Demetrovics, Z.d , Must, A.a
Spirituality mediates state anxiety but not trait anxiety and depression in alcohol recovery
(2015) Journal of Substance Use, 5 p. Article in Press. 

DOI: 10.3109/14659891.2015.1021869


a Department of Psychiatry, Faculty of Medicine, University of Szeged, Szeged, Hungary
b Institute of Psychology, University of Szeged, Szeged, Hungary
c Center for Well-Being, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
d Institute of Psychology, Eötvös Loránd University, Budapest, Hungary
e Addiction Rehabilitation Center based on the Minnesota Model, Hospital of Szigetvár, Szigetvár, Hungary


Abstract
Background and objectives: Twelve-step based interventions promote the recovery from alcohol dependence, support relapse prevention and are associated with improved mental status indices (e.g. depression). This treatment model largely relies on spiritual experience. We tested three different alcohol treatment settings, which differently involve elements of spirituality in order to reveal its possible mediator effect on the level of depressive and anxiety symptoms. Methods: Patients were involved from (1) detoxification (n = 34), (2) long-term – 12-step based – therapeutic community treatment (n = 89), (3) and from Alcoholics Anonymous (AA) groups after at least 3 years of attendance (n = 46). Anxiodepressive symptoms and spirituality/transcendence were compared and the potential mediator role of spirituality was assessed in the levels of depressive and anxiety symptoms. Results: Long-term 12-step based rehabilitation and sustained AA attendance was connected to lower levels of anxiodepressive symptoms and to more pronounced spirituality. The spiritual component of the different treatments played a mediator role in the decrease of state anxiety but this mediation was not detected in the case of depressive symptoms and trait anxiety. Conclusions/Importance: The role of spirituality in the decrease of state anxiety indicates acute beneficial effect. Therefore, long term, regular attendance in AA groups is essential. © 2015 Taylor & Francis Group, LLC


Author Keywords
Alcohol dependence;  mediation model;  spirituality


Document Type: Article in Press
Source: Scopus




King, H.R.a , Jackson, J.J.b , Morrow-Howell, N.c , Oltmanns, T.F.d
Personality Accounts for the Connection Between Volunteering and Health
(2015) The journals of gerontology. Series B, Psychological sciences and social sciences, 70 (5), pp. 691-697. 

DOI: 10.1093/geronb/gbu012


a Department of Psychology and hking@wustl.edu
b Department of Psychology and
c George Warren Brown School of Social Work, Washington University, St. Louis, Missouri
d Department of Psychology and


Abstract
OBJECTIVES: Existing literature has shown that volunteering is related to better physical and mental health outcomes. The purpose of this study is to examine whether personality traits and volunteering are independent predictors of physical and mental health.

METHODS: The current study utilizes data from the St. Louis Personality and Aging Network (SPAN), a representative sample of community-based adults between the ages of 55 and 64. Using hierarchical linear regressions, we test whether volunteering is a significant predictor of both physical and mental health while controlling for personality traits.

RESULTS: We find that volunteering is not significantly related to either physical or mental health while controlling for personality traits. We also find that lower neuroticism is related to better physical functioning and mental health, whereas higher extraversion is related to better mental health.

DISCUSSION: These results indicate that volunteering may be related to health outcomes because of the personality characteristics of volunteers, not the volunteering experience in and of itself. Future longitudinal studies are needed to further explore the relationship between personality, volunteering, and health. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.


Author Keywords
Health;  Personality;  Volunteering


Document Type: Article
Source: Scopus




Hennen, S.N.a b , Xing, W.c d , Shui, Y.-B.b , Zhou, Y.d , Kalishman, J.e , Andrews-Kaminsky, L.B.e , Kass, M.A.b , Beebe, D.C.b , Maslov, K.I.c d , Wang, L.V.c d
Photoacoustic tomography imaging and estimation of oxygen saturation of hemoglobin in ocular tissue of rabbits
(2015) Experimental Eye Research, 138, pp. 153-158. 

DOI: 10.1016/j.exer.2015.05.022


a Solo Private Practice, Minneapolis, MN, United States
b Department of Ophthalmology and Visual Sciences, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
c Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO, United States
d Optical Imaging Laboratory, Department of Biomedical Engineering, School of Engineering and Applied Science, Washington University in St. Louis, Campus Box 1097, One Brookings Drive, St. Louis, MO, United States
e Division of Comparative Medicine, School of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States


Abstract
This study evaluated in vivo imaging capabilities and safety of qualitative monitoring of oxygen saturation of hemoglobin (sO2) of rabbit ciliary body tissues obtained with acoustic resolution (AR) photoacoustic tomography (PAT). AR PAT was used to collect trans-scleral images from ciliary body vasculature of seven New Zealand White rabbits. The PAT sO2 measurements were obtained under the following conditions: when systemic sO2 as measured by pulse oximetry was between 100% and 99% (level 1); systemic sO2 as measured by pulse oximetry was between 98% and 90% (level 2); and systemic sO2 as measured by pulse oximetry was less than 90% (level 3). Following imaging, histological analysis of ocular tissue was conducted to evaluate for possible structural damage caused by the AR PAT imaging. AR PAT was able to resolve anatomical structures of the anterior segment of the eye, viewed through the cornea or anterior sclera. Histological studies revealed no ocular damage. On average, sO2 values (%) obtained with AR PAT were lower than sO2 values obtained with pulse oximetry (all p &lt; 0.001): 86.28 ± 4.16 versus 99.25 ± 0.28, 84.09 ± 1.81 vs. 95.3 ± 2.6, and 64.49 ± 7.27 vs. 71.15 ± 10.21 for levels 1, 2 and 3 respectively. AR PAT imaging modality is capable of qualitative monitoring for deep tissue sO2 in rabbits. Further studies are needed to validate and modify the AR PAT modality specifically for use in human eyes. Having a safe, non-invasive method of in vivo imaging of sO2 in the anterior segment is important to studies evaluating the role of oxidative damage, hypoxia and ischemia in pathogenesis of ocular diseases. © 2015 Published by Elsevier Ltd.


Author Keywords
Oxygen;  Photoacoustic tomography;  Rabbit;  Saturation


Document Type: Short Survey
Source: Scopus




Chung, W.K.a , Martin, K.b , Jalas, C.c , Braddock, S.R.b , Juusola, J.d , Monaghan, K.G.d , Warner, B.e , Franks, S.f , Yudkoff, M.g , Lulis, L.g , Rhodes, R.H.h , Prasad, V.i , Torti, E.b , Cho, M.T.d , Shinawi, M.a j
Mutations in COQ4, an essential component of coenzyme Q biosynthesis, cause lethal neonatal mitochondrial encephalomyopathy
(2015) Journal of Medical Genetics, 52 (9), pp. 627-635. Cited 1 time.

DOI: 10.1136/jmedgenet-2015-103140


a Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY, United States
b Genetics Division, Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, MO, United States
c Bonei Olam, Center for Rare Jewish Genetic Disorders, Brooklyn, NY, United States
d GeneDx, Gaithersburg, MD, United States
e Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
f Departments of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
g Division of Metabolism, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
h Department of Pathology, Rutgers Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, United States
i Department of Pathology, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, United States
j Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Background The identification of the molecular basis of mitochondrial disorders continues to be challenging and expensive. The increasing usage of next-generation sequencing is facilitating the discovery of the genetic aetiology of heterogeneous phenotypes associated with these conditions. Coenzyme Q10 (CoQ10) is an essential cofactor for mitochondrial respiratory chain complexes and other biochemical pathways. Mutations in genes involved in CoQ10 biosynthesis cause primary CoQ10 deficiency syndromes that can be treated with oral supplementation of ubiquinone. Methods We used whole exome sequencing to evaluate six probands from four unrelated families with clinical findings suggestive of a mitochondrial disorder. Clinical data were obtained by chart review, parental interviews, direct patient assessment and biochemical and pathological evaluation. Results We identified five recessive missense mutations in COQ4 segregating with disease in all four families. One mutation was found in a homozygous state in two unrelated Ashkenazi Jewish probands. All patients were female, and presented on the first day of life, and died in the neonatal period or early infancy. Clinical findings included hypotonia (6/6), encephalopathy with EEG abnormalities (4/4), neonatal seizures (3/6), cerebellar atrophy (4/5), cardiomyopathy (5/6) and lactic acidosis (4/6). Autopsy findings in two patients revealed neuron loss and reactive astrocytosis or cerebellar and brainstem hypoplasia and microdysgenesis. Conclusions Mutations in COQ4 cause an autosomal recessive lethal neonatal mitochondrial encephalomyopathy associated with a founder mutation in the Ashkenazi Jewish population. The early mortality in our cohort suggests that COQ4 is an essential component of the multisubunit complex required for CoQ10 biosynthesis.


Document Type: Article
Source: Scopus




Dong-Si, T.a , Gheuens, S.a , Gangadharan, A.a , Wenten, M.a , Philip, J.b , McIninch, J.b , Datta, S.b , Richert, N.c , Bozic, C.a , Bloomgren, G.a , Richman, S.a , Weber, T.d , Clifford, D.B.e
Predictors of survival and functional outcomes in natalizumab-associated progressive multifocal leukoencephalopathy
(2015) Journal of NeuroVirology, 21 (6), pp. 637-644. 

DOI: 10.1007/s13365-015-0316-4


a Drug Safety and Risk Management, Biogen Idec Inc., 225 Binney Street, Cambridge, MA, United States
b Data Sciences, Biogen Idec Inc., Cambridge, MA, United States
c Neurology Research and Development, Biogen Idec Inc., Cambridge, MA, United States
d Marienkrankenhaus, Academic Teaching Hospital, University of Hamburg, Hamburg, Germany
e Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States


Abstract
Natalizumab, a highly effective therapy for relapsing-remitting multiple sclerosis, is associated with a risk of progressive multifocal leukoencephalopathy (PML). The objective of this analysis was to examine factors predicting survival in a large natalizumab-associated PML global population. Patients with natalizumab-associated PML identified through postmarketing surveillance were followed up for up to 24 months using a structured questionnaire completed by treating physicians. Demographic and clinical characteristics, JC viral load, magnetic resonance imaging (MRI) results, and Expanded Disability Status Scale (EDSS) and Karnofsky Performance Scale (KPS) scores were compared in survivors and nonsurvivors. Kaplan-Meier analysis was used to model survival function. Among the 336 patients included in this analysis, 76 % survived, with mean follow-up time from PML diagnosis of 16.1 months for survivors; mean time from diagnosis to death was 4.7 months for nonsurvivors. Survivors were significantly younger at diagnosis, had significantly lower EDSS scores and higher KPS scores prior to PML diagnosis, and had significantly lower cerebrospinal fluid JC viral load at the time of diagnosis. Patients with less extensive disease on MRI at diagnosis had a higher survival rate than those with widespread disease. Survivors generally had less functional disability pre-PML, at PML diagnosis, and in subsequent months. In survivors, functional disability appeared to stabilize approximately 6 months post-PML diagnosis. In this analysis, younger age at diagnosis, less functional disability prior to PML diagnosis, lower JC viral load at diagnosis, and more localized brain involvement by MRI at the time of diagnosis appeared to predict improved survival in natalizumab-associated PML. © 2015, The Author(s).


Author Keywords
Expanded Disability Status Scale;  Karnofsky Performance Scale;  Natalizumab;  Progressive multifocal leukoencephalopathy;  Survival


Document Type: Article
Source: Scopus




Toomey, M.B.a , Collins, A.M.b , Frederiksen, R.c , Cornwall, M.C.c , Timlin, J.A.b , Corbo, J.C.a
A complex carotenoid palette tunes avian colour vision
(2015) Journal of the Royal Society Interface, 12 (111), art. no. 20150563, . 

DOI: 10.1098/rsif.2015.0563


a Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, United States
b Bioenergy and Defense Technologies, Sandia National Laboratories, Albuquerque, NM, United States
c Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA, United States


Abstract
The brilliantly coloured cone oil droplets of the avian retina function as long-pass cut-off filters that tune the spectral sensitivity of the photoreceptors and are hypothesized to enhance colour discrimination and improve colour constancy. Although it has long been known that these droplets are pigmented with carotenoids, their precise composition has remained uncertain owing to the technical challenges of measuring these very small, dense and highly refractile optical organelles. In this study, we integrated results from high-performance liquid chromatography, hyperspectral microscopy and microspectrophotometry to obtain a comprehensive understanding of oil droplet carotenoid pigmentation in the chicken (Gallus gallus). We find that each of the four carotenoid-containing droplet types consists of a complex mixture of carotenoids, with a single predominant carotenoid determining the wavelength of the spectral filtering cut-off. Consistent with previous reports, we find that the predominant carotenoid type in the oil droplets of long-wavelength-sensitive, medium-wavelength-sensitive and short-wavelength-sensitive type 2 cones are astaxanthin, zeaxanthin and galloxanthin, respectively. In addition, the oil droplet of the principal member of the double cone contains a mixture of galloxanthin and two hydroxycarotenoids (lutein and zeaxanthin). Short-wavelength-absorbing apocarotenoids are present in all of the droplet types, providing filtering of light in a region of the spectrum where filtering by hydroxy- and ketocarotenoids may be incomplete. Thus, birds rely on a complex palette of carotenoid pigmentswithin their cone oil droplets to achieve finely tuned spectral filtering. © 2015 The Author(s) Published by the Royal Society. All rights reserved.


Author Keywords
Carotenoid;  Hyperspectral microscopy;  Microspectrophotometry;  Vision


Document Type: Article
Source: Scopus




Freedland, K.E.a , Carney, R.M.a , Rich, M.W.b , Steinmeyer, B.C.b , Rubin, E.H.a
Cognitive behavior therapy for depression and self-care in heart failure patients a randomized clinical trial
(2015) JAMA Internal Medicine, 175 (11), pp. 1773-1782. 

DOI: 10.1001/jamainternmed.2015.5220


a Department of Psychiatry, Washington University School of Medicine, 4320 Forest Park Ave, Ste 301, St Louis, MO, United States
b Department of Medicine, Washington University School of Medicine, St Louis, MI, United States


Abstract
IMPORTANCE Depression and inadequate self-care are common and interrelated problems that increase the risks of hospitalization and mortality in patients with heart failure (HF). OBJECTIVE To determine the efficacy of an integrative cognitive behavior therapy (CBT) intervention for depression and HF self-care. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial with single-blind outcome assessments. Eligible patients were enrolled atWashington University Medical Center in St Louis between January 4, 2010, and June 28, 2013. The primary data analyses were conducted in February 2015. The participants were 158 outpatients in New York Heart Association Class I, II, and III heart failure with comorbid major depression. INTERVENTIONS Cognitive behavior therapy delivered by experienced therapists plus usual care (UC), or UC alone. Usual care was enhanced in both groups with a structured HF education program delivered by a cardiac nurse. MAIN OUTCOMES AND MEASURES The primary outcomewas severity of depression at 6 months as measured by the Beck Depression Inventory. The Self-Care of Heart Failure Index Confidence and Maintenance subscales were coprimary outcomes. Secondary outcomes included measures of anxiety, depression, physical functioning, fatigue, social roles and activities, and quality of life. Hospitalizations and deaths were exploratory outcomes. RESULTS One hundred fifty-eight patients were randomized to UC (n = 79) or CBT (n = 79). Within each arm, 26 (33%) of the patients were taking an antidepressant at baseline. One hundred thirty-two (84%) of the participants completed the 6-month posttreatment assessments; 60 (76%) of the UC and 58 (73%) of the CBT participants completed every follow-up assessment (P = .88). Six-month depression scores were lower in the CBT than the UC arm on the Beck Depression Inventory (BDI-II) (12.8 [10.6] vs 17.3 [10.7]; P = .008). Remission rates differed on the BDI-II (46%vs 19%; number needed to treat [NNT] = 3.76; 95%CI, 3.62-3.90; P .001) and the Hamilton Depression Scale (51% vs 20%; NNT = 3.29; 95%CI, 3.15-3.43; P .001). The groups did not differ on the Self-Care Maintenance or Confidence subscales. The mean (SD) Beck Depression Inventory scores 6 months after randomization were lower in the CBT (12.8 [10.6]) than the UC arm (17.3 [10.7]), P = .008. There were no statistically significant differences between the groups on the Self-Care Maintenance or Confidence subscale scores or on physical functioning measures. Anxiety and fatigue scores were lower and mental- and HF-related quality of life and social functioning scores were higher at 6 months in the CBT than the UC arm, and there were fewer hospitalizations in the intervention than the UC arm. CONCLUSIONS AND RELEVANCE A CBT intervention that targets both depression and heart failure self-care is effective for depression but not for HF self-care or physical functioning relative to enhanced UC. Additional benefits include reduced anxiety and fatigue, improved social functioning, and better health-related quality of life. Copyright © 2015 American Medical Association. All rights reserved.


Document Type: Article
Source: Scopus




Cioe, P.A.a g , Baker, J.b , Kojic, E.M.c , Onen, N.d , Hammer, J.e , Patel, P.f , Kahler, C.W.a
Elevated soluble CD14 and lower D-dimer are associated with cigarette smoking and heavy episodic alcohol use in persons living with HIV
(2015) Journal of Acquired Immune Deficiency Syndromes, 70 (4), pp. 400-405. 


a Center for Alcohol and Addiction Studies, Brown University School of Public Health, Box G-S121-4, Providence, RI, United States
b Department of Medicine, University of Minnesota, Hennepin County Medical Center, Minneapolis, MN, United States
c Department of Infectious Disease, Brown University, Providence, RI, United States
d Washington University School of Medicine in St. Louis, St. Louis, MO, United States
e Denver Infectious Disease Consultants, Denver, CO, United States
f Centers for Disease Control and Prevention, Atlanta, GA, United States


Abstract
Background: Persons living with HIV are at increased risk for cardiovascular disease in part because of persistent inflammation and coagulation activation. Methods: We examined whether smoking and heavy episodic alcohol use (defined as 5 or more drinks on one occasion) were associated with greater monocyte activation (soluble CD14) and coagulation (D-dimer) in participants in the Study to Understand the Natural History of HIV and AIDS in the Era of Effective Therapy (the "SUN" Study), a prospective observational cohort. Results: Using regression analysis (n = 689), current smoking compared with nonsmoking was associated with significantly elevated soluble CD14 (B = 135.57, 95% confidence interval: 84.95 to 186.19, P < 0.001), whereas heavy alcohol use compared with nonheavy use was associated with significantly lower D-dimer levels (B = -0.059, 95% confidence interval: -0.102 to -0.016, P = 0.007). Conclusions: Smoking cessation should be encouraged by HIV care providers to improve mortality outcomes from all causes of death, particularly cardiovascular disease. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Author Keywords
Alcohol;  Biomarkers;  Cardiovascular disease;  D-dimer;  HIV;  SCD14;  Smoking


Document Type: Article
Source: Scopus




Yarbrough, C.K.a , Ong, C.J.b , Beyer, A.B.e , Lipsey, K.c , Derdeyn, C.P.a b d
Endovascular Thrombectomy for Anterior Circulation Stroke: Systematic Review and Meta-Analysis
(2015) Stroke, 46 (11), pp. 3177-3183. 

DOI: 10.1161/STROKEAHA.115.009847


a Department of Neurological Surgery, Washington University School of Medicine, Campus Box 8131, 510 S Kingshighway Blvd, St. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Bernard Becker Medical Library, Washington University School of Medicine, St. Louis, MO, United States
d Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
e Washington University School of Medicine, St. Louis, MO, United States


Abstract
Background and Purpose-Stroke affects ≈700 000 patients annually. Recent randomized controlled trials comparing endovascular thrombectomy (ET) with medical therapy, including intravenous thrombolysis (IVT) with tissue-type plasminogen activator, have shown effectiveness of ET for some stroke patients. The study objective is to evaluate the effect of ET on good outcome in stroke patients. Methods-We searched PubMed, Embase, Web of Science, SCOPUS, ClinicalTrials.gov, and Cochrane databases to identify original research publications between 1996 and 2015 that (1) reported clinical outcomes in patients for stroke at 90 days with the modified Rankin Scale; (2) included at least 10 patients per group; (3) compared outcome with a control arm, and (4) included anterior circulation strokes in each arm. Two authors reviewed articles for inclusion independently. Results-Nine of 23 809 studies met inclusion criteria. In primary analysis, ET was associated with increased odds for good outcome (odds ratio [OR], 1.75; 95% confidence interval [CI], 1.20-2.54). In secondary analysis, younger patients (OR, 1.85; 95% CI, 1.50-2.28), older patients (OR, 1.93; 95% CI, 1.10-3.37), patients receiving intravenous thrombolysis (OR, 1.83; 95% CI, 1.46-2.31), patients with worse strokes (OR, 2.23; 95% CI, 1.56-3.18), and patients with more moderate strokes (OR, 1.72; 95% CI, 1.36-2.18) had increased odds for good outcome. Symptomatic intracranial hemorrhage and mortality were similar between ET and control patients. No evidence of publication bias was seen. Conclusions-ET improves good outcomes after anterior circulation stroke. ET should be strongly considered for all patients presenting within 6 hours of onset with a stroke affecting a proximal, anterior circulation vessel without a contraindication to ET. © 2015 American Heart Association, Inc.


Author Keywords
intracranial hemorrhage;  meta-analysis;  review, systematic;  stroke;  thrombectomy


Document Type: Article
Source: Scopus




Grucza, R.A.a , Hur, M.a , Agrawal, A.a , Krauss, M.J.a , Plunk, A.D.b , Cavazos-Rehg, P.A.a , Chaloupka, F.J.c , Bierut, L.J.a d
Erratum to "A reexamination of medical marijuana policies in relation to suicide risk" [Drug Alcohol Depend. 152 (2015) 68-72]
(2015) Drug and Alcohol Dependence, 156, art. no. 5752, p. 316. 

