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WUSTL Neuroscience Publications Archive - December 2014

December 2014

Scopus weekly report:

December 5

December 11

December 18

December 18, 2014

Power, J.D.a , Schlaggar, B.L.a b c d , Petersen, S.E.a b d e f g
Recent progress and outstanding issues in motion correction in resting state fMRI
(2015) NeuroImage, 105, pp. 536-551. 


a Dept. of Neurology, Washington University School of Medicine in St. Louis, 660 S. Euclid Ave.St. Louis, MO, United States
b Dept. of Radiology, Washington University School of Medicine in St. Louis, 660 S. Euclid Ave.St. Louis, MO, United States
c Dept. of Pediatrics, Washington University School of Medicine in St. Louis, 660 S. Euclid Ave.St. Louis, MO, United States
d Dept. of Anatomy and Neurobiology, Washington University School of Medicine in St. Louis, 660 S. Euclid Ave.St. Louis, MO, United States
e Dept. of Psychology, Washington University in St. Louis, One Brookings DriveSt. Louis, MO, United States
f Dept. of Neurosurgery, Washington University School of Medicine in St. Louis, 660 S. Euclid Ave.St. Louis, MO, United States
g Dept. of Biomedical Engineering, Washington University in St. Louis, One Brookings DriveSt. Louis, MO, United States


Abstract
The purpose of this review is to communicate and synthesize recent findings related to motion artifact in resting state fMRI. In 2011, three groups reported that small head movements produced spurious but structured noise in brain scans, causing distance-dependent changes in signal correlations. This finding has prompted both methods development and the re-examination of prior findings with more stringent motion correction. Since 2011, over a dozen papers have been published specifically on motion artifact in resting state fMRI. We will attempt to distill these papers to their most essential content. We will point out some aspects of motion artifact that are easily or often overlooked. Throughout the review, we will highlight gaps in current knowledge and avenues for future research.


Author Keywords
Artifact;  Denoising;  FMRI;  Functional connectivity;  Motion;  Resting state


Document Type: Review
Source: Scopus

Levinson, C.A.a , Rodebaugh, T.L.a , Shumaker, E.A.a , Menatti, A.R.b , Weeks, J.W.b , White, E.K.c , Heimberg, R.G.d , Warren, C.S.c , Blanco, C.e , Schneier, F.f , Liebowitz, M.R.e
Perception matters for clinical perfectionism and social anxiety
(2015) Journal of Anxiety Disorders, 29, pp. 61-71. 


a Department of Psychology, Washington University in St. LouisSt. Louis, MO, United States
b Center for Evaluation and Treatment of Anxiety, Ohio University, Athens, OH. 200, Porter Hall AthensOH, United States
c Department of Psychology, University of Nevada, Las Vegas 4505 S. Maryland Parkway MS 5030 Las VegasNV, United States
d Adult Anxiety Clinic of Temple (AACT), Department of Psychology, Temple University, Weiss Hall 1701 North 13th Street PhiladelphiaPA, United States
e Columbia University, Department of Psychiatry, P.O. Box 69, 1051 Riverside DriveNew York, NY, United States
f Professor of Psychiatry at Columbia University Medical Center, Research Scientist, NY State Psychiatric Institute, 1051 Riverside Drive, Unit 69New York, NY, United States


Abstract
Despite research documenting a relationship between social anxiety and perfectionism, very little research has examined the relationship between social anxiety and clinical perfectionism, defined as the combination of high personal standards and high maladaptive perfectionistic evaluative concern. In the current studies we examined whether clinical perfectionism predicted social anxiety in a large sample of undergraduates (. N=. 602), in a clinical sample of participants diagnosed with social anxiety disorder (SAD; N=. 180), and by using a variance decomposition model of self- and informant-report of perfectionism (. N=. 134). Using self-report, we found that an interaction of personal standards and evaluative concern predicted both social interaction anxiety and fear of scrutiny, but not in the theorized direction. Specifically, we found that self-report of low standards and high evaluative concern was associated with the highest levels of social anxiety, suggesting that when individuals with SAD hold low expectations for themselves combined with high concerns about evaluation, social anxiety symptoms may increase. Alternatively, when an informants' perspective was considered, and more consistent with the original theory, we found that the interaction of informant-only report of personal standards and shared-report (between both primary participant and informant) of concern over mistakes was associated with self-reported social anxiety, such that high concern over mistakes and high personal standards predicted the highest levels of social anxiety. Theoretical, clinical, and measurement implications for clinical perfectionism are discussed.


Author Keywords
Clinical perfectionism;  High standards;  Perfectionism;  Social anxiety;  Social anxiety disorder


Document Type: Article
Source: Scopus

Lu, S.a b , Kanekura, K.a , Hara, T.a , Mahadevan, J.a , Spears, L.D.a , Oslowski, C.M.c , Martinez, R.d , Yamazaki-Inoue, M.e , Toyoda, M.e , Neilson, A.d , Blanner, P.d , Brown, C.M.a , Semenkovich, C.F.a , Marshall, B.A.f , Hershey, T.g , Umezawa, A.e , Greer, P.A.h , Urano, F.a i
A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome
(2014) Proceedings of the National Academy of Sciences of the United States of America, 111 (49), pp. E5292-E5301. 


a Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of MedicineSt. Louis, MO, United States
b Graduate School of Biomedical Sciences, University of Massachusetts Medical SchoolWorcester, MA, United States
c Department of Medicine, Boston University School of MedicineBoston, MA, United States
d Department of Genetics, IPSC Core Facility, Washington University School of MedicineSt. Louis, MO, United States
e Department of Reproductive Biology, National Center for Child Health and DevelopmentTokyo, Japan
f Department of Pediatrics, Washington University School of MedicineSt. Louis, MO, United States
g Departments of Psychiatry, Neurology, and Radiology, Washington University School of MedicineSt. Louis, MO, United States
h Department of Pathology and Molecular Medicine, Queen's University, Queen's Cancer Research InstituteKingston, ON, Canada
i Department of Pathology and Immunology, Washington University School of MedicineSt. Louis, MO, United States


Abstract
Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration and considered as an endoplasmic reticulum (ER) disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome and the identification of two causative genes, Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2), a molecular mechanism linking the ER to death of neurons and innodatabeta cells has not been elucidated. Here we implicate calpain 2 in the mechanism of cell death in Wolfram syndrome. Calpain 2 is negatively regulated by WFS2, and elevated activation of calpain 2 by WFS2-knockdown correlates with cell death. Calpain activation is also induced by high cytosolic calcium mediated by the loss of function of WFS1. Calpain hyperactivation is observed in the WFS1 knockout mouse as well as in neural progenitor cells derived from induced pluripotent stem (iPS) cells of Wolfram syndrome patients. A small-scale small-molecule screen targeting ER calcium homeostasis reveals that dantrolene can prevent cell death in neural progenitor cells derived from Wolfram syndrome iPS cells. Our results demonstrate that calpain and the pathway leading its activation provides potential therapeutic targets for Wolfram syndrome and other ER diseases.


Author Keywords
Diabetes;  Endoplasmic reticulum;  Neurodegeneration;  Treatment;  Wolfram syndrome


Document Type: Article
Source: Scopus

Kim, H.J.a , Nemani, V.M.a , Daniel Riew, K.b
Cervical osteotomies for neurological deformities
(2014) European Spine Journal, 7 p. Article in Press. 


a Spine and Scoliosis Service, Hospital for Special Surgery, 535 E 70th StreetNew York, NY, United States
b Cervical Spine Service, Washington University Orthopaedics, Barnes Jewish HospitalSt. Louis, MO, United States


Abstract
Purpose: To report our experience and technique for performing cervical osteotomies under the setting of cervical deformity and myelopathy.

Methods: Patients who underwent cervical osteotomies for CD with myelopathy were identified in a 10 year period from 2000 to 2010. Demographics, surgery type, osteotomy type, operative details, and radiographs were collected for pre-operative and ultimate post-operative time points. Cervical lordosis (CL) and basion plumb line were collected to assess angular and translational corrections.

Results: In the study period, a total of 35 patients underwent a cervical osteotomy for fixed cervical deformity with a diagnosis of cervical myelopathy or myeloradiculopathy with an average follow-up of 3.4 years (range 1.0–6.3). The cohort was separated into two groups based on the type of surgical approach taken to correct their deformity. Anterior osteotomy with or without posterior instrumentation were performed in 31 patients (Group 1). Pedicle subtraction osteotomies were performed in 4 patients (Group 2). For Group 1, the mean angular correction achieved in this was 27.7° (range 9.0–66.0°) and the mean translational correction was 1.8 cm (range 0.1–2.4 cm). In group 2, the mean angular correction was 48.8° (range 38.4–68.3°) and the mean translational correction was 2.8 cm per PSO (range 0.1–5.6 cm). Similar improvements in pre- and post-operative Neck Disability Index scores were achieved with either osteotomy technique.

Conclusions: We present our series of patients with cervical myelopathy and/or radiculopathy and concurrent cervical deformity who were treated with cervical osteotomies. The re-alignment of the spine was a key step in preventing the progression of myelopathy and protecting the spinal cord from the continued injury.


Author Keywords
Cervical deformity;  Cervical kyphosis;  Cervical myelopathy;  Osteotomy;  Spinal cord compression


Document Type: Article in Press
Source: Scopus

Russ, J.a , Liu, E.Y.a , Wu, K.a , Neal, D.b , Suh, E.b , Irwin, D.J.b c , McMillan, C.T.c , Harms, M.B.d , Cairns, N.J.d , Wood, E.M.b , Xie, S.X.e , Elman, L.c , McCluskey, L.c , Grossman, M.c , Van Deerlin, V.M.b , Lee, E.B.a
Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier
(2014) Acta Neuropathologica, 14 p. Article in Press. 


a Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, 605B Stellar Chance Laboratories, 422 Curie BlvdPhiladelphia, PA, United States
b Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of PennsylvaniaPhiladelphia, PA, United States
c Department of Neurology, Perelman School of Medicine at the University of PennsylvaniaPhiladelphia, PA, United States
d Department of Neurology, Washington University School of MedicineSt. Louis, MO, United States
e Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of PennsylvaniaPhiladelphia, PA, United States


Abstract
C9orf72 promoter hypermethylation inhibits the accumulation of pathologies which have been postulated to be neurotoxic. We tested here whether C9orf72 hypermethylation is associated with prolonged disease in C9orf72 mutation carriers. C9orf72 methylation was quantified from brain or blood using methylation-sensitive restriction enzyme digest-qPCR in a cross-sectional cohort of 118 C9orf72 repeat expansion carriers and 19 non-carrier family members. Multivariate regression models were used to determine whether C9orf72 hypermethylation was associated with age at onset, disease duration, age at death, or hexanucleotide repeat expansion size. Permutation analysis was performed to determine whether C9orf72 methylation is heritable. We observed a high correlation between C9orf72 methylation across tissues including cerebellum, frontal cortex, spinal cord and peripheral blood. While C9orf72 methylation was not significantly different between ALS and FTD and did not predict age at onset, brain and blood C9orf72 hypermethylation was associated with later age at death in FTD (brain: β = 0.18, p = 0.006; blood: β = 0.15, p < 0.001), and blood C9orf72 hypermethylation was associated with longer disease duration in FTD (β = 0.03, p = 0.007). Furthermore, C9orf72 hypermethylation was associated with smaller hexanucleotide repeat length (β = −16.69, p = 0.033). Finally, analysis of pedigrees with multiple mutation carriers demonstrated a significant association between C9orf72 methylation and family relatedness (p < 0.0001). C9orf72 hypermethylation is associated with prolonged disease in C9orf72 repeat expansion carriers with FTD. The attenuated clinical phenotype associated with C9orf72 hypermethylation suggests that slower clinical progression in FTD is associated with reduced expression of mutant C9orf72. These results support the hypothesis that expression of the hexanucleotide repeat expansion is associated with a toxic gain of function.


Author Keywords
Amyotrophic lateral sclerosis;  Epigenetics;  Frontotemporal dementia;  Frontotemporal lobar degeneration;  Neurodegeneration


Document Type: Article in Press
Source: Scopus

Lieu, J.E.C., Chalivendra, V., Ead, B.
Pediatric quality of life in children with otolaryngologic disease: what inventories are available and what is still needed?
(2014) Current Opinion in Otolaryngology and Head and Neck Surgery, . Article in Press. 


Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, Missouri, USA


Abstract
PURPOSE OF REVIEW: Quality of life (QOL) is an important patient-oriented outcome in common disorders, particularly when one management strategy is not clearly superior to an alternative. This article reviews the recently published literature that evaluated QOL in children with common pediatric otolaryngologic problems.

RECENT FINDINGS: Among the 41 reviewed articles that used QOL as an outcome, 14 disease-specific QOL surveys and 12 generic QOL questionnaires were used. QOL instruments that had been validated in adults were frequently used in children without validation in pediatric populations. For children, parent-reported outcomes of caregiver concerns are often used as proxy measures of QOL for the child, and only a few QOL instruments asked the child to rate their own perception of their QOL. Several studies used nonvalidated QOL surveys as outcomes.

