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WUSTL Neuroscience Publications Archive - October 2015

October 2015
 
October 28, 2015
 
Gupte, R.P.a b c , Kadunganattil, S.b c , Shepherd, A.J.a b c , Merrill, R.a , Planer, W.b , Bruchas, M.R.b , Strack, S.a , Mohapatra, D.P.a b c d

Convergent phosphomodulation of the major neuronal dendritic potassium channel Kv4.2 by pituitary adenylate cyclase-activating polypeptide
(2016) Neuropharmacology, 101, pp. 291-308. 

DOI: 10.1016/j.neuropharm.2015.10.006


a Department of Pharmacology, University of Iowa Roy J. and Lucile A. Carver College of Medicine, Iowa City, IA, United States
b Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
c Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, United States
d Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO, United States


Abstract
The endogenous neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is secreted by both neuronal and non-neuronal cells in the brain and spinal cord, in response to pathological conditions such as stroke, seizures, chronic inflammatory and neuropathic pain. PACAP has been shown to exert various neuromodulatory and neuroprotective effects. However, direct influence of PACAP on the function of intrinsically excitable ion channels that are critical to both hyperexcitation as well as cell death, remain largely unexplored. The major dendritic K+ channel Kv4.2 is a critical regulator of neuronal excitability, back-propagating action potentials in the dendrites, and modulation of synaptic inputs. We identified, cloned and characterized the downstream signaling originating from the activation of three PACAP receptor (PAC1) isoforms that are expressed in rodent hippocampal neurons that also exhibit abundant expression of Kv4.2 protein. Activation of PAC1 by PACAP leads to phosphorylation of Kv4.2 and downregulation of channel currents, which can be attenuated by inhibition of either PKA or ERK1/2 activity. Mechanistically, this dynamic downregulation of Kv4.2 function is a consequence of reduction in the density of surface channels, without any influence on the voltage-dependence of channel activation. Interestingly, PKA-induced effects on Kv4.2 were mediated by ERK1/2 phosphorylation of the channel at two critical residues, but not by direct channel phosphorylation by PKA, suggesting a convergent phosphomodulatory signaling cascade. Altogether, our findings suggest a novel GPCR-channel signaling crosstalk between PACAP/PAC1 and Kv4.2 channel in a manner that could lead to neuronal hyperexcitability. © 2015 Elsevier Ltd. All Rights Reserved.


Author Keywords
Extracellular-signal-regulated kinase (ERK);  G protein-coupled receptor (GPCR);  Ion channel modulation;  Kv4.2;  Pituitary adenylate cyclase-activating peptide (PACAP);  Potassium channel;  Protein kinase A (PKA)


Document Type: Article
Source: Scopus



Diringer, M.N.
The evolution of the clinical use of osmotic therapy in the treatment of cerebral Edema
(2016) Acta Neurochirurgica, Supplementum, 121, pp. 3-6. 

DOI: 10.1007/978-3-319-18497-5_1


Neurocritical Care Division, Department of Neurology, Washington University, Campus Box 8111, 660 S Euclid Ave, St Louis, MO, United States


Document Type: Book Chapter
Source: Scopus



Pachman, D.R.a , Qin, R.a , Seisler, D.K.a , Smith, E.M.L.b , Beutler, A.S.a , Ta, L.E.a , Lafky, J.M.a , Wagner-Johnston, N.D.c , Ruddy, K.J.a , Dakhil, S.d , Staff, N.P.a , Grothey, A.a , Loprinzi, C.L.a
Clinical course of oxaliplatin-induced neuropathy: Results from the randomized phase III trial N08CB (Alliance)
(2015) Journal of Clinical Oncology, 33 (30), pp. 3416-3422. 

DOI: 10.1200/JCO.2014.58.8533


a Mayo Clinic, 200 First St, SW, Rochester, MN, United States
b University of Michigan, Ann Arbor, MI, United States
c Washington University School of Medicine, Saint Louis, MO, United States
d Cancer Center of Kansas, Wichita, KS, United States


Abstract
Purpose: Given that the clinical course of oxaliplatin-induced neuropathy is not well defined, the current study was performed to better understand clinical parameters associated with its presentation Methods: Acute and chronic neuropathy was evaluated in patients receiving adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) on study N08CB (North Central Cancer Treatment Group, Alliance) Acute neuropathy was assessed by having patients complete daily questionnaires for 6 days with each cycle of FOLFOX. Before each dose of FOLFOX and as long as 18 months after chemotherapy cessation, chronic neurotoxicity was assessed with use of the 20-item, European Organisation for Research and Treatment of Cancer quality-of-life questionnaire for patients with chemotherapy-induced peripheral neuropathy. Results: Three hundred eight (89%) of the 346 patients had at least one symptom of acute neuropathy with the first cycle of FOLFOX; these symptoms included sensitivity to touching cold items (71%), sensitivity to swallowing cold items (71%), throat discomfort (63%), or muscle cramps (42%) Acute symptoms peaked at day 3 and improved, although they did not always resolve completely between treatments. These symptoms were about twice as severe in cycles 2 through 12 as they were in cycle 1. For chronic neurotoxicity, tingling was the most severe symptom, followed by numbness and then pain. During chemotherapy, symptoms in the hands were more prominent than they were in the feet; by 18 months, symptoms were more severe in the feet than they were in the hands. Patients with more severe acute neuropathy during the first cycle of therapy experienced more chronic sensory neurotoxicity (P < .0001) Conclusion: Acute oxaliplatin-induced neuropathy symptoms do not always completely resolve between treatment cycles and are only half as severe on the first cycle as compared with subsequent cycles. There is a correlation between the severities of acute and chronic neuropathies. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.


Document Type: Article
Source: Scopus



van Stavern, R.B., Egan, R.A.
Should Patients With Acute Central Retinal Artery Occlusion Be Treated With Intra-arterial t-PA?: Response
(2015) Journal of Neuro-Ophthalmology, . Article in Press. 

DOI: 10.1097/WNO.0000000000000307


Stroke and General Neurology Sections, Washington University in St. Louis School of Medicine, St. Louis, Missouri Oregon Neurology, Tualatin, Oregon


Document Type: Article in Press
Source: Scopus



Carney, R.M., Freedland, K.E., Steinmeyer, B., Rubin, E.H., Mann, D.L., Rich, M.W.
Cardiac Risk Markers and Response to Depression Treatment in Patients With Coronary Heart Disease
(2015) Psychosomatic Medicine, . Article in Press. 

DOI: 10.1097/PSY.0000000000000245


From the Departments of Psychiatry (Carney, Freedland, Steinmeyer, Rubin) and Medicine (Mann, Rich), Washington University School of Medicine, St Louis, Missouri.


Abstract
BACKGROUND: Depression is associated with an increased risk of mortality in patients with coronary heart disease. There is evidence that this risk may be reduced in patients who respond to depression treatment. The purpose of this study was to determine whether cardiac risk markers predict poor response to depression treatment and, second, whether they improve with successful treatment. METHODS: One hundred fifty-seven patients with stable coronary heart disease who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for a moderate to severe major depressive episode were treated with cognitive behavior therapy, either alone or combined with an antidepressant, for up to 16 weeks. Depression, physical activity, sleep quality, thyroid hormones (total thyroxine [T4] and free T4), and inflammatory blood markers (C-reactive protein, interleukin-6, tumor necrosis factor) were assessed at baseline and after 16 weeks of treatment. RESULTS: The mean (SD) Beck Depression Inventory scores were 30.2 (8.5) at baseline and 8.5 (7.8) at 16 weeks. More than 50% of the participants met the criteria for depression remission (17-item Hamilton Rating Scale for Depression ≤7) at 16 weeks. Only free T4 thyroid hormone at baseline predicted poor response to depression treatment after adjustment for potential confounders (p = .004). Improvement in sleep quality (p = .012) and physical activity level (p = .041) correlated with improvement in depression. None of the inflammatory markers predicted posttreatment depression or changed with depression. CONCLUSIONS: Thyroid hormone (T4) level predicted depression treatment outcome, and improvement in depression correlated with improvement in sleep and physical activity. More detailed studies of thyroid function and objective assessments of sleep and physical activity in relation to depression improvement and cardiac outcomes are needed. © 2015 by American Psychosomatic Society.


Document Type: Article in Press
Source: Scopus



Narayanan, R., Tyagi, M., Hussein, A., Chhablani, J., Apte, R.S.
SCLERAL BUCKLING WITH WIDE-ANGLED ENDOILLUMINATION AS A SURGICAL EDUCATIONAL TOOL
(2015) Retina, . Article in Press. 

DOI: 10.1097/IAE.0000000000000792


*L. V. Prasad Eye Institute, Hyderabad, India; and †Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri.


Abstract
PURPOSE:: To describe a technique of wide-angle viewing as an educational tool in scleral buckling for rhegmatogenous retinal detachment. METHODS:: Retrospective comparative study of the reported technique was performed. Fourteen consecutive patients each who underwent Chandelier-assisted scleral buckling (CSB) or standard scleral buckling (SSB) using indirect ophthalmoscope were included. The primary outcome measure was the proportion of eyes that had successful reattachment of retina. RESULTS:: Mean study eye baseline visual acuity was 20/160 in the CSB group and 20/320 in SSB group. The primary reattachment rate was similar, with 13 of 14 eyes (92.85%) successfully attached in the CSB group and 12 of 14 eyes (85.71%) in the SSB group. The mean visual acuity improved from 20 of 160 to 20 of 80 in the CSB group, and 20 of 320 to 20 of 160 in the SSB group. The surgical time was significantly less in the CSB group (77.85 ± 16.37 minutes) compared with the SSB group (95.71 ± 26.59 minutes, P = 0.037). CONCLUSION:: Chandelier-assisted buckling had similar outcomes compared with standard buckling. It could be used as a valuable educational tool for teaching fellows by allowing them to simultaneously view the operative steps along with the surgeon. © 2015 by Ophthalmic Communications Society, Inc.


Document Type: Article in Press
Source: Scopus



Soto, F.a , Kerschensteiner, D.a b c d
Synaptic remodeling of neuronal circuits in early retinal degeneration
(2015) Frontiers in Cellular Neuroscience, 9 (OCT), art. no. 395, . 

DOI: 10.3389/fncel.2015.00395


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


Abstract
Photoreceptor degenerations are a major cause of blindness and among the most common forms of neurodegeneration in humans. Studies of mouse models revealed that synaptic dysfunction often precedes photoreceptor degeneration, and that abnormal synaptic input from photoreceptors to bipolar cells causes circuits in the inner retina to become hyperactive. Here, we provide a brief overview of frequently used mouse models of photoreceptor degenerations. We then discuss insights into circuit remodeling triggered by early synaptic dysfunction in the outer and hyperactivity in the inner retina. We discuss these insights in the context of other experimental manipulations of synaptic function and activity. Knowledge of the plasticity and early remodeling of retinal circuits will be critical for the design of successful vision rescue strategies. © 2015 Soto and Kerschensteiner.


Author Keywords
Circuit remodeling;  Developmental plasticity;  Lamination;  Mosaic;  Retina


Document Type: Review
Source: Scopus



Fritz, B.A., Kalarickal, P.L., Maybrier, H.R., Muench, M.R., Dearth, D., Chen, Y., Escallier, K.E., Ben Abdallah, A., Lin, N., Avidan, M.S.
Intraoperative Electroencephalogram Suppression Predicts Postoperative Delirium
(2015) Anesthesia and Analgesia, . Article in Press. 

DOI: 10.1213/ANE.0000000000000989


From the *Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri; and †Department of Mathematics, Washington University, St. Louis, Missouri.


Abstract
BACKGROUND:: Postoperative delirium is a common complication associated with increased morbidity and mortality, longer hospital stays, and greater health care expenditures. Intraoperative electroencephalogram (EEG) slowing has been associated previously with postoperative delirium, but the relationship between intraoperative EEG suppression and postoperative delirium has not been investigated. METHODS:: In this observational cohort study, 727 adult patients who received general anesthesia with planned intensive care unit admission were included. Duration of intraoperative EEG suppression was recorded from a frontal EEG channel (FP1 to F7). Delirium was assessed twice daily on postoperative days 1 through 5 with the Confusion Assessment Method for the intensive care unit. Thirty days after surgery, quality of life, functional independence, and cognitive ability were measured using the Veterans RAND 12-item survey, the Barthel index, and the PROMIS Applied Cognition-Abilities-Short Form 4a survey. RESULTS:: Postoperative delirium was observed in 162 (26%) of 619 patients assessed. When we compared patients with no EEG suppression with those divided into quartiles based on duration of EEG suppression, patients with more suppression were more likely to experience delirium (χ(4) = 25, P < 0.0001). This effect remained significant after we adjusted for potential confounders (odds ratio for log(EEG suppression) 1.22 [99% confidence interval, 1.06–1.40, P = 0.0002] per 1-minute increase in suppression). EEG suppression may have been associated with reduced functional independence (Spearman partial correlation coefficient −0.15, P = 0.02) but not with changes in quality of life or cognitive ability. Predictors of EEG suppression included greater end-tidal volatile anesthetic concentration and lower intraoperative opioid dose. CONCLUSIONS:: EEG suppression is an independent risk factor for postoperative delirium. Future studies should investigate whether anesthesia titration to minimize EEG suppression decreases the incidence of postoperative delirium. This is a substudy of the Systematic Assessment and Targeted Improvement of Services Following Yearlong Surgical Outcomes Surveys (SATISFY-SOS) surgical outcomes registry (NCT02032030). © 2015 International Anesthesia Research Society.


Document Type: Article in Press
Source: Scopus



Arias, E.J., Vajapey, S., Reynolds, M.R., Chicoine, M.R., Rich, K.M., Dacey, R.G., Jr., Dorward, I.G., Derdeyn, C.P., Moran, C.J., Cross, D.T., III, Zipfel, G.J., Dhar, R.
Utility of Screening for Cerebral Vasospasm Using Digital Subtraction Angiography
(2015) Stroke, . Article in Press. 

DOI: 10.1161/STROKEAHA.115.010081


From the Department of Neurological Surgery (E.J.A., S.V., M.R.R., M.R.C., K.M.R., R.G.D., I.G.D., C.P.D., C.J.M., D.T.C., G.J.Z.), Department of Neurology (C.P.D., C.J.M., D.T.C., G.J.Z., R.D.), and Mallinckrodt Institute of Radiology (C.P.D.,C.J.M., D.T.C.), Washington University School of Medicine, St Louis, MO.


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.


Document Type: Article in Press
Source: Scopus



Yarbrough, C.K., Ong, C.J., Beyer, A.B., Lipsey, K., Derdeyn, C.P.
Endovascular Thrombectomy for Anterior Circulation Stroke: Systematic Review and Meta-Analysis
(2015) Stroke, . Article in Press. 

DOI: 10.1161/STROKEAHA.115.009847


From the Department of Neurological Surgery (C.K.Y., C.P.D.), Department of Neurology (C.J.O., C.P.D.), Bernard Becker Medical Library (K.L.), and Mallinckrodt Institute of Radiology (C.P.D.), Washington University School of Medicine, St. Louis, MO; and Washington University School of Medicine, St. Louis, MO (A.B.B.).


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 not receiving intravenous thrombolysis (OR, 1.59; 95% CI, 0.86–2.95), 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.


Document Type: Article in Press
Source: Scopus



Ray, W.Z., Chang, J., Hawasli, A., Wilson, T.J., Yang, L.
Motor Nerve Transfers: A Comprehensive Review
(2015) Neurosurgery, . Article in Press. 

DOI: 10.1227/NEU.0000000000001029


*Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri; ‡Department of Neurological Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan


Abstract
: Brachial plexus and peripheral nerve injuries are exceedingly common. Traditional nerve grafting reconstruction strategies and techniques have not changed significantly over the last 3 decades. Increased experience and wider adoption of nerve transfers as part of the reconstructive strategy have resulted in a marked improvement in clinical outcomes. We review the options, outcomes, and indications for nerve transfers to treat brachial plexus and upper- and lower-extremity peripheral nerve injuries, and we explore the increasing use of nerve transfers for facial nerve and spinal cord injuries. Each section provides an overview of donor and recipient options for nerve transfer and of the relevant anatomy specific to the desired function. ABBREVIATIONS:: AIN, anterior interosseous nerveECRB, extensor carpi radialis brevisFCR, flexor carpi radialisFCU, flexor carpi ulnarisFDP, flexor digitorum profundusFDS, flexor digitorum superficialisFPL, flexor pollicis longusMCN, musculocutaneous nerveMPN, medial pectoral nerveMRC, Medical Research CouncilPIN, posterior interosseous nerveSAN, spinal accessory nerveSCI, spinal cord injuryTDN, thoracodorsal nerve © by the Congress of Neurological Surgeons.


Document Type: Article in Press
Source: Scopus



Lang, C.E., Lohse, K.R., Birkenmeier, R.L.
Dose and timing in neurorehabilitation: prescribing motor therapy after stroke
(2015) Current Opinion in Neurology, . Article in Press. 

DOI: 10.1097/WCO.0000000000000256


aProgram in Physical Therapy bProgram in Occupational Therapy, Department of Neurology, Washington University School of Medicine, Saint Louis, Missouri cSchool of Kinesiology, Auburn University, Auburn, Alabama, USA


Abstract
PURPOSE OF REVIEW: Prescribing the most appropriate dose of motor therapy for individual patients is a challenge because minimal data are available and a large number of factors are unknown. This review explores the concept of dose and reviews the most recent findings in the field of neurorehabilitation, with a focus on relearning motor skills after stroke. RECENT FINDINGS: Appropriate dosing involves the prescription of a specific amount of an active ingredient, at a specific frequency and duration. Dosing parameters, particularly amount, are not well defined or quantified in most studies. Compiling data across studies indicates a positive, moderate dose–response relationship, indicating that more movement practice results in better outcomes. This relationship is confounded by time after stroke, however, wherein longer durations of scheduled therapy may not be beneficial in the first few hours, days, and/or weeks. SUMMARY: These findings suggest that substantially more movement practice may be necessary to achieve better outcomes for people living with the disabling consequences of stroke. Preclinical investigations are needed to elucidate many of the unknowns and allow for a more biologically driven rehabilitation prescription process. Likewise, clinical investigations are needed to determine the dose–response relationships and examine the potential dose–timing interaction in humans. © 2015 Wolters Kluwer Health, Inc. All rights resereved.


Document Type: Article in Press
Source: Scopus



Kharasch, E.D., Regina, K.J., Blood, J., Friedel, C.
Methadone Pharmacogenetics: CYP2B6 Polymorphisms Determine Plasma Concentrations, Clearance, and Metabolism
(2015) Anesthesiology, . Article in Press. 

DOI: 10.1097/ALN.0000000000000867


From the Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri (E.D.K., K.J.R., J.B., C.F.); and Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St. Louis, Missouri (E.D.K.).


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 CYP2B6*6 polymorphism, deficiently catalyzes methadone metabolism in vitro. This investigation determined the influence of CYP2B6*6, and other allelic variants encountered, on methadone concentrations, clearance, and metabolism. METHODS:: Healthy volunteers in genotype cohorts CYP2B6*1/*1 (n = 21), CYP2B6*1/*6 (n = 20), and CYP2B6*6/*6 (n = 17), and also CYP2B6*1/*4 (n = 1), CYP2B6*4/*6 (n = 3), and CYP2B6*5/*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 CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively, compared with CYP2B6*1/*1. R-methadone apparent oral clearance was 25 and 35% lower in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively, compared with CYP2B6*1/*1. R- and S-methadone apparent oral clearance was threefold and fourfold greater in CYP2B6*4 carriers. IV and oral R- and S-methadone metabolism was significantly lower in CYP2B6*6 carriers compared with that of CYP2B6*1 homozygotes and greater in CYP2B6*4 carriers. Methadone metabolism and clearance were lower in African Americans in part because of the CYP2B6*6 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. © by 2015, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved.


Document Type: Article in Press
Source: Scopus



Aravamuthan, B.R., Mar, S.S., Williams, K.G.
Factors Associated With Discharge After Initial Emergency Treatment of Pediatric Migraine
(2015) Pediatric Emergency Care, . Article in Press. 

DOI: 10.1097/PEC.0000000000000533


From the *St. Louis Children's Hospital; and Department of †Neurology, and ‡Pediatrics Washington University in St. Louis, St. Louis, MO.


Abstract
OBJECTIVE: Migraine treatment varies widely in the pediatric emergency department (ED). Factors associated with discharge after only initial emergency treatment were examined. METHODS: A retrospective chart analysis was conducted on patients 6 to 18 years old who presented to the St. Louis Children's Hospital ED between January 1, 2008, and December 31, 2011, with a discharge diagnosis of migraine (n = 700 visits). Associations between patient characteristics, initial treatments, and rates of discharge after only initial treatment were examined using a generalized linear model and receiver operating characteristic curves. RESULTS: If exclusively oral or intranasal (PO/IN) medications were given initially (n = 285), ibuprofen alone was associated with lower discharge rates compared with other PO/IN medication regimens (P < 0.05). The only other variable associated with discharge was arrival pain score (P < 0.05). When ibuprofen alone was administered, pain scores equal to or lower than 5/10 were associated with the greatest sensitivity and specificity for discharge. With administration of other PO/IN regimens, pain scores equal to or lower than 8/10 were associated with the greatest sensitivity and specificity for discharge. If intravenous (IV) medications were given initially (n = 415), ketorolac given with an antinausea medication was associated with higher discharge rates compared with independent administration of these medications (P < 0.05). Intravenous medications were associated with higher discharge rates compared with PO/IN medications (P < 0.001). CONCLUSIONS: Arrival pain score may be used to help select initial migraine treatment in the pediatric ED. Initial use of PO/IN regimens including triptans or an antiemetic and concurrent administration of IV ketorolac with an antiemetic may be associated with higher rates of discharge after initial treatment alone. © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Document Type: Article in Press
Source: Scopus



Zhang, B.a b , Guan, F.a f g , Chen, G.b , Lin, H.c , Zhang, T.d , Feng, J.e , Li, L.b , Fu, D.b g
Common variants in SLC1A2 and schizophrenia: Association and cognitive function in patients with schizophrenia and healthy individuals
(2015) Schizophrenia Research, . Article in Press. 

DOI: 10.1016/j.schres.2015.10.012


a Department of Forensic Psychiatry, School of Medicine and Forensics, Xi'an Jiaotong University, Xi'an, China
b Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine and Forensics, Xi'an Jiaotong University, Xi'an, Shaanxi, China
c Xi'an Mental Health Center, Xi'an, Shannxi, China
d Department of Biology and Biomedical Sciences, Washington University in Saint Louis, MO, USA
e School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, China
f Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, China
g Institute of Human Genomics and Forensic Sciences, Xi'an, China


Abstract
SLC1A2 is reported to be responsible for the majority of glutamate uptake, which has a crucial role in neural development and synaptic plasticity, and a disturbance in glutamatergic transmission has been suggested to be involved in the pathophysiology of schizophrenia (SCZ) and cognition. To evaluate the relationship of common variants within SLC1A2 with SCZ and cognition in Han Chinese, 28 tag SNPs were genotyped in the discovery stage, which included 1117 cases and 2289 controls; significantly associated markers were genotyped in the replication stage with 2128 cases and 3865 controls. The rs4354668 SNP was identified to be significantly associated with SCZ in both datasets, and a similar pattern was also observed in the two-stage study on conducting imputation and haplotype association analyses. In addition, significant associations between the rs4354668 SNP and cognition were observed when processing the perseverative error of the Wisconsin Card Sorting Test in patients and controls. Our results provide supportive evidence for an effect of SLC1A2 on the etiology of SCZ, suggesting that genetic variation (rs4354668 and its haplotypes) in SLC1A2 may be involved in impaired executive function, which adds to the current body of knowledge regarding the risk of SCZ and the impairment of cognitive performance. © 2015.


Author Keywords
Cognitive performance;  Glutamate uptake;  Perseverative errors;  Schizophrenia susceptibility;  SLC1A2 gene


Document Type: Article in Press
Source: Scopus



Aschenbrenner, A.J.a , Balota, D.A.a b , Fagan, A.M.b c , Duchek, J.M.a , Benzinger, T.L.S.c d e , Morris, J.C.b c
Alzheimer Disease Cerebrospinal Fluid Biomarkers Moderate Baseline Differences and Predict Longitudinal Change in Attentional Control and Episodic Memory Composites in the Adult Children Study
(2015) Journal of the International Neuropsychological Society, 21 (8), pp. 573-583. 

DOI: 10.1017/S1355617715000776


a Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
c The Knight Alzheimer Disease Research Center, Washington University in St. Louis, St. Louis, MO, United States
d Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
e Department of Neurological Surgery, Washington University in St. Louis, St. Louis, MO, United States


Abstract
Cognitive measures that are sensitive to biological markers of Alzheimer disease (AD) pathology are needed to (a) facilitate preclinical staging, (b) identify individuals who are at the highest risk for developing clinical symptoms, and (c) serve as endpoints for evaluating the efficacy of interventions. The present study assesses the utility of two cognitive composite scores of attentional control and episodic memory as markers for preclinical AD pathology in a group of cognitively normal older adults (N=238), as part of the Adult Children Study. All participants were given a baseline cognitive assessment and follow-up assessments every 3 years over an 8-year period, as well as a lumbar puncture within 2 years of the initial assessment to collect cerebrospinal fluid (CSF) and amyloid tracer Pittsburgh compound-B scan for amyloid imaging. Results indicated that attentional control was correlated with levels of Aβ42 at the initial assessment whereas episodic memory was not. Longitudinally, individuals with high CSF tau exhibited a decline in both attention and episodic memory over the course of the study. These results indicate that measures of attentional control and episodic memory can be used to evaluate cognitive decline in preclinical AD and provide support that CSF tau may be a key mechanism driving longitudinal cognitive change. (JINS, 2015, 21, 573-583) Copyright © The International Neuropsychological Society 2015.