DOI: 10.1016/j.drugalcdep.2015.07.003


a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA, United States
c Department of Economics and Health Policy Center, University of Illinois at Chicago, Chicago, IL, United States
d Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States


Document Type: Erratum
Source: Scopus




Omrani, A.a b j , Van Der Vaart, T.a b c , Mientjes, E.a b , Van Woerden, G.M.a b , Hojjati, M.R.a d , Li, K.W.e , Gutmann, D.H.f , Levelt, C.N.g , Smit, A.B.e , Silva, A.J.h , Kushner, S.A.b i , Elgersma, Y.a b
HCN channels are a novel therapeutic target for cognitive dysfunction in Neurofibromatosis type 1
(2015) Molecular Psychiatry, 20 (11), pp. 1311-1321. Cited 1 time.

DOI: 10.1038/mp.2015.48


a Department of Neuroscience, Erasmus Medical Center, PO Box 2040, CA Rotterdam, Netherlands
b ENCORE Center for Neurodevelopmental Disorders, Erasmus Medical Center, Rotterdam, Netherlands
c Department of Pediatrics, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, Netherlands
d Department of Physiology, Shahrekord University of Medical Sciences, Shahrekord, Iran
e Department of Molecular and Cellular Neurobiology, CNCR, Neuroscience Campus Amsterdam, VU University, Amsterdam, Netherlands
f Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
g Department of Molecular Visual Plasticity, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam, Netherlands
h Department of Neurobiology, Brain Research Institute, University of California Los Angeles, Los Angeles, CA, United States
i Department of Psychiatry, Erasmus Medical Center, Rotterdam, Netherlands
j Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands


Abstract
Cognitive impairments are a major clinical feature of the common neurogenetic disease neurofibromatosis type 1 (NF1). Previous studies have demonstrated that increased neuronal inhibition underlies the learning deficits in NF1, however, the molecular mechanism underlying this cell-type specificity has remained unknown. Here, we identify an interneuron-specific attenuation of hyperpolarization-activated cyclic nucleotide-gated (HCN) current as the cause for increased inhibition in Nf1 mutants. Mechanistically, we demonstrate that HCN1 is a novel NF1-interacting protein for which loss of NF1 results in a concomitant increase of interneuron excitability. Furthermore, the HCN channel agonist lamotrigine rescued the electrophysiological and cognitive deficits in two independent Nf1 mouse models, thereby establishing the importance of HCN channel dysfunction in NF1. Together, our results provide detailed mechanistic insights into the pathophysiology of NF1-associated cognitive defects, and identify a novel target for clinical drug development. © 2015 Macmillan Publishers Limited Molecular Psychiatry.


Document Type: Article
Source: Scopus




Chardon, J.W.a d e , Smith, A.C.b , Woulfe, J.c d , Pena, E.f , Rakhra, K.d f , Dennie, C.d f g , Beaulieu, C.b , Huang, L.b , Schwartzentruber, J.h , Hawkins, C.i , Harms, M.B.j , Dojeiji, S.k , Zhang, M.d , Majewski, J.l , Bulman, D.E.b m , Boycott, K.M.a b , Dyment, D.A.a b , Boycott, K.n , Friedman, J.o , Michaud, J.p , Bernier, F.q , Brudno, M.r , Fernandez, B.s , Knoppers, B.t , Samuels, M.p , Scherer, S.r
LIMS2 mutations are associated with a novel muscular dystrophy, severe cardiomyopathy and triangular tongues
(2015) Clinical Genetics, 88 (6), pp. 558-564. 

DOI: 10.1111/cge.12561


a Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada
b Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada
c Department of Pathology, The Ottawa Hospital, Ottawa, ON, Canada
d Ottawa Hospital Research Institute, Ottawa, ON, Canada
e Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada
f Department of Medical Imaging, The Ottawa Hospital, Ottawa, ON, Canada
g University of Ottawa Heart Institute, Ottawa, ON, Canada
h McGill University and Genome Quebec Innovation Center, Montreal, QC, Canada
i Department of Laboratory Medicine and Pathobiology, The Hospital for Sick Children, Toronto, ON, Canada
j Department of Neurology and Hope Center for Neurological Disorders, Washington University, Saint Louis, MO, United States
k The Ottawa Hospital Rehabilitation Center, Ottawa, ON, Canada
l Department of Human Genetics, McGill University, Montreal, QC, Canada
m Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada
n University of Ottawa, Canada
o University of British Columbia, Canada
p University of Montreal, Canada
q University of Calgary, Canada
r University of Toronto, Canada
s Memorial University, Canada
t McGill University, Canada


Abstract
Limb girdle muscular dystrophy (LGMD) is a heterogeneous group of genetic disorders leading to progressive muscle degeneration and often associated with cardiac complications. We present two adult siblings with childhood-onset of weakness progressing to a severe quadriparesis with the additional features of triangular tongues and biventricular cardiac dysfunction. Whole exome sequencing identified compound heterozygous missense mutations that are predicted to be pathogenic in LIMS2. Biopsy of skeletal muscle demonstrated disrupted immunostaining of LIMS2. This is the first report of mutations in LIMS2 and resulting disruption of the integrin linked kinase (ILK)-LIMS-parvin complex associated with LGMD. © 2015 John Wiley & Sons A/S.


Author Keywords
Cardiomyopathy;  Exome sequencing;  Limb girdle muscular dystrophy;  LIMS2


Document Type: Article
Source: Scopus




Lieu, J.E.C.
Management of Children with Unilateral Hearing Loss
(2015) Otolaryngologic Clinics of North America, . Article in Press. 

DOI: 10.1016/j.otc.2015.07.006


Department of Otolaryngology - Head and Neck Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8115, St Louis, MO 63110, USA


Abstract
Children with impaired hearing in one ear (unilateral hearing loss [UHL]) and normal hearing in the other ear experience challenges in understanding speech in noisy backgrounds and localizing the source of sounds in 3-dimensional space. They are at a high risk for speech and language delay and need educational help in school. However, definitive evidence of benefit from amplification is currently lacking to recommend placement of hearing aids or cochlear implants in all young children with UHL. Management of UHL in children should be guided by the child's development, performance in school, and personal/family values and preferences. © 2015 Elsevier Inc.


Author Keywords
Amplification;  Children;  Quality of life;  Speech-language development;  Unilateral hearing loss


Document Type: Article in Press
Source: Scopus




Kim, J.a b , Yoon, H.a b , Horie, T.c , Burchett, J.M.b , Restivo, J.L.b , Rotllan, N.d , Ramírez, C.M.d , Verghese, P.B.b , Ihara, M.e , Hoe, H.-S.f , Esau, C.g , Fernández-Hernando, C.d , Holtzman, D.M.b , Cirrito, J.R.b , Ono, K.c , Kim, J.a b
Microrna-33 regulates apoe lipidation and amyloid-β metabolism in the brain
(2015) Journal of Neuroscience, 35 (44), pp. 14717-14726. 

DOI: 10.1523/JNEUROSCI.2053-15.2015


a Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, United States
b Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
c Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
d Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, United States
e Department of Stroke and Cerebrovascular Diseases, National Cerebral and Cardiovascular Center, Osaka, Japan
f Departments of Neuroscience and Neurology, Georgetown University Medical Center, Washington, DC, United States
g Regulus Therapeutics, San Diego, CA, United States


Abstract
Dysregulation of amyloid-β (Aβ) metabolism is critical for Alzheimer’s disease (AD) pathogenesis. Mounting evidence suggests that apolipoprotein E (ApoE) is involved in Aβ metabolism. ATP-binding cassette transporter A1 (ABCA1) is a key regulator of ApoE lipidation, which affects Aβ levels. Therefore, identifying regulatory mechanisms of ABCA1 expression in the brain may provide new therapeutic targets for AD. Here, we demonstrate that microRNA-33 (miR-33) regulates ABCA1 and Aβ levels in the brain. Overexpression of miR-33 impaired cellular cholesterol efflux and dramatically increased extracellular Aβ levels by promoting Aβ secretion and impairing Aβ clearance in neural cells. In contrast, genetic deletion of mir-33 in mice dramatically increased ABCA1 levels and ApoE lipidation, but it decreased endogenous Aβ levels in cortex. Most importantly, pharmacological inhibition of miR-33 via antisense oligonucleotide specifically in the brain markedly decreased Aβ levels in cortex of APP/PS1 mice, representing a potential therapeutic strategy for AD. © 2015 the authors.


Author Keywords
ABCA1;  Abeta;  Alzheimer’s disease;  ApoE;  MiR-33


Document Type: Article
Source: Scopus




Wilby, D.a b c , Toomey, M.B.d , Olsson, P.e , Frederiksen, R.f , Cornwall, M.C.f , Oulton, R.b , Kelber, A.e , Corbo, J.C.d , Roberts, N.W.a c
Optics of cone photoreceptors in the chicken (Gallus gallus domesticus)
(2015) Journal of the Royal Society Interface, 12 (111), art. no. 20150591, . 

DOI: 10.1098/rsif.2015.0591


a School of Biological Sciences, University of Bristol, Bristol Life Sciences Building, Tyndall Avenue, Bristol, United Kingdom
b H.H. Wills Physics Laboratory, University of Bristol, Tyndall Avenue, Bristol BS8 1TL, United Kingdom
c Bristol Centre for Functional Nanomaterials, Centre for Nanoscience and Quantum Information, University of Bristol, Tyndall Avenue, Bristol, United Kingdom
d Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, United States
e Vision Group, Department of Biology, Lund University, Sölvegatan 35, Lund, Sweden
f Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA, United States


Abstract
Vision is the primary sensory modality of birds, and its importance is evident in the sophistication of their visual systems. Coloured oil droplets in the cone photoreceptors represent an adaptation in the avian retina, acting as long-pass colour filters. However, we currently lack understanding of how the optical properties and morphology of component structures (e.g. oil droplet, mitochondrial ellipsoid and outer segment) of the cone photoreceptor influence the transmission of light into the outer segment and the ultimate effect they have on receptor sensitivity. In this study, we use data from microspectrophotometry, digital holographic microscopy and electron microscopy to inform electromagnetic models of avian cone photoreceptors to quantitatively investigate the integrated optical function of the cell. We find that pigmented oil droplets primarily function as spectral filters, not light collection devices, although the mitochondrial ellipsoid improves optical coupling between the inner segment and oil droplet. In contrast, unpigmented droplets found in violet-sensitive cones double sensitivity at its peak relative to other cone types. Oil droplets and ellipsoids both narrow the angular sensitivity of single cone photoreceptors, but not as strongly as those in human cones. & 2015 The Authors.


Author Keywords
Birds;  Colour vision;  Cone;  FDTD;  Optics;  Photoreceptors


Document Type: Article
Source: Scopus




Godzik, J.a , Ravindra, V.M.b , Ray, W.Z.c , Eskandari, R.d , Dailey, A.T.b
Primary repair of open neural tube defect in adulthood: Case example and review of management strategies
(2015) Spine Journal, 15 (11), pp. e57-e63. 

DOI: 10.1016/j.spinee.2015.07.463


a Department of Neurosurgery, Barrow Neurological Institute, 350 West Thomas Road, Phoenix, AZ, United States
b Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, 175 N. Medical Drive East, Salt Lake City, UT, United States
c Department of Neurosurgery, Washington University in St. Louis, 660 S. Euclid, Box 8057, St. Louis, MO, United States
d Department of Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas Street, CSB 301, MSC 606, Charleston, SC, United States


Abstract
Background Context Neural tube defects are congenital malformations that develop when the neural plate fails to close during embryogenesis. The most common open neural tube defect, myelomeningocele (MMC), is declining in frequency in North America. If identified, an MMC must be closed in the perinatal period to prevent lethal complications. Lesions presenting in older adults are, thus, very uncommon. Purpose The purpose of this study was to describe the surgical management of an adult with an unrepaired ulcerated lumbosacral MMC who presented with persistent cerebrospinal fluid (CSF) leakage and to review the management strategies for adult patients with unrepaired MMC. Study Design A case report was used for this study. Methods The patient was a 62-year-old woman with an unrepaired ulcerated lumbosacral MMC and associated lower extremity weakness. She sought medical care for persistent lumbar tenderness and ulceration after sustaining a fall 4 months before admission. Physical and radiological assessment revealed a lumbosacral MMC at the L5 and S1 levels and a tethered cord. Surgical resection of the placode and de-tethering were performed. Results One week after repair of the lumbosacral MMC, the patient was readmitted for management of continued CSF leakage and hydrocephalus, requiring external ventricular drainage, wound revision, and placement of lumboperitoneal shunt. The patient experienced complete resolution of back pain without additional episodes of CSF leakage. Conclusions This rare case and review of management strategies suggests that proper surgical management of open MMC in adulthood can successfully be performed and improve patient symptoms and prevent further complications. © 2015 Elsevier Inc.


Author Keywords
Cerebrospinal fluid;  Hydrocephalus;  Lumboperitoneal shunt;  Myelomeningocele;  Spinal dysraphism;  Tethered cord


Document Type: Article
Source: Scopus




Reynolds, M.R.a b e , Sweeney, K.J.b , Crilly, S.M.b , Farrell, M.c , Jaffe, E.S.d , Javadpour, M.b
Rapid, de novo development of isolated intracranial Rosai-Dorfman Disease: A case report
(2015) British Journal of Neurosurgery, 29 (1), pp. 82-84. 

DOI: 10.3109/02688697.2014.950634


a Department of Neurological Surgery, Washington University in St. Louis, St. Louis, MO, United States
b Department of Neurological Surgery, National Centre for Neurosurgery, Beaumont Hospital, Dublin, Ireland
c Department of Neuropathology, National Centre for Neurosurgery, Beaumont Hospital, Dublin, Ireland
d Department of Pathology, National Institute of Health, National Cancer Institute, Bethesda, MD, United States
e Department of Neurological Surgery, Barnes-Jewish Hospital, Campus Box 8057, 660 South Euclid Avenue, St. Louis, MO, United States


Abstract
Isolated intracranial Rosai-Dorfman Disease is rare. Here, we describe a patient who developed an asymptomatic, right parietal RDD lesion over 18 months while being followed radiographically for another brain lesion. To our knowledge, rapid, de novo radiographic formation of isolated intracranial RDD has never been reported in an asymptomatic patient. Copyright © 2014 The Neurosurgical Foundation.


Author Keywords
De novo development;  Intracranial;  Isolated;  Rosai-Dorfman Disease;  Sinus histiocytosis with massive lymphadenopathy


Document Type: Article
Source: Scopus




Porto, A.a , Sebastião, H.b , Pavan, S.E.c d , Vandeberg, J.L.e , Marroig, G.b , Cheverud, J.M.f
Rate of evolutionary change in cranial morphology of the marsupial genus Monodelphis is constrained by the availability of additive genetic variation
(2015) Journal of Evolutionary Biology, 28 (4), pp. 973-985. 

DOI: 10.1111/jeb.12628


a Department of Biology, Washington University in St Louis, St Louis, MO, United States
b Laboratório de Evolução de Mamíferos, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, Brazil
c Division of Vertebrate Zoology (Mammalogy), American Museum of Natural History, New York, NY, United States
d Department of Biology, City College of New York, City University of New York, New York, NY, United States
e Department of Genetics and Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, United States
f Department of Biology, Loyola University Chicago, Chicago, IL, United States


Abstract
We tested the hypothesis that the rate of marsupial cranial evolution is dependent on the distribution of genetic variation in multivariate space. To do so, we carried out a genetic analysis of cranial morphological variation in laboratory strains of Monodelphis domestica and used estimates of genetic covariation to analyse the morphological diversification of the Monodelphis brevicaudata species group. We found that within-species genetic variation is concentrated in only a few axes of the morphospace and that this strong genetic covariation influenced the rate of morphological diversification of the brevicaudata group, with between-species divergence occurring fastest when occurring along the genetic line of least resistance. Accounting for the geometric distribution of genetic variation also increased our ability to detect the selective regimen underlying species diversification, with several instances of selection only being detected when genetic covariances were taken into account. Therefore, this work directly links patterns of genetic covariation among traits to macroevolutionary patterns of morphological divergence. Our findings also suggest that the limited distribution of Monodelphis species in morphospace is the result of a complex interplay between the limited dimensionality of available genetic variation and strong stabilizing selection along two major axes of genetic variation. © 2015 European Society For Evolutionary Biology.


Author Keywords
Constraints;  Mammals;  Morphospace;  Quantitative genetics


Document Type: Article
Source: Scopus




Yap, M.J.a , Sibley, D.E.b , Balota, D.A.c , Ratcliff, R.d , Rueckl, J.e
Responding to nonwords in the lexical decision task: Insights from the english Lexicon project
(2015) Journal of Experimental Psychology: Learning Memory and Cognition, 41 (3), pp. 597-613. 

DOI: 10.1037/xlm0000064


a Department of Psychology, National University of Singapore, Block AS4, #02-07, Singapore
b Haskins Laboratories, New Haven, CT, United States
c Department of Psychology, Washington University in St. Louis, United States
d Department of Psychology, Ohio State University, United States
e Department of Psychology, University of Connecticut, United States


Abstract
Researchers have extensively documented how various statistical properties of words (e.g., word frequency) influence lexical processing. However, the impact of lexical variables on nonword decisionmaking performance is less clear. This gap is surprising, because a better specification of the mechanisms driving nonword responses may provide valuable insights into early lexical processes. In the present study, item-level and participant-level analyses were conducted on the trial-level lexical decision data for almost 37,000 nonwords in the English Lexicon Project in order to identify the influence of different psycholinguistic variables on nonword lexical decision performance and to explore individual differences in how participants respond to nonwords. Item-level regression analyses reveal that nonword response time was positively correlated with number of letters, number of orthographic neighbors, number of affixes, and base-word number of syllables, and negatively correlated with Levenshtein orthographic distance and base-word frequency. Participant-level analyses also point to within- and between-session stability in nonword responses across distinct sets of items, and intriguingly reveal that higher vocabulary knowledge is associated with less sensitivity to some dimensions (e.g., number of letters) but more sensitivity to others (e.g., base-word frequency). The present findings provide well-specified and interesting new constraints for informing models of word recognition and lexical decision. © 2014 American Psychological Association.


Author Keywords
Diffusion model;  Ex-gaussian analysis;  Individual differences;  Nonwords;  Visual word recognition


Document Type: Article
Source: Scopus




Cicero, T.J., Ellis, M.S., Harney, J.
Shifting patterns of prescription opioid and heroin abuse in the United States
(2015) New England Journal of Medicine, 373 (18), pp. 1789-1790. 

DOI: 10.1056/NEJMc1505541


Washington University, St. Louis, MO, United States


Document Type: Letter
Source: Scopus




Schechter, E.
The Subject in Neuropsychology: Individuating Minds in the Split-Brain Case
(2015) Mind and Language, 30 (5), pp. 501-525. 

DOI: 10.1111/mila.12088


Philosophy Department, Washington University in St. Louis, One Brookings Drive, St. Louis, MO, United States


Abstract
Many experimental findings with split-brain subjects intuitively suggest that each such subject has two minds. The conceptual and empirical basis of this duality intuition has never been fully articulated. This article fills that gap, by offering a reconstruction of early neuropsychological literature on the split-brain phenomenon. According to that work, the hemispheres operate independently of each other insofar as they interact via the mediation of effection and transduction-via behavior and sensation, essentially. This is how your mind and my mind interact with each other, however, giving rise to the intuition that a split-brain subject has two minds. © 2015 John Wiley & Sons Ltd.


Document Type: Article
Source: Scopus




Rothman, A.L.a , Sevilla, M.B.a , Mangalesh, S.a , Gustafson, K.E.b , Edwards, L.b , Cotten, C.M.b , Shimony, J.S.c , Pizoli, C.E.b , El-Dairi, M.A.a b , Freedman, S.F.a b , Toth, C.A.a d
Thinner Retinal Nerve Fiber Layer in Very Preterm Versus Term Infants and Relationship to Brain Anatomy and Neurodevelopment
(2015) American Journal of Ophthalmology, . Article in Press. 

DOI: 10.1016/j.ajo.2015.09.015


a Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina
b Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina
c Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri
d Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, North Carolina


Abstract
Purpose: To assess retinal nerve fiber layer (RNFL) thickness at term-equivalent age in very preterm (&lt;32 weeks gestational age) vs term-born infant cohorts, and compare very preterm infant RNFL thickness with brain anatomy and neurodevelopment. Design: Cohort study. Methods: RNFL was semi-automatically segmented (1 eye per infant) in 57 very preterm and 50 term infants with adequate images from bedside portable, handheld spectral-domain optical coherence tomography imaging at 37-42 weeks postmenstrual age. Mean RNFL thickness was calculated for the papillomacular bundle (-15 degrees to +15 degrees) and temporal quadrant (-45 degrees to +45 degrees) relative to the fovea-optic nerve axis. Brain magnetic resonance imaging (MRI) scans clinically obtained in 26 very preterm infants were scored for global structural abnormalities by an expert masked to data except for age. Cognitive, language, and motor skills were assessed in 33 of the very preterm infants at 18-24 months corrected age. Results: RNFL was thinner for very preterm vs term infants at the papillomacular bundle ([mean ± standard deviation] 61 ± 17 vs 72 ± 13 μm, P &lt; .001) and temporal quadrant (72 ± 21 vs 82 ± 16 μm, P = .005). In very preterm infants, thinner papillomacular bundle RNFL correlated with higher global brain MRI lesion burden index (R2 = 0.35, P = .001) and lower cognitive (R2 = 0.18, P = .01) and motor (R2 = 0.17, P = .02) scores. Relationships were similar for temporal quadrant. Conclusions: Thinner RNFL in very preterm infants relative to term-born infants may relate to brain structure and neurodevelopment. © 2015 Elsevier Inc.


Document Type: Article in Press
Source: Scopus




Arias, E.J.a , Vajapey, S.a , Reynolds, M.R.a , Chicoine, M.R.a , Rich, K.M.a , Dacey, R.G.a , Dorward, I.G.a , Derdeyn, C.P.b c , Moran, C.J.a b c , Cross, D.T.a b c , Zipfel, G.J.a b , Dhar, R.b
Utility of Screening for Cerebral Vasospasm Using Digital Subtraction Angiography
(2015) Stroke, 46 (11), pp. 3137-3141. 