SUMMARY: QOL is being evaluated in an increasing number of pediatric otolaryngologic disorders. Although there are numerous surveys to measure generic pediatric QOL, validated disease-specific surveys for children are less common, especially those that utilize child self-report. The lack of disease-specific pediatric surveys for otolaryngologic disorders hampers the ability to document change or differences in patient-oriented outcomes with interventions.


Document Type: Article in Press
Source: Scopus

Hawasli, A.H., Chicoine, M.R., Dacey, R.G., Jr
Choosing Wisely: A Neurosurgical Perspective on Neuroimaging for Headaches
(2014) Neurosurgery, . Article in Press. 


Department of Neurosurgery, Washington University School of Medicine. St. Louis, Missouri


Abstract
ABSTRACT: Multiple national initiatives seek to curb spending in order to address increasing health care costs in the United States. The Choosing Wisely initiative is one popular initiative that focuses on reducing health care spending by setting guidelines to limit tests and procedures requested by patients and ordered by physicians. To reduce spending on neuroimaging, the Choosing Wisely initiative and other organizations have offered guidelines to limit neuroimaging for headaches. Although the intentions are laudable, these guidelines are inconsistent with the neurosurgeon’s experience with brain tumor patients. If adopted by governing or funding organizations, these guidelines threaten to negatively impact the care and outcomes of patients with brain tumors, who frequently present with minimal symptoms or isolated headaches syndromes. As we grapple with the difficult conflict between evidence-based cost-cutting guidelines and individualized patient-tailored medicine, a physician must carefully balance the costs and benefits of discretionary services such as neuroimaging for headaches. By participating in the development of validated clinical decision rules on neuroimaging for headaches, neurosurgeons can advocate for their patients and improve their patients’ outcomes.


Document Type: Article in Press
Source: Scopus

Wobst, H.J.a b , Sharma, A.d , Diamond, M.I.d , Wanker, E.E.b , Bieschke, J.b c
The green tea polyphenol (-)-epigallocatechin gallate prevents the aggregation of tau protein into toxic oligomers at substoichiometric ratios
(2014) FEBS Letters, . Article in Press. 


a AstraZeneca-Tufts Lab for Basic and Translational Medicine, Boston, MA, USA 1
b Max Delbru¨ck Center for Molecular Medicine, Berlin, Germany
c Washington University in St. Louis, Saint Louis, MO, USA
d Department of Neurology and Neurotherapeutics, University of Texas, Southwestern Medical Center, USA


Abstract
The accumulation of amyloid-beta (Aβ) and tau aggregates is a pathological hallmark of Alzheimer's disease. Both polypeptides form fibrillar deposits, but several lines of evidence indicate that Aβ and tau form toxic oligomeric aggregation intermediates. Depleting such structures could thus be a powerful therapeutic strategy. We generated a fragment of tau (His-K18δK280) that forms stable, toxic, oligomeric tau aggregates in vitro. We show that (-)-epigallocatechin gallate (EGCG), a green tea polyphenol that was previously found to reduce Aβ aggregation, inhibits the aggregation of tau K18δK280 into toxic oligomers at ten- to hundred-fold substoichiometric concentrations, thereby rescuing toxicity in neuronal model cells.


Author Keywords
(-)-Epigallocatechin gallate;  Aggregation inhibitors;  Alzheimer's disease;  Polyphenol;  Tau oligomers;  Tau protein


Document Type: Article in Press
Source: Scopus

Zhu, H.a , Grajales-Reyes, E.b , Vázquez, V.A.d , Grajales-Reyes, J.G.b , Robinson, K.a , Pytel, P.c , Báez-Pagán, C.A.d , Lasalde-Dominicci, J.A.d , Gomez, C.M.a
Fluoxetine is neuroprotective in slow-channel congenital myasthenic syndrome
(2014) Experimental Neurology, . Article in Press. 


a Department of Neurology, The University of Chicago, Chicago, IL, USA
b School of Medicine, Washington University, St. Louis, St. Louis, MO, USA
c Department of Pathology, The University of Chicago, Chicago, IL, USA
d Department of Biology, The University of Puerto Rico, San Juan, Puerto Rico, USA


Abstract
The slow-channel congenital myasthenic syndrome (SCS) is an inherited neurodegenerative disease that caused mutations in the acetylcholine receptor (AChR) affecting neuromuscular transmission. Leaky AChRs lead to Ca2+ overload and degeneration of the neuromuscular junction (NMJ) attributed to activation of cysteine proteases and apoptotic changes of synaptic nuclei. Here we use transgenic mouse models expressing two different mutations found in SCS to demonstrate that inhibition of prolonged opening of mutant AChRs using fluoxetine not only improves motor performance and neuromuscular transmission but also prevents Ca2+ overload, the activation of cysteine proteases, calpain, caspase-3 and 9 at endplates, and as a consequence, reduces subsynaptic DNA damage at endplates, suggesting a long term benefit to therapy. These studies suggest that prolonged treatment of SCS patients with open ion channel blockers that preferentially block mutant AChRs is neuroprotective.


Author Keywords
Acetylcholine receptor;  Ca2+ overload;  Fluoxetine;  Ion channel blockers;  Mutation;  Neurodegenerative disease;  Neuromuscular junction;  Neuromuscular transmission;  Neuroprotective;  Slow-channel congenital myasthenic syndrome;  Subsynaptic DNA damage


Document Type: Article in Press
Source: Scopus

Gereau, R.W., IVa b , Sluka, K.A.a c , Maixner, W.a d , Savage, S.R.a e , Price, T.J.a f , Murinson, B.B.a g , Sullivan, M.D.a h , Fillingim, R.B.a i
A pain research agenda for the 21st century
(2014) Journal of Pain, 15 (12), pp. 1203-1214. 


a American Pain SocietyGlenview, IL, United States
b Washington University Pain Center, Department of Anesthesiology, Washington University School of MedicineSt. Louis, MO, United States
c Department of Physical Therapy and Rehabilitation Science, Pain Research Program, University of IowaIowa City, IA, United States
d Center for Pain Research and Innovation, University of North CarolinaChapel Hill, NC, United States
e Department of Anesthesiology, Center on Addiction Recovery and Education, Dartmouth Medical SchoolHanover, NH, United States
f School of Brain and Behavioral Sciences, University of Texas at DallasDallas, TX, United States
g Department of Neurology, Johns Hopkins School of MedicineBaltimore, MD, United States
h Department of Psychiatry and Behavioral Sciences, University of WashingtonSeattle, WA, United States
i Pain Research and Intervention Center of Excellence, University of FloridaGainesville, FL, United States


Abstract
Chronic pain represents an immense clinical problem. With tens of millions of people in the United States alone suffering from the burden of debilitating chronic pain, there is a moral obligation to reduce this burden by improving the understanding of pain and treatment mechanisms, developing new therapies, optimizing and testing existing therapies, and improving access to evidence-based pain care. Here, we present a goal-oriented research agenda describing the American Pain Society's vision for pain research aimed at tackling the most pressing issues in the field.

Perspective This article presents the American Pain Society's view of some of the most important research questions that need to be addressed to advance pain science and to improve care of patients with chronic pain.


Author Keywords
Chronic pain;  pain education;  pain research;  pain treatment;  research funding


Document Type: Review
Source: Scopus

Beal, S.J.a b , Dorn, L.D.b , Sucharew, H.J.a b e , Sontag-Padilla, L.d , Pabst, S.a , Hillman, J.a c
Characterizing the longitudinal relations between depressive and menstrual symptoms in adolescent girls
(2014) Psychosomatic Medicine, 76 (7), pp. 547-554. 


a Cincinnati Children's Hospital Medical Center, Division of Behavioral Medicine and Clinical Psychology, CCHMC, 3333 Burnet Ave, MLC 10006Cincinnati, OH, United States
b Pennsylvania State UniversityState College, PA, United States
c University of CincinnatiCincinnati, OH, United States
d RAND CorporationSanta Monica, CA, United States
e Washington University in Saint LouisSt. Louis, MO, United States


Abstract
Objective: This study examined the association between depressive and menstrual symptoms in adolescent girls in a 3-year longitudinal study. It was hypothesized that menstrual symptoms would increase in early adolescence and decrease in later adolescence, that girls with greater depressive symptoms would report greater menstrual symptoms, and that effects would persist after adjusting for general somatic complaints.

Methods: A community sample of girls (n = 262) enrolled in an observational study by age cohort (11, 13, 15, 17 years) completed three annual visits. At each time point, girls completed the Menstrual Symptom Questionnaire, Children's Depression Inventory, and the Youth Self Report to assess general somatic complaints.

Results: Menstrual symptoms increased significantly across adolescence (p =.006) and began to plateau in later adolescence (p =.020). Depressive symptoms at study entry were significantly associated with menstrual symptoms (p <.001). When general somatic complaints were included in the models, the effect of depressive symptoms on menstrual symptoms remained significant for the sum score (p =.015) and the menstrual somatic symptoms subscale (p =.001). After adjusting for somatic complaints, initial report of depressive symptoms predicted change in menstrual symptoms only for girls with the lowest menstrual symptoms sum score (p =.025). Initial report of somatic complaints predicted change in menstrual symptoms (p =.020).

Conclusions: Girls with higher depressive symptoms and higher somatic complaints are at greater risk for experiencing menstrual symptoms and increasing symptoms across adolescence, with a heightened vulnerability for girls with lower baseline menstrual symptoms.


Author Keywords
Adolescence;  Depression;  Female;  Menstrual symptoms;  Menstruation;  Somatic


Document Type: Article
Source: Scopus

Meissner, K.a b , Blood, J.b , Francis, A.M.b , Yermolenka, V.b , Kharasch, E.D.b c
Cyclosporine-inhibitable cerebral drug transport does not influence clinical methadone pharmacodynamics
(2014) Anesthesiology, 121 (6), pp. 1281-1291. 


a Department of Anesthesiology, Universitätsmedizin GreifswaldGreifswald, Germany
b Departments of Anesthesiology, Washington University, 660 S. Euclid Avenue, Box 8054St. Louis, MO, United States
c Biochemistry and Molecular Biophysics, Washington UniversitySt. Louis, MO, United States


Abstract
Background: Interindividual variability and drug interaction studies suggest that blood-brain barrier drug transporters mediate human methadone brain biodistribution. In vitro and animal studies suggest that methadone is a substrate for the efflux transporter P-glycoprotein, and that P-glycoprotein-mediated transport influences brain access and pharmacologic effect. This investigation tested whether methadone is a transporter in humans sample contents.

Methods: Healthy volunteers received oral (N = 16) or IV (N = 12) methadone in different crossover protocols after nothing (control) or the validated P-glycoprotein inhibitor cyclosporine (4.5 mg/kg orally twice daily for 4 days, or 5 mg/kg IV over 2 h). Plasma and urine methadone and metabolite concentrations were measured by mass spectrometry. Methadone effects were measured by miosis and thermal analgesia (maximally tolerated temperature and verbal analog scale rating of discreet temperatures).

Results: Cyclosporine marginally but significantly decreased methadone plasma concentrations and apparent oral clearance, but had no effect on methadone renal clearance or on hepatic N-demethylation. Cyclosporine had no effect on miosis or on R-methadone concentration-miosis relationships after either oral or IV methadone. Peak miosis was similar in controls and cyclosporine-treated subjects after oral methadone (1.4 ± 0.4 and 1.3 ± 0.5 mm/mg, respectively) and IV methadone (3.1 ± 1.0 and 3.2 ± 0.8 mm, respectively). Methadone increased maximally tolerated temperature, but analgesia testing was confounded by cyclosporine-related pain.

Conclusions: Cyclosporine did not affect methadone pharmacodynamics. This result does not support a role for cyclosporineinhibitable transporters mediating methadone brain access and biodistribution. © 2014, the American Society of Anesthesiologists, Inc.


Document Type: Article
Source: Scopus

Church, D.a , Feinstein, D.b , Palmer-Hoffman, J.a , Stein, P.K.c , Tranguch, A.d
Empirically supported psychological treatments the challenge of evaluating clinical innovations
(2014) Journal of Nervous and Mental Disease, 202 (10), pp. 699-709. 


a National Institute for Integrative Healthcare, 3340 Fulton RD #442Fulton, CA, United States
b InnersourceAshland, OR, United States
c Washington University School of MedicineSt. Louis, MO, United States
d Columbia University College of Physicians and SurgeonsNew York, NY, United States


Abstract
Clear and transparent standards are required to establish whether a therapeutic method is "evidence based." Even when research demonstrates a method to be efficacious, it may not become available to patients who could benefit from it, a phenomenon known as the "translational gap." Only 30% of therapies cross the gap, and the lag between empirical validation and clinical implementation averages 17 years. To address these problems, Division 12 of the American Psychological Association published a set of standards for "empirically supported treatments" in the mid-1990s that allows the assessment of clinical modalities. This article reviews these criteria, identifies their strengths, and discusses their impact on the translational gap, using the development of a clinical innovation called Emotional Freedom Techniques (EFT) as a case study. Twelve specific recommendations for updates of the Division 12 criteria are made based on lessons garnered from the adoption of EFT within the clinical community. These recommendations would shorten the cycle from the research setting to clinical practice, increase transparency, incorporate recent scientific advances, and enhance the capacity for succinct comparisons among treatments.