Author Keywords
Alzheimer disease;  Amyloid;  Attention;  Biological markers;  Episodic memory;  Longitudinal study


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, . Article in Press. 

DOI: 10.1016/j.drugalcdep.2015.07.003


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


Document Type: Article in Press
Source: Scopus



Long, J.D.a b ae , Paulsen, J.S.a c d ae , Soriano, I.D.e , Shadrick, C.e , Miller, A.e ae , Chiu, E.f , Preston, J.f , Goh, A.f , Antonopoulos, S.f , Loi, S.f , Chua, P.g , Komiti, A.g , Raymond, L.h , Decolongon, J.h , Fan, M.h , Coleman, A.h , Ross, C.A.i , Varvaris, M.i , Ong, M.i , Yoritomo, N.i , Mallonee, W.M.j , Suter, G.j , Samii, A.k , Freney, E.P.k , Macaraeg, A.k , Jones, R.l , Wood-Siverio, C.m , Factor, S.A.m , Barker, R.A.m , Mason, S.n , Guzman, N.V.n , McCusker, e.n , Griffith, J.n , Loy, C.n , McMillan, J.n , Gunn, D.n , Orth, M.o , Submuth, S.o , Barth, K.o , Trautmann, S.o , Schwenk, D.o , Eschenbach, C.o , Quaid, K.p , Wesson, M.p , Wojcieszek, J.p , Guttman, M.q , Sheinberg, A.q , Law, A.q , Karmalkar, I.q , Perlman, S.r , Clemente, B.r , Geschwind, M.D.s , Sha, S.s , Winer, J.s , Satris, G.s , Warner, T.t , Burrows, M.t , Rosser, A.u , Price, K.u , Hunt, S.u , Marshall, F.v , Chesire, A.v , Wodarski, M.v , Hickey, C.v , Panegyres, P.w , Lee, J.w , Tedesco, M.w , Maxwell, B.w , Perlmutter, J.x , Barton, S.x , Smith, S.x , Miedzybrodzka, Z.y , Rae, D.y , Vaughan, V.y , D'Alessandro, M.y , Craufurd, D.z , Bek, J.z , Howard, E.z , Mazzoni, P.aa , Marder, K.aa , Wasserman, P.aa , Kumar, R.ab , Erickson, D.ab , Reeves, C.ab , Nickels, B.ab , Wheelock, V.ac , Kjer, L.ac , Martin, A.ac , Farias, S.ac , Martin, W.ad , Suchowersky, O.ad , King, P.ad , Wieler, M.ad , Sran, S.ad , Ahmed, A.ak , Reece, C.ak , Bura, A.ak , Mourany, L.ak , Johnson, H.J.ae ai , Brashers-Krug, T.ae aj , Danzer, P.ae , Jeremy Bockholt, H.ae , Montross, K.ae , Harrington, D.af , Westervelt, H.ag , Aylward, E.ah , Rao, S.ai , Holly, Moseraj , Williams, J.aj , Downing, N.aj , Magnotta, V.A.aj , Vaidya, J.aj , O'Leary, D.aj , Kim, E.Y.aj
Multivariate prediction of motor diagnosis in Huntington's disease: 12 years of PREDICT-HD
(2015) Movement Disorders, 30 (12), pp. 1664-1672. 

DOI: 10.1002/mds.26364


a Department of Psychiatry, Carver College of Medicine, The University of Iowa, Iowa City, IA, United States
b Department of Biostatistics, College of Public Health, The University of Iowa, Iowa City, IA, United States
c Department of Neurology, Carver College of Medicine, The University of Iowa, Iowa City, IA, United States
d Department of Psychology, The University of Iowa, Iowa City, IA, United States
e University of Iowa, Iowa City, IA, United States
f St. Vincent's Hospital, The University of Melbourne, Kew, VIC, Australia
g The University of Melbourne, Royal Melbourne Hospital, Melbourne, VIC, Australia
h University of British Columbia, Vancouver, BC, Canada
i Johns Hopkins University, Baltimore, MD, United States
j Hereditary Neurological Disease Centre, Wichita, KS, United States
k University of Washington and VA Puget Sound Health Care System, Seattle, WA, United States
l Emory University School of Medicine, Atlanta, GA, United States
m John van Geest Centre for Brain Repair, Cambridge, United Kingdom
n Westmead Hospital, Sydney, NSW, Australia
o University of Ulm, Ulm, Germany
p Indiana University School of Medicine, Indianapolis, IN, United States
q Centre for Addiction and Mental Health, University of Toronto, Markham, ON, Canada
r UCLA Medical Center, Los Angeles, CA, United States
s University of California, San Francisco, San Francisco, CA, United States
t National Hospital for Neurology and Neurosurgery, London, United Kingdom
u Cardiff University, Cardiff, Wales, United Kingdom
v University of Rochester, Rochester, NY, United States
w Neurosciences Unit, Graylands, Selby-Lemnos and Special Care Health Services, Perth, WA, Australia
x Washington University, St. Louis, MO, United States
y Clinical Genetics Centre, Aberdeen, Scotland, United Kingdom
z University of Manchester, Manchester, United Kingdom
aa Columbia University Medical Center, New York, NY, United States
ab Colorado Neurological Institute, Englewood, CO, United States
ac University of California, Davis, Sacramento, CA, United States
ad University of Alberta, Edmonton, AB, Canada
ae Cleveland Clinic Foundation, Cleveland, OH, United States
af University of California, San Diego, United States
ag Rhode Island Hospital, Alpert Medical School of Brown University, United States
ah Seattle Children's Research Institute, United States
ai Cleveland Clinic, United States
aj University of Iowa, United States


Abstract
Background: It is well known in Huntington's disease that cytosine-adenine-guanine expansion and age at study entry are predictive of the timing of motor diagnosis. The goal of this study was to assess whether additional motor, imaging, cognitive, functional, psychiatric, and demographic variables measured at study entry increased the ability to predict the risk of motor diagnosis over 12 years. Methods: One thousand seventy-eight Huntington's disease gene-expanded carriers (64% female) from the Neurobiological Predictors of Huntington's Disease study were followed up for up to 12 y (mean=5, standard deviation=3.3) covering 2002 to 2014. No one had a motor diagnosis at study entry, but 225 (21%) carriers prospectively received a motor diagnosis. Analysis was performed with random survival forests, which is a machine learning method for right-censored data. Results: Adding 34 variables along with cytosine-adenine-guanine and age substantially increased predictive accuracy relative to cytosine-adenine-guanine and age alone. Adding six of the common motor and cognitive variables (total motor score, diagnostic confidence level, Symbol Digit Modalities Test, three Stroop tests) resulted in lower predictive accuracy than the full set, but still had twice the 5-y predictive accuracy than when using cytosine-adenine-guanine and age alone. Additional analysis suggested interactions and nonlinear effects that were characterized in a post hoc Cox regression model. Conclusions: Measurement of clinical variables can substantially increase the accuracy of predicting motor diagnosis over and above cytosine-adenine-guanine and age (and their interaction). Estimated probabilities can be used to characterize progression level and aid in future studies' sample selection. © 2015 The Authors.


Author Keywords
Assessment of cognitive disorders/dementia;  Clinical trials methodology/study design;  Huntington's disease;  Prognosis


Document Type: Article
Source: Scopus



Huang, S.a , Zhou, X.b , Xue, K.c , Wan, X.d , Yang, Z.e , Xu, D.f , Ivanovic, M.g , Yu, X.h i
Neural Cognition and Affective Computing on Cyber Language
(2015) Computational Intelligence and Neuroscience, 2015, art. no. 749326, . 

DOI: 10.1155/2015/749326


a Overseas Training Center, Shanghai International Studies University, Shanghai, China
b School of Humanities and Social Science, Sichuan Conservatory of Music, Chengdu, China
c School of Media and Design, Shanghai Jiaotong University, Shanghai, China
d School of Mathematical Sciences, Fudan University, Shanghai, China
e School of Software, Fudan University, Shanghai, China
f Department of Arts Management, Tianjin Conservatory of Music, Tianjin, China
g Department of Mathematics and Informatics, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia
h College of Arts and Science, Washington University in St. Louis, St. Louis, MO, United States
i Marketing Department, J.L. Kellogg School of Management, Northwestern University, Evanston, IL, United States


Abstract
Characterized by its customary symbol system and simple and vivid expression patterns, cyber language acts as not only a tool for convenient communication but also a carrier of abundant emotions and causes high attention in public opinion analysis, internet marketing, service feedback monitoring, and social emergency management. Based on our multidisciplinary research, this paper presents a classification of the emotional symbols in cyber language, analyzes the cognitive characteristics of different symbols, and puts forward a mechanism model to show the dominant neural activities in that process. Through the comparative study of Chinese, English, and Spanish, which are used by the largest population in the world, this paper discusses the expressive patterns of emotions in international cyber languages and proposes an intelligent method for affective computing on cyber language in a unified PAD (Pleasure-Arousal-Dominance) emotional space. © 2015 Shuang Huang et al.


Document Type: Article
Source: Scopus



Zammataro, M.a b , Sortino, M.A.b , Parenti, C.a , Gereau, R.W., IVc , Chiechio, S.a
HDAC and HAT inhibitors differently affect analgesia mediated by group II metabotropic glutamate receptors
(2014) Molecular Pain, 10 (1), art. no. 68, . 

DOI: 10.1186/1744-8069-10-68


a Department of Drug Sciences, Section of Pharmacology and Toxicology, University of Catania, Catania, Italy
b Department of Biomedical and Biotechnological Sciences Section of Pharmacology, University of Catania, Catania, Italy
c Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Background: Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are key players in epigenetic regulation of gene expression. Analgesic activity by HDAC inhibitors has been reported in different pain models including inflammatory and neuropathic pain. These drugs interfere with gene expression through different mechanisms including chromatin remodeling and/or activation of transcription factors. Among other targets, HDAC inhibitors regulate metabotropic glutamate receptors type 2 (mGlu2) expression in central and peripheral central nervous system. However whether inhibition of HAT activity also regulates mGlu2 expression has not been reported. Findings: Here we report that curcumin (CUR), a naturally occurring compound endowed with p300/CREB-binding protein HAT inhibitory activity, is able to induce a drastic down-regulation of the mGlu2 receptor in the mouse spinal cord after systemic administration together with a marked hypoacetylation of histones H3 and H4 in dorsal root ganglia (DRG). Furthermore, the analgesic activity of the mGlu2/3 agonist, LY379268 is lost after a 3-day treatment with CUR. Conversely the analgesic activity of LY379268 is potentiated in mice pretreated for 5 consecutive days with the HDAC inhibitor, Suberoylanilide Hydroxamic Acid (SAHA), known to induce mGlu2-upregulation. Conclusions: Our results demonstrate that systemically injected CUR is able to inhibit H3 and H4 acetylation in the DRG and to down-regulate mGlu2 receptors in the spinal cord. We also demonstrate that long term modification of the mGlu2 expression affects the analgesic properties of the orthosteric mGlu2/3 agonist, LY379268. These data open up the possibility that epigenetic modulators might be given in combination with "traditional" drugs in a context of a multi target approach for a better analgesic efficacy. © 2014 Zammataro et al.


Author Keywords
Curcumin;  Epigenetic modulation;  HAT;  HDAC;  Inflammatory pain;  MGlu2


Document Type: Article
Source: Scopus

October 21, 2015

Jin, M.a , Li, S.a , Hu, J.b , Jin, H.H.c , Jacobson, S.G.d , Bok, D.b
Functional rescue of retinal degeneration- Associated mutant RPE65 proteins
(2016) Advances in Experimental Medicine and Biology, 854, pp. 525-535. 

DOI: 10.1007/978-3-319-17121-0_70


a Department of Ophthalmology and Neuroscience Center, Louisiana State University Health Sciences Center, 2020 Gravier St. Suite D, New Orleans, LA, United States
b Jules Stein Eye Institute, University of California, Los Angeles, CA, United States
c Department of Biology, Washington University, St. Louis, MO, United States
d Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States


Abstract
More than 100 different mutations in the RPE65 gene are associated with inherited retinal degeneration. Although some missense mutations have been shown to abolish isomerase activity of RPE65, the molecular bases leading to loss of function and retinal degeneration remain incompletely understood. Here we show that several missense mutations resulted in significant decrease in expression level of RPE65 in the human retinal pigment epithelium cells. The 26S proteasome non- ATPase regulatory subunit 13, a newly identified negative regulator of RPE65, mediated degradation of mutant RPE65s, which were misfolded and formed aggregates in the cells. Many mutations, including L22P, T101I, and L408P, were mapped on nonactive sites of RPE65. Enzyme activities of these mutant RPE65s were significantly rescued at low temperature, whereas mutant RPE65s with a distinct active site mutation could not be rescued under the same conditions. 4-phenylbutyrate (PBA) displayed a significant synergistic effect on the low temperature-mediated rescue of the mutant RPE65s. Our results suggest that a low temperature eye mask and PBA, a FDA-approved oral medicine, may provide a promising “protein repair therapy” that can enhance the efficacy of gene therapy for delaying retinal degeneration caused by RPE65 mutations. © Springer International Publishing Switzerland 2016.


Author Keywords
Chemical chaperone;  Gene therapy;  Leber congenital amaurosis;  Low temperature;  Proteasome;  PSMD13;  Retina;  Retinitis pigmentosa;  Retinoid;  RPE65;  Visual cycle


Document Type: Book Chapter
Source: Scopus



Daiger, S.P.a b , Sullivan, L.S.a , Bowne, S.J.a , Koboldt, D.C.c , Blanton, S.H.d e , Wheaton, D.K.f , Avery, C.E.a , Cadena, E.D.a , Koenekoop, R.K.g , Fulton, R.S.c , Wilson, R.K.c , Weinstock, G.M.i , Lewis, R.A.h , Birch, D.G.f
Identification of a novel gene on 10q22.1 causing autosomal dominant retinitis pigmentosa (adRP)
(2016) Advances in Experimental Medicine and Biology, 854, pp. 193-200. 

DOI: 10.1007/978-3-319-17121-0_26


a Human Genetics Center, School of Public Health, The University of Texas HSC, 1200 Pressler St., Houston, TX, United States
b Ruiz Department of Ophthalmology and Visual Science, Medical School, The University of Texas Health Science Center, Houston, TX, United States
c The Genome Institute, Washington University School of Medicine, St. Louis, MO, United States
d John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, United States
e Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, United States
f The Retina Foundation of the Southwest, Dallas, TX, United States
g McGill Ocular Genetics Laboratory, Departments of Paediatric Surgery, Human Genetics and Ophthalmology, Montreal Children’s Hospital, McGill University Health Center, Montreal, QC, Canada
h Departments of Ophthalmology, Medicine, Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
i Microbial Genomics, The Jackson Laboratory for Genomic Medicine, Farmington, CT, United States


Abstract
Whole-genome linkage mapping identified a region on chromosome 10q21.3-q22.1 with a maximum LOD score of 3.0 at 0 % recombination in a sixgeneration family with autosomal dominant retinitis pigmentosa (adRP). All known adRP genes and X-linked RP genes were excluded in the family by a combination of methods. Whole-exome next-generation sequencing revealed a missense mutation in hexokinase 1, HK1 c.2539G > A, p.Glu847Lys, tracking with disease in all affected family members. One severely-affected male is homozygous for this region by linkage analysis and has two copies of the mutation. No other potential mutations were detected in the linkage region nor were any candidates identified elsewhere in the genome. Subsequent testing detected the same mutation in four additional, unrelated adRP families, for a total of five mutations in 404 probands tested (1.2 %). Of the five families, three are from the Acadian population in Louisiana, one is French Canadian and one is Sicilian. Haplotype analysis of the affected chromosome in each family and the homozygous individual revealed a rare, shared haplotype of 450 kb, suggesting an ancient founder mutation. HK1 is a widelyexpressed gene, with multiple, abundant retinal transcripts, coding for hexokinase 1. Hexokinase catalyzes phosphorylation of glucose to glusose-6-phospate, the first step in glycolysis. The Glu847Lys mutation is in a highly-conserved site, outside of the active site or known functional sites. © Springer International Publishing Switzerland 2016.


Author Keywords
Autosomal dominant retinitis pigmentosa;  Founder effect;  Hexokinase;  Linkage mapping;  Next-generation sequencing;  Retinitis pigmentosa


Document Type: Book Chapter
Source: Scopus



Liu, X.a t , Kelsoe, J.R.b c d , Greenwood, T.A.b , Kelsoe, J.R.e , Green-Wood, T.A.e , Nievergelt, C.M.e , McKinney, R.e , Shilling, P.D.e , Smith, E.N.e , Schork, N.J.f , Bloss, C.S.f , Nurnberger, J.I., Jr.g , Edenberg, H.J.g , Foroud, T.g , Koller, D.L.g , Gershon, E.S.h , Liu, C.h , Badner, J.A.h , Scheftner, W.A.i , Lawson, W.B.j , Nwulia, E.A.j , Hipolito, M.j , Coryell, W.k , Potash, J.B.k , Rice, J.l , Byerley, W.m , McMahon, F.J.n , Schulze, T.G.n , Berrettini, W.H.o , Zandi, P.P.p , Mahon, P.B.p , McInnis, M.G.q , Zöllner, S.q , Zhang, P.q , Craig, D.W.r , Szelinger, S.r , Barrett, T.B.s
A genome-wide association study of bipolar disorder with comorbid eating disorder replicates the SOX2-OT region
(2016) Journal of Affective Disorders, 189, art. no. 7712, pp. 141-149. 

DOI: 10.1016/j.jad.2015.09.029


a Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
b Department of Psychiatry, University of California San Diego, La Jolla, CA, United States
c San Diego Veterans Affairs Healthcare System, San Diego, CA, United States
d Institute for Genomic Medicine, University of California, La Jolla, San Diego, CA, United States
e University of California, San Diego, CA, United States
f Scripps Translational Science Institute, La Jolla, CA, United States
g Indiana University, Indianapolis, IN, United States
h University of Chicago, Chicago, IL, United States
i Rush University Medical Center, Chicago, IL, United States
j Howard University, Washington, DC, United States
k University of Iowa, Iowa City, IA, United States
l Washington University, St. Louis, MO, United States
m University of California, San Francisco, CA, United States
n National Institute of Mental Health Intramural Research Program, Bethesda, MD, United States
o University of Pennsylvania, Philadelphia, PA, United States
p Johns Hopkins School of Medicine, Baltimore, MD, United States
q University of Michigan, Ann Arbor, MI, United States
r Translational Genomics Research Institute, Phoenix, AZ, United States
s Portland Veterans Affairs Medical Center, Portland, OR, United States


Abstract
Background Bipolar disorder is a heterogeneous mood disorder associated with several important clinical comorbidities, such as eating disorders. This clinical heterogeneity complicates the identification of genetic variants contributing to bipolar susceptibility. Here we investigate comorbidity of eating disorders as a subphenotype of bipolar disorder to identify genetic variation that is common and unique to both disorders. Methods We performed a genome-wide association analysis contrasting 184 bipolar subjects with eating disorder comorbidity against both 1370 controls and 2006 subjects with bipolar disorder only from the Bipolar Genome Study (BiGS). Results The most significant genome-wide finding was observed bipolar with comorbid eating disorder vs. controls within SOX2-OT (p=8.9×10-8 for rs4854912) with a secondary peak in the adjacent FXR1 gene (p=1.2×10-6 for rs1805576) on chromosome 3q26.33. This region was also the most prominent finding in the case-only analysis (p=3.5×10-7 and 4.3×10-6, respectively). Several regions of interest containing genes involved in neurodevelopment and neuroprotection processes were also identified. Limitations While our primary finding did not quite reach genome-wide significance, likely due to the relatively limited sample size, these results can be viewed as a replication of a recent study of eating disorders in a large cohort. Conclusions These findings replicate the prior association of SOX2-OT with eating disorders and broadly support the involvement of neurodevelopmental/neuroprotective mechanisms in the pathophysiology of both disorders. They further suggest that different clinical manifestations of bipolar disorder may reflect differential genetic contributions and argue for the utility of clinical subphenotypes in identifying additional molecular pathways leading to illness. © 2015 Elsevier B.V.


Author Keywords
Bipolar disorder;  Comorbidity;  Eating disorders;  Genome-wide association (GWAS);  SOX2-OT


Document Type: Article
Source: Scopus



Mankus, A.M.a , Boden, M.T.b , Thompson, R.J.a
Sources of variation in emotional awareness: Age, gender, and socioeconomic status
(2016) Personality and Individual Differences, 89, art. no. 7066, pp. 28-33. 

DOI: 10.1016/j.paid.2015.09.043


a Department of Psychology, Washington University in St. Louis, 1 Brookings Dr., St. Louis, MO, United States
b Center for Innovation to Implementation, VA Palo Alto Health Care System, 795 Willow Rd., Menlo Park, CA, United States


Abstract
The present study examined associations between emotional awareness facets (type clarity, source clarity, negative emotion differentiation, voluntary attention, involuntary attention) and sociodemographic characteristics (age, gender, and socioeconomic status [SES]) in a large US sample (N. = 919). Path analyses-controlling for variance shared between sociodemographic variables and allowing emotional awareness facets to correlate-demonstrated that (a) age was positively associated with type clarity and source clarity, and inversely associated with involuntary attention; (b) gender was associated with all facets but type clarity, with higher source clarity, negative emotion differentiation, voluntary attention, and involuntary attention reported by women then men; and (c) SES was positively associated with type clarity with a very small effect. These findings extend our understanding of emotional awareness and identify future directions for research to elucidate the causes and consequences of individual differences in emotional awareness. © 2015 Elsevier Ltd.


Author Keywords
Age differences;  Attention to emotions;  Emotion differentiation;  Emotional awareness;  Emotional clarity;  Gender differences;  Socioeconomic status


Document Type: Article
Source: Scopus



Werner, K.B.a , McCutcheon, V.V.b , Challa, M.c , Agrawal, A.b , Lynskey, M.T.d , Conroy, E.e , Statham, D.J.f , Madden, P.A.F.b , Henders, A.K.g , Todorov, A.A.b , Heath, A.C.b , Degenhardt, L.g , Martin, N.G.f , Bucholz, K.K.b , Nelson, E.C.b
The association between childhood maltreatment, psychopathology, and adult sexual victimization in men and women: results from three independent samples
(2015) Psychological Medicine, 11 p. Article in Press. 

DOI: 10.1017/S0033291715002056


a George Warren Brown School of Social Work, Washington University, St Louis, MO, USA
b Alcoholism Research Center, Washington University School of Medicine, St Louis, MO, USA
c University of Illinois–Chicago School of Medicine, Chicago, IL, USA
d Institute of Psychiatry, Psychology & Neuroscience, King's College, London, UK
e Centre for Health Research, University of Western Sydney, Sydney, Australia
f QIMR Berghofer Medical Research Institute, Brisbane, Australia
g National Drug and Alcohol Research Center, University of New South Wales, Sydney, Australia


Abstract
Background: Childhood maltreatment (CM) has consistently been linked with adverse outcomes including substance use disorders and adult sexual revictimization. Adult sexual victimization itself has been linked with psychopathology but has predominately been studied in women. The current investigation examines the impact of CM and co-occurring psychopathology on adult sexual victimization in men and women, replicating findings in three distinct samples. Method: We investigated the association between continuous CM factor scores and adult sexual victimization in the Childhood Trauma Study (CTS) sample (N = 2564). We also examined the unique relationship between childhood sexual abuse (CSA) and adult sexual victimization while adjusting for co-occurring substance dependence and psychopathology. We replicated these analyses in two additional samples: the Comorbidity and Trauma Study (CATS; N = 1981) and the Australian Twin-Family Study of Alcohol Use Disorders (OZ-ALC; N = 1537). Results: Analyses revealed a significant association with CM factor scores and adult sexual victimization for both men and women across all three samples. The CSA factor score was strongly associated with adult sexual victimization after adjusting for substance dependence and psychopathology; higher odds ratios were observed in men (than women) consistently across the three samples. Conclusions: A continuous measure of CSA is independently associated with adult sexual trauma risk across samples in models that included commonly associated substance dependence and psychopathology as covariates. The strength of the association between this CSA measure and adult sexual victimization is higher in magnitude for men than women, pointing to the need for further investigation of sexual victimization in male community samples. Copyright © Cambridge University Press 2015


Author Keywords
Adult sexual revictimization;  childhood sexual abuse;  childhood trauma;  psychopathology;  sex disparities


Document Type: Article in Press
Source: Scopus



Hancock, D.B.a , Reginsson, G.W.b , Gaddis, N.C.c , Chen, X.d e , Saccone, N.L.f , Lutz, S.M.g , Qaiser, B.h , Sherva, R.i , Steinberg, S.b , Zink, F.b , Stacey, S.N.b , Glasheen, C.a , Chen, J.d , Gu, F.j , Frederiksen, B.N.k , Loukola, A.h , Gudbjartsson, D.F.b , Brüske, I.l , Landi, M.T.j , Bickeböller, H.m , Madden, P.n , Farrer, L.i o p q r s , Kaprio, J.h t u , Kranzler, H.R.v w , Gelernter, J.x y z aa , Baker, T.B.ab , Kraft, P.ac ad , Amos, C.I.ae af ag , Caporaso, N.E.j , Hokanson, J.E.ah , Bierut, L.J.n , Thorgeirsson, T.E.b , Johnson, E.O.ai , Stefansson, K.b aj
Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence
(2015) Translational Psychiatry, 5, art. no. e651, . 