DOI: 10.1161/STROKEAHA.115.010081


a Department of Neurological Surgery, Washington University School of Medicine, Box 8057, 660 South Euclid Ave, St Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
c Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States


Abstract
Background and Purpose-Cerebral arterial vasospasm (CVS) is a common complication of aneurysmal subarachnoid hemorrhage strongly associated with neurological deterioration and delayed cerebral ischemia (DCI). The utility of screening for CVS as a surrogate for early detection of DCI, especially in patients without clinical signs of DCI, remains uncertain. Methods-We performed a retrospective analysis of 116 aneurysmal subarachnoid hemorrhage patients who underwent screening digital subtraction angiography to determine the association of significant CVS and subsequent development of DCI. Patients were stratified into 3 groups: (1) no symptoms of DCI before screening, (2) ≥1 episodes of suspected DCI symptoms before screening, and (3) unable to detect symptoms because of poor examination. Results-Patients asymptomatic before screening had significantly lower rates of CVS (18%) compared with those with transient symptoms of DCI (60%; P<0.0001). None of the 79 asymptomatic patients developed DCI after screening, regardless of digital subtraction angiography findings, compared with 56% of those with symptoms (P<0.0001). Presence of CVS was significantly associated with DCI in those with transient symptoms and in those whose examinations did not permit clear assessment (odds ratio 16.0, 95% confidence interval 2.2-118.3, P=0.003). Conclusions-Patients asymptomatic before screening have low rates of CVS and seem to be at negligible risk of developing DCI. Routine screening of asymptomatic patients seems to have little utility. Screening may still be considered in patients with possible symptoms of DCI or those with examinations too poor to clinically detect symptoms because finding CVS may be useful for risk stratification and guiding management. © 2015 American Heart Association, Inc.


Author Keywords
cerebral vasospasm;  delayed cerebral ischemia;  digital subtraction angiography;  screening;  subarachnoid hemorrhage

 


Document Type: Article
Source: Scopus

November 11, 2015

Bui, D.C., Myerson, J., Hale, S.
Age-Related Slowing in Online Samples
(2015) Psychological Record, 65 (4), pp. 649-655. 

DOI: 10.1007/s40732-015-0135-2


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


Abstract
Three experiments assessed the use of online samples recruited from the Amazon Mechanical Turk (MTurk) worker pool for studying the psychology of aging. The results replicated several. benchmark findings: Older adults’ response times (RTs) improved more with practice, but their asymptotic RTs remained longer than those of the younger adults (Experiment 1); greater age-related declines were observed in visuospatial processing speed than in verbal speed (Experiment 2); and although working memory decreased with age, age was not a significant predictor of working memory once processing speed was statistically controlled (Experiment 3). The present results establish that online samples that include adults up to at least age 70 are easily recruited via MTurk and that the relations among age, speed, and working memory ability in such samples correspond to those typically observed in laboratory settings. These findings are important because using online samples to study aging provides a cost-effective way of collecting data from large samples of participants in a fraction of the time that it takes to conduct similar studies in the laboratory. © 2015, Association for Behavior Analysis International.


Author Keywords
Aging;  Amazon Mechanical Turk;  MTurk;  Processing speed;  Working memory


Document Type: Article
Source: Scopus




Saha, D., Raman, B.
Relating early olfactory processing with behavior: A perspective
(2015) Current Opinion in Insect Science, 12, pp. 54-63. 

DOI: 10.1016/j.cois.2015.09.009


Department of Biomedical Engineering, Washington University in St. Louis, Campus Box 1097, St.Louis, MO, United States


Abstract
A fundamental goal in sensory neuroscience is to understand the rules that govern how neural activity evoked by a stimulus drives the final behavioral outcome. Here, focusing primarily on the insect olfactory system and its first two anatomical stages: olfactory sensory neurons in the insect antenna and their postsynaptic targets in the antennal lobe, we review the current understanding of the relationships between odor-evoked neural activity and behavior. The compiled evidences suggest that these olfactory circuits closer to the sensory periphery may already represent sensory information in a format that is easily translatable to behavior. © 2015 Elsevier Inc. All rights reserved.


Document Type: Article
Source: Scopus




Bei, L.a , Shui, Y.-B.a , Bai, F.a , Nelson, S.K.a , Van Stavern, G.P.a , Beebe, D.C.a b
A test of lens opacity as an indicator of preclinical Alzheimer Disease
(2015) Experimental Eye Research, 140, pp. 117-123. 

DOI: 10.1016/j.exer.2015.03.010


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


Abstract
Previous studies reported that characteristic lens opacities were present in Alzheimer Disease (AD) patients postmortem. We therefore determined whether cataract grade or lens opacity is related to the risk of Alzheimer dementia in participants who have biomarkers that predict a high risk of developing the disease. AD biomarker status was determined by positron emission tomography-Pittsburgh compound B (PET-PiB) imaging and cerebrospinal fluid (CSF) levels of Aβ42. Cognitively normal participants with a clinical dementia rating of zero (CDR = 0; N = 40) or with slight evidence of dementia (CDR = 0.5; N = 2) were recruited from longitudinal studies of memory and aging at the Washington University Knight Alzheimer's Disease Research Center. The age, sex, race, cataract type and cataract grade of all participants were recorded and an objective measure of lens light scattering was obtained for each eye using a Scheimpflug camera. Twenty-seven participants had no biomarkers of Alzheimer dementia and were CDR = 0. Fifteen participants had biomarkers indicating increased risk of AD, two of which were CDR = 0.5. Participants who were biomarker positive were older than those who were biomarker negative. Biomarker positive participants had more advanced cataracts and increased cortical light scattering, none of which reached statistical significance after adjustment for age. We conclude that cataract grade or lens opacity is unlikely to provide a non-invasive measure of the risk of developing Alzheimer dementia. © 2015 Elsevier Ltd.


Author Keywords
Alzheimer Disease biomarkers;  Cataract;  Lens opacity;  Preclinical Alzheimer Disease;  Scheimpflug imaging


Document Type: Article
Source: Scopus




Huff, M.J.a , McNabb, J.b , Hutchison, K.A.b
List blocking and longer retention intervals reveal an influence of gist processing for lexically ambiguous critical lures
(2015) Memory and Cognition, 43 (8), pp. 1193-1207. 

DOI: 10.3758/s13421-015-0533-3


a Department of Psychology, Washington University, One Brookings Drive, CB 1125, St. Louis, MO, United States
b Montana State University, Bozeman, MT, United States


Abstract
In two experiments, we examined veridical and false memory for lists of associates from two meanings (e.g., stumble, trip, harvest, pumpkin, etc.) that converged upon a single, lexically ambiguous critical lure (e.g., fall), in order to compare the activation-monitoring and fuzzy-trace false memory accounts. In Experiment 1, we presented study lists that were blocked or alternated by meaning (within subjects), followed by a free recall test completed immediately or after a 2.5-min delay. Correct recall was greater for blocked than for alternated lists. Critical-lure false recall was greater for blocked lists on an immediate test, whereas both list types produced equivalent false recall on a delayed test. In Experiment 2, lists blocked and alternated by meaning were presented via a between-subjects design, in order to eliminate possible list-type carryover effects. Correct recall replicated the result from Experiment 1; however, blocking lists increased false recall on delayed, but not on immediate, tests. Across the experiments, clustering correct recall by meaning increased across the delay selectively for the alternated lists. Our results suggest that thematic (i.e., gist) processes are influential for false recall, especially following a delay, a pattern consistent with fuzzy-trace theory. © 2015, Psychonomic Society, Inc.


Author Keywords
ARC clustering;  Blocking;  False memory;  Lexical ambiguity;  Retention interval


Document Type: Article
Source: Scopus




Sommers, M.S.a , Tye-Murray, N.b , Barcroft, J.c , Spehar, B.P.b
The Effects of Meaning-Based Auditory Training on Behavioral Measures of Perceptual Effort in Individuals with Impaired Hearing
(2015) Seminars in Hearing, 36 (4), pp. 263-272. 

DOI: 10.1055/s-0035-1564454


a Department of Psychological and Brain Sciences, Washington University in St. Louis, Campus Box 1125, St. Louis, MO, United States
b Department of Otolaryngology, Washington University, School of Medicine, United States
c Department of Romance Languages and Literatures, Washington University, St. Louis, MS, United States


Abstract
There has been considerable interest in measuring the perceptual effort required to understand speech, as well as to identify factors that might reduce such effort. In the current study, we investigated whether, in addition to improving speech intelligibility, auditory training also could reduce perceptual or listening effort. Perceptual effort was assessed using a modified version of the n-back memory task in which participants heard lists of words presented without background noise and were asked to continually update their memory of the three most recently presented words. Perceptual effort was indexed by memory for items in the three-back position immediately before, immediately after, and 3 months after participants completed the Computerized Learning Exercises for Aural Rehabilitation (clEAR), a 12-session computerized auditory training program. Immediate posttraining measures of perceptual effort indicated that participants could remember approximately one additional word compared to pretraining. Moreover, some training gains were retained at the 3-month follow-up, as indicated by significantly greater recall for the three-back item at the 3-month measurement than at pretest. There was a small but significant correlation between gains in intelligibility and gains in perceptual effort. The findings are discussed within the framework of a limited-capacity speech perception system. © 2015 by Thieme Medical Publishers, Inc.


Author Keywords
Auditory training;  cognitive resources;  perceptual effort


Document Type: Article
Source: Scopus




Frazier, T.W.a , Youngstrom, E.A.b , Hardan, A.Y.c , Georgiades, S.d , Constantino, J.N.e , Eng, C.f
Quantitative autism symptom patterns recapitulate differential mechanisms of genetic transmission in single and multiple incidence families
(2015) Molecular Autism, 6 (1), art. no. 58, . 

DOI: 10.1186/s13229-015-0050-z


a Center for Autism (CRS10), Pediatric Institute, Cleveland Clinic, 2801 Martin Luther King Jr. Drive, Cleveland, OH, United States
b Department of Psychology, University of North Carolina at Chapel Hill, Davie Hall CB No3270, 235 E. Cameron Avenue, Chapel Hill, NC, United States
c Department of Psychiatry and Behavioral Science, Stanford University, 401 Quarry Road, Stanford, CA, United States
d Department of Psychiatry and Behavioural Neurosciences, Offord Centre for Child Studies, McMaster University, 555 Sanatorium Rd, Hamilton, ON, Canada
e Department of Psychiatry, Washington University of St. Louis, 660 S. Euclid Avenue, St. Louis, MO, United States
f Genomic Medicine Institute, Taussig Cancer Institute, Stanley Shalom Zielony Institute of Nursing Excellence, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, United States


Abstract
Background: Previous studies have demonstrated aggregation of autistic traits in undiagnosed family members of children with autism spectrum disorder (ASD), which has significant implications for ASD risk in their offspring. This study capitalizes upon a large, quantitatively characterized clinical-epidemiologic family sample to establish the extent to which family transmission pattern and sex modulate ASD trait aggregation. Methods: Data were analyzed from 5515 siblings (2657 non-ASD and 2858 ASD) included in the Interactive Autism Network. Autism symptom levels were measured using the Social Responsiveness Scale (SRS) and by computing Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) symptom scores based on items from the SRS and Social Communication Questionnaire. Generalized estimating equation models evaluated the influence of family incidence types (single versus multiple incidence families; male-only ASD-affected families versus families with female ASD-affected children), diagnostic group (non-ASD children with and without a history of language delay with autistic speech and ASD-affected children), and sibling sex on ASD symptom levels. Results: Non-ASD children manifested elevated ASD symptom burden when they were members of multiple incidence families - this effect was accentuated for male children in female ASD-containing families - or when they had a history of language delay with autistic qualities of speech. In this sample, ASD-affected children from multiple incidence families had lower symptom levels than their counterparts in single incidence families. Recurrence risk for ASD was higher for children from female ASD-containing families than for children from male-only families. Conclusions: Sex and patterns of family transmission modulate the risk of autism symptom burden in undiagnosed siblings of ASD-affected children. Identification of these symptoms/traits and their molecular genetic causes may have significant implications for genetic counseling and for understanding inherited liabilities that confer risk for ASD in successive generations. Autism symptom elevations were more dramatic in non-ASD children from multiple incidence families and those with a history of language delay and autistic qualities of speech, identifying sub-groups at substantially greater transmission risk. Higher symptom burden and greater recurrence in children from female ASD-containing families indicate that familial aggregation patterns are further qualified by sex-specific thresholds, supportive of the notion that females require a higher burden of deleterious liability to cross into categorical ASD diagnosis. © 2015 Frazier et al.


Author Keywords
Autism spectrum disorder;  Autism symptoms;  DSM-5;  Genetic epidemiology;  Multiple incidence families


Document Type: Article
Source: Scopus




Yamada, K.a , Patel, T.K.b , Hochgräfe, K.c , Mahan, T.E.b , Jiang, H.b , Stewart, F.R.b , Mandelkow, E.-M.c d e , Holtzman, D.M.b
Analysis of in vivo turnover of tau in a mouse model of tauopathy
(2015) Molecular Neurodegeneration, 10 (1), art. no. 55, . 

DOI: 10.1186/s13024-015-0052-5


a Department of Neuropathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
b Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University, School of Medicine, St. Louis, MO, United States
c MPI for Neurological Research, Hamburg Outstation, C/o DESY, Notkestr. 85, Hamburg, Germany
d DZNE (German Ctr Neurodegen. Diseases), Ludwig-Erhard-Allee 2, Bonn, Germany
e CAESAR Research Center, Ludwig-Erhard-Allee 2, Bonn, Germany


Abstract
Background: Intracellular accumulation of tau as neurofibrillary tangles (NFTs) is the hallmark of Alzheimer's disease (AD) as well as in other tauopathies. Tau is present not only in the cytoplasm but also in the extracellular space such as cerebrospinal fluid (CSF) and brain interstitial fluid (ISF). Although clearance is one critical parameter leading to such intracellular/extracellular tau accumulation, in vivo turnover of tau has not been well characterized. The current study has attempted to precisely determine in vivo turnover rates of tau utilizing tet-off regulatable mice. In particular, we assessed intracellular tau and extracellular tau, soluble tau, insoluble tau and phosphorylated tau at certain sites utilizing a combination of in vivo microdialysis, biochemical analysis and specific ELISAs recognizing each species. To examine the effect of a tauopathy-associated mutation on tau clearance, half-lives of various tau species were compared between the mice with a FTDP-17 mutation that induces β-sheet formation, ΔK280 mutation (pro-aggregant mice) and control mice with additional β-sheet breaking mutations (anti-aggregant mice). Results: Here we report that tau is metabolized at much slower turnover rates in vivo than in cell culture. We found that insoluble tau in pro-aggregant mice had a significantly slower half-life (t1/2 =
34.2 days) than soluble tau (t1/2 = 9.7 days). In contrast, soluble tau phosphorylated in the proline rich region was cleared faster than total soluble tau. When comparing pro-aggregant mice to anti-agregant mice, turnover rates of soluble tau species were not significantly different. Conclusions: The current study provides a comprehensive description of in vivo turnover of various tau species present in mice that express human tau. The turnover rate of soluble tau was not significantly altered between pro-aggregant mice and anti-aggregant mice. This suggests that altered conformation by ΔK280 does not have a major impact on clearance pathways for soluble tau. In contrast, different tau species displayed different half-lives. Turnover was significantly delayed for insoluble tau whereas it was accelerated for soluble tau phosphorylated in the proline rich region. These differences in susceptibilities to clearance suggest that aggregation and phosphorylation influences tau clearance which may be important in tau pathogenesis. © 2015 Yamada et al.


Author Keywords
Alzheimer's disease;  Clearance;  Extracellular tau;  Half-life;  Tauopathy model


Document Type: Article
Source: Scopus




Duma, A., Pal, S., Helsten, D., Stein, P.K., Miller, J.P., Nagele, P.
High-Fidelity Analysis of Perioperative QTc Prolongation
(2015) Anesthesia and Analgesia, . Article in Press. 

DOI: 10.1213/ANE.0000000000001023


From the *Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri; †Cardiovascular Division, Department of Internal Medicine, Washington University in St. Louis, St. Louis, Missouri; and ‡Division of Biostatistics, Washington University in St. Louis, St. Louis, Missouri.


Abstract
BACKGROUND:: Prolongation of the QTc interval indicates abnormal cardiac repolarization. A recent study has shown that postoperative QTc prolongation is common. However, it is unknown whether QTc prolongation is an isolated postoperative phenomenon or occurs regularly during surgery, or whether the type of anesthesia influences its incidence. METHODS:: To answer this question, we conducted a prospective cohort study (n = 300), where QTc duration was continuously recorded by 12-lead Holter electrocardiogram from 30 minutes preoperatively to up to 60 minutes postoperatively. QTc prolongation was compared between adult patients with at least 1 cardiac risk factor undergoing general (n = 101) or spinal anesthesia (n = 99) for orthopedic surgery, or local anesthesia (n = 100). Primary outcome was intraoperative QTc increase (ΔQTc, as defined by the intraoperative-to-preoperative QTc duration difference). The incidence of long QTc episodes (QTc > 500 milliseconds for at least 15 minutes) was also determined. RESULTS:: Significant QTc prolongation (median; interquartile range [IQR]) occurred during general anesthesia (ΔQTc, +33 milliseconds; IQR, +22 to 46 milliseconds) and spinal anesthesia (ΔQTc, +22 milliseconds; IQR, +12 to 29 milliseconds), whereas no QTc prolongation was observed during local anesthesia (biopsy, n = 53: ΔQTc, +4 milliseconds; IQR, −4 to +7 milliseconds; coronary angiography, n = 47: ΔQTc, +6 milliseconds; IQR, −5 to +16 milliseconds). The incidence of long QTc episodes was significantly different between general anesthesia (n = 6/63, 9.5%), spinal anesthesia (n = 1/56, 1.8%), local anesthesia for biopsy (n = 0/46, 0%), and coronary angiography (n = 0/19, 0%; P = 0.045). CONCLUSIONS:: These results indicate that QTc prolongation is not an isolated postoperative phenomenon and is common during surgery under general and spinal anesthesia. © 2015 International Anesthesia Research Society


Document Type: Article in Press
Source: Scopus




Triebwasser, M.P.a , Roberson, E.D.O.a b , Yu, Y.c , Schramm, E.C.a , Wagner, E.K.c d , Raychaudhuri, S.e f g h i , Seddon, J.M.c d , Atkinson, J.P.a
Rare variants in the functional domains of complement factor H are associated with age-related macular degeneration
(2015) Investigative Ophthalmology and Visual Science, 56 (11), pp. 6873-6878. 

DOI: 10.1167/iovs.15-17432


a Washington University School of Medicine, Department of Internal Medicine, Division of Rheumatology, St. Louis, MO, United States
b Washington University School of Medicine, Department of Genetics, St. Louis, MO, United States
c Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, MA, United States
d Department of Ophthalmology, Tufts University School of Medicine, Sackler School of Graduate Medical Sciences, Tufts University, Boston, MA, United States
e Broad Institute, Cambridge, MA, United States
f Partners HealthCare Center for Personalized Genetic Medicine, Division of Genetics, Brigham and Women’s Hospital, Boston, MA, United States
g Division of Rheumatology,Immunology,and Allergy, Brigham and Women’s Hospital, Boston, MA, United States
h University of Manchester, Manchester, United Kingdom
i Department of Medicine, Karolinska Institutet, Solna, Sweden


Abstract
Purpose: Age-related macular degeneration (AMD) has a substantial genetic risk component, as evidenced by the risk from common genetic variants uncovered in the first genome-wide association studies. More recently, it has become apparent that rare genetic variants also play an independent role in AMD risk. We sought to determine if rare variants in complement factor H (CFH) played a role in AMD risk. Methods: We had previously collected DNA from a large population of patients with advanced age-related macular degeneration (A-AMD) and controls for targeted deep sequencing of candidate AMD risk genes. In this analysis, we tested for an increased burden of rare variants in CFH in 1665 cases and 752 controls from this cohort. Results: We identified 65 missense, nonsense, or splice-site mutations with a minor allele frequency ≤ 1%. Rare variants with minor allele frequency ≤ 1% (odds ratio [OR] = 1.5, P = 4.4 × 10−2), 0.5% (OR = 1.6, P = 2.6 × 10−2), and all singletons (OR = 2.3, P = 3.3 × 10−2) were enriched in A-AMD cases. Moreover, we observed loss-of-function rare variants (nonsense, splice-site, and loss of a conserved cysteine) in 10 cases and serum levels of FH were decreased in all 5 with an available sample (haploinsufficiency). Further, rare variants in the major functional domains of CFH were increased in cases (OR = 3.2; P = 1.4 × 10−3) and the magnitude of the effect correlated with the disruptive nature of the variant, location in an active site, and inversely with minor allele frequency. Conclusions: In this large A-AMD cohort, rare variants in the CFHgene were enriched and tended to be located in functional sites or led to low serum levels. These data, combined with those indicating a similar, but even more striking, increase in rare variants found inCFI, strongly implicate complement activation in A-AMD etiopathogenesis as CFH and CFI interact to inhibit the alternative pathway. © 2015 The Association for Research in Vision and Ophthalmology, Inc.


Author Keywords
Macular degeneration;  Rare genetic variants;  Sequencing


Document Type: Article
Source: Scopus




Lichtenhan, J.T.a , Wilson, U.S.a b , Hancock, K.E.c d , Guinan, J.J.c d
Medial olivocochlear efferent reflex inhibition of human cochlear nerve responses
(2015) Hearing Research, . Article in Press. 