Author Keywords
EFT;  Emotional Freedom Techniques;  Epigenetics;  Evidence-based;  Standards


Document Type: Review
Source: Scopus

Delforterie, M.a , Creemers, H.a , Agrawal, A.b , Lynskey, M.c , Jak, S.d , Van Der Ende, J.e , Verhulst, F.e , Huizink, A.a
Functioning of cannabis abuse and dependence criteria across two different countries: The United States and the Netherlands
(2014) Substance Use and Misuse, 50 (2), pp. 242-250. 


a Developmental Psychology, VU University Amsterdam, Van Der Boechorststraat 1Amsterdam, Netherlands
b Department of Psychiatry, Washington University, School of MedicineSt. Louis, Missouri, United States
c Addictions Department, King's College LondonLondon, United Kingdom
d Research Institute of Child Development and Education, University of AmsterdamAmsterdam, Netherlands
e Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, Sophia Children's HospitalRotterdam, Netherlands


Abstract
Background: Cross-national differences could affect the likelihood of endorsement of DSM cannabis abuse and dependence criteria. The present study examines whether cannabis abuse and dependence criteria function differently across U.S. and Dutch cannabis users. Method: Data on lifetime endorsement of DSM-IV cannabis abuse/dependence criteria were utilized from U.S. cannabis users who participated in the National Epidemiological Survey on Alcohol and Related Conditions (NESARC) and from Dutch cannabis users who participated in the Zuid-Holland study. In total, 1,568 cannabis users participated in the NESARC sample, and 359 cannabis users participated in the Zuid-Holland sample. The DSM-IV cannabis abuse/dependence criteria as well as cannabis withdrawal were determined using face-to-face computer-Assisted personal interviews. Results: Using Restricted Factor Analysis with Latent Moderated Structures, the cannabis abuse/dependence criteria legal problems (β =-0.43), failed quit attempts (β =-1.09), use despite problems (β =-0.32), and withdrawal (β =-0.53) showed measurement bias, and were more likely to be endorsed by U.S. than by Dutch cannabis users. Also, men were more likely than women to endorse the criteria hazardous use (β =-0.27), legal problems (β =-0.49) and tolerance (β =-0.20). Findings on failed quit attempts and withdrawal were replicated in matched subsamples, while results on legal problems (country and gender) were partly replicated. Conclusions: Several CUD criteria showed measurement bias across two countries and between males and females. Therefore, differences between countries and gender in prevalence rates of CUD should be regarded with caution.


Author Keywords
Cannabis abuse/dependence;  DSM-IV;  Factor analysis;  Measurement bias;  US vs. the Netherlands


Document Type: Article
Source: Scopus

Chole, R.A.a , Gagnon, P.M.a , Vogel, J.P.b
Inactivation of specific Pseudomonas aeruginosa biofilm factors does not alter virulence in infected cholesteatomas
(2014) Otology and Neurotology, 35 (9), pp. 1585-1591. 


a Department of Otolaryngology, Washington University School of Medicine, 660 South Euclid AvenueSt. Louis, MO, United States
b Department of Molecular Microbiology, Washington University School of MedicineSt. Louis, MO, United States


Abstract
Hypothesis: When experimental cholesteatomas are infected with Pseudomonas aeruginosa (PA) mutants lacking factors associated with the formation of biofilms, host defenses are more effective against these strains when compared with wild-type strains (PAO1 and OPPA8) in preventing tissue destruction.

Background: Previous studies have identified biofilms within chronically infected aural cholesteatomas. These infected cholesteatomas are associated with increased tissue destruction. Because biofilms are highly resistant to host defenses leading to prolonged infection, we propose that the biofilm phenotype of P. aeruginosa may be a virulence factor leading to persistence of infection and increased tissue destruction.

Methods: Aural cholesteatomas were induced in Mongolian gerbils. At the time of induction, the ear canals were inoculated with wild-type (PAO1 and OPPA8) and biofilm-deficient (PAO1 ΔpilA, PAO1 algD::aacC1 and PAO1 galU::aacC1) strains of P. aeruginosa. After 8 weeks, the size of the cholesteatomas and levels of bone destruction and deposition were measured using microCT scanning and double fluorochrome bone labeling.

Result: Infected cholesteatomas resulted in increased growth, bone destruction, and bone deposition when compared with vehicle-only controls. We observed no differences between the wild-type (biofilm forming) and the biofilm-deficient strains of P. aeruginosa.

Conclusion: Our hypothesis that biofilm formation is a virulence factor in cholesteatomas infected with P. aeruginosa was not supported. A number of interpretations of these data are reasonable. It is possible that biofilms are not critical in infected cholesteatomas. Alternatively, the mutants that are deficient in generating biofilms in vitro may be able to form effective biofilms in vivo using alternative pathways.


Author Keywords
Biofilm;  Bone erosion;  Cholesteatoma;  Chronic otitis media


Document Type: Article
Source: Scopus

Foster, E.R.
Instrumental activities of daily living performance among people with parkinson's disease without dementia
(2014) American Journal of Occupational Therapy, 68 (3), pp. 353-362. 


Departments of Neurology and Psychiatry, Washington University, School of Medicine, Campus Box 8505, 4444 Forest Park BoulevardSt. Louis, MO, United States


Abstract
OBJECTIVE: To investigate the performance of cognitively demanding instrumental activities of daily living (IADLs) among people with Parkinson's disease (PD) without dementia.

METHOD: Seventy-seven participants with PD and 57 participants without PD underwent standardized, performance-based IADL evaluation using the Performance Assessment of Self-care Skills. Activity performance was rated for independence, adequacy, and safety.

RESULTS: The PD group had lower independence and adequacy scores than the non-PD group for almost every activity. Medication management, shopping, and sharp utensil use were the activities most sensitive to group differences. In the PD group, older age, lower Mini-Mental State Examination scores, and decreased motor function were associated with poorer IADL performance.

CONCLUSIONS: People with relatively early and mild PD demonstrated measurable deficits in the performance of cognitively demanding IADLs. This work highlights the importance of using objective assessments of IADL function to detect early functional changes in people with PD.


Author Keywords
Activities of daily living;  Cognition;  Parkinson disease;  Self care;  Task performance and analysis


Document Type: Article
Source: Scopus

Farmakis, S.G.a , Siegel, M.J.b
Intrarenal neuroblastoma with pulmonary metastases mimicking a Wilms tumor
(2014) Journal of Pediatric Surgery, 49 (12), pp. 1864-1866. 


a Department of Radiology, Saint Louis University School of Medicine, 3635 Vista Ave. at Grand Blvd.St. Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd.St. Louis, MO, United States


Abstract
Primary intrarenal neuroblastoma is extremely rare and is a mimic of Wilms tumor. We present a case of a renal mass in a 14 month old male with lung metastases at the initial presentation. This was thought to represent a Wilms tumor. Histology of a biopsied lung nodule revealed neuroblastoma.


Author Keywords
Intrarenal;  Neuroblastoma;  Pediatric;  Renal tumors;  Wilms tumor


Document Type: Article
Source: Scopus

Avidan, M.S.a , Mashour, G.A.b
Mind the gap: Attitudes towards intraoperative Brain Monitoring
(2014) Anesthesia and Analgesia, 119 (5), pp. 1022-1025. 


a Department of Anesthesiology, Washington University School of Medicine, 660 S Euclid Ave.St. Louis, MO, United States
b Department of Anesthesiology, University of MichiganAnn Arbor, MI, United States


Document Type: Review
Source: Scopus

Cai, C.a , Alshehri, A.b , Choksi, R.b , Pestronk, A.a b b
Regional ischemic immune myopathy: A paraneoplastic dermatomyopathy
(2014) Journal of Neuropathology and Experimental Neurology, 73 (12), pp. 1126-1133. 


a Departments of Pathology and Immunology (CC, Washington University, School of MedicineSt. Louis, MO, United States
b Departments of Neurology, Washington University, School of Medicine, 660 South Euclid Ave, Box 8111St. Louis, MO, United States


Abstract
Necrosis and regeneration of scattered muscle fibers are common features of many active acquired and immune myopathies. We studied a series of patients with acquired myopathies with an unusual pattern of regional, rather than scattered, muscle fiber necrosis and regeneration. Retrospective review of records of 7 patients with acquired myopathies having regional muscle fiber necrosis on muscle biopsy. Clinical features of patients included proximal symmetric weakness in arms and legs with a subacute onset (100%) beginning at ages between 41 and 92 years, with dysphagia (83%), myalgias (100%), skin rash (67%), and associated malignancy (71%). Serum creatine kinase was often very high (91,600 U/L) (83%). Survival was less than 1 year in 43%. Myopathology included a regional distribution with muscle fiber necrosis and capillary loss in the border zones between intermediatesized perimysial vessels, vascular pathology with damaged walls of intermediate-sized perimysial veins, and connective tissue with expression of the ischemia marker carbonic anhydrase IX but no mononuclear cell inflammatory foci. These data indicate that regional ischemic immune myopathies are likely caused by ischemia in border zones between damaged intermediate-sized perimysial blood vessels. Regional ischemic immune myopathies are a distinctive pathologic group of acquired, probably immune, noninflammatory dermatomyopathies with weakness and often a skin rash and systemic neoplasm.


Author Keywords
Dermatomyositis;  Immune;  Ischemia;  Myopathy;  Vein


Document Type: Article
Source: Scopus

Blank, S.J.a , Grindler, D.J.a , Zerega, J.a , Blinder, M.b , Nussenbaum, B.a
Systemic effects of subcutaneous heparin use in otolaryngology patients
(2014) Otolaryngology - Head and Neck Surgery (United States), 151 (6), pp. 967-971. 


a Department of Otolaryngology-Head and Neck Surgery, Washington University, School of Medicine, 660 S. Euclid AveSt Louis, MO, United States
b Department of Medicine, School of Medicine, Washington UniversitySt Louis, MO, United States


Abstract
Objectives. To describe a population of otolaryngology patients who developed systemic anticoagulation from pharmacologic deep vein thrombosis prophylaxis using subcutaneous lowdose unfractionated heparin and describe associated adverse events and identify risk factors for this occurrence.

Study Design. Retrospective case series with chart review.

Setting. Single-institution, academic tertiary care center.

Subjects and Methods. Patients who developed prolonged partial thromboplastin times from routine administration of subcutaneous low-dose unfractionated heparin postoperatively were retrospectively identified during a 16-month period. Data regarding demographics, disease characteristics, laboratory values, associated complications, and risk factors were collected and analyzed.

Results. Five patients, all with head and neck cancer, postoperatively developed prolonged partial thromboplastin time levels with prophylactic subcutaneous low-dose unfractionated heparin. All had body mass index ≤20 kg/m2 and received 5000 units of subcutaneous low-dose unfractionated heparin 3 times daily. Four had impaired renal function. Adverse events included 5 postoperative wound hematomas, an emergent reintubation, and a case of persistent mucosal bleeding. These bleeding complications accounted for 25% of all bleeding complications in otolaryngology patients during the same period.

Conclusion. Unanticipated systemic effects of subcutaneous low-dose unfractionated heparin can cause significant morbidity in surgically treated patients with head and neck cancer. From this case series, risk factors appear to include subcutaneous low-dose unfractionated heparin 3 times daily dose frequency, low body mass index, and renal dysfunction. For this at-risk patient population, a protocol is needed to minimize both deep vein thromboses and complications of prophylactic therapy.


Author Keywords
bleeding;  deep venous thrombosis;  heparin;  pharmacologic prophylaxis;  subcutaneous

 


Document Type: Article
Source: Scopus

December 11, 2014

Delforterie, M.J.a , Creemers, H.E.b , Agrawal, A.c , Lynskey, M.T.d , Jak, S.e , Huizink, A.C.a
The influence of age and gender on the likelihood of endorsing cannabis abuse/dependence criteria
(2015) Addictive Behaviors, 42, pp. 172-175. 


a VU University, Department of Developmental Psychology, EMGO Institute for Health and Care ResearchAmsterdam, Netherlands
b Research Institute of Child Development and Education, University of AmsterdamAmsterdam, Netherlands
c Department of Psychiatry, Washington University School of MedicineSt Louis, MO, United States
d Addictions Dept, Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom
e Department of Methods and Statistics, Faculty of Social Sciences, Utrecht UniversityUtrecht, Netherlands


Abstract
Introduction: Higher prevalence rates of cannabis abuse/dependence and abuse/dependence criteria in 18-24. year old versus older cannabis users and in males versus females might reflect true differences in the prevalence of these disorders across age and gender or, alternatively, they could arise from age- and gender-related measurement bias. To understand differences in endorsement across important subgroups, we examined the influence of age and gender simultaneously on the likelihood of endorsement of the various abuse/dependence criteria. Method: The sample consisted of 1603 adult past year cannabis users participating in the National Epidemiological Survey on Alcohol and Related Conditions (NESARC), a U.S. population study (39.6% aged 18-24; 62.1% male). Past year DSM-IV cannabis abuse/dependence criteria and withdrawal were assessed with the AUDADIS-IV. A restricted factor analysis with latent moderated structures was used to detect measurement bias. Results: Although cannabis abuse and dependence diagnoses and various individual abuse/dependence criteria showed different prevalence rates across younger and older male and female cannabis users, none of the items showed uniform or non-uniform measurement bias with respect to age or gender. Conclusion: The results indicate that, although prevalence rates of cannabis abuse/dependence criteria differ across age and gender, past year abuse/dependence criteria function similarly across these groups. It can thus be concluded that the criteria are applicable to younger and older, as well as male and female, adult cannabis users.