DOI: 10.1038/tp.2015.149


a Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Research Division, Research Triangle Institute International, 3040 East Cornwallis Road, Research Triangle Park, NC, United States
b DeCODE Genetics/Amgen, Reykjavik, Iceland
c Research Computing Division, Research Triangle Institute International, Research Triangle Park, NC, United States
d Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States
e Nevada Institute of Personalized Medicine, Department of Psychology, University of Nevada, Las Vegas, NV, United States
f Department of Genetics, Washington University in St. Louis, St. Louis, MO, United States
g Department of Biostatistics and Informatics, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States
h Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland
i Department of Medicine (Biomedical Genetics), Boston University, School of Medicine, Boston, MA, United States
j Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States
k Iowa Department of Public Health, Des Moines, IA, United States
l Institute of Epidemiology I, German Research Center for Environmental Health, Neuherberg, Germany
m Department of Genetic Epidemiology, University of Göttingen-Georg-August University Göttingen, Göttingen, Germany
n Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
o Department of Neurology, Boston University, School of Medicine, Boston, MA, United States
p Department of Ophthalmology, Boston University, School of Medicine, Boston, MA, United States
q Department of Genetics and Genomics, Boston University, School of Medicine, Boston, MA, United States
r Department of Epidemiology, Boston University, School of Public Health, Boston, MA, United States
s Department of Biostatistics, Boston University, School of Public Health, Boston, MA, United States
t National Institute for Health and Welfare, Helsinki, Finland
u Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
v Department of Psychiatry, University of Pennsylvania Perelman, School of Medicine, Philadelphia, PA, United States
w VISN 4 Mental Illness Research, Education and Clinical Center, Philadelphia VA Medical Center, Philadelphia, PA, United States
x Department of Psychiatry, Yale University, School of Medicine, New Haven, CT, United States
y Department of Genetics, Yale University, School of Medicine, New Haven, CT, United States
z Department of Neurobiology, Yale University, School of Medicine, New Haven, CT, United States
aa VA CT Healthcare Center, Department of Psychiatry, West Haven, CT, United States
ab Center for Tobacco Research and Intervention, University of Wisconsin, Madison, WI, United States
ac Department of Epidemiology, Harvard University, School of Public Health, Boston, MA, United States
ad Department of Biostatistics, Harvard University, School of Public Health, Boston, MA, United States
ae Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
af Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
ag Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanoven, NH, United States
ah Department of Epidemiology, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States
ai Fellow Program and Behavioral Health and Criminal Justice Research Division, Research Triangle Institute International, Research Triangle Park, NC, United States
aj Faculty of Medicine, University of Iceland, Reykjavik, Iceland


Abstract
We conducted a 1000 Genomes-imputed genome-wide association study (GWAS) meta-analysis for nicotine dependence, defined by the Fagerström Test for Nicotine Dependence in 17 074 ever smokers from five European-ancestry samples. We followed up novel variants in 7469 ever smokers from five independent European-ancestry samples. We identified genome-wide significant association in the alpha-4 nicotinic receptor subunit (CHRNA4) gene on chromosome 20q13: lowest P=8.0 × 10 -9 across all the samples for rs2273500-C (frequency=0.15; odds ratio=1.12 and 95% confidence interval=1.08-1.17 for severe vs mild dependence). rs2273500-C, a splice site acceptor variant resulting in an alternate CHRNA4 transcript predicted to be targeted for nonsense-mediated decay, was associated with decreased CHRNA4 expression in physiologically normal human brains (lowest P=7.3 × 10 -4). Importantly, rs2273500-C was associated with increased lung cancer risk (N=28 998, odds ratio=1.06 and 95% confidence interval=1.00-1.12), likely through its effect on smoking, as rs2273500-C was no longer associated with lung cancer after adjustment for smoking. Using criteria for smoking behavior that encompass more than the single 'cigarettes per day' item, we identified a common CHRNA4 variant with important regulatory properties that contributes to nicotine dependence and smoking-related consequences.


Document Type: Article
Source: Scopus



Kung, N.H.a , Van Stavern, G.P.b
Isolated Ocular Motor Nerve Palsies
(2015) Seminars in Neurology, 35 (5), pp. 539-548. 

DOI: 10.1055/s-0035-1563568


a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, Campus Box 8096, 660 South Euclid Avenue, Saint Louis, MO, United States


Abstract
An isolated ocular motor nerve palsy is defined as dysfunction of a single ocular motor nerve (oculomotor, trochlear, or abducens) with no associated or localizing neurologic signs or symptoms. When occurring in patients aged 50 or older, the most common cause is microvascular ischemia, but serious etiologies such as aneurysm, malignancy, and giant cell arteritis should always be considered. In this article, the authors review the clinical approach, anatomy, and differential diagnosis of each isolated ocular motor nerve palsy and discuss the clinical characteristics, pathophysiology, and treatment of microvascular ischemia. © 2015 by Thieme Medical Publishers, Inc.


Author Keywords
diplopia;  microvascular ischemia;  ocular motility


Document Type: Conference Paper
Source: Scopus



Roam, J.L.a , Yan, Y.b , Nguyen, P.K.a , Kinstlinger, I.S.a , Leuchter, M.K.a , Hunter, D.A.b , Wood, M.D.b , Elbert, D.L.a
A modular, plasmin-sensitive, clickable poly(ethylene glycol)-heparin-laminin microsphere system for establishing growth factor gradients in nerve guidance conduits
(2015) Biomaterials, 72, pp. 112-124. 

DOI: 10.1016/j.biomaterials.2015.08.054


a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
b Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, Campus Box 8238, 660 South Euclid Avenue, St. Louis, MO, United States


Abstract
Peripheral nerve regeneration is a complex problem that, despite many advancements and innovations, still has sub-optimal outcomes. Compared to biologically derived acellular nerve grafts and autografts, completely synthetic nerve guidance conduits (NGC), which allow for precise engineering of their properties, are promising but still far from optimal. We have developed an almost entirely synthetic NGC that allows control of soluble growth factor delivery kinetics, cell-initiated degradability and cell attachment. We have focused on the spatial patterning of glial-cell derived human neurotrophic factor (GDNF), which promotes motor axon extension. The base scaffolds consisted of heparin-containing poly(ethylene glycol) (PEG) microspheres. The modular microsphere format greatly simplifies the formation of concentration gradients of reversibly bound GDNF. To facilitate axon extension, we engineered the microspheres with tunable plasmin degradability. 'Click' cross-linking chemistries were also added to allow scaffold formation without risk of covalently coupling the growth factor to the scaffold. Cell adhesion was promoted by covalently bound laminin. GDNF that was released from these microspheres was confirmed to retain its activity. Graded scaffolds were formed inside silicone conduits using 3D-printed holders. The fully formed NGC's contained plasmin-degradable PEG/heparin scaffolds that developed linear gradients in reversibly bound GDNF. The NGC's were implanted into rats with severed sciatic nerves to confirm in vivo degradability and lack of a major foreign body response. The NGC's also promoted robust axonal regeneration into the conduit. © 2015 Elsevier Ltd.


Author Keywords
Click chemistry;  Degradable;  Gradient;  Microsphere;  Peripheral nerve regeneration;  Scaffold


Document Type: Article
Source: Scopus



Hancock, D.B.a , Wang, J.-C.c , Gaddis, N.C.b , Levy, J.L.b , Saccone, N.L.d , Stitzel, J.A.f , Goate, A.d , Bierut, L.J.e , Johnson, E.O.b
A multiancestry study identifies novel genetic associations with CHRNA5 methylation in human brain and risk of nicotine dependence
(2015) Human Molecular Genetics, 24 (20), pp. 5940-5954. 

DOI: 10.1093/hmg/ddv303


a Behavioral Health and Criminal Justice Division, Research Triangle Institute (RTI) International, Research Triangle Park, NC, United States
b Research Computing Division, Research Triangle Institute (RTI) International, Research Triangle Park, NC, United States
c Department of Neuroscience and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
d Department of Genetics, Washington University School of Medicine, St Louis, MO, United States
e Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
f Department of Integrative Physiology, University of Colorado, Boulder, CO, United States


Abstract
Nicotine dependence is influenced by chromosome 15q25.1 single nucleotide polymorphisms (SNPs), including the missense SNP rs16969968 that alters function of the α5 nicotinic acetylcholine receptor (CHRNA5) and noncoding SNPs that regulate CHRNA5 mRNA expression. We tested for cis-methylation quantitative trait loci (cis-meQTLs) using SNP genotypes and DNA methylation levels measured across the IREB2-HYKK-PSMA4-CHRNA5-CHRNA3-CHRNB4 genes on chromosome 15q25.1 in the BrainCloud and Brain QTL cohorts [total N = 175 European-Americans and 65 African-Americans (AAs)]. We identified eight SNPs that were significantly associated with CHRNA5 methylation in prefrontal cortex: P ranging from 6.0 × 10-10 to 5.6 × 10-5. These SNP-methylation associationswere also significant in frontal cortex, temporal cortex and pons: P ranging from4.8 × 10-12 to 3.4 × 10-3. Of the eight cis-meQTL SNPs, only the intronic CHRNB4 SNP rs11636753 was associated with CHRNA5 methylation independently of the known SNP effects in prefrontal cortex, and it was the most significantly associated SNP with nicotine dependence across five independent cohorts (total N = 7858 European ancestry and 3238 AA participants): P = 6.7 × 10-4, odds ratio (OR) [95% confidence interval (CI)] = 1.11 (1.05-1.18). The rs11636753 major allele (G) was associated with lower CHRNA5 DNA methylation, lower CHRNA5 mRNA expression and increased nicotine dependence risk. Haplotype analyses showed that rs11636753-G and the functional rs16969968-A alleles together increased risk of nicotine dependence more than each variant alone: P = 3.1 × 10-12, OR (95% CI) = 1.32 (1.22-1.43). Our findings identify a novel regulatory SNP association with nicotine dependence and connect, for the first time, previously observed differences in CHRNA5 mRNA expression and nicotine dependence risk to underlying DNA methylation differences. © The Author 2015.


Document Type: Article
Source: Scopus



Vinberg, F.a , Wang, T.b , Molday, R.S.c , Chen, J.b , Kefalov, V.J.a
A new mouse model for stationary night blindness with mutant Slc24a1 explains the pathophysiology of the associated human disease
(2015) Human Molecular Genetics, 24 (20), pp. 5915-5929. 

DOI: 10.1093/hmg/ddv319


a Washington University School of Medicine, St. Louis, MO, United States
b Zilkha Neurogenetic Institute, University of Southern California, Los AngelesCA, United States
c University of British Columbia, Vancouver, Canada


Abstract
Mutations that affect calcium homeostasis (Ca2+) in rod photoreceptors are linked to retinal degeneration and visual disorders such as retinitis pigmentosa and congenital stationary night blindness (CSNB). It is thought that the concentration of Ca2+ in rod outer segments is controlled by a dynamic balance between influx via cGMP-gated (CNG) channels and extrusion via Na+/Ca2+, K+ exchangers (NCKX1). The extrusion-driven lowering of rod [Ca2+]i following light exposure controls their light adaptation and response termination. Mutant NCKX1 has been linked to autosomal-recessive stationary night blindness. However, whether NCKX1 contributes to light adaptation has not been directly tested and the mechanisms by which human NCKX1 mutations cause night blindness are not understood. Here, we report that the deletion of NCKX1 in mice results in malformed outer segment disks, suppressed expression and function of rod CNG channels and a subsequent 100-fold reduction in rod responses, while preserving normal cone responses. The compensating loss of CNG channel function in the absence of NCKX1-mediated Ca2+ extrusion may prevent toxic Ca2+ buildup and provides an explanation for the stationary nature of the associated disorder in humans. Surprisingly, the lack of NCKX1 did not compromise rod background light adaptation, suggesting additional Ca2+-extruding mechanisms exist in these cells. © The Author 2015.


Document Type: Article
Source: Scopus



Hing, B.a , Ramos, E.b , Braun, P.a , McKane, M.a , Jancic, D.a , Tamashiro, K.L.K.c , Lee, R.S.c , Michaelson, J.J.a , Druley, T.E.b , Potash, J.B.a
Adaptation of the targeted capture Methyl-Seq platform for the mouse genome identifies novel tissue-specific DNA methylation patterns of genes involved in neurodevelopment
(2015) Epigenetics, 10 (7), pp. 581-596. 

DOI: 10.1080/15592294.2015.1045179


a Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, United States
b Department of Pediatrics and Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States


Abstract
Methyl-Seq was recently developed as a targeted approach to assess DNA methylation (DNAm) at a genome-wide level in human. We adapted it for mouse and sought to examine DNAm differences across liver and 2 brain regions: cortex and hippocampus. A custom hybridization array was designed to isolate 99 Mb of CpG islands, shores, shelves, and regulatory elements in the mouse genome. This was followed by bisulfite conversion and sequencing on the Illumina HiSeq2000. The majority of differentially methylated cytosines (DMCs) were present at greater than expected frequency in introns, intergenic regions, near CpG islands, and transcriptional enhancers. Liver-specific enhancers were observed to be methylated in cortex, while cortex specific enhancers were methylated in the liver. Interestingly, commonly shared enhancers were differentially methylated between the liver and cortex. Gene ontology and pathway analysis showed that genes that were hypomethylated in the cortex and hippocampus were enriched for neuronal components and neuronal function. In contrast, genes that were hypomethylated in the liver were enriched for cellular components important for liver function. Bisulfite-pyrosequencing validation of 75 DMCs from 19 different loci showed a correlation of r = 0.87 with Methyl-Seq data. We also identified genes involved in neurodevelopment that were not previously reported to be differentially methylated across brain regions. This platform constitutes a valuable tool for future genome-wide studies involving mouse models of disease. © 2015, Taylor and Francis Group, LLC.


Author Keywords
Brain;  DNA methylation;  Epigenetics;  Genome-wide;  Methylation array


Document Type: Article
Source: Scopus



Smagula, S.F.a b , Butters, M.A.a , Anderson, S.J.c , Lenze, E.J.d , Dew, M.A.a b c e f , Mulsant, B.H.g h , Lotrich, F.E.a , Aizenstein, H.a , Reynolds, C.F., IIIa i
Antidepressant response trajectories and associated clinical prognostic factors among older adults
(2015) JAMA Psychiatry, 72 (10), pp. 1021-1028. 

DOI: 10.1001/jamapsychiatry.2015.1324


a Department of Psychiatry, Western Psychiatric Institute, Clinic of University, Pittsburgh Medical Center, 3811 O'Hara St, Pittsburgh, PA, United States
b Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
c Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
d Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
e Department of Psychology, University of Pittsburgh, Pittsburgh, PA, United States
f Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA, United States
g Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada
h Department of Psychiatry, University of Toronto, Toronto, ON, Canada
i Department of Behavioral and Community Health Sciences, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States


Abstract
IMPORTANCE More than 50% of older adults with late-life major depressive disorder fail to respond to initial treatment with first-line pharmacological therapy. OBJECTIVES To assess typical patterns of response to an open-label trial of extended-release venlafaxine hydrochloride (venlafaxine XR) for late-life depression and to evaluate which clinical factors are associated with the identified longitudinal response patterns. DESIGN, SETTING, AND PARTICIPANTS Group-based trajectory modelingwas applied to data from a 12-week open-label pharmacological trial conducted in specialty care as part of the Incomplete Response in Late Life: Getting to Remission Study. Clinical prognostic factors, including domain-specific cognitive performance and individual depression symptoms, were examined in relation to response trajectories. Participants included 453 adults aged 60 years or older with current major depressive disorder. The study was conducted between August 2009 and August 2014. INTERVENTION Open-label venlafaxine XR (titrated up to 300mg/d) for 12 weeks. MAIN OUTCOMES AND MEASURES Subgroups exhibiting similar response patternswere derived from repeated measures of overall depression severity obtained using the Montgomery-Asberg Depression Rating Scale. RESULTS Among the 453 study participants, 3 subgroups with differing baseline depression severity clearly responded to treatment: one group with the lowest baseline severity had a rapid response (n = 69 [15.23%]), and distinct responses were also apparent among groups starting at moderate (n = 108 [23.84%]) and higher (n = 25 [5.52%]) baseline symptom levels. Three subgroups had nonresponding trajectories: 2 with high baseline symptom levels (totaling 35.98%: high, nonresponse 1, n = 110 [24.28%]; high, nonresponse 2, n = 53 [11.70%]) and 1 with moderate baseline symptom levels (n = 88 [19.43%]). Several factors were independently associated with having a nonresponsive trajectory, including greater baseline depression severity, longer episode duration, less subjective sleep loss, more guilt, and more work/activity impairment (P < .05). Higher delayed memory (list recognition) performance was independently associated with having a rapid response (adjusted odds ratio = 2.22; 95%CI, 1.18-4.20). CONCLUSIONS AND RELEVANCE Based on the observed trajectory patterns, patients who have late-life depression with high baseline depression severity are unlikely to respond after 12 weeks of treatment with venlafaxine XR. However, high baseline depression severity alone may be neither a necessary nor sufficient predictor of treatment nonresponse. Copyright © 2015 American Medical Association. All rights reserved.


Document Type: Article
Source: Scopus



Petersen, S.E.a b c d , Sporns, O.e f
Brain Networks and Cognitive Architectures
(2015) Neuron, 88 (1), art. no. 12832, pp. 207-219. 

DOI: 10.1016/j.neuron.2015.09.027


a 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 Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States
f Indiana University Network Science Institute, Indiana University, Bloomington, IN, United States


Abstract
Most accounts of human cognitive architectures have focused on computational accounts of cognition while making little contact with the study of anatomical structures and physiological processes. A renewed convergence between neurobiology and cognition is well under way. A promising area arises from the overlap between systems/cognitive neuroscience on the one side and the discipline of network science on the other. Neuroscience increasingly adopts network tools and concepts to describe the operation of collections of brain regions. Beyond just providing illustrative metaphors, network science offers a theoretical framework for approaching brain structure and function as a multi-scale system composed of networks of neurons, circuits, nuclei, cortical areas, and systems of areas. This paper views large-scale networks at the level of areas and systems, mostly on the basis of data from human neuroimaging, and how this view of network structure and function has begun to illuminate our understanding of the biological basis of cognitive architectures. © 2015 Elsevier Inc.


Document Type: Review
Source: Scopus



Lee, K.a , Cherel, M.a , Budin, F.a , Gilmore, J.a , Consing, K.Z.a , Rasmussen, J.c , Wadhwa, P.D.c , Entringer, S.c d , Glasser, M.F.e , Van Essen, D.C.e , Buss, C.c d , Styner, M.a b
Early postnatal myelin content estimate of white matter via T1w/T2w ratio
(2015) Progress in Biomedical Optics and Imaging - Proceedings of SPIE, 9417, art. no. 94171R, . 

DOI: 10.1117/12.2082198


a Department of Psychiatry, University of North Carolina, Chapel Hill, United States
b Department of Computer Science, University of North Carolina, Chapel Hill, United States
c Department of Pediatrics, University of California, Irvine, United States
d Institute for Medical Psychology, Charité University Medicine, Berlin, Germany
e Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, United States


Abstract
Purpose: To develop and evaluate a novel processing framework for the relative quantification of myelin content in cerebral white matter (WM) regions from brain MRI data via a computed ratio of T1 to T2 weighted intensity values. Data: We employed high resolution (1mm3 isotropic) T1 and T2 weighted MRI from 46 (28 male, 18 female) neonate subjects (typically developing controls) scanned on a Siemens Tim Trio 3T at UC Irvine. Methods: We developed a novel, yet relatively straightforward image processing framework for WM myelin content estimation based on earlier work by Glasser et al. We first co-register the structural MRI data to correct for motion. Then, background areas are masked out via a joint T1w and T2 foreground mask computed. Raw T1w/T2w-ratios images are computed next. For purpose of calibration across subjects, we first coarsely segment the fat-rich facial regions via an atlas co-registration. Linear intensity rescaling based on median T1w/T2w-ratio values in those facial regions yields calibrated T1w/T2wratio images. Mean values in lobar regions are evaluated using standard statistical analysis to investigate their interaction with age at scan. Results: Several lobes have strongly positive significant interactions of age at scan with the computed T1w/T2w-ratio. Most regions do not show sex effects. A few regions show no measurable effects of change in myelin content change within the first few weeks of postnatal development, such as cingulate and CC areas, which we attribute to sample size and measurement variability. Conclusions: We developed and evaluated a novel way to estimate white matter myelin content for use in studies of brain white matter development. © 2015 SPIE.


Author Keywords
Image processing;  Magnetic resonance imaging;  Myelin content;  White matter


Document Type: Conference Paper
Source: Scopus



Shao, M.a b c , Liu, C.b , Song, Y.b d , Ye, W.b , He, W.b , Yuan, G.b e , Gu, S.b , Lin, C.f , Ma, L.f , Zhang, Y.d , Tian, W.a , Hu, T.a , Chen, Y.b d
FGF8 signaling sustains progenitor status and multipotency of cranial neural crest-derived mesenchymal cells in vivo and in vitro
(2015) Journal of Molecular Cell Biology, 7 (5), pp. 441-454. 

DOI: 10.1093/jmcb/mjv052


a State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
b Department of Cell and Molecular Biology, Tulane University, New Orleans, LA, United States
c College of Life Sciences, Sichuan University, Chengdu, China
d Southern Center for Biomedical Research, Fujian Key Laboratory of Developmental and Neural Biology, College of Life Sciences, Fujian Normal University, Fuzhou, China
e Hubei-MOST KLOS, KLOBM School, Hospital of Stomatology, Wuhan University, Wuhan, China
f Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States


Abstract
The cranial neural crest (CNC) cells play a vital role in craniofacial development and regeneration. They are multi-potent progenitors, being able to differentiate into various types of tissues. Both pre-migratory and post-migratory CNC cells are plastic, taking on diverse fates by responding to different inductive signals. However, what sustains the multipotency of CNC cells and derivatives remains largely unknown. In this study, we present evidence that FGF8 signaling is able to sustain progenitor status and multipotency of CNC-derived mesenchymal cells both in vivo and in vitro. We show that augmented FGF8 signaling in pre-migratory CNC cells prevents cell differentiation and organogenesis in the craniofacial region by maintaining their progenitor status. CNC-derived mesenchymal cells with Fgf8 overexpression or control cells in the presence of exogenous FGF8 exhibit prolonged survival, proliferation, and multi-potent differentiation capability in cell cultures. Remarkably, exogenous FGF8 also sustains the capability of CNC-derived mesenchymal cells to participate in organogenesis such as odontogenesis. Furthermore, FGF8-mediated signaling strongly promotes adipogenesis but inhibits osteogenesis of CNC-derived mesenchymal cells in vitro. Our results reveal a specific role for FGF8 in the maintenance of progenitor status and in fate determination of CNC cells, implicating a potential application in expansion and fate manipulation of CNC-derived cells in stem cell-based craniofacial regeneration. © 2015 The Author. Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.


Author Keywords
cell fate;  cranial neural crest;  differentiation;  FGF8;  tooth


Document Type: Article
Source: Scopus



Daniels, B.P.a , Klein, R.S.a b c
Knocking on Closed Doors: Host Interferons Dynamically Regulate Blood-Brain Barrier Function during Viral Infections of the Central Nervous System
(2015) PLoS Pathogens, 11 (9), art. no. e1005096, 5 p. 

DOI: 10.1371/journal.ppat.1005096


a Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States
c Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States


Document Type: Review
Source: Scopus



Martinez, R.E.a , Dhawan, S.a , Sumner, W.b , Williams, B.J.a
On-line chemical composition analysis of refillable electronic cigarette aerosol- measurement of nicotine and nicotyrine
(2015) Nicotine and Tobacco Research, 17 (10), pp. 1263-1269. Cited 1 time.

DOI: 10.1093/ntr/ntu334


a School of Engineering and Applied Science, Washington University in St. Louis, St. Louis, MO, United States
b School of Medicine, Washington University in St. Louis, St. Louis, MO, United States


Abstract
Introduction: Electronic cigarettes (e-cigs) generate aerosols that users inhale. Analyses of e-liquids inconsistently report nicotyrine, a nicotine analog that could impede nicotine metabolism, raising questions about nicotyrine formation. Methods: E-cig aerosols were analyzed on-line using a Thermal Desorption Aerosol Gas Chromatograph. Three e-liquids were tested: an unflavored solution in propylene glycol (PG); an unflavored solution in PG and vegetable glycerin (VG), and a flavored solution in PG and VG. A heating duration experiment determined the nicotyrine to nicotine ratio (NNR) in particle phase as a function of the duration of e-cig activation. An aging experiment determined the NNR in e-liquids and aerosols as a function of time since initial exposure to air and storage condition. Results: Nicotine and nicotyrine were quantified in all 3 e-liquids and aerosols. Duration of e-cig activation was inversely related to NNR (NNR = 0.04 with 3-s activation, 0.26 with 0.5 s). Aging influenced both e-liquid NNR and aerosol NNR. On average, the e-liquid NNR increased from 0.03 at 11 days after opening to 0.08 after 60 days. For similar heating durations, aerosol NNR increased from 0.05 at 11 days to 0.23 after 60 days. Storage conditions had little effect on NNR. Conclusions: E-cig aerosols have variable nicotyrine quantities. Aerosol NNR depends on vaping technique and time elapsed since the e-liquid was exposed to air. It is hypothesized that aerosolized nicotyrine could facilitate nicotine absorption, inhibit the metabolism of nicotine, and reduce a user's urge to smoke. © The Author 2014.