DOI: 10.1016/j.heares.2015.09.001


a Washington University School of Medicine, Department of Otolaryngology, Saint Louis, MO 63110, USA
b Missouri State University, Communications Sciences and Disorders, Springfield, MO 65897, USA
c Massachusetts Eye and Ear Infirmary, Eaton-Peabody Laboratory of Auditory Physiology, Boston, MA 02114, USA
d Harvard Medical School, Department of Otology and Laryngology, Boston, MA 02115, USA


Abstract
Inhibition of cochlear amplifier gain by the medial olivocochlear (MOC) efferent system has several putative roles: aiding listening in noise, protection against damage from acoustic overexposure, and slowing age-induced hearing loss. The human MOC reflex has been studied almost exclusively by measuring changes in otoacoustic emissions. However, to help understand how the MOC system influences what we hear, it is important to have measurements of the MOC effect on the total output of the organ of Corti, i.e., on cochlear nerve responses that couple sounds to the brain. In this work we measured the inhibition produced by the MOC reflex on the amplitude of cochlear nerve compound action potentials (CAPs) in response to moderate level (52-60 dB peSPL) clicks from five, young, normal hearing, awake, alert, human adults. MOC activity was elicited by 65 dB SPL, contralateral broadband noise (CAS). Using tympanic membrane electrodes, approximately 10 h of data collection were needed from each subject to yield reliable measurements of the MOC reflex inhibition on CAP amplitudes from one click level. The CAS produced a 16% reduction of CAP amplitude, equivalent to a 1.98 dB effective attenuation (averaged over five subjects). Based on previous reports of efferent effects as functions of level and frequency, it is possible that much larger effective attenuations would be observed at lower sound levels or with clicks of higher frequency content. For a preliminary comparison, we also measured MOC reflex inhibition of DPOAEs evoked from the same ears with f 2's near 4 kHz. The resulting effective attenuations on DPOAEs were, on average, less than half the effective attenuations on CAPs. © 2015 Elsevier B.V.


Author Keywords
Cochlear amplifier;  Compound action potential;  Medial olivocochlear reflex;  Olivocochlear efferents;  Otoacoustic emissions


Document Type: Article in Press
Source: Scopus




Salminen, L.E.a , Schofield, P.R.b c , Pierce, K.D.b , Luo, X.d , Zhao, Y.d , Laidlaw, D.H.e , Cabeen, R.P.e , Conturo, T.E.f , Lane, E.M.g , Heaps, J.M.h , Bolzenius, J.D.a , Baker, L.M.a , Cooley, S.A.a , Scott, S.h , Cagle, L.M.a , Paul, R.H.a h
Genetic markers of cholesterol transport and gray matter diffusion: a preliminary study of the CETP I405V polymorphism
(2015) Journal of Neural Transmission, 122 (11), pp. 1581-1592. 

DOI: 10.1007/s00702-015-1434-0


a Department of Psychological Sciences, University of Missouri-St. Louis, 1 University Blvd., Stadler Hall 442A, St. Louis, MO, United States
b Neuroscience Research Australia, Barker Street Randwick, Sydney, NSW, Australia
c School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
d Department of Biostatistics and Center for Statistical Sciences, Brown University, Providence, RI, United States
e Computer Science Department, Brown University, Providence, RI, United States
f Washington University School of Medicine, Mallinckrodt Institute of Radiology, 510 S. Kingshighway, St. Louis, MO, United States
g Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN, United States
h Missouri Institute of Mental Health, 4633 World Parkway Circle, Berkeley, MO, United States


Abstract
Variations of the cholesteryl ester transfer protein polymorphism (CETP I405V/rs5882) have been associated with an increased risk for neurodegeneration, particularly when examined in conjunction with the epsilon 4 isoform of apolipoprotein E (ApoE4). Despite these identified relationships, the impact of I405V on gray matter microstructure remains unknown. The present study examined the impact of the CETP I405V polymorphism on gray matter integrity among 52 healthy adults between ages 51 and 85. Gray matter was measured bilaterally using diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Participants were grouped according to a dominant statistical model (II genotype vs. IV/VV genotypes) and secondary analyses were completed to examine the interactive effects of CETP and ApoE4 on DTI metrics. Compared to individuals with the IV/VV genotypes, II homozygotes demonstrated significantly higher MD in bilateral temporal, parietal, and occipital gray matter. Secondary analyses revealed higher FA and AD in the left temporal lobe of IV/VV genotypes with an ApoE4 allele. Our results provide preliminary evidence that CETP II homozygosity is a predisposing risk factor for gray matter abnormalities in posterior brain regions in healthy older adults, independent of an ApoE4 allele. © 2015, Springer-Verlag Wien.


Author Keywords
APOE;  CETP;  DTI;  Gray matter


Document Type: Article
Source: Scopus




Ng, K.W.a , Connolly, A.M.a b , Zaidman, C.M.a b
Quantitative muscle ultrasound measures rapid declines over time in children with SMA type 1
(2015) Journal of the Neurological Sciences, . Article in Press. 

DOI: 10.1016/j.jns.2015.08.1532


a Washington University School of Medicine, Department of Neurology, St. Louis, MO 63110, United States
b Washington University School of Medicine, Department of Pediatrics, St. Louis, MO 63110, United States


Abstract
Muscles are small in spinal muscular atrophy (SMA). It is not known if muscle size changes over time in SMA type 1. We quantified changes over time in muscle size and echointensity during two repeated ultrasound examinations of unilateral proximal (biceps brachii/brachialis and quadriceps) and distal (anterior forearm flexors and tibialis anterior) muscles in three children with SMA type 1. We compared muscle thickness (MT) to body weight-dependent normal reference values. Children were 1, 6, and 11. months old at baseline and had 2, 2 and 4. months between ultrasound examinations, respectively. At baseline, MT was normal for weight in all muscles except an atrophic quadriceps in the oldest child. MT decreased and echointensity increased (worsened) over time. At follow up, MT was below normal for weight in the quadriceps in all three children, in the biceps/brachioradialis in two, and in the anterior forearm in one. Tibialis anterior MT remained normal for weight in all three children. Muscle echointensity increased over time in all muscles and, on average, more than doubled in two children. In children with SMA type 1, muscle atrophies and becomes hyperechoic over time. Quantitative muscle ultrasound measures disease progression in SMA type 1 that warrants additional study in more children. © 2015.


Author Keywords
Backscatter;  Children;  Muscle;  Spinal muscular atrophy;  Ultrasound


Document Type: Article in Press
Source: Scopus




Anderson, A.M.a , Fennema-Notestine, C.b h , Umlauf, A.b h , Taylor, M.J.b h , Clifford, D.B.c , Marra, C.M.d , Collier, A.C.d , Gelman, B.B.e , McArthur, J.C.f , McCutchan, J.A.b h , Simpson, D.M.g , Morgello, S.g , Grant, I.b h , Letendre, S.L.b h
CSF biomarkers of monocyte activation and chemotaxis correlate with magnetic resonance spectroscopy metabolites during chronic HIV disease
(2015) Journal of NeuroVirology, 21 (5), pp. 559-567. 

DOI: 10.1007/s13365-015-0359-6


a Emory School of Medicine, Emory University, Atlanta, GA, United States
b University of California, San Diego, La Jolla, CA, United States
c Washington University School of Medicine, Washington University, St. Louis, MO, United States
d University of Washington, Seattle, WA, United States
e University of Texas Medical Branch, University of Texas System, Galveston, TX, United States
f John Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, United States
g The Mount Sinai Hospital, New York, NY, United States
h HIV Neurobehavioral Research Center and Antiviral Research Center, University of California, San Diego, 220 Dickinson Street, Suite A, San Diego, CA, United States


Abstract
Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) persist despite combination antiretroviral therapy (cART), supporting the need to better understand HIV neuropathogenesis. Magnetic resonance spectroscopy (MRS) of the brain has demonstrated abnormalities in HIV-infected individuals despite cART. We examined the associations between MRS metabolites and selected cerebrospinal fluid (CSF) biomarkers reflecting monocyte/macrophage activation and chemotaxis. A multicenter cross-sectional study involving five sites in the USA was conducted. The following CSF biomarkers were measured: soluble CD14 (sCD14), monocyte chemotactic protein-1 (MCP-1), interferon inducible protein 10 (IP-10), and stromal cell-derived growth factor 1 alpha (SDF-1α). The following MRS metabolites were measured from basal ganglia (BG), frontal white matter (FWM), and frontal gray matter (FGM): N-acetylaspartate (NAA), myo-inositol (MI), choline (Cho), and creatine (Cr). CSF biomarkers were compared to absolute MRS metabolites as well as metabolite/Cr ratios using linear regression. Eighty-three HIV-infected individuals were included, 78 % on cART and 37 % with HAND. The most robust positive correlations were between MCP-1 and Cho in BG (R2 0.179, p &lt; 0.001) as well as MCP-1 and MI in FWM (R2 0.137, p = 0.002). Higher Cr levels in FWM were associated with MCP-1 (R2 0. 075, p = 0.01) and IP-10 (R2 0.106, p = 0.003). Comparing biomarkers to MRS metabolite/Cr ratios impacted some relationships, e.g., higher sCD14 levels were associated with lower Cho/Cr ratios in FGM (R2 0.224, p &lt; 0.001), although higher MCP-1 levels remained associated with Cho/Cr in BG. These findings provide evidence that monocyte activation and chemotaxis continue to contribute to HIV-associated brain abnormalities in cART-treated individuals. © 2015, Journal of NeuroVirology, Inc.


Author Keywords
Acquired immunodeficiency syndrome;  Biomarkers;  Cerebrospinal fluid;  HIV-associated neurocognitive disorder;  Human immunodeficiency virus


Document Type: Article
Source: Scopus




Schöneberg, T.a , Liebscher, I.a , Luo, R.b , Monk, K.R.c d , Piao, X.b
Tethered agonists: A new mechanism underlying adhesion G protein-coupled receptor activation
(2015) Journal of Receptors and Signal Transduction, 35 (3), pp. 220-223. 

DOI: 10.3109/10799893.2015.1072978


a Institute of Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany
b Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
c Department of Developmental Biology, Washington University, School of Medicine, St. Louis, MO, United States
d Hope Center for Neurological Disorders, Washington University, School of Medicine, St. Louis, MO, United States


Abstract
The family of adhesion G protein-coupled receptors (aGPCRs) comprises 33 members in the human genome, which are subdivided into nine subclasses. Many aGPCRs undergo an autoproteolytic process via their GPCR Autoproteolysis-INducing (GAIN) domain during protein maturation to generate an N- and a C-terminal fragments, NTF and CTF, respectively. The NTF and CTF are non-covalently reassociated on the plasma membrane to form a single receptor unit. How aGPCRs are activated upon ligand binding remains one of the leading questions in the field of aGPCR research. Recent work from our labs and others shows that ligand binding can remove the NTF from the plasma membrane-bound CTF, exposing a tethered agonist which potently activates downstream signaling. © 2015 Taylor & Francis.


Author Keywords
adhesion GPCR;  G proteincoupled signaling;  tethered agonist


Document Type: Article
Source: Scopus




Coorg, R.a b c d , Weisenberg, J.L.Z.a
Successful Treatment of Electrographic Status Epilepticus Of Sleep With Felbamate in a Patient With SLC9A6 Mutation
(2015) Pediatric Neurology, . Article in Press. 

DOI: 10.1016/j.pediatrneurol.2015.07.007


a Department of Neurology, Washington University School of Medicine, St. Louis, Missouri
b Department of Pediatrics, Baylor College of Medicine, Houston, Texas
c Department of Neurology, Baylor College of Medicine, Houston, Texas
d Department of Pediatrics and Neurology; 6701 Fannin; Suite 1250; Houston, TX77030


Abstract
Background: Mutations of SLC9A6 may cause an X-linked clinical syndrome first described by Christianson in 1999 in which affected males exhibited profound intellectual disability, autism, drug-resistant epilepsy, ophthalmoplegia, mild craniofacial dysmorphism, microcephaly, and ataxia. Methods: We describe a child with an SLC9A6 mutation and an electroencephalographic pattern consistent with electrographic status epilepticus of sleep. Results: Our patient's electrographic status epilepticus of sleep resolved after treatment with felbamate. Following treatment, he remained seizure-free but did not make significant or lasting gains in language. Conclusion: Our report extends the clinical epilepsy phenotype in children with SLC9A6 mutations to include electrographic status epilepticus of sleep. In addition, felbamate was an effective treatment for electrographic status epilepticus of sleep in our patient. © 2015 Elsevier Inc.


Author Keywords
SLC9A6;  Christianson syndrome;  Epilepsy;  ESES;  Felbamate


Document Type: Article in Press
Source: Scopus




Cirulli, E.T.a , Lasseigne, B.N.b , Petrovski, S.c , Sapp, P.C.d , Dion, P.A.e , Leblond, C.S.e , Couthouis, J.f , Lu, Y.-F.c , Wang, Q.c , Krueger, B.J.c , Ren, Z.c , Keebler, J.g , Han, Y.g , Levy, S.E.b , Boone, B.E.b , Wimbish, J.R.b , Waite, L.L.b , Jones, A.L.b , Carulli, J.P.h , Day-Williams, A.G.h , Staropoli, J.F.h , Xin, W.W.i , Chesi, A.f , Raphael, A.R.f , McKenna-Yasek, D.d , Cady, J.j , De Jong, J.M.B.V.k , Kenna, K.P.l , Smith, B.N.m , Topp, S.m , Miller, J.m , Gkazi, A.m , Al-Chalabi, A.m , Van Den Berg, L.H.n , Veldink, J.n , Silani, V.o p , Ticozzi, N.o p , Shaw, C.E.m , Baloh, R.H.q , Appel, S.r s , Simpson, E.r s , Lagier-Tourenne, C.t , Pulst, S.M.u , Gibson, S.u , Trojanowski, J.Q.v , Elman, L.w , McCluskey, L.w , Grossman, M.w , Shneider, N.A.x , Chung, W.K.y , Ravits, J.M.z , Glass, J.D.aa , Sims, K.B.i , Van Deerlin, V.M.v , Maniatis, T.ab , Hayes, S.D.h ad , Ordureau, A.ac , Swarup, S.ac , Landers, J.d , Baas, F.k , Allen, A.S.ad , Bedlack, R.S.ae , Harper, J.W.ac , Gitler, A.D.f , Rouleau, G.A.e , Brown, R.d , Harms, M.B.j , Cooper, G.M.b , Harris, T.h , Myers, R.M.b , Goldstein, D.B.c
Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways
(2015) Science, 347 (6229), pp. 1436-1441. Cited 21 times.

DOI: 10.1126/science.aaa3650


a Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, United States
b HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States
c Institute for Genomic Medicine, Columbia University, New York, NY, United States
d Department of Neurology, University of Massachusetts Medical School, Worcester, MA, United States
e Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
f Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States
g Duke University School of Medicine, Durham, NC, United States
h Biogen Idec, Cambridge, MA, United States
i Department of Neurology, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, United States
j Neurology, Washington University School of Medicine, St. Louis, MO, United States
k Department of Genome Analysis, Academic Medical Center, Meibergdreef 9, Amsterdam, Netherlands
l Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
m Department of Basic and Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom
n Department of Neurology, Brain Center Rudolf Magnus, University Medical Centre Utrecht, Utrecht, Netherlands
o Department of Neurology, Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy
p Department of Pathophysiology and Transplantation, Dino Ferrari Center, Università Degli Studi di Milano, Milan, Italy
q Cedars Sinai Medical Center, Los Angeles, CA, United States
r Houston Methodist Hospital, Houston, TX, United States
s Weill Cornell Medical College, Cornell University, New York, NY, United States
t Ludwig Institute for Cancer Research, Department of Neurosciences, University of California, San Diego, San Diego, CA, United States
u Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, United States
v Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
w Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
x Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY, United States
y Department of Pediatrics and Medicine, Columbia University, New York, NY, United States
z Department of Neurosciences, University of California, San Diego, San Diego, CA, United States
aa Department of Neurology, Emory University, Atlanta, GA, United States
ab Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, United States
ac Department of Cell Biology, Harvard Medical School, Boston, MA, United States
ad Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, United States
ae Duke ALS Clinic, Durham VA Medical Center, Durham, NC, United States


Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment.We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.


Document Type: Article
Source: Scopus




Fowler, P.J.a , McGrath, L.M.b , Henry, D.B.c , Schoeny, M.d , Chavira, D.e , Taylor, J.J.f , Day, O.g
Housing mobility and cognitive development: Change in verbal and nonverbal abilities
(2015) Child Abuse and Neglect, . Article in Press. 

DOI: 10.1016/j.chiabu.2015.06.002


a Washington University in St. Louis, 1 Brookings Drive, Campus Box 1196, St. Louis, MO 63130, USA
b American University, 4400 Massachusetts Avenue, NW, Washington, DC 20016, USA
c University of Illinois at Chicago, University of Illinois at Chicago, 1747 West Roosevelt Road, Chicago, IL 60608, USA
d University of Chicago, 969 E. 60th Street, Chicago, IL 60637, USA
e DePaul University, 2219 N Kenmore Avenue, Chicago, IL 60614, USA
f Collaborative for Academic, Social, and Emotional Learning, 815 W. Van Buren St. Ste. 210, Chicago, IL 60607-3567, USA
g Research Triangle International, 3040 East Cornwallis Road, Research Triangle Park, NC 27709-2194, USA


Abstract
This study investigates the influence of housing instability on verbal and nonverbal cognitive development among at-risk children and adolescents involved in the child welfare system. Frequent residential changes threaten child mental health, especially among low-income families. Little is known regarding disruptions to cognitive growth, specifically the impact on verbal and nonverbal abilities. The study tests whether developmental timing of housing mobility affects cognitive development beyond individual and family risks. A nationally representative study of families (n =2,442) susceptible to housing and family instability tracked children and adolescents aged 4-14 years (M =8.95 years) over 36 months following investigation by the child welfare system. Youth completed standardized cognitive assessments while caregivers reported on behavior problems and family risk at three time points. Latent growth models examined change in cognitive abilities over time. Housing mobility in the 12 months prior to baseline predicts lower verbal cognitive abilities that improve marginally. Similar effects emerge for all age groups; however, frequent moves in infancy diminish the influence of subsequent housing mobility on verbal tasks. Housing instability threatened cognitive development beyond child maltreatment, family changes, poverty, and other risks. Findings inform emerging research on environmental influences on neurocognitive development, as well as identify targets for early intervention. Systematic assessment of family housing problems, including through the child welfare system, provides opportunities for coordinated responses to prevent instability and cognitive threats. © 2015 Elsevier Ltd.


Author Keywords
Child welfare;  Cognitive development;  Developmental timing;  Family stability;  Housing mobility


Document Type: Article in Press
Source: Scopus




Patera, A.C.g , Butler, S.L.a , Cinque, P.b , Clifford, D.B.c , Elston, R.d , Garcea, R.L.e , Major, E.O.f , Pavlovic, D.h , Peterson, I.S.i , Ryan, A.M.j , Tyler, K.L.k , Weber, T.l , On Behalf Of The Pml Consortiumm
2nd International Conference on Progressive Multifocal Leukoencephalopathy (PML) 2015: JCV virology, progressive multifocal leukoencephalopathy pathogenesis, diagnosis and risk stratification, and new approaches to prevention and treatment
(2015) Journal of NeuroVirology, 21 (6), 4 p. 

DOI: 10.1007/s13365-015-0392-5


a Inflammation and Immunology, Worldwide Research and Development, Pfizer Inc, Cambridge, MA, United States
b Department of Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
c Washington University School of Medicine, St. Louis, MO, United States
d Roche Pharma Research & Early Development, Roche Products Limited, Welwyn Garden City, United Kingdom
e Department of Molecular, Cellular, and Developmental Biology and the BioFrontiers Institute, University of Colorado Boulder, Boulder, CO, United States
f 16214 Hidden Ponds Way, Darnestown, MD, United States
g Infectious Disease and Vaccines, MedImmune LLC, Gaithersburg, MD, United States
h Global Regulatory Affairs, Patient Safety and Quality Assurance, AstraZeneca, Gaithersburg, MD, United States
i PML Consortium Secretariat, Drinker Biddle & Reath LLP, Washington, DC, United States
j Drug Safety R&D, Worldwide Research and Development, Pfizer Inc, Groton, CT, United States
k Department of Neurology, University of Colorado School of Medicine, Aurora, CO, United States
l Department of Neurology, Marienkrankenhaus, Hamburg, Germany


Document Type: Article
Source: Scopus




Smith, S.M.a , Nichols, T.E.b , Vidaurre, D.c , Winkler, A.M.a , Behrens, T.E.J.a , Glasser, M.F.d , Ugurbil, K.e , Barch, D.M.d , Van Essen, D.C.d , Miller, K.L.a
A positive-negative mode of population covariation links brain connectivity, demographics and behavior
(2015) Nature Neuroscience, 18 (11), pp. 1565-1567. Cited 1 time.

DOI: 10.1038/nn.4125


a Oxford University, Centre for Functional MRI of the Brain (FMRIB), Oxford, United Kingdom
b Department of Statistics, Warwick Manufacturing Group, University of Warwick, Coventry, United Kingdom
c Oxford University, Centre for Human Brain Activity (OHBA), Oxford, United Kingdom
d Washington University, School of Medicine, St. Louis, MO, United States
e Center for Magnetic Resonance Research, University of Minnesota, Minnesota, United States


Abstract
We investigated the relationship between individual subjects' functional connectomes and 280 behavioral and demographic measures in a single holistic multivariate analysis relating imaging to non-imaging data from 461 subjects in the Human Connectome Project. We identified one strong mode of population co-variation: subjects were predominantly spread along a single 'positive-negative' axis linking lifestyle, demographic and psychometric measures to each other and to a specific pattern of brain connectivity. © 2015 Nature America, Inc.


Document Type: Short Survey
Source: Scopus




Green, R.C.a b , Christensen, K.D.a , Cupples, L.A.c , Relkin, N.R.d , Whitehouse, P.J.e , Royal, C.D.M.f , Obisesan, T.O.g , Cook-Deegan, R.h , Linnenbringer, E.i , Butson, M.B.e , Fasaye, G.-A.j , Levinson, E.k , Roberts, J.S.l , Bhatt, D.m , Biesecker, B.n , Blacker, D.o , Chen, C.p , Cox, E.q , Davis, J.G.q , Farrer, L.r , Griffith, P.s , Harkins, K.t , Hiraki, S.u , Johnson, M.v , Johnson, S.v , Juengst, E.w , Karlawish, J.t , Le, L.x , McCarty Wood, E.t , Obisesan, T.v , Post, S.y , Quaid, K.z , Ravdin, L.q , Roter, D.aa , Stern, R.ab , Sadovnick, A.ac , Sami, S.ad , Sankar, P.t , Topol, E.ae , Uhlmann, W.af , Waterston, L.ag , Wright, L.ah
A randomized noninferiority trial of condensed protocols for genetic risk disclosure of Alzheimer's disease
(2015) Alzheimer's and Dementia, 11 (10), pp. 1222-1230. 