Author Keywords
Age;  Cannabis abuse/dependence;  DSM-IV;  Factor analysis;  Gender;  Measurement bias


Document Type: Article
Source: Scopus

Eory, A.a , Rozsa, S.b c , Gonda, X.d e f , Dome, P.d f , Torzsa, P.a , Simavorian, T.i , Fountoulakis, K.N.g , Pompili, M.h , Serafini, G.h , Akiskal, K.K.i , Akiskal, H.S.i , Rihmer, Z.d f , Kalabay, L.a
The association of affective temperaments with smoking initiation and maintenance in adult primary care patients
(2015) Journal of Affective Disorders, 172, pp. 397-402. 


a Department of Family Medicine, Semmelweis University, 4 Kutvolgyi StreetBudapest, Hungary
b Center for Well-Being, Department of Psychiatry, Washington University School of MedicineSt. Louis, MO, United States
c Department of Personality and Health Psychology, Eötvös Loránd UniversityBudapest, Hungary
d Department of Clinical and Theoretical Mental Health, Kutvolgyi Clinical Center, Semmelweis UniversityBudapest, Hungary
e Department of Pharmacodymanics, Semmelweis UniversityBudapest, Hungary
f Laboratory for Suicide Research and Prevention, National Institute of Psychiatry and AddictionsBudapest, Hungary
g 3rd Department of Psychiatry, School of Medicine, Aristotle University of Thessaloniki, Greece
h Department of Neurosciences, Mental Health and Sensory Organs, Sant Andrea Hospital, Sapienza University of RomeRome, Italy
i International Mood Center, University of CaliforniaSan Diego, CA, United States


Abstract
Background Smoking behaviour and its course is influenced by personality factors. Affective temperaments could allow a more specific framework of the role trait affectivity plays in this seriously harmful health-behaviour. The aim of our study was to investigate if such an association exists in an ageing population with a special emphasis on gender differences. Methods 459 primary care patients completed the TEMPS-A, Beck Depression Inventory (BDI) and Hamilton Anxiety Rating Scale (HAM-A). Subjects were characterized according to their smoking behaviour as current, former or never smokers. Univariate analysis ANOVA and logistic regression were performed to analyse differences in the three smoking subgroups to predict smoking initiation and maintenance. Results Current smokers were younger and less educated than former or never smokers. Males were more likely to try tobacco during their lifetime and were more successful in cessation. Depressive, cyclothymic and irritable temperament scores showed significant differences between the three smoking subgroups. Irritable temperament was a predictor of smoking initiation in females whereas depressive temperament predicted smoking maintenance in males with a small, opposite effect of HAM-A scores independent of age, education, lifetime depression and BDI scores. Whereas smoking initiation was exclusively predicted by a higher BDI score in males, smoking maintenance was predicted by younger age and lower education in females. Limitations The cross-sectional nature of the study design may lead to selective survival bias and hinder drawing causal relationships. Conclusions Affective temperaments contribute to smoking initiation and maintenance independently of age, education, and depression. The significant contribution of depressive temperament in males and irritable temperament in females may highlight the role of gender-discordant temperaments in vulnerable subgroups.


Author Keywords
Affective temperament;  Mood disorder;  Sex;  Smoking


Document Type: Article
Source: Scopus

Lloyd, H.M.a , Tafoya, A.E.b , Merritt, R.K.c
Underage Drinking and Antisocial Behavior: Research to Inform a U.K. Behavioral Intervention
(2015) Journal of Child and Adolescent Substance Abuse, 24 (1), pp. 46-53. 


a NIHR CLAHRC South West Peninsula (PenCLAHRC), Plymouth University Peninsula Schools of Medicine & DentistryPlymouth, United Kingdom
b Washington University in St. LouisSt. Louis, MO, United States
c National Social Marketing CentreLondon, United Kingdom


Abstract
This study aimed to identify and describe the motivators for underage, curbside drinking leading to antisocial behavior and to use these insights to develop a suitable intervention to tackle this. A cross-sectional study was conducted with youths and key stakeholders. “Street drinking” was identified as the most common recreational activity for youths and was motivated by a lack of appropriate leisure services, peer pressure and behavior, and the local accessibility of alcohol. Antisocial behavior was a major theme associated with street drinking. Few studies have examined the root causes of youth drinking and antisocial behavior. Our findings show that deprivation, social bonds, and the symbolic capital attached to alcohol along with its relative cost and availability enhance its appeal to the young, and provide some illumination to the relationship between these related problems.


Author Keywords
alcohol;  antisocial behavior;  intervention;  street;  underage;  youth


Document Type: Article
Source: Scopus

Eaton, M.M.a , Bracamontes, J.a , Shu, H.-J.b c , Li, P.a , Mennerick, S.c , Steinbach, J.H.a , Akk, G.a c
γ-aminobutyric acid type A α4, β2, and δ subunits assemble to produce more than one functionally distinct receptor type
(2014) Molecular Pharmacology, 86 (6), pp. 647-656. 


a Department of Anesthesiology, Washington University, Campus-Box-8054, 660 South Euclid AvenueSt. Louis, MO, United States
b Department of Psychiatry, Washington University School of MedicineSt. Louis, MO, United States
c Taylor Family Institute for Innovative Psychiatric Research, Washington University School of MedicineSt. Louis, MO, United States


Abstract
Native γ-aminobutyric acid (GABA)A receptors consisting of α4, β1-3, and d subunits mediate responses to the low, tonic concentration of GABA present in the extracellular milieu. Previous studies on heterologously expressed α4βδ receptors have shown a large degree of variability in functional properties, including sensitivity to the transmitter. We studied properties of α4β2δ receptors employing free subunits and concatemeric constructs, expressed in Xenopus oocytes, HEK 293 cells, and cultured hippocampal neurons. The expression system had a strong effect on the properties of receptors containing free subunits. The midpoint of GABA activation curve was 10 nM for receptors in oocytes versus 2300 nM in HEK cells. Receptors activated by the steroid alfaxalone had an estimated maximal open probability of 0.6 in oocytes and 0.01 in HEK cells. Irrespective of the expression system, receptors resulting from combining the tandem construct β2-δ and a free α4 subunit exhibited large steroid responses. We propose that free α4, β2, and δ subunits assemble in different configurations with distinct properties in oocytes and HEK cells, and that subunit linkage can overcome the expression system-dependent preferential assembly of free subunits. Hippocampal neurons transfected with α4 and the picrotoxin-resistant δ(T269Y) subunit showed large responses to alfaxalone in the presence of picrotoxin, suggesting that α4βδ receptors may assemble in a similar configuration in neurons and oocytes.


Document Type: Article
Source: Scopus

Akbari, S.H.A.a , Holekamp, T.F.a , Murphy, T.M.a , Mercer, D.a , Leonard, J.R.c d , Smyth, M.D.a b , Park, T.S.a b , Limbrick, D.D., Jr.a b
Surgical management of complex multiloculated hydrocephalus in infants and children
(2014) Child's Nervous System, 7 p. Article in Press. 


a Department of Neurological Surgery, St. Louis Children’s Hospital, Washington University School of Medicine, Washington University in St. Louis, One Children’s Place, Suite 4S20St. Louis, MO, United States
b Department of Pediatrics, St. Louis Children’s Hospital, Washington University School of Medicine, Washington University in St. LouisSt. Louis, MO, United States
c Department of Neurosurgery, Nationwide Children’s Hospital, The Ohio State University College of Medicine, The Ohio State UniversityColumbus, OH, United States
d Department of Neurosciences, Nationwide Children’s Hospital, The Ohio State University College of Medicine, The Ohio State UniversityColumbus, OH, United States


Abstract
Objective: Multiloculated hydrocephalus may occur as a consequence of intraventricular hemorrhage or infection and is characterized by enlargement of multiple noncommunicating intraventricular and/or periventricular cysts. In this study, we report the outcomes of open and endoscopic fenestration for multiloculated hydrocephalus at our institution.

Methods: Records of children who underwent endoscopic or open fenestration at St. Louis Children’s Hospital from 1999 to 2011 were analyzed. The cause of MLH, operative parameters, length of hospital stay, and subsequent shunt intervention rate were recorded.

Results: Twenty-five subjects were identified for study. Twelve subjects underwent open craniotomy and 13 underwent endoscopic fenestration. Endoscopic fenestration was associated with decreased blood loss, operative time, and length of stay (p = 0.003, 0.002, 0.02, respectively). Subjects undergoing craniotomy had an average of 5.1 ± 4.5 subsequent shunt-related interventions versus 3.1 ± 4.0 in the endoscopy group (p = 0.25). The craniotomy group’s median subsequent shunt revision rate was 0.74 interventions per year versus 0.50 interventions per year in the endoscopy group (p = 0.51). Fifty percent of subjects in the open fenestration group required additional fenestration surgery compared to 38.5 % in the endoscopic group (p = 0.70).

Conclusion: Both open and endoscopic fenestration appeared effective at improving shunt management. The endoscopic technique may offer advantages in operative time, blood loss, and length of hospital stay. These data suggest that endoscopic fenestration may be used as the initial approach for treatment of multiloculated hydrocephalus, with craniotomy and open fenestration used for more severe or refractory cases.


Author Keywords
Cystic hydrocephalus;  Fenestration;  Intraventricular hemorrhage;  Loculated hydrocephalus;  Multiloculated hydrocephalus;  Ventriculitis


Document Type: Article in Press
Source: Scopus

Hawasli, A.H.a , Hullar, T.E.c , Dorward, I.G.a b
Idiopathic scoliosis and the vestibular system
(2014) European Spine Journal, 7 p. Article in Press. 


a Department of Neurosurgery, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8057Saint Louis, MO, United States
b Department of Orthopaedic Surgery, Washington University School of MedicineSt. Louis, MO, United States
c Department of Otolaryngology, Washington University School of MedicineSt. Louis, MO, United States


Abstract
Purpose: Despite its high prevalence, the etiology underlying idiopathic scoliosis remains unclear. Although initial scrutiny has focused on genetic, biochemical, biomechanical, nutritional and congenital causes, there is growing evidence that aberrations in the vestibular system may play a role in the etiology of scoliosis. In this article, we discuss putative mechanisms for adolescent idiopathic scoliosis and review the current evidence supporting a role for the vestibular system in adolescent idiopathic scoliosis.

Methods: A comprehensive search of the English literature was performed using PubMed (http://www.ncbi.nlm.nih.gov/pubmed). Research articles studying interactions between adolescent idiopathic scoliosis and the vestibular system were selected and evaluated for inclusion in a literature review.

Results: Eighteen manuscripts of level 3–4 clinical evidence to support an association between adolescent idiopathic scoliosis (AIS) and dysfunction of the vestibular system were identified. These studies include data from physiologic and morphologic studies in humans. Clinical data are supported by animal model studies to suggest a causative link between the vestibular system and AIS.

Conclusions: Clinical data and a limited number of animal model studies suggest a causative role of the vestibular system in AIS, although this association has not been reproduced in all studies.


Author Keywords
Adolescent idiopathic scoliosis;  Labyrinth;  Scoliosis;  Vestibular;  Vestibular System


Document Type: Article in Press
Source: Scopus

Graham, S.a , Ye, S.b , Qian, M.c , Sanford, A.R.c , Tullio, M.R.D.b , Sacco, R.L.d , Mann, D.L.e , Levin, B.c , Pullicino, P.M.f , Freudenberger, R.S.g , Teerlink, J.R.h , Mohr, J.P.i , Labovitz, A.J.j , Lip, G.Y.H.k , Estol, C.J.l , Lok, D.J.m , Ponikowski, P.n , Anker, S.D.o , Thompson, J.L.P.c , Homma, S.c
Cognitive function in ambulatory patients with systolic heart failure: Insights from the warfarin versus aspirin in reduced cardiac ejection fraction (warcef) trial
(2014) PLoS ONE, 9 (11), art. no. e113447, . 


a Division of Cardiology, Department of Medicine, State University of New York Upstate Medical UniversityBuffalo, NY, United States
b Division of Cardiology, Department of Medicine, Columbia University Medical CenterNew York, NY, United States
c Department of Biostatistics, Columbia University Mailman School of Public HealthNew York, NY, United States
d Department of Neurology, University of Miami Miller School of MedicineMiami, FL, United States
e Department of Medicine, Washington UniversitySt. Louis, MO, United States
f Kent Institute of Medicine and Health Sciences, University of KentCanterbury, United Kingdom
g Division of Cardiology, Department of Medicine, Lehigh Valley HospitalAllentown, PA, United States
h Department of Medicine, San Francisco Veterans Affairs Medical Center, University of California San FranciscoSan Francisco, CA, United States
i Department of Neurology, Columbia University Medical CenterNew York, NY, United States
j Department of Cardiovascular Medicine, University of South FloridaTampa, FL, United States
k University of Birmingham Centre for Cardiovascular Sciences, City HospitalBirmingham, United Kingdom
l Centro Neurológico de Tratamiento Y RehabilitaciónBuenos Aires, Argentina
m Department of Cardiology, Deventer HospitalDeventer, Overijssel, Netherlands
n Department of Heart Diseases, Wroclaw Medical University, Military HospitalWroclaw, Lower Silesia, Poland
o Department of Innovative Clinical Trials, University Medical Centre GöttingenGöttingen, Lower Saxony, Germany

Abstract

We sought to determine whether cognitive function in stable outpatients with heart failure (HF) is affected by HF severity. A retrospective, cross-sectional analysis was performed using data from 2, 043 outpatients with systolic HF and without prior stroke enrolled in the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial. Multivariable regression analysis was used to assess the relationship between cognitive function measured using the Mini-Mental Status Exam (MMSE) and markers of HF severity (left ventricular ejection fraction [LVEF], New York Heart Association [NYHA] functional class, and 6-minute walk distance). The mean (SD) for the MMSE was 28.6 (2.0), with 64 (3.1%) of the 2,043 patients meeting the cut-off of MMSE ,<24 that indicates need for further evaluation of cognitive impairment. After adjustment for demographic and clinical covariates, 6-minute walk distance (β-coefficient 0.002, p<0.0001), but not LVEF or NYHA functional class, was independently associated with the MMSE as a continuous measure. Age, education, smoking status, body mass index, and hemoglobin level were also independently associated with the MMSE. In conclusion, six-minute walk distance, but not LVEF or NYHA functional class, was an important predictor of cognitive function in ambulatory patients with systolic heart failure.