Document Type: Article
Source: Scopus



Gardner, J.R.a , Song, X.a , Weinberger, K.Q.a , Barbour, D.a , Cunningham, J.P.b
Psychophysical detection testing with Bayesian active learning
(2015) Uncertainty in Artificial Intelligence - Proceedings of the 31st Conference, UAI 2015, pp. 286-295. 


a Washington University in St. Louis, St. Louis, MO, United States
b Columbia University, New York, NY, United States


Abstract
Psychophysical detection tests are ubiquitous in the study of human sensation and the diagnosis and treatment of virtually all sensory impairments. In many of these settings, the goal is to recover, from a series of binary observations from a human subject, the latent function that describes the discriminability of a sensory stimulus over some relevant domain. The auditory detection test, for example, seeks to understand a subject's likelihood of hearing sounds as a function of frequency and amplitude. Conventional methods for performing these tests involve testing stimuli on a pre-determined grid. This approach not only samples at very uninformative locations, but also fails to learn critical features of a subject's latent discriminability function. Here we advance active learning with Gaussian processes to the setting of psychophysical testing. We develop a model that incorporates strong prior knowledge about the class of stimuli, we derive a sensible method for choosing sample points, and we demonstrate how to evaluate this model efficiently. Finally, we develop a novel likelihood that enables testing of multiple stimuli simultaneously. We evaluate our method in both simulated and real auditory detection tests, demonstrating the merit of our approach.


Document Type: Conference Paper
Source: Scopus



Macauley, S.L., Holtzman, D.M.
Recent Advances from the Bench Toward the Bedside in Alzheimer's Disease
(2015) EBioMedicine, 2 (2), pp. 94-95. 

DOI: 10.1016/j.ebiom.2015.01.002


Washington University, Department of Neurology, Hope Center for Neurological Disorders, The Knight Alzheimer's Disease Research Center, 660 S. Euclid Ave., St. Louis, MO, United States


Document Type: Note
Source: Scopus



Pagliaccio, D.a , Barch, D.M.b c d , Bogdan, R.c , Wood, P.K.e , Lynskey, M.T.f , Heath, A.C.b , Agrawal, A.b
Shared predisposition in the association between cannabis use and subcortical brain structure
(2015) JAMA Psychiatry, 72 (10), pp. 994-1001. Cited 1 time.

DOI: 10.1001/jamapsychiatry.2015.1054


a Program in Neuroscience, Washington University in St Louis, Campus B. 1125, 1 Brookings Dr, St Louis, MO, United States
b Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
c Department of Psychology, Washington University in St Louis, St Louis, MO, United States
d Department of Radiology, Washington University in St Louis, St Louis, MO, United States
e Department of Psychological Sciences, University of Missouri, Columbia, United States
f Institute of Psychiatry, Psychology and Neuroscience, Department of Addictions, King's College London, London, United Kingdom


Abstract
IMPORTANCE Prior neuroimaging studies have suggested that alterations in brain structure may be a consequence of cannabis use. Siblings discordant for cannabis use offer an opportunity to use cross-sectional data to disentangle such causal hypotheses from shared effects of genetics and familial environment on brain structure and cannabis use. OBJECTIVES To determine whether cannabis use is associated with differences in brain structure in a large sample of twins/siblings and to examine sibling pairs discordant for cannabis use to separate potential causal and predispositional factors linking lifetime cannabis exposure to volumetric alterations. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional diagnostic interview, behavioral, and neuroimaging data were collected from community sampling and established family registries from August 2012 to September 2014. This study included data from 483 participants (22-35 years old) enrolled in the ongoing Human Connectome Project, with 262 participants reporting cannabis exposure (ie, ever used cannabis in their lifetime). MAIN OUTCOMES AND MEASURES Cannabis exposurewas measured with the Semi-Structured Assessment for the Genetics of Alcoholism. Whole-brain, hippocampus, amygdala, ventral striatum, and orbitofrontal cortex volumes were related to lifetime cannabis use (ever used, age at onset, and frequency of use) using linear regressions. Genetic (ρg) and environmental (ρe) correlations between cannabis use and brain volumes were estimated. Linear mixed models were used to examine volume differences in sex-matched concordant unexposed (n = 71 pairs), exposed (n = 81 pairs), or exposure discordant (n = 89 pairs) sibling pairs. RESULTS Among 483 study participants, cannabis exposure was related to smaller left amygdala (approximately 2.3%; P = .007) and right ventral striatum (approximately 3.5%; P &lt; .005) volumes. These volumetric differences were within the range of normal variation. The association between left amygdala volume and cannabis use was largely owing to shared genetic factors (ρg = -0.43; P = .004), while the origin of the association with right ventral striatum volumes was unclear. Importantly, brain volumes did not differ between sex-matched siblings discordant for use (fixed effect = -7.43; t = -0.93, P = .35). Both the exposed and unexposed siblings in pairs discordant for cannabis exposure showed reduced amygdala volumes relative to members of concordant unexposed pairs (fixed effect = 12.56; t = 2.97; P = .003). CONCLUSIONS AND RELEVANCE In this study, differences in amygdala volume in cannabis users were attributable to common predispositional factors, genetic or environmental in origin, with little support for causal influences. Causal influences, in isolation or in conjunction with predispositional factors, may exist for other brain regions (eg, ventral striatum) or at more severe levels of cannabis involvement and deserve further study. Copyright © 2015 American Medical Association. All rights reserved.


Document Type: Article
Source: Scopus



Lenze, E.J.
Solving the geriatric mental health crisis in the 21st century
(2015) JAMA Psychiatry, 72 (10), pp. 967-968. 

DOI: 10.1001/jamapsychiatry.2015.1306


Healthy Mind Lab, Department of Psychiatry, Washington University School of Medicine, Box 8134, 660 S. Euclid Ave, St Louis, MO, United States


Document Type: Editorial
Source: Scopus



Berkowitz, B.A.a b , Kern, T.S.c , Bissig, D.a , Patel, P.a , Bhatia, A.a , Kefalov, V.J.d , Roberts, R.a
Systemic retinaldehyde treatment corrects retinal oxidative stress, rod dysfunction, and impaired visual performance in diabetic mice
(2015) Investigative Ophthalmology and Visual Science, 56 (11), pp. 6294-6303. 

DOI: 10.1167/iovs.15-16990


a Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, United States
b Department of Ophthalmology, Wayne State University School of Medicine, Detroit, MI, United States
c Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
d Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States


Abstract
PURPOSE. Diabetes appears to induce a visual cycle defect because rod dysfunction is correctable with systemic treatment of the visual cycle chromophore 11-cis-retinaldehyde. However, later studies have found no evidence for visual cycle impairment. Here, we further examined whether photoreceptor dysfunction is corrected with 11-cis-retinaldehyde. Because antioxidants correct photoreceptor dysfunction in diabetes, the hypothesis that exogenous visual chromophores have antioxidant activity in the retina of diabetic mice in vivo was tested. METHODS. Rod function in 2-month-old diabetic mice was evaluated using transretinal electrophysiology in excised retinas and apparent diffusion coefficient (ADC) MRI to measure light-evoked expansion of subretinal space (SRS) in vivo. Optokinetic tracking was used to evaluate cone-based visual performance. Retinal production of superoxide free radicals, generated mostly in rod cells, was biochemically measured with lucigenin. Diabetic mice were systemically treated with a single injection of either 11-cis-retinaldehyde, 9-cisretinaldehyde (a chromophore surrogate), or all-trans-retinaldehyde (the photoisomerization product of 11-cis-retinaldehyde). RESULTS. Consistent with previous reports, diabetes significantly reduced (1) dark-adapted rod photo responses (transretinal recording) by ~18%, (2) rod-dominated light-stimulated SRS expansion (ADC MRI) by ~21%, and (3) cone-dominated contrast sensitivity (using optokinetic tracking [OKT]) by ~30%. Both 11-cis-retinaldehyde and 9-cis-retinaldehyde largely corrected these metrics of photoreceptor dysfunction. Higher-than-normal retinal superoxide production in diabetes by ~55% was also significantly corrected following treatment with 11-cis-retinaldehyde, 9-cis-retinaldehyde, or all-trans-retinaldehyde. CONCLUSIONS. Collectively, data suggest that retinaldehydes improve photoreceptor dysfunction in diabetic mice, independent of the visual cycle, via an antioxidant mechanism. © 2015 The Association for Research in Vision and Ophthalmology, Inc.


Author Keywords
ADC MRI;  Diabetes;  MEMRI;  Oxidative stress;  Retina;  Transretinal recordings


Document Type: Article
Source: Scopus



McDermott, K.B., Gilmore, A.W.
The role of context in understanding similarities and differences in remembering and episodic future thinking
(2015) Psychology of Learning and Motivation - Advances in Research and Theory, 63, pp. 45-76. 

DOI: 10.1016/bs.plm.2015.03.004


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


Abstract
Remembering events from one's lifetime (autobiographical remembering) and envisioning events one might experience in the future (episodic future thought) call upon many similar cognitive processes, yet humans can routinely distinguish between the two. How can we understand their similarities and differences (in phenomenological and processing terms)? This chapter suggests that the greater accessibility of contextual associations for remembered events than imagined events plays a key role in understanding this puzzle, and we present behavioral and neuroimaging evidence that converges on this conclusion. © 2015 Elsevier Inc.


Document Type: Book Chapter
Source: Scopus

 
October 14, 2015 
 
Paran, C.W.a b c , Zou, K.a c , Ferrara, P.J.a c , Song, H.d , Turk, J.d , Funai, K.a b c 
Lipogenesis mitigates dysregulated sarcoplasmic reticulum calcium uptake in muscular dystrophy
(2015) Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, 1851 (12), pp. 1530-1538. 

DOI: 10.1016/j.bbalip.2015.09.001

a Department of Kinesiology, East Carolina University, 115 Heart Drive, Greenville, North Carolina, United States
b Department of Physiology, East Carolina University, 115 Heart Drive, Greenville, North Carolina, United States
c East Carolina Diabetes and Obesity Institute, East Carolina University, 115 Heart Drive, Greenville, North Carolina, United States
d Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri, United States

Abstract
Muscular dystrophy is accompanied by a reduction in activity of sarco/endoplasmic reticulum Ca2 +-ATPase (SERCA) that contributes to abnormal Ca2 + homeostasis in sarco/endoplasmic reticulum (SR/ER). Recent findings suggest that skeletal muscle fatty acid synthase (FAS) modulates SERCA activity and muscle function via its effects on SR membrane phospholipids. In this study, we examined muscle's lipid metabolism in mdx mice, a mouse model for Duchenne muscular dystrophy (DMD). De novo lipogenesis was ~ 50% reduced in mdx muscles compared to wildtype (WT) muscles. Gene expressions of lipogenic and other ER lipid-modifying enzymes were found to be differentially expressed between wildtype (WT) and mdx muscles. A comprehensive examination of muscles' SR phospholipidome revealed elevated phosphatidylcholine (PC) and PC/phosphatidylethanolamine (PE) ratio in mdx compared to WT mice. Studies in primary myocytes suggested that defects in key lipogenic enzymes including FAS, stearoyl-CoA desaturase-1 (SCD1), and Lipin1 are likely contributing to reduced SERCA activity in mdx mice. Triple transgenic expression of FAS, SCD1, and Lipin1 (3TG) in mdx myocytes partly rescued SERCA activity, which coincided with an increase in SR PE that normalized PC/PE ratio. These findings implicate a defect in lipogenesis to be a contributing factor for SERCA dysfunction in muscular dystrophy. Restoration of muscle's lipogenic pathway appears to mitigate SERCA function through its effects on SR membrane composition. © 2015 Published by Elsevier B.V.

Author Keywords
Calcium;  Lipogenesis;  Membrane phospholipid;  Muscular dystrophy;  Sarcoplasmic reticulum

Document Type: Article
Source: Scopus
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Siuda, E.R.a b c d , McCall, J.G.a b c d , Al-Hasani, R.a b d , Shin, G.e , Park, S.I.e , Schmidt, M.J.a b d , Anderson, S.L.a b , Planer, W.J.a b , Rogers, J.A.e f g h , Bruchas, M.R.a b c d i 
Optodynamic simulation of β-adrenergic receptor signalling
(2015) Nature Communications, 6, art. no. 9480, . 

DOI: 10.1038/ncomms9480

a Department of Anesthesiology, Division of Basic Research, Washington University School of Medicine, St Louis, MI, United States
b Washington University Pain Center, Washington University School of Medicine, St Louis, MI, United States
c Division of Biology and Biomedical Sciences, Washington University School of Medicine, St Louis, MI, United States
d Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MI, United States
e Department of Materials Science and Engineering, Frederick Seitz Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, United States
f Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, United States
g Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, United States
h Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, United States
i Department of Biomedical Engineering, Washington University in St Louis, St Louis, MI, United States

Abstract
Optogenetics has provided a revolutionary approach to dissecting biological phenomena. However, the generation and use of optically active GPCRs in these contexts is limited and it is unclear how well an opsin-chimera GPCR might mimic endogenous receptor activity. Here we show that a chimeric rhodopsin/β<inf>2</inf> adrenergic receptor (opto-β<inf>2</inf> AR) is similar in dynamics to endogenous β<inf>2</inf> AR in terms of: cAMP generation, MAP kinase activation and receptor internalization. In addition, we develop and characterize a novel toolset of optically active, functionally selective GPCRs that can bias intracellular signalling cascades towards either G-protein or arrestin-mediated cAMP and MAP kinase pathways. Finally, we show how photoactivation of opto-β<inf>2</inf> AR in vivo modulates neuronal activity and induces anxiety-like behavioural states in both fiber-tethered and wireless, freely moving animals when expressed in brain regions known to contain β<inf>2</inf> ARs. These new GPCR approaches enhance the utility of optogenetics and allow for discrete spatiotemporal control of GPCR signalling in vitro and in vivo. © 2015 Macmillan Publishers Limited. All rights reserved.

Document Type: Article
Source: Scopus
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Sansone, A.a b , Hassenklöver, T.a b , Offner, T.a b , Fu, X.c , Holy, T.E.c , Manzini, I.a b 
Dual processing of sulfated steroids in the olfactory system of an anuran amphibian
(2015) Frontiers in Cellular Neuroscience, 9 (September), 10 p. 

DOI: 10.3389/fncel.2015.00373

a Institute of Neurophysiology and Cellular Biophysics, University of Göttingen, Göttingen, Germany
b Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany
c Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Chemical communication is widespread in amphibians, but if compared to later diverging tetrapods the available functional data is limited. The existing information on the vomeronasal system ofanurans is particularly sparse. Amphibians representatransitional stage in the evolution ofthe olfactory system. Most species have anatomically separated main and vomeronasal systems, but recent studies have shown that in anurans their molecular separation is still underway. Sulfated steroids function as migratory pheromones in lamprey and have recently been identified as natural vomeronasal stimuli in rodents. Here we identified sulfated steroids as the first known class of vomeronasal stimuli in the amphibian Xenopus laevis. We show that sulfated steroids are detected and concurrently processed by the two distinct olfactory subsystems of larval Xenopus laevis, the main olfactory system and the vomeronasal system. Our data revealed a similar but partially different processing of steroid-induced responses in the two systems. Differences of detection thresholds suggest that the two information channels are not just redundant, but rather signal different information. Furthermore, we found that larval and adult animals excrete multiple sulfated compounds with physical properties consistent with sulfated steroids. Breeding tadpole and frog water including these compounds activated a large subset of sensory neurons that also responded to synthetic steroids, showing that sulfated steroids are likely to convey intraspecific information. Our findings indicate that sulfated steroids are conserved vomeronasal stimuli functioning in phylogenetically distant classes of tetrapods living in aquatic and terrestrial habitats. © 2015 Sansone, Hassenklöver, Offner, Fu, Holy and Manzini.

Author Keywords
Intraspecific chemical communication;  Main olfactory system;  Pipidae;  Vomeronasal system;  Xenopus laevis

Document Type: Article
Source: Scopus
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Zhu, L.a b , Zhong, M.c , Elder, G.A.a , Sano, M.a b , Holtzman, D.M.d , Gandy, S.a b , Cardozo, C.e f g , Haroutunian, V.b h , Robakis, N.K.h , Cai, D.a b 
Phospholipid dysregulation contributes to apoe4-associated cognitive deficits in Alzheimer's disease pathogenesis
(2015) Proceedings of the National Academy of Sciences of the United States of America, 112 (38), pp. 11965-11970. 

DOI: 10.1073/pnas.1510011112

a Research and Development, James J. Peters VA Medical Center, Bronx, NY, United States
b Department of Neurology, Alzheimer Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States
c Department of Pathology, Westchester Medical Center, New York Medical College, Valhalla, NY, United States
d Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
e National Center of Excellence for the Medical Consequences of SCI, James J. Peters VA Medical Center, Bronx, NY, United States
f Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
g Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
h Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Abstract
The apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for developing sporadic Alzheimer's disease (AD). However, the mechanisms underlying the pathogenic nature of ApoE4 are not well understood. In this study, we have found that ApoE proteins are critical determinants of brain phospholipid homeostasis and that the ApoE4 isoform is dysfunctional in this process. We have found that the levels of phosphoinositol biphosphate (PIP2) are reduced in postmortem human brain tissues of ApoE4 carriers, in the brains of ApoE4 knock-in (KI) mice, and in primary neurons expressing ApoE4 alleles compared with those levels in ApoE3 counterparts. These changes are secondary to increased expression of a PIP<inf>2</inf>-degrading enzyme, the phosphoinositol phosphatase synaptojanin 1(synj1), in ApoE4 carriers. Genetic reduction of synj1 in ApoE4 KI mouse models restores PIP<inf>2</inf> levels and, more important, rescues AD-related cognitive deficits in these mice. Further studies indicate that ApoE4 behaves similar to ApoE null conditions, which fails to degrade synj1 mRNA efficiently, unlike ApoE3 does. These data suggest a loss of function of ApoE4 genotype. Together, our data uncover a previously unidentified mechanism that links ApoE4-induced phospholipid changes to the pathogenic nature of ApoE4 in AD.

Author Keywords
Alzheimer's disease;  Apolipoprotein E4;  Cognitive deficits;  Dysregulation;  Phospholipid

Document Type: Conference Paper
Source: Scopus
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Hirbe, A.C.a , Dahiya, S.b , Miller, C.A.c , Li, T.c , Fulton, R.S.c , Zhang, X.b , McDonald, S.b , DeSchryver, K.b , Duncavage, E.J.b , Walrath, J.d e , Reilly, K.M.d e , Abel, H.J.f , Pekmezci, M.g , Perry, A.g h , Ley, T.J.c , Gutmann, D.H.h 
Whole exome sequencing reveals the order of genetic changes during malignant transformation and metastasis in a single patient with NF1-plexiform neurofibroma
(2015) Clinical Cancer Research, 21 (18), pp. 4201-4211. 

DOI: 10.1158/1078-0432.CCR-14-3049

a Division of Medical Oncology, 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 Genetics, Genome Institute, Washington University, St. Louis, MO, United States
d Rare Tumors Initiative, National Cancer Institute, Bethesda, MD, United States
e Division of Statistical Genomics, St. Louis, MO, United States
f Department of Pathology, UCSF School of Medicine, San Francisco, CA, United States
g Department of Neurological Surgery, UCSF School of Medicine, San Francisco, CA, United States
h Department of Neurology, Washington University, School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, United States

Abstract
Purpose: Malignant peripheral nerve sheath tumors (MPNST) occur at increased frequency in individuals with neurofibromatosis type 1 (NF1), where they likely arise from benign plexiform neurofibroma precursors. While previous studies have used a variety of discovery approaches to discover genes associated with MPNST pathogenesis, it is currently unclear what molecular events are associated with the evolution of MPNST from plexiform neurofibroma. Experimental Design: Whole-exome sequencing was performed on biopsy materials representing plexiform neurofibroma (n=3), MPNST, and metastasis from a single individual with NF1 over a 14-year period. Additional validation cases were used to assess candidate genes involved in malignant progression, while a murine MPNST model was used for functional analysis. Results: There was an increasing proportion of cells with a somatic NF1 gene mutation as the tumors progressed from benign to malignant, suggesting a clonal process in MPNST development. Copy number variations, including loss of one copy of the TP53 gene, were identified in the primary tumor and the metastatic lesion, but not in benign precursor lesions. A limited number of genes with nonsynonymous somatic mutations (bIII-spectrin and ZNF208) were discovered, several of which were validated in additional primary and metastatic MPNST samples. Finally, increased bIII-spectrin expression was observed in the majority of MPNSTs, and shRNA-mediated knockdown reduced murine MPNST growth in vivo. Conclusions: Collectively, the ability to track the molecular evolution of MPNST in a single individual with NF1 offers new insights into the sequence of genetic events important for disease pathogenesis and progression for future mechanistic study. © 2015 AACR.

Document Type: Article
Source: Scopus
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Jezzini, A.a , Rozzi, S.b , Borra, E.b , Gallese, V.b , Caruana, F.b c , Gerbella, M.b 
A shared neural network for emotional expression and perception: An anatomical study in the macaque monkey
(2015) Frontiers in Behavioral Neuroscience, 9 (September), art. no. 243, 17 p. 

DOI: 10.3389/fnbeh.2015.00243

a Department of Anatomy and Neurobiology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Neuroscience, University of Parma, Parma, Italy
c Brain Center for Social and Motor Cognition, Istituto Italiano di Tecnologia, Parma, Italy

Abstract
Over the past two decades, the insula has been described as the sensory “interoceptive cortex”. As a consequence, human brain imaging studies have focused on its role in the sensory perception of emotions. However, evidence from neurophysiological studies in non-human primates have shown that the insula is also involved in generating emotional and communicative facial expressions. In particular, a recent study demonstrated that electrical stimulation of the mid-ventral sector of the insula evoked affiliative facial expressions. The present study aimed to describe the cortical connections of this “affiliative field”. To this aim, we identified the region with electrical stimulation and injected neural tracers to label incoming and outgoing projections. Our results show that the insular field underlying emotional expression is part of a network involving specific frontal, cingulate, temporal, and parietal areas, as well as the amygdala, the basal ganglia, and thalamus, indicating that this sector of the insula is a site of integration of motor, emotional, sensory and social information. Together with our previous functional studies, this result challenges the classic view of the insula as a multisensory area merely reflecting bodily and internal visceral states. In contrast, it supports an alternative perspective; that the emotional responses classically attributed to the insular cortex are endowed with an enactive component intrinsic to each social and emotional behavior. © 2015 Jezzini, Rozzi, Borra, Gallese, Caruana and Gerbella.

Author Keywords
Affiliative field;  Emotion expression;  Emotion perception;  Insula;  Interoception;  Lip-smacking

Document Type: Article
Source: Scopus
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Perogamvros, L.a b c , Aberg, K.b d , Gex-Fabry, M.a , Perrig, S.a , Cloninger, C.R.e , Schwartz, S.b d 
Increased reward-related behaviors during sleep and wakefulness in sleepwalking and idiopathic nightmares
(2015) PLoS ONE, 10 (8), art. no. e0134504, . 

DOI: 10.1371/journal.pone.0134504

a Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland
b Department of Neuroscience, University of Geneva, Geneva, Switzerland
c Department of Psychiatry, University of Wisconsin, Madison, WI, United States
d Swiss Center for Affective Sciences, University of Geneva, Geneva, Switzerland
e Department of Psychiatry, Washington University School of Medicine, St. Louis, MI, United States

Abstract
Background We previously suggested that abnormal sleep behaviors, i.e., as found in parasomnias, may often be the expression of increased activity of the reward system during sleep. Because nightmares and sleepwalking predominate during REM and NREM sleep respectively, we tested here whether exploratory excitability, a waking personality trait reflecting high activity within the mesolimbic dopaminergic (ML-DA) system, may be associated with specific changes in REM and NREM sleep patterns in these two sleep disorders. Methods Twenty-four unmedicated patients with parasomnia (12 with chronic sleepwalking and 12 with idiopathic nightmares) and no psychiatric comorbidities were studied. Each patient spent one night of sleep monitored by polysomnography. The Temperament and Character Inventory (TCI) was administered to all patients and healthy controls from the Geneva population (n = 293). Results Sleepwalkers were more anxious than patients with idiopathic nightmares (Spielberger Trait anxiety/STAI-T), but the patient groups did not differ on any personality dimension as estimated by the TCI. Compared to controls, parasomnia patients (sleepwalkers together with patients with idiopathic nightmares) scored higher on the Novelty Seeking (NS) TCI scale and in particular on the exploratory excitability/curiosity (NS1) subscale, and lower on the Self-directedness (SD) TCI scale, suggesting a general increase in reward sensitivity and impulsivity. Furthermore, parasomnia patients tended to worry about social separation persistently, as indicated by greater anticipatory worry (HA1) and dependence on social attachment (RD3). Moreover, exploratory excitability (NS1) correlated positively with the severity of parasomnia (i.e., the frequency of self-reported occurrences of nightmares and sleepwalking), and with time spent in REM sleep in patients with nightmares. Conclusions These results suggest that patients with parasomnia might share common waking personality traits associated to reward-related brain functions. They also provide further support to the notion that reward-seeking networks are active during human sleep. Copyright: © 2015 Perogamvros et al.

Document Type: Article
Source: Scopus
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Sadler, B.a , Haller, G.b , Edenberg, H.c , Tischfield, J.d , Brooks, A.d , Kramer, J.e , Schuckit, M.f , Nurnberger, J.g , Goate, A.h 
Positive selection on loci associated with drug and alcohol dependence
(2015) PLoS ONE, 10 (8), art. no. e0134393, . 