DOI: 10.1016/j.jalz.2014.10.014


a Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
b Partners Personalized Medicine, Boston, MA, United States
c Departments of Biostatistics and Epidemiology, Boston University, School of Public Health, Boston, MA, United States
d Department of Neurology, Weill Medical College, Cornell University, New York, NY, United States
e Department of Neurology, Case Western Reserve University, Cleveland, OH, United States
f Department of African and African American Studies, Duke University, Durham, NC, United States
g Department of Medicine, Howard University, School of Medicine, Washington, DC, United States
h Sanford School of Public Policy, Duke University, Durham, NC, United States
i Division of Public Health Sciences, Department of Surgery, Washington University, School of Medicine, St. Louis, MO, United States
j Walter Reed National Military Medical Center, Bethesda, MD, United States
k Department of Surgery, Columbia University, New York, NY, United States
l Department of Health Behavior and Health Education, University of Michigan, School of Public Health, Ann Arbor, MI, United States
m Brigham and Women's Hospital, Harvard Medical School, Boston, United States
n National Human Genome Research Institute, Bethesda, United States
o Mass General Hospital, Harvard Medical School, Harvard School of Public Health, Boston, United States
p Boston University, School of Public Health, Boston, United States
q Weill Cornell Medical College, New York, United States
r Boston University School of Medicine, Boston University School of Public Health, Boston, United States
s Morehouse School of Medicine, Atlanta, United States
t Perelman School of Medicine, Philadelphia, United States
u Albert Einstein College of Medicine, Bronx, United States
v Howard University, Washington, DC, United States
w University of North Carolina, School of Medicine, Chapel Hill, United States
x University of Michigan, School of Public Health, Ann Arbor, DC, United States
y Stony Brook University, Stony Brook, United States
z Indiana University, School of Medicine, Indianapolis, United States
aa Johns Hopkins Bloomberg School of Public Health, Baltimore, United States
ab Boston University, School of Medicine, Boston, United States
ac University of British Columbia, Vancouver, Canada
ad Case Western Reserve University, Cleveland, United States
ae Scripps Research Institute, La Jolla, United States
af University of Michigan, Ann Arbor, United States
ag Maine Medical Center Research Institute, Portland, United States
ah Medical College of Georgia, Athens, Greece


Abstract
Introduction Conventional multisession genetic counseling is currently recommended when disclosing apolipoprotein E (APOE) genotype for the risk of Alzheimer's disease (AD) in cognitively normal individuals. The objective of this study was to evaluate the safety of brief disclosure protocols for disclosing APOE genotype for the risk of AD. Methods A randomized, multicenter noninferiority trial was conducted at four sites. Participants were asymptomatic adults having a first-degree relative with AD. A standard disclosure protocol by genetic counselors (SP-GC) was compared with condensed protocols, with disclosures by genetic counselors (CP-GC) and by physicians (CP-MD). Preplanned co-primary outcomes were anxiety and depression scales 12 months after disclosure. Results Three hundred and forty-three adults (mean age 58.3, range 33-86 years, 71% female, 23% African American) were randomly assigned to the SP-GC protocol (n = 115), CP-GC protocol (n = 116), or CP-MD protocol (n = 112). Mean postdisclosure scores on all outcomes were well below cut-offs for clinical concern across protocols. Comparing CP-GC with SP-GC, the 97.5% upper confidence limits at 12 months after disclosure on co-primary outcomes of anxiety and depression ranged from a difference of 1.2 to 2.0 in means (all P < .001 on noninferiority tests), establishing noninferiority for condensed protocols. Results were similar between European Americans and African Americans. Conclusions These data support the safety of condensed protocols for APOE disclosure for those free of severe anxiety or depression who are actively seeking such information. © 2015 The Alzheimer's Association.


Author Keywords
Alzheimer;  APOE;  Genetics;  Genomics;  Personalized medicine;  Risk assessment


Document Type: Article
Source: Scopus




Few, L.R.a , Werner, K.B.b , Sartor, C.E.a c , Grant, J.D.a , Trull, T.J.d , Nock, M.K.e , Bucholz, K.K.a , Deitz, S.K.a , Glowinski, A.L.a , Martin, N.G.f , Nelson, E.C.a , Statham, D.J.g , Madden, P.A.F.a , Heath, A.C.a , Lynskey, M.T.h , Agrawal, A.a
Early Onset Alcohol Use and Self-Harm: A Discordant Twin Analysis
(2015) Alcoholism: Clinical and Experimental Research, 39 (11), pp. 2134-2142. 

DOI: 10.1111/acer.12889


a Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
b George Warren Brown School of Social Work, Washington University, Saint Louis, MO, United States
c Department of Psychiatry, Yale University School of Medicine, West Haven, CT, United States
d Department of Psychological Sciences, University of Missouri, Columbia, MO, United States
e Department of Psychology, Harvard University, Cambridge, MA, United States
f QIMR Medical Research Institute, Brisbane, QLD, Australia
g School of Social Sciences, University of the Sunshine Coast, Sippy Downs, QLD, Australia
h Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom


Abstract
Background: Self-harm has considerable societal and economic costs and has been extensively studied in relation to alcohol involvement. Although early onset alcohol use (EAU) has been causally linked to maladaptive clinical outcomes, its association with self-harm is less well characterized. This study aimed to further examine the link between EAU and both nonsuicidal self-injury (NSSI) and suicide attempt (SA), and elucidate shared familial and causal/individual-specific pathways that explain this co-occurrence. Methods: Using data from 6,082 Australian same-sex twin pairs (1,732 monozygotic [MZ] and 1,309 dizygotic [DZ]), ages 23 to 40, we examined prevalence rates of NSSI and SA among twin pairs concordant and discordant for EAU. Conditional logistic regression, controlling for early clinical covariates and the influence of zygosity on EAU, was used to examine the odds ratio (OR) of self-harm within twin pairs discordant for EAU. Results: Prevalence rates of both NSSI and SA were highest among twin pairs concordant for EAU and for twins who reported EAU within discordant twin pairs. Results from discordant twin analyses revealed nearly 4-fold increased odds of SA for the twin who endorsed EAU, and this OR was equal across MZ and DZ twins. EAU also was associated with elevated odds of NSSI (OR = 7.62), although this was only the case for DZ twins in discordant pairs. Conclusions: The equivalent increase in odds of SA for both MZ and DZ twins suggests that causal or individual-specific influences explain the link between EAU and SA. For NSSI, elevated odds for DZ twins and nonsignificant findings for MZ twins implicate correlated genetic factors in the association between EAU and NSSI. Future studies should test mechanisms through which EAU may causally influence SA, as well as examine whether genetic risk for third variables (e.g., negative urgency, stress reactivity) may explain the genetic overlap between EAU and NSSI. © 2015 Research Society on Alcoholism.


Author Keywords
Early Alcohol Use;  Self-Harm


Document Type: Article
Source: Scopus




Lenze, E.J.a , Mulsant, B.H.b c , Blumberger, D.M.b , Karp, J.F.c , Newcomer, J.W.d , Anderson, S.J.e , Dew, M.A.c , Butters, M.A.c , Stack, J.A.c , Begley, A.E.c , Reynolds, C.F.c e
Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: A randomised, double-blind, placebo-controlled trial
(2015) The Lancet, . Article in Press. 

DOI: 10.1016/S0140-6736(15)00308-6


a Washington University School of Medicine, St Louis, MO, USA
b Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, ON, Canada
c University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
d Charles E Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA
e University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA


Abstract
Background: Treatment-resistant major depression is common and potentially life-threatening in elderly people, in whom little is known about the benefits and risks of augmentation pharmacotherapy. We aimed to assess whether aripiprazole is associated with a higher probability of remission than is placebo. Methods: We did a randomised, double-blind, placebo-controlled trial at three centres in the USA and Canada to test the efficacy and safety of aripiprazole augmentation for adults aged older than 60 years with treatment-resistant depression (Montgomery Asberg Depression Rating Scale [MADRS] score of ≥15). Patients who did not achieve remission during a pre-trial with venlafaxine extended-release (150-300 mg/day) were randomly assigned (1:1) to the addition of aripiprazole (target dose 10 mg [maximum 15 mg] daily) daily or placebo for 12 weeks. The computer-generated randomisation was done in blocks and stratified by site. Only the database administrator and research pharmacists had knowledge of treatment assignment. The primary endpoint was remission, defined as an MADRS score of 10 or less (and at least 2 points below the score at the start of the randomised phase) at both of the final two consecutive visits, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00892047. Findings: From July 20, 2009, to Dec 30, 2013, we recruited 468 eligible participants, 181 (39%) of whom did not remit and were randomly assigned to aripiprazole (n=91) or placebo (n=90). A greater proportion of participants in the aripiprazole group achieved remission than did those in the placebo group (40 [44%] vs 26 [29%] participants; odds ratio [OR] 2·0 [95% CI 1·1-3·7], p=0·03; number needed to treat [NNT] 6·6 [95% CI 3·5-81·8]). Akathisia was the most common adverse effect of aripiprazole (reported in 24 [26%] of 91 participants on aripiprazole vs one [1%] of 90 on placebo). Compared with placebo, aripiprazole was also associated with more Parkinsonism (15 [17%] of 86 vs two [2%] of 81 participants), but not with treatment-emergent suicidal ideation (13 [21%] of 61 vs 19 [29%] of 65 participants) or other measured safety variables. Interpretation: In adults aged 60 years or older who do not achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include the potential for akathisia and Parkinsonism. Funding: National Institute of Mental Health, UPMC Endowment in Geriatric Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, National Center for Advancing Translational Sciences, and the Campbell Family Mental Health Research Institute. © 2015 Elsevier Ltd.


Document Type: Article in Press
Source: Scopus




Jbabdi, S.a , Sotiropoulos, S.N.a , Haber, S.N.b , Van Essen, D.C.c , Behrens, T.E.a d
Measuring macroscopic brain connections in vivo
(2015) Nature Neuroscience, 18 (11), pp. 1546-1555. 

DOI: 10.1038/nn.4134


a Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), University of Oxford, Oxford, United Kingdom
b Department of Pharmacology and Physiology, University of Rochester, School of Medicine, Rochester, NY, United States
c Department of Anatomy and Neurobiology, Washington University, St. Louis, MO, United States
d Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom


Abstract
Decades of detailed anatomical tracer studies in non-human animals point to a rich and complex organization of long-range white matter connections in the brain. State-of-the art in vivo imaging techniques are striving to achieve a similar level of detail in humans, but multiple technical factors can limit their sensitivity and fidelity. In this review, we mostly focus on magnetic resonance imaging of the brain. We highlight some of the key challenges in analyzing and interpreting in vivo connectomics data, particularly in relation to what is known from classical neuroanatomy in laboratory animals. We further illustrate that, despite the challenges, in vivo imaging methods can be very powerful and provide information on connections that is not available by any other means. © 2015 Nature America, Inc.


Document Type: Review
Source: Scopus




Kharasch, E.D.a b , Regina, K.J.a , Blood, J.a , Friedel, C.a
Methadone pharmacogenetics: CYP2B6 polymorphisms determine plasma concentrations, clearance, and metabolism
(2015) Anesthesiology, 123 (5), pp. 1142-1153. 


a Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St. Louis, Campus Box 8054, 660 S Euclid Avenue, St. Louis, MO, United States
b Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St. Louis, MO, United States


Abstract
Background: Interindividual variability in methadone disposition remains unexplained, and methadone accidental overdose in pain therapy is a significant public health problem. Cytochrome P4502B6 (CYP2B6) is the principle determinant of clinical methadone elimination. The CYP2B6 gene is highly polymorphic, with several variant alleles. CYP2B6.6, the protein encoded by the CYP2B66 polymorphism, deficiently catalyzes methadone metabolism in vitro. This investigation determined the influence of CYP2B66, and other allelic variants encountered, on methadone concentrations, clearance, and metabolism. Methods: Healthy volunteers in genotype cohorts CYP2B61/1 (n = 21), CYP2B61/6 (n = 20), and CYP2B66/6 (n = 17), and also CYP2B61/4 (n = 1), CYP2B64/6 (n = 3), and CYP2B65/5 (n = 2) subjects, received single doses of IV and oral methadone. Plasma and urine methadone and metabolite concentrations were determined by tandem mass spectrometry. Results: Average S-methadone apparent oral clearance was 35 and 45% lower in CYP2B61/6 and CYP2B66/6 genotypes, respectively, compared with CYP2B61/1. R-methadone apparent oral clearance was 25 and 35% lower in CYP2B61/6 and CYP2B66/6 genotypes, respectively, compared with CYP2B61/1. R-and S-methadone apparent oral clearance was threefold and fourfold greater in CYP2B64 carriers. IV and oral R-and S-methadone metabolism was significantly lower in CYP2B66 carriers compared with that of CYP2B61 homozygotes and greater in CYP2B64 carriers. Methadone metabolism and clearance were lower in African Americans in part because of the CYP2B66 genetic polymorphism. Conclusions: CYP2B6 polymorphisms influence methadone plasma concentrations, because of altered methadone metabolism and thus clearance. Genetic influence is greater for oral than IV methadone and S-than R-methadone. CYP2B6 pharmacogenetics explains, in part, interindividual variability in methadone elimination. CYP2B6 genetic effects on methadone metabolism and clearance may identify subjects at risk for methadone toxicity and drug interactions. Copyright © 2015, the American Society of Anesthesiologists, Inc.


Document Type: Article
Source: Scopus




Ju, Y.-E.
Monitoring synaptic integrity
(2015) Science Translational Medicine, 7 (309), art. no. 309ec177, . 

DOI: 10.1126/scitranslmed.aad4443


Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States


Document Type: Note
Source: Scopus




Fitzsimmons-Craft, E.E.a , Accurso, E.C.b , Ciao, A.C.c , Crosby, R.D.d e , Cao, L.d e , Pisetsky, E.M.f , Le Grange, D.g , Peterson, C.B.f h , Crow, S.J.f h , Engel, S.G.d e , Mitchell, J.E.d e , Wonderlich, S.A.d e
Restrictive eating in anorexia nervosa: Examining maintenance and consequences in the natural environment
(2015) International Journal of Eating Disorders, 48 (7), pp. 923-931. 

DOI: 10.1002/eat.22439


a Department of Psychiatry, Washington University School of Medicine, Campus Box 8134, 660 S. Euclid Ave., St. Louis, MO, United States
b Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, United States
c Department of Psychology, Western Washington University, Bellingham, WA, United States
d Neuropsychiatric Research Institute, Fargo, ND, United States
e Department of Psychiatry and Behavioral Science, University of North Dakota, School of Medicine and Health Sciences, Fargo, ND, United States
f Department of Psychiatry, University of Minnesota, Minneapolis, MN, United States
g Department of Psychiatry, University of California, San Francisco, CA, United States
h Emily Program, St. Paul, MN, United States


Abstract
Objective This study examined negative and positive affect in relation to restrictive eating episodes (i.e., meals/snacks perceived as restrictive) and whether restrictive eating was associated with likelihood of subsequent eating disorder behaviors (i.e., additional restrictive eating, binge eating, vomiting, laxative use, weighing, exercising, meal skipping, drinking fluids to curb appetite, body checking). Method Women with anorexia nervosa (N-=-118) completed a 2-week ecological momentary assessment protocol. Results For both restrictive and nonrestrictive eating, negative affect significantly increased from prebehavior to the time of the behavior but remained stable thereafter, while positive affect remained stable from prebehavior to the time of the behavior but decreased significantly thereafter. Across time, negative affect was significantly lower and positive affect was significantly greater in restrictive than nonrestrictive episodes. Engagement in restrictive eating was associated with an increased likelihood of subsequent restrictive eating, laxative use, and body checking, but not other behaviors. Engagement in nonrestrictive eating was associated with a decreased likelihood of subsequent restrictive eating, binge eating, vomiting, laxative use, weighing, meal skipping, drinking fluids to curb appetite, and body checking. Discussion Despite similar patterns of affect across eating episodes over time, results suggest affect may be involved in the maintenance of restrictive eating in anorexia nervosa since restrictive episodes were associated with lower negative and greater positive affect across time compared to nonrestrictive episodes. Further, while restrictive episodes increased the likelihood of only three subsequent eating disorder behaviors, nonrestrictive episodes were protective since they decreased likelihood of all but one behavior. © 2015 Wiley Periodicals, Inc.


Author Keywords
anorexia nervosa;  ecological momentary assessment;  negative affect;  positive affect;  restrictive eating


Document Type: Article
Source: Scopus




Bourgault, S.a b , Baril, C.a b , Vincent, A.c d , Héon, E.c d , Ali, A.c d , MacDonald, I.e , Lueder, G.T.f , Colleaux, K.M.g h , Laliberté, I.a i
Retinal degeneration in autoimmune polyglandular syndrome type 1: A case series
(2015) British Journal of Ophthalmology, 99 (11), pp. 1536-1542. 

DOI: 10.1136/bjophthalmol-2014-305897


a Département D'ophtalmologie et ORL-Chirurgie Cervico-faciale, Faculté de Médecine, Université Laval, 1050 Chemin Sainte-Foy, Québec, QC, Canada
b Centre Universitaire D'ophtalmologie, Hôpital du Saint-Sacrement, CHU de Québec, Québec, QC, Canada
c Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada
d Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, Toronto, ON, Canada
e Department of Ophthalmology and Visual Sciences, University of Alberta, Edmonton, Canada
f Departments of Ophthalmology and Visual Sciences and Pediatrics, Washington University School of Medicine, St Louis, MI, United States
g Department of Ophthalmology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
h Saskatoon Retina Consultants, Saskatoon, Saskatchewan, Canada
i Centre Mére-enfant Soleil, CHUL, CHU de Québec, Québec, QC, Canada


Abstract
Background Autoimmune polyglandular syndrome type 1 (APS1) is a rare autosomal recessive disorder due to mutations in the AIRE gene. Aim To report the ocular features and characterise the retinal phenotype in molecularly confirmed APS1. Method This retrospective case series reviewed five molecularly confirmed cases with APS1 known to have ocular involvement (age range: 19 months-44 years; mean follow-up of 8 years). The medical history, ocular history and evaluation, visual field testing, full-field electroretinogram (ERG) and antiretinal antibody results were reviewed. Results All but one case had decreased vision at first presentation. All cases had peripheral pigmentary retinal changes; macular atrophy was noted in 80% of cases. The most common feature on spectral-domain optical coherence tomography was a disruption of the external limiting membrane and inner segment ellipsoid band (n=3). Fundus autofluorescence imaging demonstrated a parafoveal ring of hyper-autofluorescence (n=1) or a stippled and patchy autofluorescence pattern in the macula (n=1). The visual fields were constricted in all tested patients (n=3). The rod ERG was abnormal in all cases; the relative involvement of rods and cones differed. Four patients who were tested for antiretinal antibodies were found positive by immunohistochemistry (n=3) and/or western blot (n=2). Conclusions Photoreceptor degeneration is part of APS1 phenotype and the presence of antiretinal antibodies strongly supports an aetiology similar to that of non-paraneoplastic autoimmune retinopathy. Periodic retinal evaluation and imaging, visual field testing and ERG would assist in monitoring the retinopathy in APS1-related disease.


Document Type: Article
Source: Scopus




Moore, R.A.a , Wiffen, P.J.a , Eccleston, C.b , Derry, S.a , Baron, R.c , Bell, R.F.d , Furlan, A.D.e , Gilron, I.f , Haroutounian, S.g , Katz, N.P.h , Lipman, A.G.i , Morley, S.j , Peloso, P.M.k , Quessy, S.N.l , Seers, K.m , Strassels, S.A.n , Straube, S.o
Systematic review of enriched enrolment, randomised withdrawal trial designs in chronic pain: A new framework for design and reporting
(2015) Pain, 156 (8), pp. 1382-1395. 

DOI: 10.1097/j.pain.0000000000000088


a Pain Research, Nuffield Division of Anaesthetics, Nuffield Department of Clinical Neurosciences, University of Oxford, Churchill, Oxford, United Kingdom
b Centre for Pain Research, University of Bath, Bath, United Kingdom
c Division of Neurological Pain Research and Therapy, Department of Neurology, University Hospital, Kiel, Germany
d Centre for Pain Management and Palliative Care, Regional Centre for Excellence in Palliative Care, Haukel and University Hospital, Bergen, Norway
e Institute for Work and Health, Toronto, ON, Canada
f Queen's University, Kingston General Hospital, Departments of Anesthesiology and Perioperative Medicine and Biomedical and Molecular Sciences, Kingston, ON, Canada
g Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States
h Analgesic Solutions, Natick, MA, United States
i Department of Pharmacotherapy, University of Utah, Salt Lake City, UT, United States
j Leeds Institute of Health Sciences, University of Leeds, Leeds, United Kingdom
k Department R449, AbbVie, North Chicago, IL, United States
l Qd Consulting, LLC, Durham, NC, United States
m RCN Research Institute, Warwick Medical School, University of Warwick, Coventry, United Kingdom
n 8002 Davis Dr, Clayton, MO, United States
o Division of Preventive Medicine, University of Alberta, Edmonton, AB, Canada


Abstract
Enriched enrolment, randomised withdrawal (EERW) pain trials select, before randomisation, patients who respond by demonstrating a predetermined degree of pain relief and acceptance of adverse events. There is uncertainty over the value of this design. We report a systematic review of EERW trials in chronic noncancer pain together with a critical appraisal of methods and potential biases in the methods used and recommendations for the design and reporting of future EERWtrials. Electronic and other searches found 25 EERW trials published between 1995 and June 2014, involving 5669 patients in a randomised withdrawal phase comparing drug with placebo; 13 (median, 107 patients) had a randomised withdrawal phase of 6weeks or less, and 12 (median, 334) lasted 12 to 26weeks. Risks of bias included short duration, inadequate outcome definition, incomplete outcome data reporting, small size, and inadequate dose tapering on randomisation to placebo. Active treatment was usually better than placebo (22/25 trials). This review reduces the uncertainty around the value of EERW trials in pain. If properly designed, conducted, and reported, they are feasible and useful for making decisions about pain therapies. Shorter, small studies can be explanatory; longer, larger studies can inform practice. Current evidence is inadequate for valid comparisons in outcome between EERW and classical trials, although no gross differences were found. This systematic review provides a framework for assessing potential biases and the value of the EERW trials, and for the design of future studies by making recommendations for the conduct and reporting of EERW trials. © 2015 International Association for the Study of Pain.