Document Type: Article
Source: Scopus

Mattson, M.P.a b , Allison, D.B.c , Fontana, L.d e f , Harvie, M.g , Longo, V.D.h , Malaisse, W.J.i , Mosley, M.j , Notterpek, L.k , Ravussin, E.l , Scheer, F.A.J.L.m , Seyfried, T.N.n , Varady, K.A.o , Panda, S.p
Meal frequency and timing in health and disease
(2104) Proceedings of the National Academy of Sciences of the United States of America, 111 (47), pp. 16647-16653. 


a Laboratory of Neurosciences, National Institute on AgingBaltimore, MD, United States
b Department of Neuroscience, Johns Hopkins University School of MedicineBaltimore, MD, United States
c Nutrition and Obesity Research Center, University of Alabama at BirminghamBirmingham, AL, United States
d Department of Medicine, Washington University in St. LouisSt. Louis, MO, United States
e Department of Clinical and Experimental Sciences, Brescia UniversityBrescia, Italy
f CEINGE Biotecnologie AvanzateNaples, Italy
g Genesis Breast Cancer Prevention Centre, University Hospital South ManchesterWythenshaw, Manchester, United Kingdom
h Longevity Institute, Davis School of Gerontology, Department of Biological SciencesLos Angeles, CA, United States
i Laboratory of Experimental Hormonology, Brussels Free UniversityBrussels, Belgium
j British Broadcasting CorporationLondon, United Kingdom
k Department of Neuroscience, College of Medicine, McKnight Brain InstituteGainesville, FL, United States
l Pennington Biomedical Research CenterBaton Rouge, LA, United States
m Harvard Medical School, Brigham and Women's HospitalBoston, MA, United States
n Biology Department, Boston CollegeChestnut Hill, MA, United States
o Department of Kinesiology and Nutrition, University of Illinois at ChicagoChicago, IL, United States
p Regulatory Biology Laboratory, Salk Institute for Biological StudiesLa Jolla, CA, United States


Abstract
Although major research efforts have focused on how specific components of foodstuffs affect health, relatively little is known about a more fundamental aspect of diet, the frequency and circadian timing of meals, and potential benefits of intermittent periods with no or very low energy intakes. The most common eating pattern in modern societies, three meals plus snacks every day, is abnormal from an evolutionary perspective. Emerging findings from studies of animal models and human subjects suggest that intermittent energy restriction periods of as little as 16 h can improve health indicators and counteract disease processes. The mechanisms involve a metabolic shift to fat metabolism and ketone production, and stimulation of adaptive cellular stress responses that prevent and repair molecular damage. As data on the optimal frequency and timing of meals crystalizes, it will be critical to develop strategies to incorporate those eating patterns into health care policy and practice, and the lifestyles of the population.


Author Keywords
Circadian rhythm;  Feeding behavior;  Metabolism;  Obesity;  Time-restricted feeding


Document Type: Article
Source: Scopus

Tye-Murray, N.a , Spehar, B.P.a , Myerson, J.b , Hale, S.b , Sommers, M.S.b
The self-advantage in visual speech processing enhances audiovisual speech recognition in noise
(2014) Psychonomic Bulletin and Review, 6 p. Article in Press. 


a Department of Otolaryngology, Washington University School of Medicine, Campus Box 8115, 660 South Euclid AvenueSt. Louis, MO, United States
b Department of Psychology, Washington University in St. LouisSt. Louis, MO, United States


Abstract
Individuals lip read themselves more accurately than they lip read others when only the visual speech signal is available (Tye-Murray et al., Psychonomic Bulletin & Review, 20, 115–119, 2013). This self-advantage for vision-only speech recognition is consistent with the common-coding hypothesis (Prinz, European Journal of Cognitive Psychology, 9, 129–154, 1997), which posits (1) that observing an action activates the same motor plan representation as actually performing that action and (2) that observing one’s own actions activates motor plan representations more than the others’ actions because of greater congruity between percepts and corresponding motor plans. The present study extends this line of research to audiovisual speech recognition by examining whether there is a self-advantage when the visual signal is added to the auditory signal under poor listening conditions. Participants were assigned to sub-groups for round-robin testing in which each participant was paired with every member of their subgroup, including themselves, serving as both talker and listener/observer. On average, the benefit participants obtained from the visual signal when they were the talker was greater than when the talker was someone else and also was greater than the benefit others obtained from observing as well as listening to them. Moreover, the self-advantage in audiovisual speech recognition was significant after statistically controlling for individual differences in both participants’ ability to benefit from a visual speech signal and the extent to which their own visual speech signal benefited others. These findings are consistent with our previous finding of a self-advantage in lip reading and with the hypothesis of a common code for action perception and motor plan representation.


Author Keywords
Audiovisual speech recognition;  Common coding hypothesis;  Lip reading;  Self-advantage;  Visual speech benefit


Document Type: Article in Press
Source: Scopus

Hong, A.R., Sheybani, A., Huang, A.J.W.
Intraoperative management of posterior capsular rupture
(2014) Current Opinion in Ophthalmology, . Article in Press. 


Washington University School of Medicine, St. Louis, Missouri, USA


Abstract
PURPOSE OF REVIEW: Posterior capsular rupture (PCR) and vitreous loss are inevitable complications encountered in cataract surgery across all levels of surgical experience and in spite of technological advances to improve safety. Thus, cataract surgeons must always be prepared to practice safe and effective intraoperative management strategies for capsular rupture.

RECENT FINDINGS: Novel approaches for lens fragment removal, vitrectomy, and lens implantation have expanded the available options for cataract surgery in the setting of an open posterior capsule. Intraoperative PCR management strategies should prioritize safety and strive to minimize vitreous traction, stabilize anterior chamber volume, maintain capsular and zonular integrity, and protect the corneal endothelium and other anterior segment structures.

SUMMARY: With appropriate management of PCR and vitreous, surgeons may still deliver safe and satisfactory visual outcomes for modern cataract surgery.


Document Type: Article in Press
Source: Scopus

Whitlock, E.L., Rodebaugh, T.L., Hassett, A.L., Shanks, A.M., Kolarik, E., Houghtby, J., West, H.M., Burnside, B.A., Shumaker, E., Villafranca, A., Edwards, W.A., Levinson, C.A., Langer, J.K., Fernandez, K.C., El-Gabalawy, R., Zhou, E.Y., Sareen, J., Jacobsohn, E., Mashour, G.A., Avidan, M.S.
Psychological Sequelae of Surgery in a Prospective Cohort of Patients from Three Intraoperative Awareness Prevention Trials
(2014) Anesthesia and Analgesia, . Article in Press. 


From the *Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri; †Department of Psychology, Washington University in St. Louis, St. Louis, Missouri; ‡Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan; §Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri; ?Department of Anesthesia and Perioperative Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; #Department of Psychology and Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada; and **Department of Anesthesiology and Surgery, Washington University in St. Louis, St. Louis, Missouri.


Abstract
BACKGROUND:: Elective surgery can have long-term psychological sequelae, especially for patients who experience intraoperative awareness. However, risk factors, other than awareness, for symptoms of posttraumatic stress disorder (PTSD) after surgery are poorly defined, and practical screening methods have not been applied to a broad population of surgical patients.

METHODS:: The Psychological Sequelae of Surgery study was a prospective cohort study of patients previously enrolled in the United States and Canada in 3 trials for the prevention of intraoperative awareness. The 68 patients who experienced definite or possible awareness were matched with 418 patients who denied awareness based on age, sex, surgery type, and awareness risk. Participants completed the PTSD Checklist-Specific (PCL-S) and/or a modified Mini-International Neuropsychiatric Interview telephone assessment to identify symptoms of PTSD and symptom complexes consistent with a PTSD diagnosis. We then used structural equation modeling to produce a composite PTSD score and examined potential risk factors.

RESULTS:: One hundred forty patients were unreachable; of those contacted, 303 (88%) participated a median of 2 years postoperatively. Forty-four of the 219 patients (20.1%) who completed the PCL-S exceeded the civilian screening cutoff score for PTSD symptoms resulting from their surgery (15 of 35 [43%] with awareness and 29 of 184 [16%] without). Nineteen patients (8.7%; 5 of 35 [14%] with awareness and 14 of 184 [7.6%] without) both exceeded the cutoff and endorsed a breadth of symptoms consistent with the Diagnostic and Statistical Manual Fourth Edition diagnosis of PTSD attributable to their surgery. Factors independently associated with PTSD symptoms were poor social support, previous PTSD symptoms, previous mental health treatment, dissociation related to surgery, perceiving that one’s life was threatened during surgery, and intraoperative awareness (all P ≤ 0.017). Perioperative dissociation was identified as a potential mediator for perioperative PTSD symptoms.

CONCLUSIONS:: Events in the perioperative period can precipitate psychological symptoms consistent with subsyndromal and syndromal PTSD. We not only confirmed the high rate of postoperative PTSD in awareness patients but also identified a significant rate in matched nonawareness controls. Screening surgical patients, especially those with potentially mediating risk factors such as intraoperative awareness or perioperative dissociation, for postoperative PTSD symptoms with the PCL-S is practical and could promote early referral, evaluation, and treatment.


Document Type: Article in Press
Source: Scopus

Cai, C., Alshehri, A., Choksi, R., Pestronk, A.
Regional Ischemic Immune Myopathy: A Paraneoplastic Dermatomyopathy
(2014) Journal of Neuropathology and Experimental Neurology, . Article in Press. 


From the Departments of Pathology and Immunology (CC, AP), and Neurology (AA, RC, AP), Washington University School of Medicine, St. Louis, Missouri.


Abstract
ABSTRACT: Necrosis and regeneration of scattered muscle fibers are common features of many active acquired and immune myopathies. We studied a series of patients with acquired myopathies with an unusual pattern of regional, rather than scattered, muscle fiber necrosis and regeneration. Retrospective review of records of 7 patients with acquired myopathies having regional muscle fiber necrosis on muscle biopsy. Clinical features of patients included proximal symmetric weakness in arms and legs with a subacute onset (100%) beginning at ages between 41 and 92 years, with dysphagia (83%), myalgias (100%), skin rash (67%), and associated malignancy (71%). Serum creatine kinase was often very high (>1,600 U/L) (83%). Survival was less than 1 year in 43%. Myopathology included a regional distribution with muscle fiber necrosis and capillary loss in the border zones between intermediate-sized perimysial vessels, vascular pathology with damaged walls of intermediate-sized perimysial veins, and connective tissue with expression of the ischemia marker carbonic anhydrase IX but no mononuclear cell inflammatory foci. These data indicate that regional ischemic immune myopathies are likely caused by ischemia in border zones between damaged intermediate-sized perimysial blood vessels. Regional ischemic immune myopathies are a distinctive pathologic group of acquired, probably immune, noninflammatory dermatomyopathies with weakness and often a skin rash and systemic neoplasm.


Document Type: Article in Press
Source: Scopus

Murray, D.J.
Progress in simulation education: developing an anesthesia curriculum
(2014) Current Opinion in Anaesthesiology, . Article in Press. 


Howard and Joyce Wood Simulation Center, Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri, USA


Abstract
PURPOSE: Simulation's role in anesthesia education is expanding to include more advanced skills and training for subspecialty practice. This review will provide an overview of many recent studies that expand the simulation curriculum for anesthesia education.

RECENT FINDINGS: Recent studies describe a curriculum that uses a range of simulation modalities, including part-task trainers, mannequin-based simulation, virtual reality, in-situ techniques, screen-based simulations as well as encounters with ‘standardized’ patients, nurses or physician colleagues. A variety of studies describe the use of task-training devises to more effectively acquire skills, such as fibre-optic intubation, ultrasound-guided regional anesthesia and transthoracic echocardiography as well as expand on a variety of teamwork skills particularly in subspecialty anesthesia practice.