DOI: 10.1371/journal.pone.0134393

a Department of Psychiatry, Washington University, St. Louis, MO, United States
b Department of Orthopedic Surgery, Washington University, St. Louis, MO, United States
c Department of Molecular Biology, Indiana University, Indianapolis, IN, United States
d Department of Genetics, Rutgers University, Piscataway, NJ, United States
e Department of Psychiatry, University of Iowa, Iowa City, IA, United States
f Department of Psychiatry, University of San Diego, San Diego, CA, United States
g Department of Psychiatry, Indiana University, Indianapolis, IN, United States
h Department of Neuroscience, Mount Sinai, New York City, NY, United States

Abstract
Much of the evolution of human behavior remains a mystery, including how certain disadvantageous behaviors are so prevalent. Nicotine addiction is one such phenotype. Several loci have been implicated in nicotine related phenotypes including the nicotinic receptor gene clusters (CHRNs) on chromosomes 8 and 15. Here we use 1000 Genomes sequence data from 3 populations (Africans, Asians and Europeans) to examine whether natural selection has occurred at these loci. We used Tajima's D and the integrated haplotype score (iHS) to test for evidence of natural selection. Our results provide evidence for strong selection in the nicotinic receptor gene cluster on chromosome 8, previously found to be significantly associated with both nicotine and cocaine dependence, as well as evidence selection acting on the region containing the CHRNA5 nicotinic receptor gene on chromosome 15, that is genome wide significant for risk for nicotine dependence. To examine the possibility that this selection is related to memory and learning, we utilized genetic data from the Collaborative Studies on the Genetics of Alcoholism (COGA) to test variants within these regions with three tests of memory and learning, the Wechsler Adult Intelligence Scale (WAIS) Block Design, WAIS Digit Symbol and WAIS Information tests. Of the 17 SNPs genotyped in COGA in this region, we find one significantly associated with WAIS digit symbol test results. This test captures aspects of reaction time and memory, suggesting that a phenotype relating to memory and learning may have been the driving force behind selection at these loci. This study could begin to explain why these seemingly deleterious SNPs are present at their current frequencies. Copyright:© 2015 Sadler et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Document Type: Article
Source: Scopus
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Kumar, G.a , Uhrig, D.a , Fowler, S.b , Delaney, M.C.c , Alexandrov, A.V.d 
Intravenous recombinant tissue plasminogen activator does not impact mortality in acute ischemic stroke at any time point up to 6 months: A systematic review and meta-analysis of randomized controlled clinical trials
(2015) CNS Drugs, 29 (8), pp. 659-667. 

DOI: 10.1007/s40263-015-0265-8

a Department of Neurology, Comprehensive Stroke Center, University of Alabama at Birmingham, 1813 6th Ave South, RWUH M226, Birmingham, AL, United States
b Becker Medical Library, Washington University in St. Louis, St. Louis, MO, United States
c Department of Emergency Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
d Department of Neurology, University of Tennessee-Memphis, Memphis, TN, United States

Abstract
Background and Objective: Concerns about the harms of intravenous alteplase (recombinant tissue plasminogen activator) continue to deter physicians from treating patients with acute ischemic stroke with the only drug proven to positively impact outcomes and reduce disability. Recent literature indicates an increase in mortality with alteplase within 7 days, an effect that does not persist from 3 months onwards. The objective of this meta-analysis was to pool mortality estimates from randomized controlled clinical trials (RCTs) at 7 days, 30 days, 90 days, and 6 months after stroke onset. Methods: PubMed, Embase, Scopus, CENTRAL, and clinicaltrials.gov were searched through to April 2014, using "hedges" for tissue plasminogen activator, acute ischemic stroke, and placebo. Two independent authors abstracted data and assessed study quality. Data were pooled using Dersimonian and Laird's random effects model. Results: Eleven RCTs (n = 6905) were included in the final analysis. Two authors independently performed study selection and data abstraction. There was no publication bias and total variance attributable to heterogeneity was not significant (I 2 < 50 %) at any time point. There was no difference in mortality between alteplase and placebo groups at any time point. Trials that randomized patients beyond 3 h (excluded patients within the 3-h window) did not drive the mortality difference seen at any time point. Exclusion sensitivity analysis revealed that exclusion of the NINDS trial rendered the 7-day difference significant towards increased mortality with alteplase. Quality adjustment did not alter the results. Conclusion: Intravenous alteplase did not impact mortality in patients with acute ischemic stroke at any of the measured time points up to 6 months (i.e., there was no increase in the risk of death with alteplase). Therefore, intravenous alteplase should be given to all eligible patients with acute ischemic stroke to improve long-term neurologic outcomes. The effects of alteplase on early survival are more complex than previously understood. © 2015 Springer International Publishing Switzerland.

Document Type: Review
Source: Scopus
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Armstrong, R.A.a , Cairns, N.J.b c 
Erratum to: Comparative quantitative study of ‘signature’ pathological lesions in the hippocampus and adjacent gyri of 12 neurodegenerative disorders [J Neural Transm, DOI 10.1007/s00702-015-1402-8]
(2015) Journal of Neural Transmission, 122 (10), pp. 1369-1370. 

DOI: 10.1007/s00702-015-1412-6

a Vision Sciences, Aston University, Birmingham, United Kingdom
b Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
c Department Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States

Document Type: Erratum
Source: Scopus
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Armstrong, R.A.a , Cairns, N.J.b c 
Comparative quantitative study of ‘signature’ pathological lesions in the hippocampus and adjacent gyri of 12 neurodegenerative disorders
(2015) Journal of Neural Transmission, 122 (10), pp. 1355-1367. 

DOI: 10.1007/s00702-015-1402-8

a Vision Sciences, Aston University, Birmingham, United Kingdom
b Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
c Department Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
The hippocampus (HC) and adjacent gyri are implicated in dementia in several neurodegenerative disorders. To compare HC pathology among disorders, densities of ‘signature’ pathological lesions were measured at a standard location in eight brain regions of 12 disorders. Principal components analysis of the data suggested that the disorders could be divided into three groups: (1) Alzheimer’s disease (AD), Down’s syndrome (DS), sporadic Creutzfeldt–Jakob disease, and variant Creutzfeldt–Jakob disease in which either β-amyloid (Aβ) or prion protein deposits were distributed in all sectors of the HC and adjacent gyri, with high densities being recorded in the parahippocampal gyrus and subiculum; (2) Pick’s disease, sporadic frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions, and neuronal intermediate filament inclusion disease in which relatively high densities of neuronal cytoplasmic inclusions were present in the dentate gyrus (DG) granule cells; and (3) Parkinson’s disease dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy in which densities of signature lesions were relatively low. Variation in density of signature lesions in DG granule cells and CA1 were the most important sources of neuropathological variation among disorders. Hence, HC and adjacent gyri are differentially affected in dementia reflecting either variation in vulnerability of hippocampal neurons to specific molecular pathologies or in the spread of pathological proteins to the HC. Information regarding the distribution of pathology could ultimately help to explain variations in different cognitive domains, such as memory, observed in various disorders. © 2015, Springer-Verlag Wien.

Author Keywords
Cellular inclusions;  Dentate gyrus (DG);  Hippocampus (HC);  Neurodegenerative disease;  Synucleinopathies;  Tauopathies

Document Type: Article
Source: Scopus
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Lutsep, H.L.a , Barnwell, S.L.b , Larsen, D.T.a , Lynn, M.J.c , Hong, M.c , Turan, T.N.d , Derdeyn, C.P.e , Fiorella, D.f , Janis, L.S.g , Chimowitz, M.I.d 
Outcome in patients previously on antithrombotic therapy in the SAMMPRIS trial subgroup analysis
(2015) Stroke, 46 (3), pp. 775-779. 

DOI: 10.1161/STROKEAHA.114.007752

a Department of Neurology, Dotter Interventional Institute, Oregon Health and Science University, Oregon Stroke Center, 3181 SW Sam Jackson Park Rd, CR131, Portland, OR, United States
b Department of Neurological Surgery, Dotter Interventional Institute, Oregon Health and Science University, Portland, United States
c Department of Biostatistics and Bioinformatics, Emory University, Rollins School of Public Health, Atlanta, GA, United States
d Department of Neurology, Medical University of South Carolina, Charleston, United States
e Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
f Department of Neurological Surgery, State University of New York, Stony Brook, NY, United States
g National Institutes of Health, Bethesda, MD, United States

Abstract
Background and Purpose:-Stenting has been used as a rescue therapy in patients with intracranial arterial stenosis and a transient ischemic attack or stroke when on antithrombotic therapy (AT). We determined whether the stenting versus aggressive medical therapy for intracranial arterial stenosis (SAMMPRIS) trial supported this approach by comparing the treatments within subgroups of patients whose qualifying event (QE) occurred on versus off of AT. Methods:-The primary outcome, 30-day stroke and death and later strokes in the territory of the qualifying artery, was compared between (1) percutaneous transluminal angioplasty and stenting plus aggressive medical therapy (PTAS) versus aggressive medical management therapy alone (AMM) for patients whose QE occurred on versus off AT and between (2) patients whose QE occurred on versus off AT separately for the treatment groups. Results:-Among the 284/451 (63%) patients who had their QE on AT, the 2-year primary end point rates were 15.6% for those randomized to AMM (n=140) and 21.6% for PTAS (n=144; P=0.043, log-rank test). In the 167 patients not on AT, the 2-year primary end point rates were 11.6% for AMM (n=87) and 18.8% for PTAS (n=80; P=0.31, log-rank test). Within both treatment groups, there was no difference in the time to the primary end point between patients who were on or off AT (AMM, P=0.96; PTAS, P=0.52; log-rank test). Conclusions:-SAMMPRIS results indicate that the beneft of AMM over PTAS is similar in patients on versus off AT at the QE and that failure of AT is not a predictor of increased risk of a primary end point. Clinical Trial Registration:-URL: http://www.clinicaltrials.gov. Unique identifer: NCT00576693. © 2015 American Heart Association, Inc.

Author Keywords
Antiplatelet agents;  Intracranial arteriosclerosis;  Stroke

Document Type: Article
Source: Scopus
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Tanenbaum, A.B.a , Snyder, A.Z.a b , Brier, M.R.a , Ances, B.M.a b 
A method for reducing the effects of motion contamination in arterial spin labeling magnetic resonance imaging
(2015) Journal of Cerebral Blood Flow and Metabolism, 35 (10), pp. 1697-1702. 

DOI: 10.1038/jcbfm.2015.124

a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Arterial spin labeling (ASL) is a noninvasive method to measure cerebral blood flow (CBF). Arterial spin labeling is susceptible to artifact generated by head motion; this artifact is propagated through the subtraction procedure required to calculate CBF. We introduce a novel strategy for mitigating this artifact based on weighting tag/control volumes according to a noise estimate. We evaluated this strategy (DVARS weighting) in application to both pulsed ASL (PASL) and pseudo-continuous ASL (pCASL) in a cohort of normal adults (N=57). Application of DVARS weighting significantly improved test-retest repeatability as assessed by the intra-class correlation coefficient. Before the application of DVARS weighting, mean gray matter intra-class correlation (ICC) between subsequent ASL runs was 0.48 and 0.51 in PASL and pCASL, respectively. With weighting, ICC was significantly improved to 0.63 and 0.58. © 2015 ISCBFM.

Author Keywords
arterial spin labeling;  ASL;  cerebral blood flow measurement;  perfusion-weighted MRI

Document Type: Article
Source: Scopus
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Kaul, A.a , Toonen, J.A.a , Cimino, P.J.b , Gianino, S.M.a , Gutmann, D.H.a 
Akt- or MEK-mediated mTOR inhibition suppresses Nf1 optic glioma growth
(2015) Neuro-Oncology, 17 (6), pp. 843-853. Cited 2 times.

DOI: 10.1093/neuonc/nou329

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

Abstract
Background. Children with neurofibromatosis type 1 (NF1) develop optic pathway gliomas, which result from impaired NF1 protein regulation of Ras activity. One obstacle to the implementation of biologically targeted therapies is an incomplete understanding of the individual contributions of the downstream Ras effectors (mitogen-activated protein kinase kinase [MEK], Akt) to optic glioma maintenance. This study was designed to address the importance of MEK and Akt signaling to Nf1 optic glioma growth. Methods. Primary neonatal mouse astrocyte cultures were employed to determine the consequence of phosphatidylinositol-3 kinase (PI3K)/Akt and MEK inhibition on Nf1-deficient astrocyte growth. Nf1 optic glioma-bearing mice were used to assess the effect of Akt and MEK inhibition on tumor volume, proliferation, and retinal ganglion cell dysfunction. Results. Both MEK and Akt were hyperactivated in Nf1-deficient astrocytes in vitro and in Nf1 murine optic gliomas in vivo. Pharmacologic PI3K or Akt inhibition reduced Nf1-deficient astrocyte proliferation to wild-type levels, while PI3K inhibition decreased Nf1 optic glioma volume and proliferation. Akt inhibition of Nf1-deficient astrocyte and optic glioma growth reflected Akt-dependent activation of mammalian target of rapamycin (mTOR). Sustained MEK pharmacologic blockade also attenuated Nf1-deficient astrocytes as well as Nf1 optic glioma volume and proliferation. Importantly, these MEK inhibitory effects resulted from p90RSK-mediated, Akt-independent mTOR activation. Finally, both PI3K and MEK inhibition reduced optic glioma-associated retinal ganglion cell loss and nerve fiber layer thinning. Conclusion. These findings establish that the convergence of 2 distinct Ras effector pathways on mTOR signaling maintains Nf1 mouse optic glioma growth, supporting the evaluation of pharmacologic inhibitors that target mTOR function in future human NF1-optic pathway glioma clinical trials. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.

Author Keywords
MEK;  mTOR;  Neurofibromin;  Optic glioma;  PI3K/Akt

Document Type: Article
Source: Scopus
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Broderick, J.P.a , Jauch, E.C.b , Derdeyn, C.P.c 
American Stroke Association Stroke Council Update: Sea Change for Stroke and the American Stroke Association
(2015) Stroke, 46 (6), pp. e145-e146. 

DOI: 10.1161/STROKEAHA.115.008739

a Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Neuroscience Institute, 260 Stetson St, Cincinnati, OH, United States
b Department of Emergency Medicine, Medical University of South Carolina, Charleston, United States
c Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States

Author Keywords
mortality

Document Type: Review
Source: Scopus
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Plunk, A.D.a , Agrawal, A.b , Tate, W.F.c , Cavazos-Rehg, P.b , Bierut, L.J.b , Grucza, R.A.b 
Did the 18 drinking age promote high school dropout? Implications for current policy
(2015) Journal of Studies on Alcohol and Drugs, 76 (5), pp. 680-689. 

DOI: 10.15288/jsad.2015.76.680

a Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA, United States
b Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
c Department of Education, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Objective: Disagreement exists over whether permissive minimum legal drinking age (MLDA) laws affected underage adolescents (e.g., those age 17 years with the MLDA of 18). We used MLDA changes during the 1970s and 1980s as a natural experiment to investigate how underage exposure to permissive MLDA affected high school dropout. Method: MLDA exposure was added to two data sets: (a) the 5% public use microdata samples of the 1990 and 2000 censuses (n = 3,671,075), and (b) a combined data set based on the 1991–1992 National Longitudinal Alcohol Epidemiological Survey (NLAES) and the 2001–2002 National Epidemiological Survey on Alcohol and Related Conditions (NESARC; n = 16,331). We used logistic regression to model different thresholds of MLDA on high school dropout. We also estimated models conditioned on demographic variables and familial risk of developing alcohol problems. Results: Only the MLDA of 18 predicted high school dropout. Exposure was associated with 4% and 13% higher odds of high school dropout for the census and NLAES/NESARC samples, respectively. We noted greater impact on women (5%–18%), Blacks (5%–19%), and Hispanics (6%). Self-report of parental alcohol problems was associated with 40% higher odds, which equals a 4.14-point increase in dropout rate for that population. Conclusions: The MLDA of 18 likely had a large impact on high school dropout rates, suggesting that the presence of legal-aged peers in a high school setting increased access to alcohol for younger students. Our results also suggest that policy can promote less dangerous drinking behavior even when familial risk of alcohol use disorders is high. © 2015 Alcohol Research Documentation, Inc.

Document Type: Article
Source: Scopus
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Shroff, S.R., Kushnir, V.M., Wani, S.B., Gupta, N., Jonnalagadda, S.S., Murad, F., Early, D.S., Mullady, D.K., Edmundowicz, S.A., Azar, R.R.
Efficacy of endoscopic mucosal resection for management of small duodenal neuroendocrine tumors
(2015) Surgical Laparoscopy, Endoscopy and Percutaneous Techniques, 25 (5), pp. e134-e139. 

Division of Gastroenterology and Hepatology, Department of Medicine, Washington University, 660 South Euclid Ave, P.O. Box 8124, St Louis, MO, United States

Abstract
Background: Endoscopic mucosal resection (EMR) for small (< 20 mm) duodenal neuroendocrine tumors (NETs) remains controversial because of their rarity. Materials and Methods: This is a retrospective cohort study of patients with surgically or endoscopically resected duodenal NETs from 2001 to 2011. The primary outcome is the rate of disease-free status following resection. A secondary outcome is the sensitivity of endoscopic ultrasound (EUS) in determining NET appropriateness for EMR. Results: Thirty patients underwent resection of duodenal NETs (EMR 20, surgery 10). Tumor was present at the margins in 40% of EMR-resected NETs and 10% of surgically resected NETs. Five patients who underwent EMR had residual disease treated with repeat EMR (3) and surgery (2). EUS demonstrated 96% sensitivity in determining lesions limited to the submucosa. Conclusions: EMR for small duodenal NETs can be a safe and effective alternative to surgery in carefully selected patients. EUS is a useful adjunct in determining depth of invasion for duodenal NETs. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Author Keywords
Carcinoid;  Duodenum;  EMR;  EUS;  Neuroendocrine;  Tumor

Document Type: Article
Source: Scopus
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Green, M.F.a b , Horan, W.P.a b , Barch, D.M.c , Gold, J.M.d 
Effort-based decision making: A novel approach for assessing motivation in schizophrenia
(2015) Schizophrenia Bulletin, 41 (5), pp. 1035-1044. 

DOI: 10.1093/schbul/sbv071

a Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, United States
b Department of Veterans Affairs, Desert Pacific Mental Illness Research, Education, and Clinical Center, Los Angeles, CA, United States
c Departments of Psychology, Psychiatry and Radiology, Washington University, St. Louis, MO, United States
d Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MA, United States

Abstract
Because negative symptoms, including motivational deficits, are a critical unmet need in schizophrenia, there are many ongoing efforts to develop new pharmacological and psychosocial interventions for these impairments. A common challenge of these studies involves how to evaluate and select optimal endpoints. Currently, all studies of negative symptoms in schizophrenia depend on ratings from clinician-conducted interviews. Effort-based decision-making tasks may provide a more objective, and perhaps more sensitive, endpoint for trials of motivational negative symptoms. These tasks assess how much effort a person is willing to exert for a given level of reward. This area has been well-studied with animal models of effort and motivation, and effort-based decision-making tasks have been adapted for use in humans. Very recently, several studies have examined physical and cognitive types of effort-based decision-making tasks in cross-sectional studies of schizophrenia, providing evidence for effort-related impairment in this illness. This article covers the theoretical background on effort-based decision-making tasks to provide a context for the subsequent articles in this theme section. In addition, we review the existing literature of studies using these tasks in schizophrenia, consider some practical challenges in adapting them for use in clinical trials in schizophrenia, and discuss interpretive challenges that are central to these types of tasks. © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.

Author Keywords
Clinical trials;  Effort-based decision making;  Motivation;  Negative symptoms;  Schizophrenia

Document Type: Article
Source: Scopus
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Horan, W.P.a b , Felice Reddy, L.a b , Barch, D.M.c , Buchanan, R.W.d , Dunayevich, E.e , Gold, J.M.d , Marder, S.R.a b , Wynn, J.K.a b , Young, J.W.f g , Green, M.F.a b 
Effort-based decision-making paradigms for clinical trials in schizophrenia: Part 2 - External validity and correlates
(2015) Schizophrenia Bulletin, 41 (5), pp. 1055-1065. 

DOI: 10.1093/schbul/sbv090

a Department of Veterans Affairs VISN 22, Los Angeles, CA, United States
b UCLA Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, Los Angeles, CA, United States
c Departments of Psychology, Psychiatry and Radiology, Washington University, St. Louis, MO, United States
d Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, United States
e Amgen Inc., Thousand Oaks, CA, United States
f Department of Psychiatry, University of California San Diego, San Deigo, CA, United States
g Research Service, VA San Diego Healthcare System, San Diego, CA, United States

Abstract
Effort-based decision making has strong conceptual links to the motivational disturbances that define a key subdomain of negative symptoms. However, the extent to which effort-based decision-making performance relates to negative symptoms, and other clinical and functionally important variables has yet to be systematically investigated. In 94 clinically stable outpatients with schizophrenia, we examined the external validity of 5 effort-based paradigms, including the Effort Expenditure for Rewards, Balloon Effort, Grip Strength Effort, Deck Choice Effort, and Perceptual Effort tasks. These tasks covered 3 types of effort: physical, cognitive, and perceptual. Correlations between effort related performance and 6 classes of variables were examined, including: (1) negative symptoms, (2) clinically rated motivation and community role functioning, (3) self-reported motivational traits, (4) neurocognition, (5) other psychiatric symptoms and clinical/demographic characteristics, and (6) subjective valuation of monetary rewards. Effort paradigms showed small to medium relationships to clinical ratings of negative symptoms, motivation, and functioning, with the pattern more consistent for some measures than others. They also showed small to medium relations with neurocognitive functioning, but were generally unrelated to other psychiatric symptoms, self-reported traits, antipsychotic medications, side effects, and subjective valuation of money. There were relatively strong interrelationships among the effort measures. In conjunction with findings from a companion psychometric article, all the paradigms warrant further consideration and development, and 2 show the strongest potential for clinical trial use at this juncture. © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.

Author Keywords
Decision making;  Effort;  Functional outcome;  Schizophrenia

Document Type: Article
Source: Scopus
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Reddy, L.F.a b , Horan, W.P.a b , Barch, D.M.c , Buchanan, R.W.d , Dunayevich, E.e , Gold, J.M.d , Lyons, N.a , Marder, S.R.a b , Treadway, M.T.f, Wynn, J.K.a b , Young, J.W.g h , Green, M.F.a b 
Effort-based decision-making paradigms for clinical trials in schizophrenia: Part 1 - Psychometric characteristics of 5 paradigms
(2015) Schizophrenia Bulletin, 41 (5), pp. 1045-1054. 

DOI: 10.1093/schbul/sbv089

a Department of Veterans Affairs, VISN 22 Mental Illness Research, Education, and Clinical Center, Los Angeles, CA, United States
b UCLA Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, Los Angeles, CA, United States
c Departments of Psychology, Psychiatry, and Radiology, Washington University, St. Louis, MO, United States
d Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, United States
e Amgen, Inc., Thousand Oaks, CA, United States
f Department of Psychology, Emory University, Atlanta, GA, United States
g Department of Psychiatry, University of California, San Diego, CA, United States
h Research Service, VA San Diego Healthcare System, San Diego, CA, United States

Abstract
Impairments in willingness to exert effort contribute to the motivational deficits characteristic of the negative symptoms of schizophrenia. The current study evaluated the psychometric properties of 5 new or adapted paradigms to determine their suitability for use in clinical trials of schizophrenia. This study included 94 clinically stable participants with schizophrenia and 40 healthy controls. The effort-based decision-making battery was administered twice to the schizophrenia group (baseline, 4-week retest) and once to the control group. The 5 paradigms included 1 that assesses cognitive effort, 1 perceptual effort, and 3 that assess physical effort. Each paradigm was evaluated on (1) patient vs healthy control group differences, (2) test-retest reliability, (3) utility as a repeated measure (ie, practice effects), and (4) tolerability. The 5 paradigms showed varying psychometric strengths and weaknesses. The Effort Expenditure for Rewards Task showed the best reliability and utility as a repeated measure, while the Grip Effort Task had significant patient-control group differences, and superior tolerability and administration duration. The other paradigms showed weaker psychometric characteristics in their current forms. These findings highlight challenges in adapting effort and motivation paradigms for use in clinical trials. © 2015, Oxford University Press. All rights reserved.

Author Keywords
Effort;  Motivation;  Psychometric;  Schizophrenia

Document Type: Article
Source: Scopus
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Thompson, R.J.a , Kuppens, P.b , Mata, J.c d , Jaeggi, S.M.e , Buschkuehl, M.f g , Jonides, J.f , Gotlib, I.H.c 
Emotional clarity as a function of neuroticism and major depressive disorder
(2015) Emotion, 15 (5), pp. 615-624. 

DOI: 10.1037/emo0000067

a Department of Psychology, Washington University, St. Louis, United States
b Department of Psychology, KU Leuven - University of Leuven, Belgium
c Department of Psychology, Stanford University, United States
d Department of Psychology, University of Basel, Switzerland
e School of Education, University of California, Irvine, United States
f Department of Psychology, University of Michigan, United States
g MIND Research Institute, Irvine, United States

Abstract
Investigators have begun to document links between emotional clarity and forms of negative emotionality, including neuroticism and major depressive disorder (MDD). Researchers to date have relied almost exclusively on global self-reports of emotional clarity; moreover, no studies have examined emotional clarity as a function of valence, although this may prove to be crucial in understanding the relation of emotional clarity to maladjustment. In 2 studies, we used experience-sampling methodology and multilevel modeling to examine the associations between emotional clarity and 2 constructs that have been linked theoretically with emotional clarity: neuroticism and depression. In Study 1 we assessed 95 college students who completed a self-report measure of neuroticism. In Study 2 we examined 53 adults diagnosed with MDD and 53 healthy adults. Reaction times to negative and positive emotion ratings during the experience-sampling protocols were used as an indirect measure of emotional clarity. Neuroticism was related to lower clarity of negative, but not of positive, emotion. Similarly, compared with the healthy controls, individuals with MDD had lower clarity of negative, but not of positive, emotion. It is important to note, findings from both studies held after controlling for baseline RTs and current levels of negative and positive emotion. These findings highlight the importance of assessing valence when examining emotional clarity and increase our understanding of the nature of the emotional disturbances that characterize neuroticism and MDD. © 2015 American Psychological Association.