Author Keywords
Enriched enrolment;  Methods;  Randomised withdrawal;  Recommendations;  Systematic review


Document Type: Note
Source: Scopus




Vulin, A.a , Wein, N.a , Simmons, T.R.a , Rutherford, A.M.a , Findlay, A.R.a d , Yurkoski, J.A.a , Kaminoh, Y.a e , Flanigan, K.M.a b c
The first exon duplication mouse model of Duchenne muscular dystrophy: A tool for therapeutic development
(2015) Neuromuscular Disorders, 25 (11), art. no. 3082, pp. 827-834. 

DOI: 10.1016/j.nmd.2015.08.005


a The Center for Gene Therapy, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, United States
b Department of Pediatrics, The Ohio State University, Columbus, OH, United States
c Department of Neurology, The Ohio State University, Columbus, OH, United States
d Department of Neurology, Washington University, St. Louis, MO, United States
e School of Osteopathic Medicine, Ohio University, Athens, OH, United States


Abstract
Exon duplication mutations account for up to 11% of all cases of Duchenne muscular dystrophy (DMD), and a duplication of exon 2 is the most common duplication in patients. For use as a platform for testing of duplication-specific therapies, we developed a mouse model that carries a Dmd exon 2 duplication. By using homologous recombination we duplicated exon 2 within intron 2 at a location consistent with a human duplication hotspot. mRNA analysis confirms the inclusion of a duplicated exon 2 in mouse muscle. Dystrophin expression is essentially absent by immunofluorescent and immunoblot analysis, although some muscle specimens show very low-level trace dystrophin expression. Phenotypically, the mouse shows similarities to mdx, the standard laboratory model of DMD. In skeletal muscle, areas of necrosis and phagocytosis are seen at 3 weeks, with central nucleation prominent by four weeks, recapitulating the "crisis" period in mdx. Marked diaphragm fibrosis is noted by 6 months, and remains unchanged at 12 months. Our results show that the Dup2 mouse is both pathologically (in degree and distribution) and physiologically similar to mdx. As it recapitulates the most common single exon duplication found in DMD patients, this new model will be a useful tool to assess the potential of duplicated exon skipping. © 2015 Elsevier B.V..


Author Keywords
Duchenne muscular dystrophy;  Duplication;  Exon skipping;  Mouse model


Document Type: Article
Source: Scopus




Grant, J.D.a , Lynskey, M.T.b , Madden, P.A.F.a , Nelson, E.C.a , Few, L.R.a , Bucholz, K.K.a , Statham, D.J.c , Martin, N.G.d , Heath, A.C.a , Agrawal, A.a
The role of conduct disorder in the relationship between alcohol, nicotine and cannabis use disorders
(2015) Psychological Medicine, 45 (16), pp. 3505-3515. 

DOI: 10.1017/S0033291715001518


a Department of Psychiatry, Washington University, School of Medicine, St Louis, MO, United States
b Institute of Psychiatry, Psychology and Neuroscience, Addictions Department, King's College London, London, United Kingdom
c University of the Sunshine CoastQLD, Australia
d QIMR, Berghofer Medical Research InstituteQLD, Australia


Abstract
Genetic influences contribute significantly to co-morbidity between conduct disorder and substance use disorders. Estimating the extent of overlap can assist in the development of phenotypes for genomic analyses. Method. Multivariate quantitative genetic analyses were conducted using data from 9577 individuals, including 3982 complete twin pairs and 1613 individuals whose co-twin was not interviewed (aged 24-37 years) from two Australian twin samples. Analyses examined the genetic correlation between alcohol dependence, nicotine dependence and cannabis abuse/dependence and the extent to which the correlations were attributable to genetic influences shared with conduct disorder. Results. Additive genetic (a2 = 0.48-0.65) and non-shared environmental factors explained variance in substance use disorders. Familial effects on conduct disorder were due to additive genetic (a2 = 0.39) and shared environmental (c2 = 0.15) factors. All substance use disorders were influenced by shared genetic factors (rg = 0.38-0.56), with all genetic overlap between substances attributable to genetic influences shared with conduct disorder. Genes influencing individual substance use disorders were also significant, explaining 40-73% of the genetic variance per substance. Conclusions. Among substance users in this sample, the well-documented clinical co-morbidity between conduct disorder and substance use disorders is primarily attributable to shared genetic liability. Interventions targeted at generally reducing deviant behaviors may address the risk posed by this shared genetic liability. However, there is also evidence for genetic and environmental influences specific to each substance. The identification of these substance-specific risk factors (as well as potential protective factors) is critical to the future development of targeted treatment protocols. © 2015 Cambridge University Press.


Author Keywords
Alcohol;  cannabis;  conduct disorder;  genetic overlap;  nicotine;  substance use disorders;  twins


Document Type: Article

Source: Scopus

 

November 4, 2015

Knopik, V.S.a b , Marceau, K.a c , Palmer, R.H.C.a b , Smith, T.F.a d , Heath, A.C.e
Maternal Smoking During Pregnancy and Offspring Birth Weight: A Genetically-Informed Approach Comparing Multiple Raters
(2015) Behavior Genetics, 12 p. Article in Press. 

DOI: 10.1007/s10519-015-9750-6


a Division of Behavioral Genetics, Department of Psychiatry, Rhode Island Hospital, Coro West Suite 204, 1 Hoppin St, Providence, RI, United States
b Department of Psychiatry and Human Behavior, Brown University, Providence, RI, United States
c Center for Alcohol and Addiction Studies, Brown University, Providence, RI, United States
d Department of Psychology and Child Development, California Polytechnic State University, San Luis Obispo, CA, United States
e Midwest Alcoholism Research Center, Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States


Abstract
Maternal smoking during pregnancy (SDP) is a significant public health concern with adverse consequences to the health and well-being of the fetus. There is considerable debate about the best method of assessing SDP, including birth/medical records, timeline follow-back approaches, multiple reporters, and biological verification (e.g., cotinine). This is particularly salient for genetically-informed approaches where it is not always possible or practical to do a prospective study starting during the prenatal period when concurrent biological specimen samples can be collected with ease. In a sample of families (N = 173) specifically selected for sibling pairs discordant for prenatal smoking exposure, we: (1) compare rates of agreement across different types of report—maternal report of SDP, paternal report of maternal SDP, and SDP contained on birth records from the Department of Vital Statistics; (2) examine whether SDP is predictive of birth weight outcomes using our best SDP report as identified via step (1); and (3) use a sibling-comparison approach that controls for genetic and familial influences that siblings share in order to assess the effects of SDP on birth weight. Results show high agreement between reporters and support the utility of retrospective report of SDP. Further, we replicate a causal association between SDP and birth weight, wherein SDP results in reduced birth weight even when accounting for genetic and familial confounding factors via a sibling comparison approach. © 2015 Springer Science+Business Media New York


Author Keywords
Birth weight;  Genetics;  Multiple reporters;  Sibling comparison design;  Smoking during pregnancy


Document Type: Article in Press
Source: Scopus




Lopez-Garcia, P.a b c , Lesh, T.A.c , Salo, T.c , Barch, D.M.d , MacDonald, A.W., IIIe , Gold, J.M.f , Ragland, J.D.c , Strauss, M.g , Silverstein, S.M.h , Carter, C.S.c
The neural circuitry supporting goal maintenance during cognitive control: a comparison of expectancy AX-CPT and dot probe expectancy paradigms
(2015) Cognitive, Affective and Behavioral Neuroscience, 12 p. Article in Press. 

DOI: 10.3758/s13415-015-0384-1


a Universidad Autonoma de Madrid, Madrid, Spain
b Madrid, Spain
c University of California at Davis, Davis, CA, United States
d Washington University in St Louis, St Louis, MO, United States
e University of Minnesota, Minneapolis, MN, United States
f University of Maryland, College Park, MD, United States
g Case Western Reserve University, Cleveland, OH, United States
h Rutgers University, New Brunswick, NJ, United States


Abstract
Goal maintenance is an aspect of cognitive control that has been identified as critical for understanding psychopathology according to criteria of the NIMH-sponsored CNTRICS (Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia) and Research Domain Criteria (RDoC) initiatives. CNTRICS proposed the expectancy AX-CPT, and its visual-spatial parallel the dot probe expectancy (DPX), as valid measures of the cognitive and neural processes thought to be relevant for goal maintenance. The goal of this study was to specifically examine the functional neural correlates and connectivity patterns of both goal maintenance tasks in the same subset of subjects to further validate their neural construct validity and clarify our understanding of the nature and function of the neural circuitry engaged by the tasks. Twenty-six healthy control subjects performed both the letter (AX) and dot pattern (DPX) variants of the CPT during fMRI. Behavioral performance was similar between tasks. The 2 tasks engaged the same brain networks including dorsolateral prefrontal cortex (DLPFC) and dorsal parietal regions, supporting their validity as complementary measures of the goal maintenance construct. Interestingly there was greater engagement of the frontal opercular insula region during the expectancy AX-CPT (letter) and greater functional connectivity between the PFC and medial temporal lobe in the DPX (dot pattern). These differences are consistent with differential recruitment of phonological and visual-spatial processes by the two tasks and suggest that additional long-term memory systems may be engaged by the dot probe version. © 2015 Psychonomic Society, Inc.


Author Keywords
Cognitive control;  Connectivity;  Context processing;  Goal maintenance


Document Type: Article in Press
Source: Scopus




Brier, M.R.a , Wu, Q.a b , Tanenbaum, A.B.a , Westerhaus, E.T.a , Kharasch, E.D.d , Ances, B.M.a b c
Effect of HAART on Brain Organization and Function in HIV-Negative Subjects
(2015) Journal of Neuroimmune Pharmacology, 5 p. Article in Press. 

DOI: 10.1007/s11481-015-9634-9


a Department of Neurology, School of Medicine, Washington University in St Louis, St Louis, MO, United States
b Department of Biomedical Engineering, Washington University in St Louis, St Louis, MO, United States
c Department of Radiology, Washington University in St Louis, St Louis, MO, United States
d Department of Anesthesiology, Washington University in St Louis, St Louis, MO, United States


Abstract
HIV causes neural dysfunction in infected individuals. This dysfunction often manifests as cognitive symptoms and can be detected using neuroimaging. Highly active anti-retroviral therapy (HAART), in addition to providing virologic control, has reduced the number of profoundly impaired individuals but more mild forms of neurocognitive disorders remains prevalent. A potential confound in previous studies of HIV-associated cognitive dysfunction is that HAART may be neurotoxic. Thus, observed effects, attributed to HIV, may be in part due to HAART. It is unclear whether and to what extent current medications contribute to observed brain dysfunction. We studied changes in functional connectivity and cerebral blood flow in HIV uninfected (HIV–) individuals before and after being given two common antiretroviral medications: efavirenz and ritonavir. Neither drug was associated with significant changes in functional connectivity or cerebral blood flow. Our results suggests that previous changes in functional connectivity and cerebral blood flow in HIV infected individuals receiving HAART may largely due to the virus and remaining reservoirs and less due to toxic action of these anti-retroviral medications. © 2015 Springer Science+Business Media New York


Author Keywords
cART;  HAART;  HIV;  Neurotoxicity


Document Type: Article in Press
Source: Scopus




Dhar, R.a , Yuan, K.a , Kulik, T.a , Chen, Y.c , Heitsch, L.b , An, H.c , Ford, A.a , Lee, J.-M.a
CSF Volumetric Analysis for Quantification of Cerebral Edema After Hemispheric Infarction
(2015) Neurocritical Care, 8 p. Article in Press. 

DOI: 10.1007/s12028-015-0204-z


a Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, Box 8111, St. Louis, MO, United States
b Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
c Department of Radiology, University of North Carolina, Chapel Hill, NC, United States


Abstract
Background: Malignant cerebral edema (CED) complicates at least 20 % of large hemispheric infarcts (LHI) and may result in neurological deterioration or death. Midline shift (MLS) is a standard but crude measure of edema severity. We propose that volumetric analysis of shifts in cerebrospinal fluid (CSF) over time provides a reliable means of quantifying the spectrum of edema severity after LHI. Methods: We identified 38 patients from 2008 to 2014 with NIHSS ≥8, baseline CT <6 h after stroke onset, at least 1 follow-up (FU) CT, and no parenchymal hematoma. The volumes of CSF (sulci, ventricles, and cisterns) ipsilateral (IL) and contralateral (CL) to infarct on baseline and FU CTs were quantified by manually assisted outlining with MIPAV image analysis software, as was infarct volume and MLS on FU CTs. Percentage change in CSF volumes (?CSF) from baseline to FU scans was correlated with MLS and compared in those with vs. without malignant edema (defined as hemicraniectomy, osmotic therapy, or death/neurological deterioration with MLS ≥5 mm). Results: 11 of 38 subjects (29 %) developed malignant edema. Neither baseline NIHSS nor CSF volume differed between those with and without edema (median NIHSS 18 vs. 13, p = 0.12, CSF volume 102 vs. 124 ml, p = 0.16). Inter-rater reliability for CSF measurements was excellent (intraclass correlation coefficient 0.97). ?CSF correlated strongly with MLS at peak edema (r = −0.75), even adjusting for infarct volume (p = 0.009). ?CSF was also greater in those with malignant edema [−55 % (IQR −49 to −62) vs. −36 % (−27 to −45), p = 0.004]. ?CSF was the greatest within IL sulci [−97 % (−86 to −99) vs. −71 % (−41 to −79), p = 0.002] but also significantly greater within CL sulci in those with malignant edema [−50 % (−29 to −65) vs. −25 % (0 to −31), p = 0.014]. More than half this CSF volume reduction occurred by the time of first FU CT around 24 h after stroke, while MLS rose later. Conclusions: Volumetric CSF analysis reliably quantifies CED and distinguishes those with malignant edema and MLS from those with a more benign course after LHI. ?CSF may provide an earlier and more sensitive indicator of edema severity across a broader dynamic range than MLS. © 2015 Springer Science+Business Media New York


Author Keywords
Brain edema;  Cerebrospinal fluid;  Neuroimaging;  Stroke


Document Type: Article in Press
Source: Scopus




Miller, C.M.a , Pineda, J.b , Corry, M.c , Brophy, G.d , Smith, W.S.e
Emergency Neurologic Life Support (ENLS): Evolution of Management in the First Hour of a Neurological Emergency
(2015) Neurocritical Care, 4 p. Article in Press. 

DOI: 10.1007/s12028-015-0170-5


a Neurocritical Care and Cerebrovascular Diseases, OhioHealth, Columbus, OH, United States
b Departments of Pediatrics and Neurology, Washington University School of Medicine, St. Louis, MO, United States
c City College of San Francisco Paramedic Program, San Francisco, CA, United States
d Departments of Pharmacotherapy and Outcomes Science and Neurosurgery, Virginia Commonwealth University, Richmond, VA, United States
e Department of Neurology, University of California, San Francisco, CA, United States


Abstract
Emergency neurological life support (ENLS) is an educational program designed to provide users advisory instruction regarding management for the first few hours of a neurological emergency. The content of the course is divided into 14 modules, each addressing a distinct category of neurological injury. The course is appropriate for practitioners and providers from various backgrounds who work in environments of variable medical complexity. The focus of ENLS is centered on a standardized treatment algorithm, checklists to guide early patient care, and a structured format for communication of findings and concerns to other healthcare professionals. Certification and training in ENLS is hosted by the Neurocritical Care Society. This document introduces the concept of ENLS and describes the revisions that constitute this second version. © 2015 Springer Science+Business Media New York


Author Keywords
Algorithm;  Critical care;  Emergency;  Neurocritical care;  Resuscitation


Document Type: Article in Press
Source: Scopus




Stevens, R.D.a , Cadena, R.S.b , Pineda, J.c
Emergency Neurological Life Support: Approach to the Patient with Coma
(2015) Neurocritical Care, 7 p. Article in Press. 

DOI: 10.1007/s12028-015-0174-1


a Departments of Anesthesiology and Critical Care Medicine; Neurology; Neurosurgery; and Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
b Departments of Neurology, Neurosurgery, and Emergency Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, United States
c Department of Pediatrics, Division of Critical Care Medicine, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Coma is an acute failure of neuronal systems governing arousal and awareness and represents a medical emergency. When encountering a comatose patient, the clinician must have an organized approach to detect easily remediable causes, prevent ongoing neurologic injury, and determine a hierarchical plan for diagnostic tests, treatments, and neuromonitoring. Coma was chosen as an Emergency Neurological Life Support protocol because timely medical and surgical interventions can be life-saving, and the initial work-up of such patients is critical to establishing a correct diagnosis. © 2015 Springer Science+Business Media New York


Author Keywords
Coma;  Consciousness;  Critical care;  Neurocritical care


Document Type: Article in Press
Source: Scopus




Jauch, E.C.a , Pineda, J.A.b , Claude Hemphill, J.c
Emergency Neurological Life Support: Intracerebral Hemorrhage
(2015) Neurocritical Care, 11 p. Article in Press. 

DOI: 10.1007/s12028-015-0167-0


a Division of Emergency Medicine and Department of Neurosciences, Medical University of South Carolina, Charleston, United States
b Department of Pediatrics and Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, University of California, San Francisco, United States


Abstract
Intracerebral hemorrhage (ICH) is a subset of stroke due to bleeding within the parenchyma of the brain. It is potentially lethal, and survival depends on ensuring an adequate airway, reversal of coagulopathy, and proper diagnosis. ICH was chosen as an Emergency Neurological Life Support protocol because intervention within the first critical hour may improve outcome, and it is critical to have site-specific protocols to drive care quickly and efficiently. © 2015 Springer Science+Business Media New York


Author Keywords
Coagulopathy;  ICH Score;  Intracerebral hemorrhage


Document Type: Article in Press
Source: Scopus




Stevens, R.D.a , Shoykhet, M.b , Cadena, R.c
Emergency Neurological Life Support: Intracranial Hypertension and Herniation
(2015) Neurocritical Care, 7 p. Article in Press. 

DOI: 10.1007/s12028-015-0168-z


a Departments of Anesthesiology and Critical Care Medicine, Neurology, Neurosurgery, and Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
b Pediatric Critical Care Medicine, Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
c Departments of Neurology, Neurosurgery, and Emergency Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, United States


Abstract
Sustained intracranial hypertension and acute brain herniation are “brain codes,” signifying catastrophic neurological events that require immediate recognition and treatment to prevent irreversible injury and death. As in cardiac arrest, a brain code mandates the organized implementation of a stepwise management algorithm. The goal of this emergency neurological life support protocol is to implement an evidence-based, standardized approach to the evaluation and management of patients with intracranial hypertension and/or herniation. © 2015 Springer Science+Business Media New York


Author Keywords
Brain edema;  Herniation;  Hyperventilation;  Osmotherapy


Document Type: Article in Press
Source: Scopus




Brophy, G.M.a , Human, T.b , Shutter, L.c
Emergency Neurological Life Support: Pharmacotherapy
(2015) Neurocritical Care, 21 p. Article in Press. 

DOI: 10.1007/s12028-015-0158-1


a Departments of Pharmacotherapy & Outcomes Science and Neurosurgery, Virginia Commonwealth University, Richmond, VA, United States
b Department of Clinical Pharmacy, Barnes-Jewish Hospital, Washington University in St. Louis, St. Louis, MO, United States
c Departments of Critical Care Medicine, Neurology & Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States


Abstract
The appropriate use of medications during Emergency Neurological Life Support (ENLS) is essential to optimize patient care. Important considerations when choosing the appropriate agent include the patient’s organ function and medication allergies, potential adverse drug effects, drug interactions, and critical illness and aging pathophysiologic changes. Critical medications used during ENLS include hyperosmolar therapy, anticonvulsants, antithrombotics, anticoagulant reversal and hemostatic agents, anti-shivering agents, neuromuscular blockers, antihypertensive agents, sedatives, vasopressors and inotropes, and antimicrobials. This article focuses on the important pharmacokinetic and pharmacodynamics characteristics, advantages and disadvantages, and clinical pearls of these therapies, providing practitioners with essential drug information to optimize pharmacotherapy in acutely ill neurocritical care patients. © 2015 Springer Science+Business Media New York


Author Keywords
Adverse drug event;  Drug interaction;  ENLS;  Medication;  Pharmacotherapy


Document Type: Article in Press
Source: Scopus




Rittenberger, J.C.a , Friess, S.b , Polderman, K.H.c
Emergency Neurological Life Support: Resuscitation Following Cardiac Arrest
(2015) Neurocritical Care, 10 p. Article in Press. 

DOI: 10.1007/s12028-015-0171-4


a Department of Emergency Medicine, University of Pittsburgh, Pittsburgh, PA, United States
b Department of Pediatrics, Washington University School of Medicine, St. Louis, St. Louis, MO, United States
c Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States


Abstract
Cardiac arrest is the most common cause of death in North America. Neurocritical care interventions, including targeted temperature management (TTM), have significantly improved neurological outcomes in patients successfully resuscitated from cardiac arrest. Therefore, resuscitation following cardiac arrest was chosen as an emergency neurological life support protocol. Patients remaining comatose following resuscitation from cardiac arrest should be considered for TTM. This protocol will review induction, maintenance, and re-warming phases of TTM, along with management of TTM side effects. Aggressive shivering suppression is necessary with this treatment to ensure the maintenance of a target temperature. Ancillary testing, including electrocardiography, computed tomography and/or magnetic resonance imaging of the brain, continuous electroencephalography monitoring, and correction of electrolyte, blood gas, and hematocrit changes, are also necessary to optimize outcomes. © 2015 Springer Science+Business Media New York


Author Keywords
Brain cooling;  Cardiac arrest;  Hypothermia;  Myocardial infarction;  Sudden death;  Temperature management


Document Type: Article in Press
Source: Scopus




Garvin, R.a , Venkatasubramanian, C.b , Lumba-Brown, A.c , Miller, C.M.d
Emergency Neurological Life Support: Traumatic Brain Injury
(2015) Neurocritical Care, 12 p. Article in Press. 