SUMMARY: A curriculum is emerging that utilizes a variety of simulation modalities as part of a more comprehensive educational strategy for anesthesia specialty training.


Document Type: Article in Press
Source: Scopus

Roberts, K.F.a , Elbert, D.L.b , Kasten, T.P.a , Patterson, B.W.c , Sigurdson, W.C.a , Connors, R.E.a , Ovod, V.a , Munsell, L.Y.a , Mawuenyega, K.G.a , Miller-Thomas, M.M.d , Moran, C.J.d e , Cross, D.T., IIIi , Derdeyn, C.P.a d e , Bateman, R.J.a f g h
Amyloid-β efflux from the central nervous system into the plasma
(2014) Annals of Neurology, 76 (6), pp. 837-844. 


a Washington University School of Medicine, 660 S Euclid, Campus Box 8111St Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, United States
c Department of Biomedical Engineering, Washington University in St Louis, United States
d Medicine, United States
e Radiology, United States
f Neurological Surgery, United States
g Knight Alzheimer's Disease Research Center, United States
h Hope Center for Neurological Disorders, Washington University School of MedicineSt Louis, MO, United States


Abstract
Objective: The aim of this study was to measure the flux of amyloid-β (Aβ) across the human cerebral capillary bed to determine whether transport into the blood is a significant mechanism of clearance for Ab produced in the central nervous system (CNS).

Methods: Time-matched blood samples were simultaneously collected from a cerebral vein (including the sigmoid sinus, inferior petrosal sinus, and the internal jugular vein), femoral vein, and radial artery of patients undergoing inferior petrosal sinus sampling. For each plasma sample, Ab concentration was assessed by 3 assays, and the venous to arterial A β concentration ratios were determined.

Results: A β concentration was increased by
7.5% in venous blood leaving the CNS capillary bed compared to arterial blood, indicating efflux from the CNS into the peripheral blood (p < 0.0001). There was no difference in peripheral venous Ab concentration compared to arterial blood concentration.

Interpretation: Our results are consistent with clearance of CNS-derived A β into the venous blood supply with no increase from a peripheral capillary bed. Modeling these results suggests that direct transport of Ab across theblood-brain barrier accounts for
25% of Aβ clearance, and reabsorption of cerebrospinal fluid Ab accounts for 25% of the total CNS Aβ clearance in humans.


Document Type: Article
Source: Scopus

Duncan, R.P.a , Earhart, G.M.a b c
Are the effects of community-based dance on Parkinson disease severity, balance, and functional mobility reduced with time? A 2-year prospective pilot study
(2014) Journal of Alternative and Complementary Medicine, 20 (10), pp. 757-763. 


a Program in Physical Therapy, Washington University School of Medicine in St. Louis, Campus Box 8502, 4444 Forest Park BoulevardSt. Louis, MO, United States
b Department of Anatomy and Neurobiology, Washington University School of Medicine in St. LouisSt. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine in St. LouisSt. Louis, MO, United States


Abstract
Objective: To determine the effects of participation in a 2-year community-based dance class on disease severity and functional mobility in people with Parkinson disease (PD). Design: Randomized controlled trial. Settings/Location: Dance classes took place in a community-based location. Outcome measures were collected in a university laboratory. Patients: Ten individuals with PD were randomly assigned to the Argentine tango (AT) group (n = 5 [4 men]; mean age ± standard deviation, 69.6 ± 6.6 years) or the control group (n = 5 [4 men]; mean age ± standard deviation, 66 ± 11.0 years). Interventions: The AT group participated in a community-based AT class for 1 hour twice weekly for 2 years. Control group participants were given no prescribed exercise. Blinded assessments occurred at baseline and 12 and 24 months. Outcome measures: Movement Disorder Society-Unified Parkinson Disease Rating Scale (MDS-UPDRS) III, Mini-Balance Evaluation Systems Test (Mini-BESTest), gait velocity (forward and backward), Timed Up and Go and dual-task Timed Up and Go, Six-Minute Walk Test (6MWT), MDS-UPDRS II, MDS-UPDRS I, and Freezing of Gait Questionnaire. Results: There were no differences between groups at baseline. A significant group-by-time interaction (F [2,8] = 17.59; p < 0.0001) was noted for the MDS-UPDRS III, with the AT group having lower scores at 12 and 24 months than the controls. Significant interactions were also noted for the Mini-BESTest, MDS-UPDRS II and I, and 6MWT. Conclusion: This is believed to be one of the longest-duration studies to examine the effects of exercise on PD. Participation in community-based dance classes over 2 years was associated with improvements in motor and nonmotor symptom severity, performance on activities of daily living, and balance in a small group of people with PD. This is noteworthy given the progressive nature of PD and the fact that the control group declined on some outcome measures over 2 years.


Document Type: Article
Source: Scopus

Shaibani, A.a , Wong, L.-J.b , Wei Zhang, V.b , Lewis, R.A.b c , Shinawi, M.d
Autosomal recessive posterior column ataxia with retinitis pigmentosa caused by novel mutations in the FLVCR1 gene
(2014) International Journal of Neuroscience, 125 (1), pp. 43-49. 


a Nerve and Muscle Center of TexasHouston, TX, United States
b Departments of Molecular and Human Genetics Baylor College of MedicineHouston, TX, United States
c Department of Ophthalmology, Baylor College of MedicineHouston, TX, United States
d Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, Campus Box 8116St. Louis, MO, United States


Abstract
Posterior column ataxia with retinitis pigmentosa (PCARP) is an autosomal recessive disorder characterized by severe sensory ataxia, muscle weakness and atrophy, and progressive pigmentary retinopathy. Recently, mutations in the FLVCR1 gene were described in four families with this condition. We investigated the molecular basis and studied the phenotype of PCARP in a new family. The proband is a 33-year-old woman presented with sensory polyneuropathy and retinitis pigmentosa (RP). The constellation of clinical findings with normal metabolic and genetic evaluation, including mitochondrial DNA (mtDNA) analysis and normal levels of phytanic acid and vitamin E, prompted us to seek other causes of our patient's condition. Sequencing of FLVCR1 in the proband and targeted mutation testing in her two affected siblings revealed two novel variants, c.1547G>A (p.R516Q) and c.1593+5-+8delGTAA predicted, respectively, to be highly conserved throughout evolution and affecting the normal splicing, therefore, deleterious. This study supports the pathogenic role of FLVCR1 in PCARP and expands the molecular and clinical spectra of PCARP. We show for the first time that nontransmembrane domain (TMD) mutations in the FLVCR1 can cause PCARP, suggesting different mechanisms for pathogenicity. Our clinical data reveal that impaired sensation can be part of the phenotypic spectrum of PCARP. This study along with previously reported cases suggests that targeted sequencing of the FLVCR1 gene should be considered in patients with severe sensory ataxia, RP, and peripheral sensory neuropathy.


Author Keywords
Autosomal recessive;  FLVCR1;  Neuropathy;  Posterior column ataxia;  Retinitis pigmentosa


Document Type: Article
Source: Scopus

Pagliaccio, D., Luby, J.L., Luking, K.R., Belden, A.C., Barch, D.M.
Brain-behavior relationships in the experience and regulation of negative emotion in healthy children: Implications for risk for childhood depression
(2014) Development and Psychopathology, 26, pp. 1289-1303. 


Washington University in St. Louis, Program in Neuroscience, Campus-Box 1125, One Brookings DriveSt. Louis, MO, United States


Abstract
Structural and functional alterations in a variety of brain regions have been associated with depression and risk for depression across the life span. A majority of these regions are associated with emotion reactivity and/or regulation. However, it is generally unclear what mechanistic role these alterations play in the etiology of depression. A first step toward understanding this is to characterize the relationships between variation in brain structure/function and individual differences in depression severity and related processes, particularly emotion regulation. To this end, the current study examines how brain structure and function predict concurrent and longitudinal measures of depression symptomology and emotion regulation skills in psychiatrically healthy school-age children (N = 60). Specifically, we found that smaller hippocampus volumes and greater responses to sad faces in emotion reactivity regions predict increased depressive symptoms at the time of scan, whereas larger amygdala volumes, smaller insula volumes, and greater responses in emotion reactivity regions predict decreased emotion regulation skills. In addition, larger insula volumes predict improvements in emotion regulation skills even after accounting for emotion regulation at the time of scan. Understanding brain-behavior relationships in psychiatrically healthy samples, especially early in development, will help inform normative developmental trajectories and neural alterations in depression and other affective pathology.


Document Type: Article
Source: Scopus

Raghavan, R.a b , Brown, D.S.a , Allaire, B.T.c , Garfield, L.D.a , Ross, R.E.a
Medicaid expenditures on psychotropic medications for maltreated children: A study of 36 states
(2014) Psychiatric Services, 65 (12), pp. 1445-1451. 


a Brown School, Washington University in St. LouisSt. Louis MO, United States
b Department of Psychiatry, Washington University in St. LouisSt. Louis MO, United States
c RTI InternationalResearch Triangle Park NC, United States


Abstract
Objective: Children with histories of abuse or neglect are the most expensive child population to insure for their mental health needs. This study aimed to quantify the magnitude of Medicaid expenditures incurred in the purchase of psychotropic drugs for these children. Methods: Children (N=4,445) participating in the National Survey of Child and Adolescent Well-Being (NSCAW) and from households under investigation for suspected child abuse and neglect were linked to their Medicaid claims from 36 states. Expenditures on psychotropic medications between the NSCAW sample and a propensity score-matched comparison sample of Medicaid-enrolled children were compared in a two-part regression of logistic and generalized linear models. Results: Children in the NSCAW sample had twice the odds of psychotropic drug use and $190 higher mean annual expenditures on psychotropic drugs than children in the comparison sample. Increased expenditures on antidepressants and antimanic drugs were the primary drivers of these increased expenditures. Male gender and white race-ethnicity were associated with significantly increased expenditures. Children in primary care case management had $325 lower expenditures than those in fee-for-service Medicaid. Among NSCAW children alone, male gender, older age, being in poorer health, and scoring in the clinical range of the Child Behavior Checklist (CBCL) all increased expenditures on psychotropic drugs. Conclusions: Medicaid agencies should focus their cost containment strategies on antidepressants and antimanic drugs, consider expanding primary care case management arrangements, and expand use of instruments such as the CBCL to identify and treat high-need children.


Document Type: Article
Source: Scopus

Perlmutter, J.S.a c , Norris, S.A.b
Neuroimaging biomarkers for Parkinson disease: Facts and fantasy
(2014) Annals of Neurology, 76 (6), pp. 769-783. 


a Departmentof Neurology, Radiology, Anatomy and Neurobiology, Washington UniversitySt Louis, MO, United States
b Departmentof Neurology, Washington UniversitySt Louis, MO, United States
c Washington University, School of Medicine, 660 S. Euclid,Campus Box 8111St. Louis, MO, United States


Abstract
In this grand rounds, we focus on development, validation, and application of neuroimaging biomarkers for Parkinson disease (PD). We cover whether such biomarkers can be used to identify presymptomatic individuals (probably yes), provide a measure of PD severity (in a limited fashion, but frequently done poorly), investigate pathophysiology of parkinsonian disorders (yes, if done carefully), play a role in differential diagnosis of parkinsonism (not well), and investigate pathology underlying cognitive impairment (yes, in conjunction with postmortem data). Along the way, we clarify several issues about definitions of biomarkers and surrogate endpoints. The goal of this lecture is to provide a basis for interpreting current literature and newly proposed clinical tools in PD. In the end, one should be able to critically distinguish fact from fantasy.


Document Type: Article
Source: Scopus

Appu, M., Mar, S.
Novel familial pathogenic mutation in gap junction protein, beta-1 gene (GJB1) associated with transient neurological deficits in a patient with X-linked Charcot-Marie-Tooth disease
Muscle and Nerve, 50 (6), pp. 1023-1024. 


Division of Pediatric Neurology, Department of Neurology, Washington University in St. Louis, St. LouisMissouri, United States


Document Type: Letter
Source: Scopus

Pullicino, P.M.a , Qian, M.b , Sacco, R.L.c , Freudenberger, R.d , Graham, S.e , Teerlink, J.R.f , Mann, D.g , Di Tullio, M.R.b , Ponikowski, P.h , Lok, D.J.i , Anker, S.D.j , Lip, G.Y.H.k , Estol, C.l , Levin, B.b , Mohr, J.P.b , Thompson, J.L.P.b , Homma, S.b
Recurrent stroke in the warfarin versus aspirin in reduced cardiac ejection fraction (WARCEF) trial
(2014) Cerebrovascular Diseases, 38 (3), pp. 176-181. 


a KentHealth, University of Kent, Rutherford BuildingCanterbury, United Kingdom
b Columbia UniversityNew York, NY, United States
c Fla., University of MiamiMiami, United States
d LeHigh Valley HospitalAllentown, PA, United States
e SUNY BuffaloBuffalo, NY, United States
f University of California at San Fancisco, San Francisco VA Medical CenterSan Francisco, CA, United States
g Washington UniversitySt. Louis, MO, United States
h Medical UniversityWroclaw, Poland
i Hospital DeventerDeventer, Netherlands
j Campus-Virchow-Klinikum, Charité UniversitätsmedizinBerlin, Germany
k University of Birmingham Centre for Cardiovascular SciencesBirmingham, United Kingdom
l Centro Neurológico de Tratamiento Y RehabilitaciónBuenos Aires, Argentina


Abstract
Background and Purpose: WARCEF randomized 2,305 patients in sinus rhythm with ejection fraction (EF) ≤ 35% to warfarin (INR 2.0-3.5) or aspirin 325 mg. Warfarin reduced the incident ischemic stroke (IIS) hazard rate by 48% over aspirin in a secondary analysis. The IIS rate in heart failure (HF) is too low to warrant routine anticoagulation but epidemiologic studies show that prior stroke increases the stroke risk in HF. In this study, we explore IIS rates in WARCEF patients with and without baseline stroke to look for risk factors for IIS and determine if a subgroup with an IIS rate high enough to give a clinically relevant stroke risk reduction can be identified.