Author Keywords
Depression;  Emotional clarity;  Major depressive disorder;  Negative emotionality;  Neuroticism

Document Type: Article
Source: Scopus
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Amin-Hanjani, S.a , Du, X.a , Rose-Finnell, L.a , Pandey, D.K.b , Richardson, D.b d , Thulborn, K.R.c , Elkind, M.S.V.e , Zipfel, G.J.f , Liebeskind, D.S.g , Silver, F.L.h , Kasner, S.E.i , Aletich, V.A.a , Caplan, L.R.j , Derdeyn, C.P.f k , Gorelick, P.B.l , Charbel, F.T.a 
Hemodynamic Features of Symptomatic Vertebrobasilar Disease
(2015) Stroke, 46 (7), pp. 1850-1856. 

DOI: 10.1161/STROKEAHA.115.009215

a Department of Neurosurgery, Neuropsychiatric Institute, University of Illinois at Chicago, 912 S Wood St, Chicago, IL, United States
b Department of Neurology and Rehabilitation, United States
c Center for Magnetic Resonance Research, University of Illinois, Chicago, United States
d Department of Mathematics and Computer Science, Lake Forest College, Lake Forest, IL, United States
e Departments of Neurology and Epidemiology, Columbia University, New York, NY, United States
f Departments of Neurosurgery and Neurology, Washington University, St. Louis, MO, United States
g Department of Neurology, University of California, Los Angeles, United States
h Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada
i Department of Neurology, University of Pennsylvania, Philadelphia, United States
j Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United States
k Departments of Radiology, Neurology and Neurological Surgery, Mallinkrodt Institute of Radiology, Washington University, St. Louis, MO, United States
l Department of Translational Science and Molecular Medicine, Michigan State University, College of Human Medicine, and Mercy Health Hauenstein Neurosciences, Grand Rapids, United States

Abstract
Background and Purpose-Atherosclerotic vertebrobasilar disease is an important cause of posterior circulation stroke. To examine the role of hemodynamic compromise, a prospective multicenter study, Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke (VERiTAS), was conducted. Here, we report clinical features and vessel flow measurements from the study cohort. Methods-Patients with recent vertebrobasilar transient ischemic attack or stroke and ≥50% atherosclerotic stenosis or occlusion in vertebral or basilar arteries (BA) were enrolled. Large-vessel flow in the vertebrobasilar territory was assessed using quantitative MRA. Results-The cohort (n=72; 44% women) had a mean age of 65.6 years; 72% presented with ischemic stroke. Hypertension (93%) and hyperlipidemia (81%) were the most prevalent vascular risk factors. BA flows correlated negatively with percentage stenosis in the affected vessel and positively to the minimal diameter at the stenosis site (P<0.01). A relative threshold effect was evident, with flows dropping most significantly with ≥80% stenosis/occlusion (P<0.05). Tandem disease involving the BA and either/both vertebral arteries had the greatest negative impact on immediate downstream flow in the BA (43 mL/min versus 71 mL/min; P=0.01). Distal flow status assessment, based on an algorithm incorporating collateral flow by examining distal vessels (BA and posterior cerebral arteries), correlated neither with multifocality of disease nor with severity of the maximal stenosis. Conclusions-Flow in stenotic posterior circulation vessels correlates with residual diameter and drops significantly with tandem disease. However, distal flow status, incorporating collateral capacity, is not well predicted by the severity or location of the disease. © 2015 American Heart Association, Inc.

Author Keywords
magnetic resonance angiography;  magnetic resonance imaging;  regional blood flow;  stroke;  vertebrobasilar ischemia

Document Type: Article
Source: Scopus
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Liebeskind, D.S.a b , Albers, G.W.c , Crawford, K.e , Derdeyn, C.P.f , George, M.S.g i , Palesch, Y.Y.h , Toga, A.W.e , Warach, S.j , Zhao, W.h , Brott, T.G.k , Sacco, R.L.l , Khatri, P.m , Saver, J.L.b , Cramer, S.C.n , Wolf, S.L.o , Broderick, J.P.m , Wintermark, M.d 
Imaging in StrokeNet: Realizing the Potential of Big Data
(2015) Stroke, 46 (7), pp. 2000-2006. 

DOI: 10.1161/STROKEAHA.115.009479

a Neurovascular Imaging Research Core, UCLA Department of Neurology, Neuroscience Research Bldg, 635 Charles E Young, Los Angeles, CA, United States
b Department of Neurology, Geffen School of Medicine, University of California, Los Angeles, United States
c Departments of Neurology, United States
d Departments of Radiology, Stanford University, Palo Alto, CA, United States
e Laboratory of Neuro Imaging, Institute for Neuroimaging and Informatics, University of Southern California, Los Angeles, United States
f Departments of Neurology and Neurological Surgery, Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, United States
g Departments of Psychiatry, Radiology, and Neuroscience, United States
h Public Health Sciences, Medical University of South Carolina, Charleston, United States
i Ralph H Johnson VA Medical Center, Charleston, SC, United States
j University of Texas Southwestern Medical Center, Austin, United States
k Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
l Departments of Neurology, Public Health Sciences, Human Genetics, and Neurosurgery, University of Miami, Miami, FL, United States
m Department of Neurology, University of Cincinnati, Cincinnati, OH, United States
n Department of Neurology, University of California, Irvine, United States
o Department of Rehabilitation Medicine, Emory University, Center for Visual and Cognitive Neurorehabilitation, Atlanta, GA, United States

Author Keywords
collateral circulation;  diagnostic imaging;  stroke

Document Type: Article
Source: Scopus
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Vila, P.M.a , Hullar, T.E.b , Buchman, C.A.c , Lieu, J.E.C.a 
Is There a Need for Performance Measures for Cochlear Implant Centers?
(2015) Otolaryngology - Head and Neck Surgery (United States), 153 (4), pp. 484-487. 

DOI: 10.1177/0194599815575006

a Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, United States
b Department of Otolaryngology-Head and Neck Surgery, Oregon Health and Science University, Portland, OR, United States
c Department of Otolaryngology-Head and Neck Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

Abstract
Performance measures (PMs), or quality indicators, are metrics based on objective data that allow one to assess whether a system achieves a prespecified goal. Given the relatively high level of resource utilization and potential morbidity associated with cochlear implantation (CI), PMs could be used to evaluate quality of care provided by implant centers and, ultimately, optimize care delivery. This article discusses PMs currently in use, how PMs are developed, potential downsides of using PMs, and various examples of PMs that could be used in CI centers. © Official journal of the American Academy of Otolaryngology-Head and Neck Surgery Foundation.

Author Keywords
cochlear implants;  delivery of health care;  health care;  hearing loss;  performance measures;  quality indicators

Document Type: Article
Source: Scopus
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Aravamuthan, B.R.a , Shoykhet, M.a b 
Long-term increase in coherence between the basal ganglia and motor cortex after asphyxial cardiac arrest and resuscitation in developing rats
(2015) Pediatric Research, 78 (4), pp. 371-379. 

DOI: 10.1038/pr.2015.114

a Department of Pediatrics, St. Louis Children's Hospital, St. Louis, MO, United States
b Department of Pediatrics, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States

Abstract
Background:The basal ganglia are vulnerable to injury during cardiac arrest. Movement disorders are a common morbidity in survivors. Yet, neuronal motor network changes post-arrest remain poorly understood.Methods:We compared function of the motor network in adult rats that, during postnatal week 3, underwent 9.5 min of asphyxial cardiac arrest (n = 9) or sham intervention (n = 8). Six months after injury, we simultaneously recorded local field potentials (LFP) from the primary motor cortex (MCx) and single neuron firing and LFP from the rat entopeduncular nucleus (EPN), which corresponds to the primate globus pallidus pars interna. Data were analyzed for firing rates, power, and coherence between MCx and EPN spike and LFP activity.Results:Cardiac arrest survivors display chronic motor deficits. EPN firing rate is lower in cardiac arrest survivors (19.5 ± 2.4 Hz) compared with controls (27.4 ± 2.7 Hz; P < 0.05). Cardiac arrest survivors also demonstrate greater coherence between EPN single neurons and MCx LFP (3 - 100 Hz; P < 0.001).Conclusions:This increased coherence indicates abnormal synchrony in the neuronal motor network after cardiac arrest. Increased motor network synchrony is thought to be antikinetic in primary movement disorders. Characterization of motor network synchrony after cardiac arrest may help guide management of post-hypoxic movement disorders. © 2015 International Pediatric Research Foundation, Inc.

Document Type: Article
Source: Scopus
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Yan, P.a , Zhu, A.a , Liao, F.a , Xiao, Q.a , Kraft, A.W.a , Gonzales, E.a , Perez, R.a , Greenberg, S.M.b , Holtzman, D.M.a , Lee, J.-M.a 
Minocycline Reduces Spontaneous Hemorrhage in Mouse Models of Cerebral Amyloid Angiopathy
(2015) Stroke, 46 (6), pp. 1633-1640. 

DOI: 10.1161/STROKEAHA.115.008582

a Department of Neurology, Washington University, School of Medicine, 660 S Euclid Ave, St. Louis, MO, United States
b Department of Neurology, Philip Kistler Stroke Research Center, Harvard Medical School, Boston, MA, United States

Abstract
Background and Purpose-Cerebral amyloid angiopathy (CAA) is a common cause of recurrent intracerebral hemorrhage in the elderly. Previous studies have shown that CAA induces inflammation and expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 (gelatinases) in amyloid-laden vessels. Here, we inhibited both using minocycline in CAA mouse models to determine whether spontaneous intracerebral hemorrhage could be reduced. Methods-Tg2576 (n=16) and 5xFAD/ApoE4 knockin mice (n=16), aged 17 and 12 months, respectively, were treated with minocycline (50 mg/kg, IP) or saline every other day for 2 months. Brains were extracted and stained with X-34 (to quantify amyloid), Perls' blue (to quantify hemorrhage), and immunostained to examined β-amyloid peptide load, gliosis (glial fibrillary acidic protein [GFAP], Iba-1), and vascular markers of blood-brain barrier integrity (zonula occludins-1 [ZO-1] and collagen IV). Brain extracts were used to quantify mRNA for a variety of inflammatory genes. Results-Minocycline treatment significantly reduced hemorrhage frequency in the brains of Tg2576 and 5xFAD/ApoE4 mice relative to the saline-treated mice, without affecting CAA load. Gliosis (GFAP and Iba-1 immunostaining), gelatinase activity, and expression of a variety of inflammatory genes (matrix metalloproteinase-9, NOX4, CD45, S-100b, and Iba-1) were also significantly reduced. Higher levels of microvascular tight junction and basal lamina proteins were found in the brains of minocycline-treated Tg2576 mice relative to saline-treated controls. Conclusions-Minocycline reduced gliosis, inflammatory gene expression, gelatinase activity, and spontaneous hemorrhage in 2 different mouse models of CAA, supporting the importance of matrix metalloproteinase-related and inflammatory pathways in intracerebral hemorrhage pathogenesis. As a Food and Drug Administration-approved drug, minocycline might be considered for clinical trials to test efficacy in preventing CAA-related intracerebral hemorrhage. © 2015 American Heart Association, Inc.

Author Keywords
apolipoproteins E;  cerebral amyloid angiopathy;  cerebral hemorrhage;  gliosis;  matrix metalloproteinase-9;  minocycline

Document Type: Article
Source: Scopus
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Kung, N.H.a , Bucelli, R.C.a , McClelland, C.M.b , Van Stavern, G.P.b 
Ocular Neuromyotonia Associated with Chronic Inflammatory Demyelinating Polyneuropathy
(2015) Neuro-Ophthalmology, 39 (5), pp. 240-242. 

DOI: 10.3109/01658107.2015.1059464

a Department of Neurology, Washington University in St. Louis, St. Louis, MI, United States
b Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, 660 South Euclid Avenue, Saint Louis, MO, United States

Abstract
Ocular neuromyotonia (ONM) is a neuro-ophthalmic disorder characterized by episodic diplopia caused by contraction of one or more ocular muscles due to spontaneous excitation of the respective ocular motor nerve. We report a patient whose ocular neuromyotonia arose in the setting of a subacute demyelinating polyneuropathy consistent with chronic inflammatory demyelinating polyneuropathy (CIDP) and subsequently resolved following the initiation of intravenous immunoglobulin (IVIg) for her neuropathy. Our patient provides additional evidence towards the role of demyelination and ephaptic neurotransmission in ocular neuromyotonia and also represents the first reported case of ocular neuromyotonia associated with a systemic neurological condition. © 2015 © 2015 Taylor & Francis, LLC.

Author Keywords
Chronic inflammatory demyelinating polyneuropathy;  diplopia;  ocular motility;  ocular neuromyotonia

Document Type: Article
Source: Scopus
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Park, A.M.a b , Patil, R.D.a b c , Paniello, R.C.a b 
Prevention of post-traumatic reinnervation with microtubule inhibitors
(2015) Laryngoscope, 125 (10), pp. E333-E337. 

DOI: 10.1002/lary.25258

a Department of Otolaryngology-Head and Neck Surgery, Washington University, School of Medicine in St. Louis, Box 8115, 660 S. Euclid Avenue, St. Louis, MO, United States
b St. Louis V.A. Medical Center, St. Louis, MO, United States
c Department of Otolaryngology, University of Cincinnati, Cincinnati, OH, United States

Abstract
Objectives/Hypothesis Functional recovery after a recurrent laryngeal nerve or facial nerve injury may be impaired due to aberrant reinnervation. Previous work in a rat peripheral nerve injury model found vincristine to be a potent inhibitor of reinnervation, and it has since been used to effectively block neural regeneration in other animal models. However, vincristine's narrow therapeutic index may limit its utility; therefore, another microtubule inhibitor, paclitaxel, which has a higher therapeutic index, was tested. Study Design Animal (rat) study. Methods After controlled injury to the rat posterior tibial (PT) nerve, the gastrocnemius/soleus complex was injected with saline (control, n = 14), vincristine (n = 30), or paclitaxel (n = 20). Injections without a crush injury were performed using saline (n = 5) or paclitaxel (n = 9). The functional recovery (FR) of the PT nerve was assessed using walking track analysis. Results At 6 weeks, controls had already recovered to baseline (FR = 1.0), whereas the paclitaxel group had FR = 0.724 ± 0.064 and the vincristine group had FR = 0.709 ± 0.078. At 6 months, the paclitaxel rats had FR = 0.798 ± 0.167 and the vincristine rats had FR = 0.754 ± 0.240. These differences were significantly different from baseline, but the two agents were not different from each other. Paclitaxel did not affect the FR in the absence of a nerve injury. Conclusions Intramuscular paclitaxel and vincristine both significantly inhibit regeneration of the PT nerve after crush injury for at least 6 months. Potential clinical uses of inhibition of reinnervation are discussed. © 2015 The American Laryngological, Rhinological and Otological Society, Inc.

Author Keywords
laryngeal nerve;  larynx;  neural regeneration;  neurotoxin;  paclitaxel;  Unilateral vocal fold paralysis;  vincristine

Document Type: Conference Paper
Source: Scopus
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Racette, B.A.a b , Willis, A.W.c d 
Time to change the blind men and the elephant approach to Parkinson disease?
(2015) Neurology, 85 (2), pp. 190-196. 

DOI: 10.1212/WNL.0000000000001739

a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa
c Department of Neurology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, United States
d Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, United States

Abstract
Parkinson disease (PD) is a progressive neurodegenerative disease that is associated with substantial morbidity and early mortality. Disease-related costs exceed 10 billion, not including medications, out-of-pocket expenses, or societal costs. Symptomatic treatment with levodopa, which has been available for over 30 years, and advanced therapies such as deep brain stimulation improve outcomes. Yet most new medications for PD provide a therapeutic benefit that is relatively modest compared to the benefits from levodopa. Despite dozens of neuroprotective clinical trials, there are no medications proven to slow the progression of the disease. Given these limitations, we provide evidence of the potential public health impact of a research agenda that emphasizes identification of risk factors to reduce disease burden through exposure mitigation. In addition, we emphasize health care policy that focuses on increasing health care expenditures for neurologic evaluation andmanagement services to increase access to specialists to improve disease outcomes and reduce costs through better disease management. © 2015 American Academy of Neurology.

Document Type: Review
Source: Scopus
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Upah, R.a , Jacob, T.a , Price, R.K.b 
Trajectories of lifetime comorbid alcohol and other drug use disorders through midlife
(2015) Journal of Studies on Alcohol and Drugs, 76 (5), pp. 721-732. 

DOI: 10.15288/jsad.2015.76.721

a Family Research Center, Veterans Affairs Palo Alto Healthcare System, Menlo Park, CA, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective: Very few studies have examined the developmental nature of comorbid alcohol use disorders and drug use disorders (AUD-DUD). The current study sought to extend our understanding of the nature of AUD-DUD comorbidity by characterizing the developmental course of AUD-DUD comorbidity, determining the degree to which the two disorders occur during the same period, and eliciting differences in AUD-DUD trajectories over the life course. Method: Vietnam-era male veterans and matched civilians provided retrospective accounts of alcohol- and other drug–related experiences spanning 25 years. Concurrent growth mixture modeling was used to describe the course of AUDDUD lifetime comorbidity. Results: Five trajectories were identified based on the probabilities of diagnosing with AUD-DUD: substance switching (increasing AUD, decreasing DUD); young adult (both AUD and DUD decreasing rapidly after young adulthood); severe nonchronic (both AUD and DUD decreasing slowly in the third decade of life); severe chronic alcohol–severe nonchronic drug (AUD remains high and DUD decreases in the fourth decade); and young adult alcohol–severe chronic drug (decreasing AUD in the second decade and DUD remains high). Conclusions: For the majority of this sample, substance use disorders continued or worsened through adulthood, indicating a problem that extends far beyond young adulthood. Demographic characteristics differed among the trajectories; however, psychiatric diagnoses did not differ except for the number of years with diagnoses of antisocial personality disorder. Subthreshold symptoms in adulthood may be present for a significant period before diagnosis, making this period important for intervention and prevention. Integration of efforts into healthcare, employment, and public policy will help target those at highest risk. © 2015 Alcohol Research Documentation, Inc.

Document Type: Article
Source: Scopus
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Helwani, M.A.
When should cilostazol (Pletal) and dipyridamole be discontinued before neuroaxial block?
(2015) Regional Anesthesia and Pain Medicine, 40 (3), pp. 295-296. 

DOI: 10.1097/AAP.0000000000000246

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

Document Type: Letter
Source: Scopus

 
October 7, 2015
 
Yue, X., Bognar, C., Zhang, X., Gaehle, G.G., Moerlein, S.M., Perlmutter, J.S., Tu, Z.
Automated production of [18F]VAT suitable for clinical PET study of vesicular acetylcholine transporter
(2016) Applied Radiation and Isotopes, 107, art. no. 7141, pp. 40-46. 

DOI: 10.1016/j.apradiso.2015.09.010

Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Automated production of a promising radiopharmaceutical (-)-(1-(8-(2-[18F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone ([18F]VAT) for the vesicular acetylcholine transporter(VAChT) was achieved using a two-step procedure in a current Good Manufacturing Practices fashion. The production of [18F]VAT was accomplished in approximately 140min, with radiochemical yield of ~15.0% (decay corrected), specific activity>111GBq/μmol, radiochemical purity>99% and mass of VAT ~3.4μg/batch (n>10). The radiopharmaceutical product meets all quality control criteria for human use, and is suitable for clinical PET studies of VAChT. © 2015 Elsevier Ltd.

Author Keywords
Automation;  Clinical studies;  Fluorine-18;  Positron emission tomography;  Vesicular acetylcholine transporter

Document Type: Article
Source: Scopus
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Prichep, L.S.a , Ghosh Dastidar, S.b , Jacquin, A.b , Koppes, W.b , Miller, J.b , O'Neil, B.c , Naunheim, R.d , Stephen Huff, J.e 
Response to letter to the Editor regarding 'Classification algorithms for the identification of structural injury in TBI using brain electrical activity'
(2015) Computers in Biology and Medicine, 65, pp. 147-148. 

DOI: 10.1016/j.compbiomed.2015.04.021

a Brain Research Laboratories, Department of Psychiatry, NYU School of Medicine, New York, NY, United States
b Algorithm Development, BrainScope Co., Inc., Bethesda, MD, United States
c Wayne State University, School of Medicine, Department of Emergency Medicine, Detroit, MI, United States
d Washington University School of Medicine, Division of Emergency Medicine, St. Louis, MO, United States
e Departments of Emergency Medicine and Neurology, University of Virginia, Charlottesville, VA, United States

Author Keywords
Acute traumatic brain injury;  Classifier algorithms;  Quantitative brain electrical activity;  TBI;  TBI triage

Document Type: Letter
Source: Scopus
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Fowler, K.D.a , Funt, J.M.a , Artyomov, M.N.a b , Zeskind, B.a , Kolitz, S.E.a , Towfic, F.a 
Leveraging existing data sets to generate new insights into Alzheimer's disease biology in specific patient subsets
(2015) Scientific Reports, 5, art. no. 14324, . 

DOI: 10.1038/srep14324

a Immuneering Corporation, Cambridge, MA, United States
b Department of Immunology and Pathology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
To generate new insights into the biology of Alzheimer's Disease (AD), we developed methods to combine and reuse a wide variety of existing data sets in new ways. We first identified genes consistently associated with AD in each of four separate expression studies, and confirmed this result using a fifth study. We next developed algorithms to search hundreds of thousands of Gene Expression Omnibus (GEO) data sets, identifying a link between an AD-associated gene (NEUROD6) and gender. We therefore stratified patients by gender along with APOE4 status, and analyzed multiple SNP data sets to identify variants associated with AD. SNPs in either the region of NEUROD6 or SNAP25 were significantly associated with AD, in APOE4+ females and APOE4+ males, respectively. We developed algorithms to search Connectivity Map (CMAP) data for medicines that modulate AD-associated genes, identifying hypotheses that warrant further investigation for treating specific AD patient subsets. In contrast to other methods, this approach focused on integrating multiple gene expression datasets across platforms in order to achieve a robust intersection of disease-affected genes, and then leveraging these results in combination with genetic studies in order to prioritize potential genes for targeted therapy. © 2015 Macmillan Publishers Limited.

Document Type: Article
Source: Scopus
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Myerson, J.a , Green, L.a , van Den Berk-Clark, C.b , Grucza, R.A.c 
Male, But Not Female, Alcohol-Dependent African Americans Discount Delayed Gains More Steeply than Propensity-Score Matched Controls
(2015) Psychopharmacology, 11 p. Article in Press. 

DOI: 10.1007/s00213-015-4076-x

a Department of Psychology, Washington University, St. Louis, MO, United States
b Department of Family and Community Medicine, Saint Louis University School of Medicine, St. Louis, MO, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Rationale: Alcohol dependence is known to be associated with steep discounting of delayed rewards, but its relation to the discounting of delayed losses and probabilistic rewards is unclear. Moreover, patterns of alcohol consumption vary considerably between communities, but previous research has not examined the relation between discounting and alcohol dependence in low-income African Americans. Objectives: The goal of the present study was to determine whether low-income, alcohol-dependent African Americans differ from controls in the degree to which they discount delayed rewards, delayed losses, or probabilistic rewards. Methods: African–American participants, both cases and controls, were recruited from the same low-income neighborhoods, and propensity-score matching was used to further control for demographic differences. Participants performed three tasks that assessed their discounting of hypothetical monetary outcomes: delayed rewards, delayed losses, and probabilistic rewards. Results: Alcohol-dependent cases discounted delayed gains, but not delayed losses or probabilistic gains, more steeply than their matched controls. The difference in discounting of delayed gains was localized to the male cases, whose discounting was steeper than either the male controls or the female cases; no gender difference was observed between male and female controls. Conclusions: The present results extend findings regarding discounting by substance abusers to a previously unstudied group, low-income African Americans, and suggest that in this group at least, alcohol dependence, particularly in males, may be more a reflection of choosing immediate rewards than of ignoring their delayed negative consequences. © 2015 Springer-Verlag Berlin Heidelberg

Author Keywords
African Americans;  Alcohol dependence;  Delayed gains;  Delayed losses;  Discounting;  Gender;  Income;  Probabilistic gains

Document Type: Article in Press
Source: Scopus
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Gonzalez-Perez, V., Xia, X.-M., Lingle, C.J.
Two classes of regulatory subunits coassemble in the same BK channel and independently regulate gating
(2015) Nature Communications, 6, art. no. 8341, . 

DOI: 10.1038/ncomms9341

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

Abstract
High resolution proteomics increasingly reveals that most native ion channels are assembled in macromolecular complexes. However, whether different partners have additive or cooperative functional effects, or whether some combinations of proteins may preclude assembly of others are largely unexplored topics. The large conductance Ca2+ -and-voltage activated potassium channel (BK) is well-suited to discern nuanced differences in regulation arising from combinations of subunits. Here we examine whether assembly of two different classes of regulatory proteins, β and γ, in BK channels is exclusive or independent. Our results show that both γ1 and up to four β2-subunits can coexist in the same functional BK complex, with the gating shift caused by β2-subunits largely additive with that produced by the γ1-subunit(s). The multiplicity of β:γ3 combinations that can participate in a BK complex therefore allow a range of BK channels with distinct functional properties tuned by the specific stoichiometry of the contributing subunits. © 2015 Macmillan Publishers Limited. All rights reserved.