DOI: 10.1007/s12028-015-0176-z


a University of Texas Science Health Science Center, San Antonio, TX, United States
b Stanford University, Stanford, CA, United States
c Pediatric Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
d OhioHealth, Columbus, OH, United States


Abstract
Traumatic Brain Injury (TBI) was chosen as an Emergency Neurological Life Support topic due to its frequency, the impact of early intervention on outcomes for patients with TBI, and the need for an organized approach to the care of such patients within the emergency setting. This protocol was designed to enumerate the practice steps that should be considered within the first critical hour of neurological injury. © 2015 Springer Science+Business Media New York


Author Keywords
Emergency;  Neurocritical care;  Trauma;  Traumatic brain injury


Document Type: Article in Press
Source: Scopus




Stein, D.M.a , Pineda, J.A.b , Roddy, V.c , Knight, W.A., IVd
Emergency Neurological Life Support: Traumatic Spine Injury
(2015) Neurocritical Care, 10 p. Article in Press. 

DOI: 10.1007/s12028-015-0169-y


a R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, University of Maryland School of Medicine, Baltimore, United States
b Department of Pediatrics and Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Emergency Medicine, Broward Health Medical Center, Fort Lauderdale, FL, United States
d Departments of Emergency Medicine and Neurosurgery, University of Cincinnati, Cincinnati, OH, United States


Abstract
Traumatic spine injuries (TSIs) carry significantly high risks of morbidity, mortality, and exorbitant health care costs from associated medical needs following injury. For these reasons, TSI was chosen as an ENLS protocol. This article offers a comprehensive review on the management of spinal column injuries using the best available evidence. Alhough the review focuses primarily on cervical spinal column injuries, thoracolumbar injuries are briefly discussed as well. The initial emergency department clinical evaluation of possible spinal fractures and cord injuries, along with the definitive early management of confirmed injuries, is also covered. © 2015 Springer Science+Business Media New York


Author Keywords
Neurotrauma;  Spine fracture;  Traumatic myelopathy


Document Type: Article in Press
Source: Scopus




Stein, L.R.a b d , Zorumski, C.F.b c , Imai, S.-I.a , Izumi, Y.b
Nampt is required for long-term depression and the function of GluN2B subunit-containing NMDA receptors
(2015) Brain Research Bulletin, 119, pp. 41-51. 

DOI: 10.1016/j.brainresbull.2015.10.005


a Department of Developmental Biology, Washington University School of Medicine, Campus Box 8103, 660 South Euclid Avenue, St. Louis, MO, United States
b Department of Psychiatry, The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, Campus Box 8134, 660 South Euclid Avenue, St. Louis, MO, United States
c Department of Anatomy and Neurobiology, Washington University School of Medicine, Campus Box 8134, 660 South Euclid Avenue, St. Louis, MO, United States
d Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, CA, United States


Abstract
Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme/cosubstrate for many biological processes in cellular metabolism. The rate-limiting step in the major pathway of mammalian NAD+ biosynthesis is mediated by nicotinamide phosphoribosyltransferase (Nampt). Previously, we showed that mice lacking Nampt in forebrain excitatory neurons (CamKIIαNampt-/- mice) exhibited hyperactivity, impaired learning and memory, and reduced anxiety-like behaviors. However, it remained unclear if these functional effects were accompanied by synaptic changes. Here, we show that CamKIIαNampt-/- mice have impaired induction of long-term depression (LTD) in the Schaffer collateral pathway, but normal induction of long-term potentiation (LTP), at postnatal day 30. Pharmacological assessments demonstrated that CamKIIαNampt-/- mice also display dysfunction of synaptic GluN2B (NR2B)-containing N-methyl-d-aspartate receptors (NMDARs) prior to changes in NMDAR subunit expression. These results support a novel, important role for Nampt-mediated NAD+ biosynthesis in LTD and in the function of GluN2B-containing NMDARs. © 2015 .


Author Keywords
GluN2B;  Long-term depression;  N-methyl-d-aspartate receptor;  NAD+;  Nampt;  NR2B


Document Type: Article
Source: Scopus




Ma, Q.a g , Vaida, F.a , Wong, J.a , Sanders, C.A.a , Kao, Y.-T.a , Croteau, D.a , Clifford, D.B.b , Collier, A.C.c , Gelman, B.B.d , Marra, C.M.c , McArthur, J.C.e , Morgello, S.f , Simpson, D.M.f , Heaton, R.K.a , Grant, I.a , Letendre, S.L.a , For The Charter Grouph
Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients
(2015) Journal of NeuroVirology, 9 p. Article in Press. 

DOI: 10.1007/s13365-015-0382-7


a University of California, San Diego, 220 Dickinson Street, Suite A, San Diego, CA, United States
b Washington University, St. Louis, MO, United States
c University of Washington, Seattle, WA, United States
d University of Texas Medical Branch, Galveston, TX, United States
e Johns Hopkins University, Baltimore, MD, United States
f Mount Sinai School of Medicine, New York, NY, United States
g Department of Pharmacy Practice, University at Buffalo, 315 Kapoor Hall, Buffalo, NY, United States


Abstract
Neurocognitive (NC) complications continue to afflict a substantial proportion of HIV-infected people taking effective antiretroviral therapy (ART). One contributing mechanism for this is antiretroviral neurotoxicity. Efavirenz (EFV) is associated with short-term central nervous system (CNS) toxicity, but less is known about its long-term effects. Our objective was to compare NC functioning with long-term use of EFV to that of a comparator, lopinavir-ritonavir (LPV/r), in a cohort of well-characterized adults. Four hundred forty-five patients were selected from the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort based on their use of either EFV (n = 272, mean duration 17.9 months) or LPV/r (n = 173, mean duration 16.4 months) and the lack of severe NC comorbidities. All patients had undergone standardized comprehensive NC testing. Univariable and multivariable analyses to predict NC outcomes were performed. Compared with LPV/r users, EFV users were more likely to be taking their first ART regimen (p < 0.001), were less likely to have AIDS (p < 0.001) or hepatitis C virus (HCV) coinfection (p < 0.05), had higher CD4+ T cell nadirs (p < 0.001), had lower peak (p < 0.001) and current (p < 0.001) plasma HIV RNA levels, and were less likely to have detectable HIV RNA in cerebrospinal fluid (CSF) (p < 0.001). Overall, EFV users had worse speed of information processing (p = 0.04), verbal fluency (p = 0.03), and working memory (p = 0.03). An interaction with HCV serostatus was present: Overall among HCV seronegatives (n = 329), EFV users performed poorly, whereas among HCV seropositives (n = 116), LPV/r users had overall worse performance. In the subgroup with undetectable plasma HIV RNA (n = 269), EFV users had worse speed of information processing (p = 0.02) and executive functioning (p = 0.03). Substantial differences exist between EFV and LPV/r users in this observational cohort, possibly because of channeling by clinicians who may have prescribed LPV/r to more severely ill patients or as second-line therapy. Despite these differences, EFV users had worse functioning in several cognitive abilities. A potentially important interaction was identified that could indicate that the NC consequences of specific antiretroviral drugs may differ based on HCV coinfection. The complexity of these data is substantial, and findings would best be confirmed in a randomized clinical trial. © 2015 Journal of NeuroVirology, Inc.


Author Keywords
Efavirenz;  Hepatitis C virus coinfection;  Long-term antiretroviral therapy;  Lopinavir/ritonavir;  Neurocognitive function;  Neurotoxicity


Document Type: Article in Press
Source: Scopus




Schwantes-An, T.-H.a b , Zhang, J.a bq , Chen, L.-S.c , Hartz, S.M.c , Culverhouse, R.C.d , Chen, X.e , Coon, H.f , Frank, J.g , Kamens, H.M.h i j , Konte, B.k , Kovanen, L.l , Latvala, A.m , Legrand, L.N.n , Maher, B.S.o , Melroy, W.E.h i , Nelson, E.C.c , Reid, M.W.p , Robinson, J.D.q , Shen, P.-H.r , Yang, B.-Z.s , Andrews, J.A.p , Aveyard, P.t , Beltcheva, O.u , Brown, S.A.v , Cannon, D.S.f , Cichon, S.w x , Corley, R.P.h , Dahmen, N.y , Degenhardt, L.z aa , Foroud, T.ab , Gaebel, W.ac , Giegling, I.k , Glatt, S.J.ad , Grucza, R.A.c , Hardin, J.ae , Hartmann, A.M.k , Heath, A.C.c , Herms, S.w x , Hodgkinson, C.A.r , Hoffmann, P.w x , Hops, H.p , Huizinga, D.ag , Ising, M.ah , Johnson, E.O.ai , Johnstone, E.aj , Kaneva, R.P.u , Kendler, K.S.e , Kiefer, F.ak , Kranzler, H.R.al , Krauter, K.S.h am , Levran, O.an , Lucae, S.ah , Lynskey, M.T.ao , Maier, W.af , Mann, K.ap , Martin, N.G.aq , Mattheisen, M.w ar as , Montgomery, G.W.aq , Müller-Myhsok, B.ah , Murphy, M.F.at , Neale, M.C.e , Nikolov, M.A.c u , Nishita, D.ae , Nöthen, M.M.w , Nurnberger, J.au , Partonen, T.l , Pergadia, M.L.c , Reynolds, M.av , Ridinger, M.aw bo , Rose, R.J.ax , Rouvinen-Lagerström, N.l , Scherbaum, N.ay , Schmäl, C.ap , Soyka, M.az ba , Stallings, M.C.h bb , Steffens, M.bc , Treutlein, J.g , Tsuang, M.v , Wall, T.L.v , Wodarz, N.aw , Yuferov, V.an , Zill, P.bd , Bergen, A.W.ae , Chen, J.e , Cinciripini, P.M.q , Edenberg, H.J.be , Ehringer, M.A.h i , Ferrell, R.E.bf , Gelernter, J.s bg bh , Goldman, D.r , Hewitt, J.K.h bb , Hopfer, C.J.bi , Iacono, W.G.n , Kaprio, J.l m bj , Kreek, M.J.an , Kremensky, I.M.u , Madden, P.A.F.c , McGue, M.n , Munafò, M.R.bk , Philibert, R.A.bl , Rietschel, M.g , Roy, A.bm , Rujescu, D.k , Saarikoski, S.T.l , Swan, G.E.bp , Todorov, A.A.c , Vanyukov, M.M.av , Weiss, R.B.bn , Bierut, L.J.c , Saccone, N.L.a
Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts
(2015) Behavior Genetics, 19 p. Article in Press. 

DOI: 10.1007/s10519-015-9737-3


a Department of Genetics, Washington University School of Medicine, 4523 Clayton Avenue, Campus Box 8232, St. Louis, MO, United States
b Genometrics Section, Computational and Statistical Genomics Branch, Division of Intramural Research, National Human Genome Research Institute, US National Institutes of Health (NIH), Baltimore, MD, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
d Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States
e Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States
f Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, United States
g Department of Genetic Epidemiology in Psychiatry, Medical Faculty Mannheim, Central Institute of Mental Health, Heidelberg University, Mannheim, Germany
h Institute for Behavioral Genetics, University of Colorado, Boulder, CO, United States
i Department of Integrative Physiology, University of Colorado, Boulder, CO, United States
j Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA, United States
k Department of Psychiatry, Universitätsklinikum Halle (Saale), Halle (Saale), Germany
l Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland
m Department of Public Health, University of Helsinki, Helsinki, Finland
n Department of Psychology, University of Minnesota, Minneapolis, MN, United States
o Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States
p Oregon Research Institute, Eugene, OR, United States
q Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
r Section of Human Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, United States
s Department of Psychiatry, Yale University, New Haven, CT, United States
t Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom
u Department of Medical Chemistry and Biochemistry, Molecular Medicine Center, Medical University-Sofia, Sofia, Bulgaria
v Department of Psychiatry, University of California San Diego, La Jolla, CA, United States
w Department. of Genomics, Life and Brain Center, Institute of Human Genetics, University of Bonn, Bonn, Germany
x Division of Medical Genetics, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
y Ökumenisches Hainich-Klinikum, Mühlhausen/Thüringen, Germany
z National Drug and Alcohol Research Centre, University of New South Wales, Randwick, NSW, Australia
aa School of Population and Global Health, University of Melbourne, Melbourne, Australia
ab Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
ac University of Düsseldorf, Düsseldorf, Germany
ad Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, United States
ae Center for Health Sciences, Biosciences Division, SRI International, Menlo Park, CA, United States
af University of Bonn, Bonn, Germany
ag Institute of Behavioral Science, University of Colorado, 80309, Boulder, CO, United States
ah Max-Planck-Institute of Psychiatry, Munich, Germany
ai Behavioral Health Research Division, Research Triangle Institute International, Durham, NC, United States
aj Department of Oncology, University of Oxford, Oxford, United Kingdom
ak Department of Addictive Behavior and Addiction Medicine, Medical Faculty Mannheim, Central Institute of Mental Health, Heidelberg University, Mannheim, Germany
al Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
am Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO, United States
an Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, United States
ao Addictions Department, Institute of Psychiatry, King’s College London, London, United Kingdom
ap Medical Faculty Mannheim, Central Institute of Mental Health, Heidelberg University, Mannheim, Germany
aq Department of Genetic Epidemiology, Queensland Institute of Medical Research, Brisbane, QLD, Australia
ar Harvard School of Public Health, Boston, MA, United States
as Aarhus University, Aarhus, Denmark
at Childhood Cancer Research Group, University of Oxford, Oxford, United Kingdom
au Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
av Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, United States
aw Department of Psychiatry, University Medical Center Regensburg, University of Regensburg, Regensburg, Germany
ax Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States
ay Addiction Research Group at the Department of Psychiatry and Psychotherapy, LVR Hospital Essen, University of Duisburg-Essen, Essen, Germany
az Department of Psychiatry, University of Munich, Munich, Germany
ba Private Hospital Meiringen, Meiringen, Switzerland
bb Department of Psychology & Neuroscience, University of Colorado, Boulder, CO, United States
bc Research Department, Federal Institute for Drugs and Medical Devices (BfArM), Kurt-Georg-Kiesinger-Allee 3, Bonn, Germany
bd University of Munich, Munich, Germany
be Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
bf Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, United States
bg Department of Genetics, Yale University, New Haven, CT, United States
bh Department of Neurobiology, Yale University, New Haven, CT, United States
bi Department of Psychiatry, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
bj Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland
bk MRC Integrative Epidemiology Unit, UK Centre for Tobacco and Alcohol Studies, and School of Experimental Psychology, University of Bristol, Bristol, United Kingdom
bl Department of Psychiatry, University of Iowa, Iowa City, IA, United States
bm Psychiatry Service, Department of Veteran Affairs, New Jersey VA Health Care System, East Orange, NJ, United States
bn Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, United States
bo Psychiatric Hospital, Konigsfelden, Windisch, Switzerland
bp Department of Medicine, Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA, United States
bq Key Laboratory of Brain Function and Disease, School of Life Sciences, Chinese Academy of Sciences, University of Science and Technology of China, Hefei, Anhui, China


Abstract
The mu1 opioid receptor gene, OPRM1, has long been a high-priority candidate for human genetic studies of addiction. Because of its potential functional significance, the non-synonymous variant rs1799971 (A118G, Asn40Asp) in OPRM1 has been extensively studied, yet its role in addiction has remained unclear, with conflicting association findings. To resolve the question of what effect, if any, rs1799971 has on substance dependence risk, we conducted collaborative meta-analyses of 25 datasets with over 28,000 European-ancestry subjects. We investigated non-specific risk for “general” substance dependence, comparing cases dependent on any substance to controls who were non-dependent on all assessed substances. We also examined five specific substance dependence diagnoses: DSM-IV alcohol, opioid, cannabis, and cocaine dependence, and nicotine dependence defined by the proxy of heavy/light smoking (cigarettes-per-day >20 vs. ≤10). The G allele showed a modest protective effect on general substance dependence (OR = 0.90, 95 % C.I. [0.83–0.97], p value = 0.0095, N = 16,908). We observed similar effects for each individual substance, although these were not statistically significant, likely because of reduced sample sizes. We conclude that rs1799971 contributes to mechanisms of addiction liability that are shared across different addictive substances. This project highlights the benefits of examining addictive behaviors collectively and the power of collaborative data sharing and meta-analyses. © 2015 Springer Science+Business Media New York


Author Keywords
Addiction;  Genetic association;  Opioid receptor;  OPRM1;  Single nucleotide polymorphism (SNP);  Substance dependence


Document Type: Article in Press
Source: Scopus




Akrouh, A.a b , Kerschensteiner, D.a c d e
Morphology and function of three VIP-expressing amacrine cell types in the mouse retina
(2015) Journal of Neurophysiology, 114 (4), pp. 2431-2438. 

DOI: 10.1152/jn.00526.2015


a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
b Washington University School of Medicine, St. Louis, MO, United States
c Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, United States
e Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Amacrine cells (ACs) are the most diverse class of neurons in the retina. The variety of signals provided by ACs allows the retina to encode a wide range of visual features. Of the 30 –50 AC types in mammalian species, few have been studied in detail. Here, we combine genetic and viral strategies to identify and to characterize morphologically three vasoactive intestinal polypeptide-expressing GABAergic AC types (VIP1-, VIP2-, and VIP3-ACs) in mice. Somata of VIP1- and VIP2-ACs reside in the inner nuclear layer and somata of VIP3- ACs in the ganglion cell layer, and they show asymmetric distributions along the dorsoventral axis of the retina. Neurite arbors of VIP-ACs differ in size (VIP1-ACs ≈ VIP3-ACs > VIP2-ACs) and stratify in distinct sublaminae of the inner plexiform layer. To analyze light responses and underlying synaptic inputs, we target VIP-ACs under 2-photon guidance for patch-clamp recordings. VIP1-ACs depolarize strongly to light increments (ON) over a wide range of stimulus sizes but show size-selective responses to light decrements (OFF), depolarizing to small and hyperpolarizing to large stimuli. The switch in polarity of OFF responses is caused by pre- and postsynaptic surround inhibition. VIP2- and VIP3-ACs both show small depolarizations to ON stimuli and large hyperpolarizations to OFF stimuli but differ in their spatial response profiles. Depolarizations are caused by ON excitation outweighing ON inhibition, whereas hyperpolarizations result from pre- and postsynaptic OFF-ON crossover inhibition. VIP1-, VIP2-, and VIP3-ACs thus differ in response polarity and spatial tuning and contribute to the diversity of inhibitory and neuromodulatory signals in the retina. © 2015 the American Physiological Society.


Author Keywords
Amacrine cell;  Receptive field;  Retina;  VIP


Document Type: Article
Source: Scopus




Lee, S.J.a , Cloninger, C.R.b , Chae, H.c
Cloninger's temperament and character traits in medical students of Korea with problem eating behaviors
(2015) Comprehensive psychiatry, 59, pp. 98-106. 

DOI: 10.1016/j.comppsych.2015.02.006


a Department of Psychiatry, School of Medicine, Washington University in St. Louis, MO 63110, USA; Department of Psychotherapy, School of Nursing and Public Health, Kyungil University, Daegu, 712-701, South Korea
b Department of Psychiatry, School of Medicine, Washington University in St. Louis, MO 63110, USA
c Department of Psychiatry, School of Medicine, Washington University in St. Louis, MO 63110, USA; Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Busan, 609-735, South Korea. Electronic address:


Abstract
BACKGROUND AND OBJECTIVE: The personality profiles of patients with eating disorder have been extensively investigated, but those of people in the general population with eating behavior problems need to be evaluated to assess the relationship between personality, health behavior and level of overall well-being in non-clinical samples.

DESIGN: Temperament and character traits, reasons for over-eating, and the negative influence of functional dyspepsia on quality of life were measured by the Temperament and Character Inventory (TCI), Dutch Eating Behavior Questionnaire (DEBQ), and Functional Dyspepsia Quality of Life (FDQOL) inventory, respectively, in 199 Korean medical students. The associations among TCI, FDQOL, DEBQ and body mass index (BMI) were examined by correlational analysis. Multiple regression analysis was carried out to measure how well personality (TCI) accounted for patterns of overeating (DEBQ) and impaired quality of life from functional dyspepsia (FDQOL).

RESULTS: Individual differences in personality (especially harm-avoidance, self-transcendence, and self-directedness) were weakly associated with overeating and impaired quality of life from functional dyspepsia. Gender, social desirability and body mass index also played important roles in predicting eating behavior problems in the nonclinical population.

DISCUSSION AND CONCLUSION: We found that the personality traits observed in clinical patients with eating disorders are also found in people with eating behavior problems in the nonclinical population of Korea. The ways that personality traits affect eating behaviors were discussed along with recommendations for future studies in light of the limitations of available data. Copyright © 2015 Elsevier Inc. All rights reserved.


Document Type: Article
Source: Scopus




Nabors, L.B.a , Portnow, J.b , Ammirati, M.c , Baehring, J.d , Brem, H.e , Brown, P.f , Butowski, N.g , Chamberlain, M.C.h , Fenstermaker, R.A.i , Friedman, A.j , Gilbert, M.R.f , Hattangadi-Gluth, J.k , Holdhoff, M.e , Junck, L.l , Kaley, T.m , Lawson, R.n , Loeffler, J.S.o , Lovely, M.P.p , Moots, P.L.q , Mrugala, M.M.h , Newton, H.B.c , Parney, I.r , Raizer, J.J.s , Recht, L.t , Shonka, N.u , Shrieve, D.C.v , Sills, A.K., Jr.q , Swinnen, L.J.e , Tran, D.w , Tran, N.x , Vrionis, F.D.x , Weiss, S.y , Wen, P.Y.z , McMillian, N.aa , Engh, A.M.aa
Central nervous system cancers, version 1.2015: Featured updates to the NCCN guidelines
(2015) JNCCN Journal of the National Comprehensive Cancer Network, 13 (10), pp. 1191-1202. 