Methods: We compared potential stroke risk factors between patients with baseline stroke and those without using the exact conditional score test for Poisson variables. We looked for risk factors for IIS, by comparing IIS rates between different risk factors. For EF we tried cut-off points of 10, 15 and 20%. The cut-off point 15% was used as it was the highest EF that was associated with a significant increase in IIS rate. IIS and EF strata were balanced as to warfarin/ aspirin assignment by the stratified randomized design. A multiple Poisson regression examined the simultaneous effects of all risk factors on IIS rate. IIS rates per hundred patient years (/100PY) were calculated in patient groups with significant risk factors. Missing values were assigned the modal value.

Results: Twenty of 248 (8.1%) patients with baseline stroke and 64 of 2,048 (3.1%) without had IIS. IIS rate in patients with baseline stroke (2.37/100PY) was greater than patients without (0.89/100PY) (rate ratio 2.68, p < 0.001). Fourteen of 219 (6.4%) patients with ejection fraction EF) <15% and 70 of 2,079 (3.4%) with EF ≥ 15% had IIS. In the multiple regression analysis stroke at baseline (p < 0.001) and EF <15% vs. ≥ 15% (p = 0.005) remained significant predictors of IIS. IIS rate was 2.04/100PY in patients with EF <15% and 0.95/100PY in patients with EF ≥ 15% (p = 0.009). IIS rate in patients with baseline stroke and reduced EF was 5.88/100PY with EF <15% decreasing to 2.62/100PY with EF <30%.

Conclusions: In a WARCEF exploratory analysis, prior stroke and EF <15% were risk factors for IIS. Further research is needed to determine if a clinically relevant stroke risk reduction is obtainable with warfarin in HF patients with prior stroke and reduced EF.


Author Keywords
Ejection fraction;  Heart failure;  Stroke


Document Type: Article
Source: Scopus

Saloner, B.a , Matone, M.b , Kreider, A.R.b , Budeir, M.S.b , Miller, D.b , Huang, Y.-S.d , Raghavan, R.e , French, B.f , Rubin, D.b c
Second-generation antipsychotic use among stimulant-using children, by organization of medicaid mental health
(2014) Psychiatric Services, 65 (12), pp. 1458-1464. 


a Department of Health Care Policy, Johns Hopkins UniversityBaltimore, United States
b PolicyLab, Children's Hospital of PhiladelphiaPhiladelphia, United States
c Department of Pediatrics, Perelman School of Medicine, University of PennsylvaniaPhiladelphia, United States
d Division of General Pediatrics, Healthcare Analytics Unit, Children's Hospital of Philadelphia, United States
e George Warren Brown School of Social Work, Washington University in St. LouisSt. Louis, MO, United States
f Department of Biostatistics and Epidemiology, University of PennsylvaniaPhiladelphia, United States


Abstract
Objective: Reducing overuse of second-generation antipsychotics among Medicaid-enrolled children is a national priority, yet little is known about how service organization affects use. This study compared differences in second-generation antipsychotic utilization among Medicaid-enrolled children across fee-for-service, integrated managed care, and managed behavioral health carve-out organizational structures. Methods: Organizational structures of Medicaid programs in 82 diverse counties in 34 states were categorized and linked to child-level cross-sectional claims data from the Medicaid Analytic Extract covering fiscal years 2004, 2006, and 2008. To approximate the population at risk of antipsychotic treatment, the sample was restricted to stimulant-using children ages three to 18 (N=419,226). The sample was stratified by Medicaid eligibility group, and logistic regression models were estimated for probability of second-generation antipsychotic use. Models included indicators of county-level organizational structure as main predictors, with sequential adjustment for personal and county-level covariates. Results: With adjustment for person-level covariates, second-generation antipsychotic use was 31% higher among youths in foster care in fee-for-service counties than for youths in counties with carve-outs (odds ratio [OR]=1.69, 95%confidence interval [CI]=1.26-2.27). Foster care youths in integrated counties had the second highest adjusted odds (OR=1.31, CI=1.08-1.58). Similar patterns of use also were found for youths eligible for Supplemental Security Income but not for those eligible for Temporary Assistance for Needy Families. Differences persisted after adjustment for county-level characteristics. Conclusions: Carve-outs, versus other arrangements, were associated with lower second-generation antipsychotic use. Future research should explore carve-out features (for example, tighter management of inpatient or restricted access, as well as care coordination) contributing to lower second-generation antipsychotic use.


Document Type: Article
Source: Scopus

Pulvers, K.a , Hood, A.b
The role of positive traits and pain catastrophizing in pain perception
(2014) Current Pain and Headache Reports, 17 (5), 11 p. 


a Department of Psychology, California State University San Marcos, 333 S. Twin Oaks Valley RdSan Marcos, CA, United States
b Department of Psychology, Washington University in St. LouisSt. Louis, MT, United States


Abstract
A variety of biological, psychological, and social factors interact to influence pain. This article focuses on two distinct, but connected, psychological factors—positive personality traits and pain catastrophizing—and their link with pain perception in healthy and clinical populations. First, we review the protective link between positive personality traits, such as optimism, hope, and self-efficacy, and pain perception. Second, we provide evidence of the well-established relationship between pain catastrophizing and pain perception and other related outcomes. Third, we outline the inverse relationship between positive traits and pain catastrophizing, and offer a model that explains the inverse link between positive traits and pain perception through lower pain catastrophizing. Finally, we discuss clinical practice recommendations based on the aforementioned relationships.


Author Keywords
Hope;  Optimism;  Pain;  Pain catastrophizing;  Personality;  Positive psychology;  Self-efficacy

 
Document Type: Article
Source: Scopus

 

December 5, 2014

 

Chávez, J.C.a b , Ferreira, J.J.a , Butler, A.a , De La Vega Beltrán, J.L.b , Treviño, C.L.b , Darszon, A.b , Salkoff, L.a , Santi, C.M.a
SLO3 K+ channels control calcium entry through CATSPER channels in sperm
(2014) Journal of Biological Chemistry, 289 (46), pp. 32266-32275. 


a Department of Anatomy and Neurobiology, Washington University, School of Medicine, 660 S. Euclid Ave.St. Louis, MO, United States
b Instituto de Biotecnología, Universidad Nacional Autónoma de México (UNAM)Cuernavaca, Mexico


Abstract
Here we show how a sperm-specific potassium channel (SLO3) controls Ca2+ entry into sperm through a sperm-specific Ca2+ channel, CATSPER, in a totally unanticipated manner. The genetic deletion of either of those channels confers male infertility in mice. During sperm capacitation SLO3 hyperpolarizes the sperm, whereas CATSPER allows Ca2+ entry. These two channels may be functionally connected, but it had not been demonstrated that SLO3-dependent hyperpolarization is required for Ca2+ entry through CATSPER channels, nor has a functional mechanism linking the two channels been shown. In this study we show that Ca2+ entry through CATSPER channels is deficient in Slo3 mutant sperm lacking hyperpolarization; we also present evidence supporting the hypothesis that SLO3 channels activate CATSPER channels indirectly by promoting a rise in intracellular pH through a voltage-dependent mechanism. This mechanism may work through a Na+/H+ exchanger (sNHE) and/or a bicarbonate transporter, which utilizes the inward driving force of the Na+ gradient, rendering it intrinsically voltage-dependent. In addition, the spermspecific Na+/H+ exchanger (sNHE) possess a putative voltage sensor that might be activated by membrane hyperpolarization, thus increasing the voltage sensitivity of internal alkalization.


Document Type: Article
Source: Scopus

Izzo, N.J.a , Xu, J.b , Zeng, C.b , Kirk, M.J.e i , Mozzoni, K.a , Silky, C.a , Rehak, C.a , Yurko, R.a , Look, G.a , Rishton, G.a , Safferstein, H.a , Cruchaga, C.f , Goate, A.f , Cahill, M.A.j , Arancio, O.g , Mach, R.H.b , Craven, R.d , Head, E.d , LeVine, H., IIIc , Spires-Jones, T.L.e h , Catalano, S.M.a
Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity
(2014) PLoS ONE, 9 (11), art. no. e111899, . 


a Cognition Therapeutics Inc.Pittsburgh, PA, United States
b Mallinckrodt Institute of Radiology, Washington UniversitySt. Louis, MO, United States
c Sanders-Brown Center on Aging, University of KentuckyLexington, KY, United States
d Department of Molecular and Biological Pharmacology, University of KentuckyLexington, KY, United States
e Departmentof Neurology and Neuroscience, Massachusetts General Hospital And, Harvard Medical SchoolBoston, MA, United States
f Department of Psychiatry, Washington UniversitySt. Louis, MO, United States
g Dept. of Pathol. and Cell Biology and Taub Inst. for Res. on Alzheimer's Disease and the Aging Brain, Columbia University New YorkNY, United States
h University of Edinburgh, Center for Cognitive and Neural Systems and Euan MacDonald Centre for Motorneurone DiseaseEdinburgh, United Kingdom
i Department of Neurology, Northeastern UniversityBoston, MA, United States
j School of Biomedical Sciences, Charles Sturt UniversityWagga Wagga, NSW, Australia


Abstract
Amyloid beta (Abeta) 1-42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics.


Document Type: Article
Source: Scopus

Goyal, B.a , Duncavage, E.J.a b , Martinez, D.a , Lewis, J.S.a c , Chernock, R.D.a c
Next-generation sequencing of salivary high-grade neuroendocrine carcinomas identifies alterations in RB1 and the mTOR pathway
(2014) Experimental and Molecular Pathology, 97 (3), pp. 572-578. 


a Department of Pathology and Immunology, Division of Anatomic and Molecular Pathology, Washington University School of MedicineSaint Louis, MO, United States
b Genomics and Pathology Services, Washington University School of MedicineSaint Louis, MO, United States
c Department of Otolaryngology Head and Neck Surgery, Washington University School of MedicineSt. Louis, MO, United States


Abstract
Salivary gland high-grade neuroendocrine carcinomas are rare, aggressive tumors that are morphologically and immunohistochemically similar to cutaneous high-grade neuroendocrine (Merkel cell) carcinomas. The majority of Merkel cell carcinomas harbor Merkel cell polyomavirus, while the virus is rare or absent in salivary high-grade neuroendocrine carcinomas. Inactivation of retinoblastoma 1 (RB1) has been implicated in the pathogenesis of both virus-positive and -negative Merkel cell carcinomas but by different mechanisms. In virus-positive tumors, a portion of the viral genome, the large T antigen, may inactivate RB1, and in virus-negative Merkel cell carcinomas truncating mutations in the RB1 gene have been identified. The molecular genetics of salivary high-grade neuroendocrine carcinomas are not well understood. Here, we performed targeted next-generation sequencing of 151 cancer-related genes on 4 four Merkel cell polyomavirus-negative primary salivary gland high-grade neuroendocrine carcinoma cases. Somatic mutations were predominantly found within tumor suppressor genes [ TP53 (3 cases), PTEN (2 cases), RB1 (1 case)]. Truncating RB1 mutations, as seen in virus-negative Merkel cell carcinomas, were not identified. However, 3 of 4 cases had RB1 deletions by copy number variation analysis. The 4th case had loss of heterozygosity for RB1. Fluorescence in situ hybridization confirmed RB1 deletions in 2 of 3 cases, and the absence of RB1 deletion in the 4th case that had loss of heterozygosity. All 4 cases showed loss of RB1 protein expression by immunohistochemistry, indicating that RB1 inactivation is important. However, the mechanism of RB1 inactivation appears different than that seen in Merkel cell carcinomas. In addition, copy number variation consistent with activation of the PI3KCA/AKT/mTOR pathway was also observed in all 4 cases. The mTOR pathway may be a potential therapeutic target in these tumors as mTOR inhibitors are currently used to treat other tumor types.


Author Keywords
MTOR;  Neuroendocrine carcinoma;  Retinoblastoma 1 (RB1);  Salivary;  Targeted next generation sequencing


Document Type: Article
Source: Scopus

Gallardo, G., Barowski, J., Ravits, J., Siddique, T., Lingrel, J.B., Robertson, J., Steen, H., Bonni, A.
An α2-Na/K ATPase/α-adducin complex in astrocytes triggers non–cell autonomous neurodegeneration
(2014) Nature Neuroscience, . Article in Press. 


1] Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri, USA.