Document Type: Article
Source: Scopus
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Athiraman, U.a b , Ravishankar, M.b , Jahagirdhar, S.b 
Performance of computer simulated inhalational anesthetic uptake model in comparison with real time isoflurane concentration
(2015) Journal of Clinical Monitoring and Computing, 6 p. Article in Press. 

DOI: 10.1007/s10877-015-9776-6

a Department of Anesthesiology, Washington University, St. Louis, MO, United States
b Department of Anesthesiology, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth, Pondicherry, India

Abstract
Gas Man software was developed to enhance our understanding of the pharmacokinetics of inhalational anaesthetics. To date the Gas Man software has not been validated in humans. In this study we compared the Gas Man software with real time measured end tidal isoflurane concentrations while using a semi closed circle system in anesthetised patients. Thirty-four ASA I and II patients 18–60 years of age were selected for the study. After a standardized induction anesthesia was maintained with N<inf>2</inf>O + O<inf>2</inf> mixture and isoflurane using the circle system. The fresh gas flow or dial setting of Isoflurane vaporizer were changed at random. The inspired and end-tidal concentration values of isoflurane measured at 1 min intervals were retrieved from the patient monitor. Real time anesthetic settings for the patient were simultaneously simulated in the Gas Man software to generate the inspired and end-tidal concentration of isoflurane values at every minute for comparison. Varvel’s criteria have been used to assess this model. The median absolute performance error was 9.39 %, median performance error was −5.30 %, wobble was 5.16 %, and divergence was −1.82 %. All criteria were within limits of the acceptable performance of the model. The end-tidal concentration values of isoflurane in real patients are very close to those predicted by Gas Man software. The pharmocokinetics of inhalational anesthetic administration in patients can be taught accurately using Gas Man technology. This technology may also help in developing different kinetic models of inhalational agents in the body. © 2015 Springer Science+Business Media New York

Author Keywords
Gas Man;  Inhalational anesthetics;  Pharmacokinetics;  Real time patients

Document Type: Article in Press
Source: Scopus
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Shu, L.a c , Laurila, A.b , Räsänen, K.a 
Acid stress mediated adaptive divergence in ion channel function during embryogenesis in Rana arvalis
(2015) Scientific Reports, 5, art. no. 14201, . 

DOI: 10.1038/srep14201

a Eawag, Department of Aquatic Ecology, ETH Zurich, Institute of Integrative Biology, Switzerland
b Animal Ecology, Department of Ecology and Genetics, Evolutionary Biology Center, Uppsala University, Sweden
c Department of Biology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Ion channels and pumps are responsible for ion flux in cells, and are key mechanisms mediating cellular function. Many environmental stressors, such as salinity and acidification, are known to severely disrupt ionic balance of organisms thereby challenging fitness of natural populations. Although ion channels can have several vital functions during early life-stages (e.g. embryogenesis), it is currently not known i) how developing embryos maintain proper intracellular conditions when exposed to environmental stress and ii) to what extent environmental stress can drive intra-specific divergence in ion channels. Here we studied the moor frog, Rana arvalis, from three divergent populations to investigate the role of different ion channels and pumps for embryonic survival under acid stress (pH 4 vs 7.5) and whether populations adapted to contrasting acidities differ in the relative role of different ion channel/pumps. We found that ion channels that mediate Ca2+ influx are essential for embryonic survival under acidic pH, and, intriguingly, that populations differ in calcium channel function. Our results suggest that adaptive divergence in embryonic acid stress tolerance of amphibians may in part be mediated by Ca2+ balance. We suggest that ion flux may mediate adaptive divergence of natural populations at early life-stages in the face of environmental stress. © 2015 Macmillan Publishers Limited.

Document Type: Article
Source: Scopus
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Galor, A.a b , Batawi, H.a b , Felix, E.R.a c , Margolis, T.P.d , Sarantopoulos, K.D.a e , Martin, E.R.f g , Levitt, R.C.a e f g 
Incomplete response to artificial tears is associated with features of neuropathic ocular pain
(2015) British Journal of Ophthalmology, . Article in Press. 

DOI: 10.1136/bjophthalmol-2015-307094

a Department of Ophthalmology, Miami Veterans Administration Medical Center, Miami, Florida, USA
b Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA
c Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine, Miami, Florida, USA
d Departement of Ophthalmology, Washington University School of Medicine, St Louis, Missouri, USA
e Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, Florida, USA
f John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA
g John T Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA

Abstract
Aims Artificial tears are first-line therapy for patients with dry eye symptoms. It is not known, however, which patient factors associate with a positive response to therapy. The purpose of this study was to evaluate whether certain ocular and systemic findings are associated with a differential subjective response to artificial tears. Methods Cross-sectional study of 118 individuals reporting artificial tears use (hypromellose 0.4%) to treat dry eye-associated ocular pain. An evaluation was performed to assess dry eye symptoms (via the dry eye questionnaire 5 and ocular surface disease index), ocular and systemic (non-ocular) pain complaints and ocular signs (tear osmolarity, tear breakup time, corneal staining, Schirmer testing with anaesthesia, and eyelid and meibomian gland assessment). The main outcome measures were factors associated with differential subjective response to artificial tears. Results By self-report, 23 patients reported no improvement, 73 partial improvement and 22 complete improvement in ocular pain with artificial tears. Patients who reported no or partial improvement in pain with artificial tears reported higher levels of hot-burning ocular pain and sensitivity to wind compared with those with complete improvement. Patients were also asked to rate the intensity of systemic pain elsewhere in the body (other than the eye). Patients who reported no or incomplete improvement with artificial tears had higher systemic pain scores compared with those with complete improvement. Conclusions Both ocular and systemic (non-ocular) pain complaints are associated with a differential subjective response to artificial tears. © 2015 by the BMJ Publishing Group Ltd. All rights reserved.

Document Type: Article in Press
Source: Scopus
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Wilems, T.S., Pardieck, J., Iyer, N., Sakiyama-Elbert, S.E.
Combination therapy of stem cell derived neural progenitors and drug delivery of anti-inhibitory molecules for spinal cord injury
(2015) Acta Biomaterialia, . Article in Press. 

DOI: 10.1016/j.actbio.2015.09.018

Department of Biomedical Engineering, Washington University, St. Louis, MO 63130, United States

Abstract
Regeneration of lost synaptic connections following spinal cord injury (SCI) is limited by local ischemia, cell death, and an excitotoxic environment, which leads to the development of an inhibitory glial scar surrounding a cystic cavity. While a variety of single therapy interventions provide incremental improvements to functional recovery after SCI, they are limited; a multifactorial approach that combines several single therapies may provide a better chance of overcoming the multitude of obstacles to recovery. To this end, fibrin scaffolds were modified to provide sustained delivery of neurotrophic factors and anti-inhibitory molecules, as well as encapsulation of embryonic stem cell-derived progenitor motor neurons (pMNs). In vitro characterization of this combination scaffold confirmed that pMN viability was unaffected by culture alongside sustained delivery systems. When transplanted into a rat sub-acute SCI model, fibrin scaffolds containing growth factors (GFs), anti-inhibitory molecules without pMNs, or pMNs with GFs had lower chondroitin sulfate proteoglycan levels compared to scaffolds containing anti-inhibitory molecules with pMNs. Scaffolds containing pMNs, but not anti-inhibitory molecules, showed survival, differentiation into neuronal cell types, axonal extension in the transplant area, and the ability to integrate into host tissue. However, the combination of pMNs with sustained-delivery of anti-inhibitory molecules led to reduced cell survival and increased macrophage infiltration. While combination therapies retain potential for effective treatment of SCI, further work is needed to improve cell survival and to limit inflammation. Statement of Significance: Spinal cord injury (SCI) creates a highly complex inhibitory environment with a multitude of obstacles that limit recovery. Many therapeutic options have been developed to overcome single obstacles, but single therapies typically only lead to limited functional improvement. Therefore combination therapies may improve recovery by targeting several inhibitory obstacles simultaneously. The present study used biomaterial scaffolds to combine the sustained release of anti-inhibitory molecules and growth factors with cell transplantation of highly purified progenitor motor neurons. This expands upon previously established biomaterial scaffolds by supporting surviving cells, limiting inhibition from the extracellular environment, and replenishing lost cell populations. We show that while promising, certain combinations may exacerbate negative side-effects instead of augmenting positive features. © 2015 Acta Materialia Inc.

Author Keywords
Chondroitinase ABC;  Controlled release;  Lipid microtubes;  NEP1-40;  PLGA microspheres;  Progenitor motor neurons

Document Type: Article in Press
Source: Scopus
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Campian, J.L.a b , Ye, X.b , Gladstone, D.E.b , Ambady, P.c , Nirschl, T.R.b , Borrello, I.b , Golightly, M.d , King, K.E.b , Holdhoff, M.b , Karp, J.b , Drake, C.G.b , Grossman, S.A.b 
Pre-radiation lymphocyte harvesting and post-radiation reinfusion in patients with newly diagnosed high grade gliomas
(2015) Journal of Neuro-Oncology, 124 (2), pp. 307-316. 

DOI: 10.1007/s11060-015-1841-y

a Departments of Medicine, Oncology Division, Washington University in St. Louis, 660 South Euclid Avenue, Campus Box 8056, St. Louis, MO, United States
b Departments of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
c Departments of Neurology, Oregon Health & Science University, Portland, OR, United States
d Departments of Pathology, Stony Brook School of Medicine, Stony Brook, NY, United States

Abstract
Radiation (RT), temozolomide (TMZ), and dexamethasone in newly diagnosed high grade gliomas (HGG) produces severe treatment-related lymphopenia (TRL) that is associated with early cancer-related deaths. This TRL may result from inadvertent radiation to circulating lymphocytes. This study reinfused lymphocytes, harvested before chemo-radiation, and assessed safety, feasibility, and trends in lymphocyte counts. Patients with newly diagnosed HGG and total lymphocyte counts (TLC) ≥ 1000 cells/mm3 underwent apheresis. Cryopreserved autologous lymphocytes were reinfused once radiation was completed. Safety, feasibility, and trends in TLC, T cell subsets and cytokines were studied. Serial TLC were also compared with an unreinfused matched control group. Ten patients were harvested (median values: age 56 years, dexamethasone 3 mg/day, TLC/CD4 1980/772 cells/mm3). After 6 weeks of RT/TMZ, TLC fell 69 % (p < 0.0001) with similar reductions in CD4, CD8 and NK cells but not Tregs. Eight patients received lymphocyte reinfusions (median = 7.0 × 107 lymphocytes/kg) without adverse events. A post-reinfusion TLC rise of ≥300 cells/mm3 was noted in 3/8 patients at 4 weeks and 7/8 at 14 weeks which was similar to 23 matched controls. The reduced CD4/CD8 ratio was not restored by lymphocyte reinfusion. Severe lymphopenia was not accompanied by elevated serum interleukin-7 (IL-7) levels. This study confirms that severe TRL is common in HGG and is not associated with high plasma IL-7 levels. Although lymphocyte harvesting/reinfusion is feasible and safe, serial lymphocyte counts are similar to unreinfused matched controls. Studies administering higher lymphocyte doses and/or IL-7 should be considered to restore severe treatment-related lymphopenia in HGG. © 2015, Springer Science+Business Media New York.

Author Keywords
High grade glioma;  IL-7;  Lymphocyte reinfusion;  Lymphopenia;  Radiation

Document Type: Article
Source: Scopus
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Akbari, S.H., Limbrick, D.D.
Response to letter to the editor for original manuscript, "Surgical management of complex multiloculated hydrocephalus in infants and children"
(2015) Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery, 31 (6), p. 835. 

DOI: 10.1007/s00381-015-2711-9

Saint Louis School of Medicine, Washington University, St. Louis, MO, USA, akbaris@wudosis.wustl.edu

Document Type: Letter
Source: Scopus
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Kamath, A.A., Limbrick, D.L., Smyth, M.D.
Characterization of postoperative fevers after hemispherotomy
(2015) Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery, 31 (2), pp. 291-296. 

DOI: 10.1007/s00381-014-2572-7

Department of Neurological Surgery, St. Louis Children's Hospital, Washington University School of Medicine, One Children's Place, Suite 4S20, St. Louis, MO, 63110, USA, kamatha@wudosis.wustl.edu

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

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

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

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

Document Type: Article
Source: Scopus
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Thompson, D.K.a b c , Lee, K.J.a c , van Bijnen, L.a , Leemans, A.d , Pascoe, L.a , Scratch, S.E.a , Cheong, J.e f , Egan, G.F.b g , Inder, T.E.h i , Doyle, L.W.a e f , Anderson, P.J.a c i 
Accelerated corpus callosum development in prematurity predicts improved outcome
(2015) Human Brain Mapping, 36 (10), pp. 3733-3748. 

DOI: 10.1002/hbm.22874

a Murdoch Childrens Research Institute, Melbourne, VIC, Australia
b Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia
c Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
d Imaging Science Institute, University Medical Center, Utrecht, Netherlands
e Royal Women's Hospital, Melbourne, VIC, Australia
f Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, VIC, Australia
g Biomedical Imaging, Monash University, Melbourne, VIC, Australia
h Brigham and Women's Hospital, Boston, MA, United States
i Department of Pediatrics, Washington University in St Louis Medical School, St Louis, MI, United States

Abstract
Objectives: To determine: (1) whether corpus callosum (CC) size and microstructure at 7 years of age or their change from infancy to 7 years differed between very preterm (VP) and full-term (FT) children; (2) perinatal predictors of CC size and microstructure at 7 years; and (3) associations between CC measures at 7 years or trajectories from infancy to 7 years and neurodevelopmental outcomes. Experimental design: One hundred and thirty-six VP (gestational age [GA] <30 weeks and/or birth weight <1,250 g) and 33 FT children had usable magnetic resonance images at 7 years of age, and of these, 76 VP and 16 FT infants had usable data at term equivalent age. The CC was traced and divided into six sub-regions. Fractional anisotropy, mean, axial, radial diffusivity and volume were measured from tractography. Perinatal data were collected, and neurodevelopmental tests administered at 7 years' corrected age. Principal observations: VP children had smaller posterior CC regions, higher diffusivity and lower fractional anisotropy compared with FT 7-year-olds. Reduction in diffusivity over time occurred faster in VP than FT children (P≤0.002). Perinatal brain abnormality and earlier GA were associated with CC abnormalities. Microstructural abnormalities at 7 years or slower development of the CC were associated with motor dysfunction, poorer mathematics and visual perception. Conclusions: This study is the first to demonstrate an accelerated trajectory of CC white matter diffusion following VP birth, associated with improved neurodevelopmental functioning. Findings suggest there is a window of opportunity for neurorestorative intervention to improve outcomes. © 2015 Wiley Periodicals, Inc.

Author Keywords
diffusion-weighted imaging;  MRI;  Neurodevelopment;  Preterm;  White matter

Document Type: Article
Source: Scopus
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Reynolds, M.R.a , Arias, E.J.a , Chatterjee, A.R.b , Chicoine, M.R.a , Cross, D.T., IIIa b 
Acute rupture of a feeding artery aneurysm after embolization of a brain arteriovenous malformation
(2015) Interventional Neuroradiology, 21 (5), pp. 613-619. 

DOI: 10.1177/1591019915591740

a Washington University Medical School, Barnes-Jewish Hospital, Department of Neurological Surgery, Campus Box 8057, 660 South Euclid Avenue, St. Louis, MO, United States
b Department of Radiology, Washington University Medical School, United States

Abstract
Background: Staged endovascular embolization of large arteriovenous malformations (AVMs) is frequently performed to gradually reduce flow and prevent abrupt hemodynamic changes. While feeding artery aneurysms have been associated with increased risk of hemorrhage in the setting of AVMs, decisions regarding if and when to treat these aneurysms vary. Acute, fatal rupture of a feeding artery aneurysm following embolization of a large, unruptured AVM has been infrequently reported in the literature. Case description: A 69-year-old female presented with headache and mild left hemiparesis referable to a 5 cm right frontoparieto- temporal AVM with surrounding vasogenic edema. The AVM was associated with numerous bilateral feeding artery aneurysms (the largest was a 2 cm right middle cerebral artery (MCA) bifurcation aneurysm). There was also a large, partially thrombosed venous varix. Staged embolization of the AVM was performed. Several hours after the third stage of her embolization, she became obtunded, with a fixed and dilated right pupil. Head computed tomography (CT) showed a large intraparenchymal hemorrhage with midline shift in the right sylvian fissure, remote from the AVM nidus. She was taken to surgery for a decompressive craniectomy and hematoma evacuation. The MCA aneurysm was confirmed to be the source of hemorrhage and it was clipped. Despite aggressive medical and surgical treatments, the patient died. Conclusions: An increase in AVM feeding artery pressure following endovascular embolization may contribute to the rupture of a feeding artery aneurysm. For this reason, treatment of large arterial aneurysms on feeding pedicles should be considered prior to embolization of the AVM nidus. © The Author(s) 2015.

Author Keywords
Arteriovenous malformation;  Feeding artery aneurysm;  Intracerebral aneurysm;  Onyx embolization;  Pedicle aneurysm

Document Type: Article
Source: Scopus
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Duncan, R.P.a b , Leddy, A.L.c , Cavanaugh, J.T.d , Dibble, L.E.e , Ellis, T.D.f , Ford, M.P.g , Foreman, K.B.e , Earhart, G.M.a b h 
Balance differences in people with Parkinson disease with and without freezing of gait
(2015) Gait and Posture, 42 (3), pp. 306-309. 

DOI: 10.1016/j.gaitpost.2015.06.007

a Washington University School of Medicine in Saint Louis, Program in Physical Therapy, St. Louis, MO, United States
b Washington University School of Medicine in Saint Louis, Department of Neurology, St. Louis, MO, United States
c Rehabilitation Hospital of the Pacific, Department of Physical Therapy, Honolulu, HI, United States
d University of New England, Department of Physical Therapy, Portland, ME, United States
e University of Utah, Department of Physical Therapy, Salt Lake City, UT, United States
f Boston University, Department of Physical Therapy and Athletic Training, Boston, MA, United States
g Samford University, Department of Physical Therapy, Birmingham, AL, United States
h Washington University School of Medicine in Saint Louis, Department of Anatomy and Neurobiology, St. Louis, MO, United States

Abstract
Background: Freezing of gait (FOG) is a relatively common and remarkably disabling impairment associated with Parkinson disease (PD). Laboratory-based measures indicate that individuals with FOG (PD+FOG) have greater balance deficits than those without FOG (PD-FOG). Whether such differences also can be detected using clinical balance tests has not been investigated. We sought to determine if balance and specific aspects of balance, measured using Balance Evaluation Systems Test (BESTest), differs between PD+FOG and PD-FOG. Furthermore, we aimed to determine if time-efficient clinical balance measures (i.e. Mini-BESTest, Berg Balance Scale (BBS)) could detect balance differences between PD+FOG and PD-FOG. Methods: Balance of 78 individuals with PD, grouped as either PD + FOG (n=32) or PD-FOG (n=46), was measured using the BESTest, Mini-BESTest, and BBS. Between-groups comparisons were conducted for these measures and for the six sections of the BESTest using analysis of covariance. A PD composite score was used as a covariate. Results: Controlling for motor sign severity, PD duration, and age, PD + FOG had worse balance than PD -FOG when measured using the BESTest (p= 0.008, F=7.35) and Mini-BESTest (p=0.002, F=10.37), but not the BBS (p=0.27, F=1.26). BESTest section differences were noted between PD+FOG and PD-FOG for reactive postural responses (p<0.001, F=14.42) and stability in gait (p=0.003, F=9.18). Conclusions: The BESTest and Mini-BESTest, which specifically assessed reactive postural responses and stability in gait, were more likely than the BBS to detect differences in balance between PD + FOG and PD - FOG. Because it is more time efficient to administer, the Mini-BESTest may be the preferred tool for assessing balance deficits associated with FOG. © 2015 Elsevier B.V.

Author Keywords
Balance;  BESTest;  Freezing of gait;  Mini-BESTest;  Parkinson disease

Document Type: Article
Source: Scopus
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Luedtke, R.R.a , Rangel-Barajas, C.a d , Malik, M.a , Reichert, D.E.b , Mach, R.H.c 
Bitropic D3 dopamine receptor selective compounds as potential antipsychotics
(2015) Current Pharmaceutical Design, 21 (26), pp. 3700-3724. Cited 1 time.

a Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort WorthTX, United States
b Mallinckrodt Institute of Radiology, Division of Radiological Sciences, Washington University School of Medicine, St. Louis, MO, United States
c Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, PA, United States
d Indiana University Bloomington, Department of Psychological and Brain Sciences Program in Neuroscience, Bloomington, IN, United States

Abstract
Neuropsychiatric disorders represent a substantial social and health care issue. The National Institutes of Health estimates that greater than 2 million adults suffer from neuropsychiatric disorders in the USA. These individuals experience symptoms that can include auditory hallucinations, delusions, unrealistic beliefs and cognitive dysfunction. Although antipsychotic medications are available, suboptimal therapeutic responses are observed for approximately one-third of patients. Therefore, there is still a need to explore new pharmacotherapeutic strategies for the treatment of neuropsychiatric disorders. Many of the medications that are used clinically to treat neuropsychiatric disorders have a pharmacological profile that includes being an antagonist at D2-like (D2, D3 and D4) dopamine receptor subtypes. However, dopamine receptor subtypes are involved in a variety of neuronal circuits that include movement coordination, cognition, emotion, affect, memory and the regulation of prolactin. Consequently, antagonism at D2-like receptors can also contribute to some of the adverse side effects associated with the long-term use of antipsychotics including the a) adverse extrapyramidal symptoms associated with the use of typical antipsychotics and b) metabolic side effects (weight gain, hyperglycemia, increased risk of diabetes mellitus, dyslipidemia and gynecomastia) associated with atypical antipsychotic use. Preclinical studies suggest that D3 versus D2 dopamine receptor selective compounds might represent an alternative strategy for the treatment of the symptoms of schizophrenia. In this review we discuss a) how bitropic Nphenylpiperazine D3 dopamine receptor selective compounds have been developed by modification of the primary (orthosteric) and secondary (allosteric or modulatory) pharmacophores to optimize D3 receptor affinity and D2/D3 binding selectivity ratios and b) the functional selectivity of these compounds. Examples of how these compounds might be modified to develop bivalent ligands capable of interacting with receptor dimers or oligomers are also provided. Preclinical studies using bitropic D3 dopamine receptor selective ligands are also discussed as strategy to pharmacologically dissect the role of the D2 and D3 dopamine receptor subtypes in animal models of neuropsychiatric, neurological and substance abuse disorders. This research has the potential to a) advance the understanding of the role of the D2 and D3 dopamine receptor subtypes in neuropsychiatric disorders and b) lead to new treatment strategies for neuropsychiatric disorders. © 2015, Bentham Science Publishers.

Author Keywords
Biased agonism;  Bitropic ligands;  Bivalent ligands;  D2-like dopamine receptors;  D3 dopamine receptor subtype;  D3 receptor preclinical studies;  Dopamine receptors;  Functional selectivity;  G-protein coupled receptors;  Receptor subtype selectivity

Document Type: Article
Source: Scopus
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Naismith, R.T.
Cortical lesions in multiple sclerosis: Clinical relevance for a hidden disease burden
(2015) JAMA Neurology, 72 (9), pp. 979-980. 

DOI: 10.1001/jamaneurol.2015.1422

Department of Neurology, Washington University, 660 S Euclid Ave, Campus Box 8111, St Louis, MO, United States

Document Type: Editorial
Source: Scopus
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Liu, A.a , Carmichael, K.A.b , Schallom, M.E.c , Riley, M.J.a , Klinkenberg, W.D.c 
Detecting and Managing Diabetes Mellitus and Prediabetes in Patients With Acute Stroke
(2015) Diabetes Educator, 41 (5), pp. 592-598. 

DOI: 10.1177/0145721715599267

a Diabetes Education Service, Barnes-Jewish Hospital, St Louis, MO, United States
b Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St Louis, MO, United States
c Department of Research for Patient Care Services, Barnes-Jewish Hospital, St Louis, MO, United States

Abstract
Purpose The purpose of the study was to determine the prevalence of undiagnosed diabetes mellitus (DM) and prediabetes (pre-DM) in acute stroke patients, to evaluate recommendations of diabetes treatment and follow-up care in a hospital setting, and to examine 1-year readmission rates based on admission A1C measure. Methods This retrospective study comprised 200 patients randomly selected from 1095 patients admitted with an acute stroke and an A1C measurement during admission. DM and pre-DM prevalence levels were determined per A1C level. Recommendations for diabetes treatment during and after hospitalization were assessed; charts were reviewed for readmission. Results Among 200 patients, 43% had known DM, and 0.5% had pre-DM. Among 113 patients without history of DM or pre-DM, 61.9% had A1C 5.7% to 6.4% (39-46 mmol/mol), and 8.8% had A1C ≥6.5% (48 mmol/mol). None of the newly diagnosed pre-DM and 60% of newly diagnosed DM were documented. Only 7 of newly diagnosed DM or pre-DM patients received diabetes education. For patients with known DM and A1C ≥7.0% (53 mmol/mol), 40.5% registered no change of diabetic regimen. Few patients were recommended for diabetes follow-up care. Patients with A1C ≥6.5% or <5.7% were more likely to be readmitted for any reason within 1 year (33.3% and 31.6%, respectively) than patients with A1C levels of 5.7% to 6.4% (16.5%). Conclusions The majority of acutely admitted stroke patients without known DM or pre-DM had A1C ≥5.7%. Newly diagnosed DM or pre-DM patients received inadequate diabetes education and follow-up care. These findings provide significant opportunities for improving acute stroke management. © 2015, © 2015 The Author(s).