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


Abstract
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Central Nervous System (CNS) Cancers provide interdisciplinary recommendations for managing adult CNS cancers. Primary and metastatic brain tumors are a heterogeneous group of neoplasms with varied outcomes and management strategies. These NCCN Guidelines Insights summarize the NCCN CNS Cancers Panel's discussion and highlight notable changes in the 2015 update. This article outlines the data and provides insight into panel decisions regarding adjuvant radiation and chemotherapy treatment options for high-risk newly diagnosed low-grade gliomas and glioblastomas. Additionally, it describes the panel's assessment of new data and the ongoing debate regarding the use of alternating electric field therapy for high-grade gliomas. © National Comprehensive Cancer Network, Inc. 2015, All rights reserved.


Document Type: Review
Source: Scopus




Whalen, D.J.a , Dixon-Gordon, K.b , Belden, A.C.a , Barch, D.a , Luby, J.L.a
Correlates and Consequences of Suicidal Cognitions and Behaviors in Children Ages 3 to 7 Years
(2015) Journal of the American Academy of Child and Adolescent Psychiatry, 54 (11), pp. 926-937. Cited 1 time.

DOI: 10.1016/j.jaac.2015.08.009


a Washington University, School of Medicine, Department of Psychiatry, 4444 Forest Park, Suite 2100, St. Louis, MO, United States
b University of Massachusetts Amherst, Amerst, MA, United States


Abstract
Objective Despite research documenting the existence of depression and other psychiatric disorders in early childhood, little is known about the nature and consequences of suicidal cognitions and behaviors (SI) in young children ages 3 to 7 years. The identification of trajectories of SI across childhood is a critical step toward preventing childhood suicide. Method Participants were 306 children enrolled in a prospective longitudinal investigation of young children and their families. Children and their families completed a baseline assessment between ages 3 and 7 years, and at least 1 follow-up assessment (ages 7-12 years). Child psychopathology, suicidal thoughts, plans, and behaviors were assessed via parent and trained interviewer report before age 9, and also with self-report after age 9. Data on maternal history of psychopathology, as well as maternal and family history of suicide attempts, were also obtained through parent report. Results Controlling for a range of clinical and demographic variables, early-childhood SI (as defined as suicidal thoughts, behavior, or any expression of plans/attempts occurring before age 7) and suicidal themes in play were concurrently associated with childhood attention-deficit/hyperactivity (ADHD) and oppositional defiant/conduct disorders (ODD/CD). Early-childhood SI also predicted school-age depression and ODD/CD; however, these findings were no longer significant after controlling for the same diagnoses at the childhood baseline. Longitudinal analysis indicated that early-childhood SI was a robust predictor of school-age SI, even after accounting for psychiatric disorders at both time points. Conclusion Extending current research, these findings demonstrate that early-childhood SI confers significant risk for continuation into school-age SI and is concurrently associated with ADHD and ODD/CD. Although the meaning of early-childhood SI remains unclear, results suggest that it is a clinically important phenomenon that should be carefully assessed and taken seriously as a marker of risk for ongoing suicidal ideation/behavior. These findings suggest that early screening for SI in childhood is indicated in clinical settings, particularly in children less than 7 years of age with depression and externalizing disorders. © 2015 American Academy of Child and Adolescent Psychiatry.


Author Keywords
early childhood;  longitudinal;  psychopathology;  suicidality


Document Type: Article
Source: Scopus




Araujo, D.J.a , Anderson, A.G.a , Berto, S.a , Runnels, W.a , Harper, M.a , Ammanuel, S.a , Rieger, M.A.b c , Huang, H.-C.a d , Rajkovich, K.a , Loerwald, K.W.a , Dekker, J.D.e , Tucker, H.O.e , Dougherty, J.D.b c , Gibson, J.R.a , Konopka, G.a
FoxP1 orchestration of ASD-relevant signaling pathways in the striatum
(2015) Genes and Development, 29 (20), pp. 2081-2096. 

DOI: 10.1101/gad.267989.115


a Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, United States
b Department of Genetics, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
d Department of Biology, Jackson State University, Jackson, MS, United States
e University of Texas at Austin, Section of Molecular Genetics and Microbiology, Austin, TX, United States


Abstract
Mutations in the transcription factor Forkhead box p1 (FOXP1) are causative for neurodevelopmental disorders such as autism. However, the function of FOXP1 within the brain remains largely uncharacterized. Here, we identify the gene expression program regulated by FoxP1 in both human neural cells and patient-relevant heterozygous Foxp1 mouse brains. We demonstrate a role for FoxP1 in the transcriptional regulation of autism-related pathways as well as genes involved in neuronal activity. We show that Foxp1 regulates the excitability of striatal medium spiny neurons and that reduction of Foxp1 correlates with defects in ultrasonic vocalizations. Finally, we demonstrate that FoxP1 has an evolutionarily conserved role in regulating pathways involved in striatal neuron identity through gene expression studies in human neural progenitors with altered FOXP1 levels. These data support an integral role for FoxP1 in regulating signaling pathways vulnerable in autism and the specific regulation of striatal pathways important for vocal communication. © 2015 Araujo et al.


Author Keywords
Autism;  Gene expression;  Neuronal activity;  Striatum;  Ultrasonic vocalizations


Document Type: Article
Source: Scopus




Greenberg, J.K.a , Yarbrough, C.K.a , Radmanesh, A.d , Godzik, J.e , Yu, M.a , Jeffe, D.B.c , Smyth, M.D.a , Park, T.S.a , Piccirillo, J.F.b , Limbrick, D.D.a
In reply: Chiari severity index: A novel grading system intended for preoperative counseling
(2015) Neurosurgery, 77 (5), p. E842. 

DOI: 10.1227/NEU.0000000000000936


a Departments of Neurological Surgery, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
b Departments of Otolaryngology, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
c Departments of Medicine, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
d Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States
e Barrow Neurological Institute, Phoenix, AZ, United States


Document Type: Letter
Source: Scopus




Fondell, E.a , Oreilly, E.J.a , Fitzgerald, K.C.a , Falcone, G.J.b c , Kolonel, L.N.d , Park, Y.e f , Gapstur, S.M.g , Ascherio, A.a b h
Intakes of caffeine, coffee and tea and risk of amyotrophic lateral sclerosis: Results from five cohort studies
(2015) Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 16 (5-6), pp. 366-371. 

DOI: 10.3109/21678421.2015.1020813


a Department of Nutrition, Harvard School of Public Health, 655 Huntington Ave, Boston, MA, United States
b Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States
c Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
d Epidemiology Program, Cancer Center, University of Hawaii, Honolulu, HI, United States
e Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States
f Division of Public Health Sciences, Washington University School of Medicine, St. Louis, MO, United States
g Epidemiology Research Program, American Cancer Society, Atlanta, GA, United States
h Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States


Abstract
Caffeine is thought to be neuroprotective by antagonizing the adenosine A2A receptors in the brain and thereby protecting motor neurons from excitotoxicity. We examined the association between consumption of caffeine, coffee and tea and risk of amyotrophic lateral sclerosis (ALS).Longitudinal analyses based on over 1,010,000 males and females in five large cohort studies (the Nurses Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the National Institutes of Health-AARP Diet and Health Study). Cohort-specific multivariable-adjusted risk ratios (RR) and 95% confidence intervals (CI) estimates of ALS incidence or death were estimated by Cox proportional hazards regression and pooled using random-effects models. Results showed that a total of 1279 cases of ALS were documented during a mean of 18 years of follow-up. Caffeine intake was not associated with ALS risk; the pooled multivariable-adjusted RR comparing the highest to the lowest quintile of intake was 0.96 (95% CI 0.81-1.16). Similarly, neither coffee nor tea was associated with ALS risk. In conclusion, the results of this large study do not support associations of caffeine or caffeinated beverages with ALS risk. © 2015 Informa Healthcare.


Author Keywords
Amyotrophic lateral sclerosis;  caffeine;  epidemiology;  longitudinal cohort studies;  motor neuron disease


Document Type: Article
Source: Scopus




Amaya, S.a , Doris, J.M.b
No excuses: Performance mistakes in morality
(2015) Handbook of Neuroethics, pp. 253-272. 

DOI: 10.1007/978-94-007-4707-4_120


a Department of Philosophy, Universidad de los Andes, Bogotá, Colombia
b Philosophy-Neuroscience-Psychology Program and Philosophy Department, Washington University, St. Louis, MT, United States


Abstract
Philosophical accounts of moral responsibility are standardly framed by two platitudes. According to them, blame requires the presence of a moral defect in the agent and the absence of excuses. In this chapter, this kind of approach is challenged. It is argued that (a) people sometimes violate moral norms due to performance mistakes, (b) it often appears reasonable to hold them responsible for it, and (c) their mistakes cannot be traced to their moral qualities or to the presence of excuses. In the end, the implications for discussions of moral responsibility are discussed. Associated Press report Posted: 01/25/2013 08:18:46 AM MSTCOLONIE, N.Y. (AP) – Authorities say a New York man who left his 1-year-old son in his car for eight hours in frigid weather only realized his mistake after a call from his wife. Police in the Albany suburb of Colonie say the man forgot to drop off his son at day care and left the child strapped in the backseat of the car when he parked outside his office Thursday morning. © Springer Science+Business Media Dordrecht 2015.


Document Type: Book Chapter
Source: Scopus




Trang, T.a b , Al-Hasani, R.c d , Salvemini, D.e , Salter, M.W.f , Gutstein, H.g , Cahill, C.M.h
Pain and poppies: The good, the bad, and the ugly of Opioid analgesics
(2015) Journal of Neuroscience, 35 (41), pp. 13879-13888. 

DOI: 10.1523/JNEUROSCI.2711-15.2015


a Departments of Comparative Biology and Experimental Medicine, Calgary, AB, Canada
b Departments of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
c Departments of Anesthesiology, St. Louis, MO, United States
d Departments of Anatomy–Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, St. Louis, MO, United States
f Hospital for Sick Children, Toronto, ON, Canada
g MD Anderson Cancer Center, Houston, TX, United States
h Department of Anaesthesiology and Perioperative Care, University of California Irvine, Irvine, CA, United States


Abstract
Treating pain is one of the most difficult challenges in medicine and a key facet of disease management. The isolation of morphine by Friedrich Sertu¨rner in 1804 added an essential pharmacological tool in the treatment of pain and spawned the discovery of a new class of drugs known collectively as opioid analgesics. Revered for their potent pain-relieving effects, even Morpheus the god of dreams could not have dreamt that his opium tincture would be both a gift and a burden to humankind. To date, morphine and other opioids remain essential analgesics for alleviating pain. However, their use is plagued by major side effects, such as analgesic tolerance (diminished pain-relieving effects), hyperalgesia (increased pain sensitivity), and drug dependence. This review highlights recent advances in understanding the key causes of these adverse effects and explores the effect of chronic pain on opioid reward. © 2015 the authors.


Document Type: Review
Source: Scopus




Pearson, C.R.a , Kaysen, D.b , Belcourt, A.c , Stappenbeck, C.A.b , Zhou, C.d , Smartlowit-Briggs, L.e , Whitefoot, P.f
Post-traumatic stress disorder and hiv risk behaviors among rural american Indian/Alaska native women
(2015) American Indian and Alaska Native Mental Health Research, 22 (3), pp. 1-22. 


a Indigenous Wellness Research Institute School of Social Work, University of Washington, PO Box 354900, Seattle, WA, United States
b Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States
c College of Health Professions and Biomedical Sciences, University of Montana, United States
d Seattle Children's Research Institute, Center for Child Health Behavior and Development, United States
e Brown School of Social Work, Washington University, St. Louis, MO, United States
f Toppenish (Washington) School District, United States


Abstract
We assessed the relationship between post-traumatic stress disorder (PTSD), binge drinking, and HIV sexual risk behavior by examining number of unprotected sex acts and number of sexual partners in the past 6 months among 129 sexually active American Indian women. A total of 51 (39.5%) young women met PTSD criteria. Among women who met the PTSD criteria, binge drinking was associated with a 35% increased rate of unprotected sex (IRR 1.35, p < .05), and there was a stronger association between increased binge drinking and risk of more sexual partners (IRR 1.21, p < .001) than among women who did not meet PTSD criteria (IRR 1.08, p < .01) with a difference of 13% (p < .05). HIV intervention and prevention interventions in this population likely would benefit from the inclusion of efforts to reduce binge drinking and increase treatment of PTSD symptoms.


Document Type: Article
Source: Scopus




Choi, D.a , Fox, Z.a , Albert, T.b , Arts, M.c , Balabaud, L.d , Bunger, C.e , Buchowski, J.M.f , Coppes, M.H.g , Depreitere, B.h , Fehlings, M.G.i , Harrop, J.b , Kawahara, N.j , Martin-Benlloch, J.A.k , Massicotte, E.M.i , Mazel, C.d , Oner, F.C.l , Peul, W.c m , Quraishi, N.n , Tokuhashi, Y.o , Tomita, K.p , Verlaan, J.J.l , Wang, M.q , Crockard, H.A.a
Prediction of quality of life and survival after surgery for symptomatic spinal metastases: A multicenter cohort study to determine suitability for surgical treatment
(2015) Neurosurgery, 77 (5), pp. 698-708. 

DOI: 10.1227/NEU.0000000000000907


a Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, University College London, London, United Kingdom
b Departments of Neurosurgery and Orthopedic Surgery, Thomas Jefferson University and Hospitals, Philadelphia, PA, United States
c Department of Neurosurgery, Medical Center Haaglanden, Haaglanden, Netherlands
d Department of Orthopedic Surgery, L'Institut Mutualiste Montsouris, Paris, France
e Department of Orthopedic Surgery, University Hospital of Aarhus, Aarhus, Denmark
f Departments of Orthopedic and Neurological Surgery, Washington University, St. Louis, MO, United States
g Department of Neurosurgery, Groningen, Netherlands
h Division of Neurosurgery, University Hospital Leuven, Leuven, Belgium
i Division of Neurosurgery and Spinal Program, University of Toronto, Toronto Western Hospital, Toronto, ON, Canada
j Department of Orthopedic Surgery, Kanazawa Medical University Hospital, Kanazawa, Japan
k Spinal Unit, Hospital Universitario Dr Peset, Valencia, Spain
l Department of Orthopedic Surgery, University Medical Center Utrecht, Utrecht, Netherlands
m Department of Neurosurgery, Leiden University Medical Centre, Leiden, Netherlands
n Centre for Spine Studies and Surgery, Queens Medical Centre, Nottingham, United Kingdom
o Department of Orthopaedic Surgery, Nihon University, School of Medicine, Japan
p Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan
q Department of Neurosurgery, Jackson Memorial Hospital, University of Miami, Miami, FL, United States


Abstract
BACKGROUND: Surgery for symptomatic spinal metastases aims to improve quality of life, pain, function, and stability. Complications in the postoperative period are not uncommon; therefore, it is important to select appropriate patients who are likely to benefit the greatest from surgery. Previous studies have focused on predicting survival rather than quality of life after surgery. OBJECTIVE: To determine preoperative patient characteristics that predict postoperative quality of life and survival in patients who undergo surgery for spinal metastases. METHODS: In a prospective cohort study of 922 patients with spinal metastases who underwent surgery, we performed preoperative and postoperative assessment of EuroQol EQ-5D quality of life, visual analog score for pain, Karnofsky physical functioning score, complication rates, and survival. RESULTS: The primary tumor type, number of spinal metastases, and presence of visceral metastases were independent predictors of survival. Predictors of quality of life after surgery included preoperative EQ-5D (P .002), Frankel score (P <.001), and Karnofsky Performance Status (P <.001). CONCLUSION: Data from the largest prospective surgical series of patients with symptomatic spinal metastases revealed that tumor type, the number of spinal metastases, and the presence of visceral metastases are the most useful predictors of survival and that quality of life is best predicted by preoperative Karnofsky, Frankel, and EQ-5D scores. The Karnofsky score predicts quality of life and survival and is easy to determine at the bedside, unlike the EQ-5D index. Karnofsky score, tumor type, and spinal and visceral metastases should be considered the 4 most important prognostic variables that influence patient management. © 2015 by the Congress of Neurological Surgeons.


Author Keywords
Prognosis;  Quality of life;  Spinal metastases;  Surgery;  Survival


Document Type: Article
Source: Scopus

Bailey, R.R., Klaesner, J.W., Lang, C.E.

Quantifying Real-World Upper-Limb Activity in Nondisabled Adults and Adults with Chronic Stroke
(2015) Neurorehabilitation and Neural Repair, 29 (10), pp. 969-978. 

DOI: 10.1177/1545968315583720


Program in Physical Therapy, Washington University, School of Medicine in St Louis, 4444 Forest Park, Campus Box 8502, St Louis, MO, United States


Abstract
Background. Motor capability is commonly assessed inside the clinic, but motor performance in real-world settings (ie, outside of the clinic) is seldom assessed because measurement tools are lacking. Objective. To quantify real-world bilateral upper-limb (UL) activity in nondisabled adults and adults with stroke using a recently developed accelerometry-based methodology. Methods. Nondisabled adults (n = 74) and adults with chronic stroke (n = 48) wore accelerometers on both wrists for 25 to 26 hours. Motor capability was assessed using the Action Research Arm Test (ARAT). Accelerometry-derived variables were calculated to quantify intensity of bilateral UL activity (ie, bilateral magnitude) and the contribution of both ULs to activity (magnitude ratio) for each second of activity. Density plots were used to examine each second of bilateral UL activity throughout the day. Results. Nondisabled adults demonstrated equivalent use of dominant and nondominant ULs, indicated by symmetrical density plots and a median magnitude ratio of -0.1 (interquartile range [IQR] = 0.3), where a value of 0 indicates equal activity between ULs. Bilateral UL activity intensity was lower (P <.001) and more lateralized in adults with stroke, as indicated by asymmetrical density plots and a lower median magnitude ratio (-2.2; IQR = 6.2, P <.001). Density plots were similar between many stroke participants who had different ARAT scores, indicating that real-world bilateral UL activity was similar despite different motor capabilities. Conclusions. Quantification and visualization of real-world bilateral UL activity can be accomplished using this novel accelerometry-based methodology and complements results obtained from clinical tests of function when assessing recovery of UL activity following neurological injury. © American Society of Neurorehabilitation.


Author Keywords
accelerometry;  bilateral upper limb activity;  motor capability;  motor performance;  outcomes assessment;  real-world activity


Document Type: Article
Source: Scopus

 

Ulrich, J.D.a b c , Huynh, T.-P.a b c , Holtzman, D.M.a b c

Re-evaluation of the Blood-Brain Barrier in the Presence of Alzheimer's Disease Pathology
(2015) Neuron, 88 (2), pp. 237-239. 

DOI: 10.1016/j.neuron.2015.10.008


a Department of Neurology, Washington University, 660 South Euclid Avenue, Box 8111, St. Louis, MO, United States
b Hope Center for Neurological Disorders, Washington University, 660 South Euclid Avenue, Box 8111, St. Louis, MO, United States
c The Knight Alzheimer's Disease Research Center, Washington University, 660 South Euclid Avenue, Box 8111, St. Louis, MO, United States


Abstract
Blood-brain barrier disruption is believed to occur in Alzheimer's disease, which could influence the bioavailability of drugs within the brain. However, in this issue of Neuron, Bien-Ly et al. (2015) report no evidence of widespread blood-brain barrier dysfunction. Blood-brain barrier disruption is believed to occur in Alzheimer's disease, which could influence the bioavailability of drugs within the brain. However, in this issue of Neuron, Bien-Ly et al. (2015) report no evidence of widespread blood-brain barrier dysfunction. © 2015 Elsevier Inc.


Document Type: Short Survey
Source: Scopus




Meltz Steinberg, K.a , Nicholas, T.J.a , Koboldt, D.C.a , Yu, B.b , Mardis, E.a , Pamphlett, R.c
Whole genome analyses reveal no pathogenetic single nucleotide or structural differences between monozygotic twins discordant for amyotrophic lateral sclerosis
(2015) Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 16 (5-6), pp. 385-392. 

DOI: 10.3109/21678421.2015.1040029


a Genome Institute, Washington University School of Medicine, St. Louis, MO, United States
b Department of Medical Genomics, Royal Prince Alfred Hospital and Sydney Medical School, University of Sydney, New South Wales, Australia
c Stacey MND Laboratory, Discipline of Pathology, Sydney Medical School, Brain and Mind Research Institute, University of Sydney, Sydney, NSW, Australia


Abstract
The contribution of genetic and environmental factors to the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) remains unclear. To investigate the genetic component of the disease, we performed whole genome sequencing on ALS discordant monozygotic twins. Illumina whole genome sequencing on white blood cell DNA of five ALS-discordant monozygotic twin pairs (10 samples in total) yielded
30x coverage per individual. All single nucleotide variants, indels, and structural variants (copy number variants, inversions and translocations) were called and evaluated for functional consequence, evolutionary conservation, population frequency and overlap with known ALS associated variants and genes. Results showed that no validated discordant coding or regulatory single nucleotide variants or indels were found, and nor were any genome-wide discordant structural variants detected. Concordant variants of particular interest were: 1) two rare, highly-conserved heterozygous non-synonymous variants in SYT9 and EWSR1, genes previously associated with ALS (out of 2044 rare heterozygous variants detected); 2) three rare homozygous missense variants; and 3) three novel copy number deletions that overlapped genes. In conclusion, no convincing coding or regulatory nucleotide or genome-wide structural differences were found between ALS discordant monozygotic twins. The results suggest that more work is needed to elucidate possible environmental, epigenetic, oligogenic and somatic genetic factors that could underlie susceptibility to sporadic ALS. © 2015 Informa Healthcare.


Author Keywords
Amyotrophic lateral sclerosis;  gene variant;  genetics;  genomics;  monozygotic twin study;  motor neuron disease;  whole genome sequencing

 


Document Type: Article
Source: Scopus