Document Type: Article
Source: Scopus
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Rogers, C.
Does it always start in childhood?
(2015) Journal of the American Academy of Child and Adolescent Psychiatry, 54 (10), p. 788. 

DOI: 10.1016/j.jaac.2015.07.004

Washington University School of Medicine, Saint Louis, United States

Document Type: Note
Source: Scopus
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Wallace, A.N.a , Chang, R.O.b , Tomasian, A.a , Jennings, J.W.a 
Drill-assisted, fluoroscopy-guided vertebral body access for radiofrequency ablation: Technical case series
(2015) Interventional Neuroradiology, 21 (5), pp. 631-634. 

DOI: 10.1177/1591019915594329

a Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, Saint Louis, MO, United States
b Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Radiofrequency ablation is a valuable therapy for palliation of painful spinal metastases and local tumor control; however, accessing the vertebral body can be difficult and time consuming with traditional manual needles. Herein, we report our initial experience using a drill-assisted, fluoroscopy-guided technique for accessing the vertebral body for radiofrequency ablation. © The Author(s) 2015.

Author Keywords
Drill system;  OnControl;  Radiofrequency ablation;  Spinal metastases

Document Type: Article
Source: Scopus
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Zaidman, C.M.a b , Wang, L.L.c , Connolly, A.M.a b , Florence, J.a , Wong, B.L.d , Parsons, J.A.e , Apkon, S.f , Goyal, N.g , Williams, E.h , Escolar, D.h , Rutkove, S.B.i , Bohorquez, J.L.c , Malkus, B.C.j , Siener, C.j , Schierbecker, J.R.j , Stover, L.k , Morehart, P.k , Miller, L.k , Yang, M.l , Terri, C.l , Gibbons, M.l , Vogel, L.m , Richardson, R.m , Townsend, E.L.m 
Electrical impedance myography in duchenne muscular dystrophy and healthy controls: A multicenter study of reliability and validity
(2015) Muscle and Nerve, 52 (4), pp. 592-597. Cited 1 time.

DOI: 10.1002/mus.24611

a Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, MO, United States
b Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
c Skulpt, Inc, Boston, MA, United States
d Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
e Department of Pediatrics and Neurology, University of Colorado, Denver, CO, United States
f Department of Rehabilitation Medicine, University of Washington, Seattle, WA, United States
g Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
h DART Therapeutics, Inc, Stockbridge, MA, United States
i Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United States
j St. Louis, MO, United States
k Cincinnati, OH, United States
l Denver, CO, United States
m Seattle, WA, United States

Abstract
Introduction: Electrical impedance myography (EIM) is a non-invasive, painless, objective technique to quantify muscle pathology. Methods: We measured EIM in 8 arm and leg muscles in 61 boys with Duchenne muscular dystrophy (DMD) and 31 healthy boys, ages 3-12 years, at 5 centers. We determined the reliability of EIM and compared results in boys with DMD to controls and to 6-minute walk distance (6MWD), North Star Ambulatory Assessment (NSAA), timed functional tests (TFTs), and strength (hand-held dynamometry). Results: EIM was well tolerated and had good inter- and intrarater reliability (intraclass correlation coefficient 0.81-0.96). The averaged EIM phase value from all muscles was higher (P<0.001) in controls (10.45±2.29) than boys with DMD (7.31±2.23), and correlated (P≤0.001) with 6MWD (r=0.55), NSAA (r=0.66), TFTs (r=-0.56), and strength (r=0.44). Conclusion: EIM is a reliable and valid measure of disease severity in DMD. Longitudinal studies comparing EIM with other assessments over time in DMD are warranted. © 2015 Wiley Periodicals, Inc.

Author Keywords
Biomarker;  Children;  Duchenne muscular dystrophy;  Electrical impedance myography;  Myopathy

Document Type: Article
Source: Scopus
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Li, C.C.a , Chen, S.S.b c , Huang, C.H.d , Chien, K.L.e , Yang, H.J.f , Fan, S.Z.d , Leighton, B.L.g , Chen, L.K.g h 
Fentanyl-induced cough is a risk factor for postoperative nausea and vomiting
(2015) British Journal of Anaesthesia, 115 (3), pp. 444-448. 

DOI: 10.1093/bja/aev157

a Department of Anesthesiology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan
b Department of Urology, School of Medicine, National Yang-Ming University, Taipei, Taiwan
c Department of Surgery, Taipei City Hospital Renai Branch, Taipei, Taiwan
d Department of Anesthesiology, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
e Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan
f Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Hsinchu City, Taiwan
g Department of Anesthesiology, Washington University in St Louis, School of Medicine, 660 South Euclid Avenue, St Louis, MO, United States
h Department of Anesthesiology, National Taiwan University Hospital, Hsin-Chu Branch, Hsinchu City, Taiwan

Abstract
Background Postoperative nausea and vomiting (PONV) and fentanyl-induced cough (FIC) are two common anaesthesia-related events, which seem to have common risk factors. In this prospective cohort study, we investigate whether patients who have FIC during induction of anaesthesia have an increased incidence of PONV. Methods We studied adult non-smoking gynaecological surgical patients enrolled between July 1, 2011 and July 30, 2012. The presence of FIC during induction and the occurrence of PONV were recorded. Fentanyl-induced cough and other perioperative variables were subjected to multivariate analysis to determine the association between FIC and PONV. Results All 502 patients enrolled in this study had at least two risk factors for PONV, and 154 (31%) developed FIC. The incidence of PONV in the FIC group was higher than in the non-FIC group (56.5 vs 38.2%; P<0.0001). Multivariate logistic regression analysis found FIC to be a predictive risk factor for the development of PONV (adjusted odds ratio 2.08, 95% confidence interval 1.41-3.07). Conclusions Non-smoking women undergoing gynaecological surgery who develop FIC during induction of anaesthesia have a higher incidence of PONV. © 2015 The Author.

Author Keywords
analgesics opioid;  cough;  fentanyl;  postoperative nausea and vomiting

Document Type: Article
Source: Scopus
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Richner, M.a , Victor, M.B.a b , Liu, Y.a , Abernathy, D.a c , Yoo, A.S.a 
MicroRNA-based conversion of human fibroblasts into striatal medium spiny neurons
(2015) Nature Protocols, 10 (10), pp. 1543-1555. 

DOI: 10.1038/nprot.2015.102

a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
b Program in Neuroscience, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, United States
c Program in Developmental, Regenerative and Stem Cell Biology, Division of Biology and Biomedical Sciences, Washington University, St. Louis, MO, United States

Abstract
The ability to generate human neurons of specific subtypes of clinical importance offers experimental platforms that may be instrumental for disease modeling. We recently published a study demonstrating the use of neuronal microRNAs (miRNAs) and transcription factors to directly convert human fibroblasts to a highly enriched population of striatal medium spiny neurons (MSNs), a neuronal subpopulation that has a crucial role in motor control and harbors selective susceptibility to cell death in Huntington's disease. Here we describe a stepwise protocol for the generation of MSNs by direct neuronal conversion of human fibroblasts in 30 d. We provide descriptions of cellular behaviors during reprogramming and crucial steps involved in gene delivery, cell adhesion and culturing conditions that promote cell survival. Our protocol offers a unique approach to combine microRNAs and transcription factors to guide the neuronal conversion of human fibroblasts toward a specific neuronal subtype. © 2015 Nature America, Inc. All rights reserved.

Document Type: Article
Source: Scopus
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Gottlieb, D.J.a b c d , Hek, K.e f , Chen, T.-H.a c , Watson, N.F.g h , Eiriksdottir, G.i , Byrne, E.M.j k , Cornelis, M.l m , Warby, S.C.n , Bandinelli, S.o , Cherkas, L.p , Evans, D.S.q , Grabe, H.J.r , Lahti, J.s t , Li, M.u , Lehtimäki, T.v , Lumley, T.w , Marciante, K.D.x y , Pérusse, L.z aa , Psaty, B.M.x y ab ac , Robbins, J.ad , Tranah, G.J.q , Vink, J.M.ae , Wilk, J.B.af , Stafford, J.M.ag , Bellis, C.ah , Biffar, R.ai , Bouchard, C.aj , Cade, B.b , Curhan, G.C.m ak , Eriksson, J.G.t al am an ao , Ewert, R.ap , Ferrucci, L.aq , Fülöp, T.ar , Gehrman, P.R.as , Goodloe, R.at , Harris, T.B.au , Heath, A.C.av , Hernandez, D.aw , Hofman, A.f , Hottenga, J.-J.ae , Hunter, D.J.ak ax , Jensen, M.K.l , Johnson, A.D.ay , Kähönen, M.az , Kao, L.u , Kraft, P.ak ax , Larkin, E.K.ba , Lauderdale, D.S.bb , Luik, A.I.f , Medici, M.bc , Montgomery, G.W.k , Palotie, A.bd be bf , Patel, S.R.b , Pistis, G.bg bh bi bj , Porcu, E.bi bj , Quaye, L.p , Raitakari, O.bk , Redline, S.b , Rimm, E.B.l m ak , Rotter, J.I.bl , Smith, A.V.i bm , Spector, T.D.p , Teumer, A.bn bo , Uitterlinden, A.G.f bc bp , Vohl, M.-C.aa bq , Widen, E.bd , Willemsen, G.ae , Young, T.br , Zhang, X.ay , Liu, Y.ag , Blangero, J.ah , Boomsma, D.I.ae , Gudnason, V.i bm , Hu, F.l m ak , Mangino, M.p , Martin, N.G.k , O'Connor, G.T.c d , Stone, K.L.q , Tanaka, T.aq , Viikari, J.bs , Gharib, S.A.h x , Punjabi, N.M.u bt , Räikkönen, K.s , Völzke, H.bo , Mignot, E.n , Tiemeier, H.e f bu 
Novel loci associated with usual sleep duration: The CHARGE Consortium Genome-Wide Association Study
(2015) Molecular Psychiatry, 20 (10), pp. 1232-1239. Cited 1 time.

DOI: 10.1038/mp.2014.133

a VA Boston Healthcare System, Boston, MA, United States
b Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States
c Department of Medicine, Boston University, School of Medicine, Boston, MA, United States
d NHLBI's Framingham Heart Study, Framingham, MA, United States
e Department of Epidemiology, Erasmus MC, Rotterdam, Netherlands
f Epidemiological and Social Psychiatric Research Institute, Department of Psychiatry, Erasmus MC, Rotterdam, Netherlands
g Department of Neurology, University of Washington, Seattle, WA, United States
h UW Medicine Sleep Center, University of Washington, Seattle, WA, United States
i Icelandic Heart Association, Kópavogur, Iceland
j University of Queensland, Queensland Brain Institute, St Lucia, QLD, Australia
k Queensland Institute of Medical Research, Brisbane, QLD, Australia
l Department of Nutrition, Harvard School of Public Health, Boston, MA, United States
m Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
n Center for Sleep Sciences and Medicine, Stanford University, Palo Alto, CA, United States
o Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy
p Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
q California Pacific Medical Center, Research Institute, San Francisco, CA, United States
r Department of Psychiatry and Psychotherapy, HELIOS-Hospital Stralsund, University Medicine Greifswald, Greifswald, Germany
s Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland
t Folkhalsan Research Centre, Helsinki, Finland
u Department of Epidemiology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, United States
v Department of Clinical Chemistry, Fimlab Laboratories, School of Medicine, University of Tampere, Tampere, Finland
w Department of Statistics, University of Auckland, Auckland, New Zealand
x Department of Medicine, University of Washington, Seattle, WA, United States
y Cardiovascular Health Research Unit, University of Washington, Seattle, WA, United States
z Department of Kinesiology, Laval UniversityQC, Canada
aa Institute of Nutrition and Functional Foods, Laval UniversityQC, Canada
ab Department of Epidemiology and Health Services, University of Washington, Seattle, WA, United States
ac Group Health Research Institute, Group Health Cooperative, Seattle, WA, United States
ad Department of Internal Medicine, University of California Davis, Sacramento, CA, United States
ae Department of Biological Psychology, Netherlands Twin Register, VU University, Amsterdam, Netherlands
af Precision Medicine, Cambridge, MA, United States
ag Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, United States
ah Texas Biomedical Research Institute, San Antonio, TX, United States
ai Department of Prosthodontics, Gerodontology and Dental Materials, Center of Oral Health, University Medicine Greifswald, Greifswald, Germany
aj Pennington Biomedical Research Center, Baton Rouge, LA, United States
ak Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States
al Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland
am Helsinki University Central Hospital, Helsinki, Finland
an National Institute for Health and Welfare, Helsinki, Finland
ao Vasa Central Hospital, Vasa, Finland
ap Dept. of Int. Med. B-Cardiology, Pulmonary Medicine, Infectious Diseases and Intensive Care Medicine, University Medicine Greifswald, Greifswald, Germany
aq Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, United States
ar Department of Medicine, University of Mississippi, Medical Center, Jackson, MS, United States
as Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
at Center for Human Genetics Research, Vanderbilt University, Medical Center, Nashville, TN, United States
au Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, MD, United States
av Department of Psychiatry, Washington University, School of Medicine, St Louis, MO, United States
aw Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, United States
ax Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, MA, United States
ay NHLBI Cardiovascular Epidemiology and Human Genomics Branch, Framingham Heart Study, Framingham, MA, United States
az Department of Clinical Physiology, Tampere University Hospital, School of Medicine, University of Tampere, Tampere, Finland
ba Department of Medicine, Vanderbilt University, School of Medicine, Nashville, TN, United States
bb Department of Health Studies, University of Chicago, Chicago, IL, United States
bc Department of Internal Medicine, Erasmus MC, Rotterdam, Netherlands
bd Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
be Program in Medical and Population Genetics and Genetic Analysis Platform, Broad Institute of MIT and Harvard, Cambridge, MA, United States
bf Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom
bg Division of Genetics and Cell Biology, San Raffaele Research Institute, Milano, Italy
bh Università Degli Studi di Trieste, Trieste, Italy
bi Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale Delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy
bj Dipartimento di Scienze Biomediche, Università di Sassari, Sassari, Italy
bk Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
bl Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, United States
bm University of Iceland, Reykjavik, Iceland
bn Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
bo Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
bp Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging, Leiden, Netherlands
bq Department of Food Science and Nutrition, Laval UniversityQC, Canada
br Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
bs Department of Medicine, Turku University Hospital, University of Turku, Turku, Finland
bt Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
bu Department of Child and Adolescent Psychiatry, Erasmus MC, Rotterdam, Netherlands

Abstract
Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10 -9). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10 -4). The strongest combined association was at rs1823125 (P=1.5 × 10 -10, minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

Document Type: Article
Source: Scopus
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Matsui, J.T.a b , Vaidya, J.G.a , Wassermann, D.c , Kim, R.E.a , Magnotta, V.A.a d e , Johnson, H.J.a e f , Paulsen, J.S.a g h , Isabella De Sorianoi , Shadrick, C.i , Miller, A.i , Edmond Chiuj , Preston, J.j , Goh, A.j , Antonopoulos, S.j , Loi, S.j , Chua, P.k, Komiti, A.k , Lynn Raymondl , Decolongon, J.l , Fan, M.l , Coleman, A.l , Christopher A. Rossm , Varvaris, M.m , Ong, M.m , Yoritomo, N.m , Mallonee, W.M.n , Suter, G.n , Samii, A.o , Freney, E.P.o , Macaraeg, A.o , Jones, R.p , Wood-Siverio, C.p , Factor, S.A.p , Barker, R.A.q , Mason, S.q , Guzman, N.V.q , McCusker, E.r , Griffith, J.r , Loy, C.r , McMillan, J.r , Gunn, D.r , Orth, M.s , Sübmuth, S.s , Barth, K.s , Trautmann, S.s , Schwenk, D.s , Eschenbach, C.s , Quaid, K.t , Wesson, M.t , Wojcieszek, J.t , Guttman, M.u , Sheinberg, A.u , Law, A.u , Karmalkar, I.u , Perlman, S.v , Clemente, B.v , Geschwind, M.D.w , Sha, S.w , Winer, J.w , Satris, G.w , Warner, T.x , Burrows, M.x , Rosser, A.y , Price, K.y , Hunt, S.y , Marshall, F.z , Chesire, A.z , Wodarski, M.z , Hickey, C.z , Panegyres, P.aa , Lee, J.aa , Tedesco, M.aa , Maxwell, B.aa , Perlmutter, J.ab , Barton, S.ab , Smith, S.ab , Miedzybrodzka, Z.ac , Rae, D.ac , Vaughan, V.ac , D'Alessandro, M.ac , Craufurd, D.ad , Bek, J.ad , Howard, E.ad , Mazzoni, P.ae , Marder, K.ae , Wasserman, P.ae , Kumar, R.af , Erickson, D.af , Reeves, C.af , Nickels, B.af , Wheelock, V.ag , Kjer, L.ag , Martin, A.ag , Farias, S.ag , Martin, W.ah , Suchowersky, O.ah , King, P.ah , Wieler, M.ah , Sran, S.ah , Ahmed, A.ai , Rao, S.ai , Reece, C.ai , Bura, A.ai , Mourany, L.ai 
Prefrontal cortex white matter tracts in prodromal Huntington disease
(2015) Human Brain Mapping, 36 (10), pp. 3717-3732. 

DOI: 10.1002/hbm.22835

a Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
b John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United States
c EPI Athena, INRIA Sophia Antipolis-Méditerranée, Sophia Antipolis, France
d Department of Radiology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
e Department of Biomedical Engineering, College of Engineering, University of Iowa, Iowa City, IA, United States
f Department of Electrical and Computer Engineering, College of Engineering, University of Iowa, Iowa City, IA, United States
g Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
h Department of Psychology, University of Iowa, Iowa City, IA, United States
i University of Iowa, Iowa City, IA, United States
j St. Vincent's Hospital, The University of Melbourne, Kew, VIC, Australia
k The University of Melbourne, Royal Melbourne Hospital, Melbourne, VIC, Australia
l University of British Columbia, Vancouver, BC, Canada
m Johns Hopkins University, Baltimore, MD, United States
n Hereditary Neurological Disease Centre, Wichita, KS, United States
o University of Washington and VA Puget Sound Health Care System, Seattle, WA, United States
p Emory University School of Medicine, Atlanta, GA, United States
q John van Geest Centre for Brain Repair, Cambridge, United Kingdom
r Westmead Hospital, Sydney, NSW, Australia
s University of Ulm, Ulm, Germany
t Indiana University School of Medicine, Indianapolis, IN, United States
u Centre for Addiction and Mental Health, University of Toronto, Markham, ON, Canada
v UCLA Medical Center, Los Angeles, CA, United States
w University of California, San Francisco, San Francisco, CA, United States
x National Hospital for Neurology and Neurosurgery, London, United Kingdom
y Cardiff University, Cardiff, Wales, United Kingdom
z University of Rochester, Rochester, NY, United States
aa Neurosciences Unit, Graylands, Selby-Lemnos and Special Care Health Services, Perth, WA, Australia
ab Washington University, St. Louis, MO, United States
ac Clinical Genetics Centre, Aberdeen, Scotland, United Kingdom
ad University of Manchester, Manchester, United Kingdom
ae Columbia University Medical Center, New York, NY, United States
af Colorado Neurological Institute, Englewood, CO, United States
ag University of California, Davis, Sacramento, CA, United States
ah University of Alberta, Edmonton, AB, Canada
ai Cleveland Clinic Foundation, Cleveland, OH, United States

Abstract
Huntington disease (HD) is most widely known for its selective degeneration of striatal neurons but there is also growing evidence for white matter (WM) deterioration. The primary objective of this research was to conduct a large-scale analysis using multisite diffusion-weighted imaging (DWI) tractography data to quantify diffusivity properties along major prefrontal cortex WM tracts in prodromal HD. Fifteen international sites participating in the PREDICT-HD study collected imaging and neuropsychological data on gene-positive HD participants without a clinical diagnosis (i.e., prodromal) and gene-negative control participants. The anatomical prefrontal WM tracts of the corpus callosum (PFCC), anterior thalamic radiations (ATRs), inferior fronto-occipital fasciculi (IFO), and uncinate fasciculi (UNC) were identified using streamline tractography of DWI. Within each of these tracts, tensor scalars for fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity coefficients were calculated. We divided prodromal HD subjects into three CAG-age product (CAP) groups having Low, Medium, or High probabilities of onset indexed by genetic exposure. We observed significant differences in WM properties for each of the four anatomical tracts for the High CAP group in comparison to controls. Additionally, the Medium CAP group presented differences in the ATR and IFO in comparison to controls. Furthermore, WM alterations in the PFCC, ATR, and IFO showed robust associations with neuropsychological measures of executive functioning. These results suggest long-range tracts essential for cross-region information transfer show early vulnerability in HD and may explain cognitive problems often present in the prodromal stage. © 2015 Wiley Periodicals, Inc.

Author Keywords
Cross-sectional analysis;  Diffusion tensor imaging;  Diffusion tractography;  Diffusion weighted MRI;  Huntington's disease;  Multicenter studies;  Prefrontal cortex

Document Type: Article
Source: Scopus
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Naselaris, T.a c , Kay, K.N.b 
Resolving Ambiguities of MVPA Using Explicit Models of Representation
(2015) Trends in Cognitive Sciences, 19 (10), art. no. 1476, pp. 551-554. 

DOI: 10.1016/j.tics.2015.07.005

a Medical University of South Carolina, Charleston, SC, United States
b Washington University in St Louis, St Louis, MO, United States
c University of Minnesota, Minneapolis, MN, United States

Abstract
We advocate a shift in emphasis within cognitive neuroscience from multivariate pattern analysis (MVPA) to the design and testing of explicit models of neural representation. With such models, it becomes possible to identify the specific representations encoded in patterns of brain activity and to map them across the brain. © 2015.

Author Keywords
Computational modeling;  Encoding model;  FMRI;  Multivariate pattern analysis;  Representation

Document Type: Short Survey
Source: Scopus
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Duguid, M.M.a , Goncalo, J.A.b 
Squeezed in the middle: The middle status trade creativity for focus
(2015) Journal of Personality and Social Psychology, 109 (4), pp. 589-603. 

DOI: 10.1037/a0039569

a Department of Organizational Behavior, Olin Business School, Washington University, Saint Louis, MO, United States
b Department of Organizational Behavior, School of Industrial and Labor Relations, Cornell University, United States

Abstract
Classical research on social influence suggested that people are the most conforming in the middle of a status hierarchy as opposed to the top or bottom. Yet this promising line of research was abandoned before the psychological mechanism behind middle-status conformity had been identified. Moving beyond the early focus on conformity, we propose that the threat of status loss may make those with middle status more wary of advancing creative solutions in fear that they will be evaluated negatively. Using different manipulations of status and measures of creativity, we found that when being evaluated, middle-status individuals were less creative than either high-status or low-status individuals (Studies 1 and 2). In addition, we found that anxiety at the prospect of status loss also caused individuals with middle status to narrow their focus of attention and to think more convergently (Study 3). We delineate the consequences of power and status both theoretically and empirically by showing that, unlike status, the relationship between power and creativity is positive and linear (Study 4). By both measuring status (Studies 2 and 3) and by manipulating it directly (Study 5), we demonstrate that the threat of status loss explains the consequences of middle status. Finally, we discuss the theoretical implications of our results for future research on status and problem solving on tasks that require either focus or flexibility. © 2015 American Psychological Association.

Author Keywords
Conformity;  Convergent thinking;  Creativity;  Status

Document Type: Article
Source: Scopus
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Kerschensteiner, D.a b c d 
Superior Colliculus Does Play Dice
(2015) Neuron, 87 (6), pp. 1121-1123. 

DOI: 10.1016/j.neuron.2015.09.023

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

Abstract
Random is not a word often used in describing nervous system organization and its development. Yet, in this issue of Neuron, Owens et al. (2015) identify stochastic interactions of molecular and activity-dependent forces that can produce heterogeneous retinocollicular maps. Random is not a word often used in describing nervous system organization and its development. Yet, in this issue of Neuron, Owens et al. (2015) identify stochastic interactions of molecular and activity-dependent forces that can produce heterogeneous retinocollicular maps. © 2015 Elsevier Inc.

Document Type: Short Survey
Source: Scopus
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Bower, E.S.a , Wetherell, J.L.b , Mon, T.c , Lenze, E.J.c 
Treating anxiety disorders in older adults: Current treatments and future directions
(2015) Harvard Review of Psychiatry, 23 (5), pp. 329-342. 

DOI: 10.1097/HRP.0000000000000064

a San Diego State University, University of California, San Diego, Joint Doctoral Program, Clinical Psychology, United States
b VA San Diego Healthcare System and University of California, San Diego, United States
c Healthy Mind Lab, Department of Psychiatry, Washington University, School of Medicine, United States

Abstract
Anxiety disorders are highly prevalent among the elderly and are associated with increased disability, poor quality of life, and cognitive impairment. Despite this high prevalence and associated morbidities, anxiety disorders in late life are underreported and understudied. In this article, we discuss the epidemiology, disease presentation, and current treatment of anxiety disorders in older adults. We also discuss limitations in the current understanding of such disorders in this population, as well as future research directions that may reveal the mechanisms and rationale for treatment regimens for anxiety disorders in late life. We present material on the application of the Research Domain Criteria (RDoC) model to geriatric anxiety. Finally, we describe optimal management strategies of anxiety disorders. © Lippincott Williams & Wilkins.

Author Keywords
anxiety;  geriatric;  late life

Document Type: Review

Source: Scopus