Abstract
Perturbations of astrocytes trigger neurodegeneration in several diseases, but the glial cell–intrinsic mechanisms that induce neurodegeneration remain poorly understood. We found that a protein complex of α2-Na/K ATPase and α-adducin was enriched in astrocytes expressing mutant superoxide dismutase 1 (SOD1), which causes familial amyotrophic lateral sclerosis (ALS). Knockdown of α2-Na/K ATPase or α-adducin in mutant SOD1 astrocytes protected motor neurons from degeneration, including in mutant SOD1 mice in vivo. Heterozygous disruption of the α2-Na/K ATPase gene suppressed degeneration in vivo and increased the lifespan of mutant SOD1 mice. The pharmacological agent digoxin, which inhibits Na/K ATPase activity, protected motor neurons from mutant SOD1 astrocyte–induced degeneration. Notably, α2-Na/K ATPase and α-adducin were upregulated in spinal cord of sporadic and familial ALS patients. Collectively, our findings define chronic activation of the α2-Na/K ATPase/α-adducin complex as a critical glial cell–intrinsic mechanism of non–cell autonomous neurodegeneration, with implications for potential therapies for neurodegenerative diseases.


Document Type: Article in Press
Source: Scopus

Olfson, E.a , Edenberg, H.J.b c , Nurnberger, J.c d , Agrawal, A.a , Bucholz, K.K.a , Almasy, L.A.e , Chorlian, D.f , Dick, D.M.g , Hesselbrock, V.M.h , Kramer, J.R.i , Kuperman, S.i , Porjesz, B.f , Schuckit, M.A.j , Tischfield, J.A.k , Wang, J..-C.a , Wetherill, L.c , Foroud, T.M.c , Rice, J.a , Goate, A.a , Bierut, L.J.a
An ADH1B variant and peer drinking in progression to adolescent drinking milestones: Evidence of a gene-by-environment interaction
Alcoholism: Clinical and Experimental Research, 38 (10), pp. 2541-2549. 


a Department of Psychiatry, Washington University School of MedicineSt. Louis, MO, United States
b Department of Biochemistry and Molecular Biology, Indiana University School of MedicineIndianapolis, IN, United States
c Department of Medical and Molecular Genetics, Indiana University School of MedicineIndianapolis, IN, United States
d Department of Psychiatry, The Institute of Psychiatric Research, Indiana University School of MedicineIndianapolis, IN, United States
e Department of Genetics, Texas Biomedical Research InstituteSan Antonio, TX, United States
f Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical CenterBrooklyn, NY, United States
g Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth UniversityRichmond, VA, United States
h Department of Psychiatry, University of Connecticut School of MedicineFarmington, CT, United States
i Department of Psychiatry, University of Iowa Carver College of MedicineIowa City, IA, United States
j Department of Psychiatry, San Diego Medical School, University of CaliforniaSan Diego, CA, United States
k Department of Genetics and the Human Genetics, Institute of New Jersey, Rutgers UniversityPiscataway, NJ, United States


Abstract
Background: Adolescent drinking is an important public health concern, one that is influenced by both genetic and environmental factors. The functional variant rs1229984 in alcohol dehydrogenase 1B (ADH1B) has been associated at a genome-wide level with alcohol use disorders in diverse adult populations. However, few data are available regarding whether this variant influences early drinking behaviors and whether social context moderates this effect. This study examines the interplay between rs1229984 and peer drinking in the development of adolescent drinking milestones. Methods: One thousand five hundred and fifty European and African American individuals who had a full drink of alcohol before age 18 were selected from a longitudinal study of youth as part of the Collaborative Study on the Genetics of Alcoholism (COGA). Cox proportional hazards regression, with G × E product terms in the final models, was used to study 2 primary outcomes during adolescence: age of first intoxication and age of first DSM-5 alcohol use disorder symptom. Results: The minor A allele of rs1229984 was associated with a protective effect for first intoxication (HR = 0.56, 95% CI 0.41 to 0.76) and first DSM-5 symptom (HR = 0.45, 95% CI 0.26 to 0.77) in the final models. Reporting that most or all best friends drink was associated with a hazardous effect for first intoxication (HR = 1.81, 95% CI 1.62 to 2.01) and first DSM-5 symptom (HR = 2.17, 95% 1.88 to 2.50) in the final models. Furthermore, there was a significant G × E interaction for first intoxication (p = 0.002) and first DSM-5 symptom (p = 0.01). Among individuals reporting none or few best friends drinking, the ADH1B variant had a protective effect for adolescent drinking milestones, but for those reporting most or all best friends drinking, this effect was greatly reduced. Conclusions: Our results suggest that the risk factor of best friends drinking attenuates the protective effect of a well-established ADH1B variant for 2 adolescent drinking behaviors. These findings illustrate the interplay between genetic and environmental factors in the development of drinking milestones during adolescence.


Author Keywords
Adolescent;  Alcohol Dehydrogenase;  Gene-Environment Interaction;  Peer Drinking


Document Type: Article
Source: Scopus

Tortelli, B.a , Fujiwara, H.a , Bagel, J.H.b , Zhang, J.a , Sidhu, R.a , Jiang, X.a , Yanjanin, N.M.c , Shankar, R.K.c , Carillo-Carasco, N.d , Heiss, J.d , Ottinger, E.e , Porter, F.D.c , Schaffer, J.E.a , Vite, C.H.b , Ory, D.S.a
Cholesterol homeostatic responses provide biomarkers for monitoring treatment for the neurodegenerative disease Niemann-Pick C1 (NPC1)
(2014) Human Molecular Genetics, 23 (22), pp. 6022-6033. 


a Diabetic Cardiovascular Disease Center and Department of Medicine, Washington University School of Medicine, 660 S. Euclid AvenueSt. Louis, MO, United States
b Department of Clinical Studies, Schoolof Veterinary Medicine, University of PennsylvaniaPhiladelphia, PA, United States
c Department of Health and Human Services, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesda, MD, United States
d Department of Health and Human Services, Surgical Neurology Branch, National Institute of Neurological Diseases and Stroke, National Institutes of HealthBethesda, MD, United States
e Therapeutics for Rare and Neglected Diseases (TRND) Program, National Center for Advancing Translational Sciences (NCATS)Bethesda, MD, United States


Abstract
Niemann-Pick C1 (NPC1) disease is a rare, neurodegenerative lysosomal cholesterol storage disorder, typified byprogressive cognitiveand motor function impairment.Affected individuals usuallysuccumbtothe disease in adolescence. 2-Hydroxypropyl-b-cyclodextrin (HP-β-CD) has emerged as a promising intervention that reduces lipid storage and prolongs survival inNPC1disease animal models.Abarrier to the development of HP-β-CD and other treatments forNPCdisease has been the lack of validated biochemical measures to evaluate efficacy. Here we explored whether cholesterol homeostatic responses resulting from HP-β-CD-mediated redistribution of sequestered lysosomal cholesterol could provide biomarkers to monitor treatment. Upon direct CNS delivery of HP-β-CD, we found increases in plasma 24(S)-HC in two independent NPC1 disease animal models, findings that were confirmed in humanNPC1 subjects receiving HP-β-CD. Since circulating 24(S)-HCis almost exclusively CNS-derived, the increase in plasma 24(S)-HC provides a peripheral, non-invasive measure of the CNS effect of HP-β-CD. Our findings suggest that plasma 24(S)-HC, along with the other cholesterol-derived markers examined in this study, can serve as biomarkers that will accelerate development of therapeutics for NPC1 disease.


Document Type: Article
Source: Scopus

Sovik, E.a b , Even, N.a , Radford, C.W.a , Barron, A.B.a
Cocaine affects foraging behaviour and biogenic amine modulated behavioural reflexes in honey bees
(2014) PeerJ, 2014 (1), art. no. e662, . 


a Department of Biological Sciences, Macquarie UniversitySydney, Australia
b Department of Biology, Washington University in St. LouisSt. Louis, United States


Abstract
In humans and other mammals, drugs of abuse alter the function of biogenic amine pathways in the brain leading to the subjective experience of reward and euphoria. Biogenic amine pathways are involved in reward processing across diverse animal phyla, however whether cocaine acts on these neurochemical pathways to cause similar rewarding behavioural effects in animal phyla other than mammals is unclear. Previously, it has been shown that bees are more likely to dance (a signal of perceived reward) when returning from a sucrose feeder after cocaine treatment. Here we examined more broadly whether cocaine altered reward-related behaviour, and biogenic amine modulated behavioural responses in bees. Bees developed a preference for locations at which they received cocaine, and when foraging at low quality sucrose feeders increase their foraging rate in response to cocaine treatment. Cocaine also increased reflexive proboscis extension to sucrose, and sting extension to electric shock. Both of these simple reflexes are modulated by biogenic amines. This shows that systemic cocaine treatment alters behavioural responses that are modulated by biogenic amines in insects. Since insect reward responses involve both octopamine and dopamine signalling, we conclude that cocaine treatment altered diverse reward-related aspects of behaviour in bees. We discuss the implications of these results for understanding the ecology of cocaine as a plant defence compound. Our findings further validate the honey bee as a model systemfor understanding the behavioural impacts of cocaine, and potentially other drugs of abuse.


Author Keywords
Addiction;  Cocaine;  Dopamine;  Drug reward;  Honey bee;  Invertebrate neuroscience;  Reward systems


Document Type: Article
Source: Scopus

Jin, S.C.a , Benitez, B.A.a , Karch, C.M.a b , Cooper, B.a , Skorupa, T.a , Carrell, D.a , Norton, J.B.a , Hsu, S.a , Harari, O.a , Cai, Y.a , Bertelsen, S.a , Goate, A.M.a b c d e , Cruchaga, C.a b
Coding variants in TREM2 increase risk for Alzheimer's disease
(2014) Human Molecular Genetics, 23 (21), pp. 5838-5846. 


a Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134St. Louis, MO, United States
b Hope Center Program on Protein Aggregation and Neurodegeneration, 660S. Euclid Ave. B8111St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, 660S. Euclid Ave. B8111St. Louis, MO, United States
d Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 4488 Forest Park Ave.St. Louis, MO, United States
e Department of Genetics, Washington University School ofMedicine, 660S. Euclid Ave.St. Louis, MO, United States


Abstract
The triggering receptor expressed on myeloid 2 (TREM2) is an immune phagocytic receptor expressed on brain microglia known to trigger phagocytosis and regulate the inflammatory response. Homozygous mutations in TREM2 cause Nasu-Hakola disease, a rare recessive form of dementia. A heterozygous TREM2 variant, p.R47H, was recently shown to increase Alzheimer"s disease (AD) risk. We hypothesized that if TREM2 is truly an AD risk gene, there would be additional rare variants in TREM2 that substantially affect AD risk. To test this hypothesis,weperformed pooled sequencing ofTREM2 coding regions in 2082ADcases and 1648 cognitively normal elderly controls of European American descent. We identified 16 non-synonymous variants, six of which were not identified in previous AD studies. Two variants, p.R47H [P 5 9.17 3 1024, odds ratio (OR) 5 2.63 (1.44-4.81)] and p.R62H [P 5 2.36 3 1024, OR 5 2.36 (1.47-3.80)] were significantly associated with disease risk in single-variant analyses. Gene-based tests demonstrate variants in TREM2 are genome-wide significantly associated with AD [PSKAT-O 5 5.37 3 1027; OR 5 2.55 (1.80-3.67)]. The association of TREM2 variants withAD is still highly significant after excluding p.R47H [PSKAT-O 5 7.72 3 1025;OR 5 2.47 (1.62-3.87)], indicating that additional TREM2 variants affect AD risk. Genotyping in available family members of probands suggested that p.R47H (P 5 4.65 3 1022) and p.R62H (P 5 6.87 3 1023) were more frequently seen in AD cases versus controls within these families. Gel electrophoresis analysis confirms that at least three TREM2 transcripts are expressed in human brains, including one encoding a soluble form of TREM2.


Document Type: Article
Source: Scopus

Melin, A.D.a b , Danosi, C.F.a c , McCracken, G.F.d , Dominy, N.J.a c
Dichromatic vision in a fruit bat with diurnal proclivities: the Samoan flying fox (Pteropus samoensis)
(2014) Journal of Comparative Physiology A: Neuroethology, Sensory, Neural, and Behavioral Physiology, 200 (12), pp. 1015-1022. 


a Department of Anthropology, Dartmouth CollegeHanover, NH, United States
b Department of Anthropology, Washington University in St. Louis, One Brookings DriveSt. Louis, MO, United States
c Department of Biological Sciences, Dartmouth CollegeHanover, NH, United States
d Department of Ecology and Evolutionary Biology, University of TennesseeKnoxville, TN, United States


Abstract
A nocturnal bottleneck during mammalian evolution left a majority of species with two cone opsins, or dichromatic color vision. Primate trichromatic vision arose from the duplication and divergence of an X-linked opsin gene, and is long attributed to tandem shifts from nocturnality to diurnality and from insectivory to frugivory. Opsin gene variation and at least one duplication event exist in the order Chiroptera, suggesting that trichromatic vision could evolve under favorable ecological conditions. The natural history of the Samoan flying fox (Pteropus samoensis) meets these conditions—it is a large bat that consumes nectar and fruit and demonstrates strong diurnal proclivities. It also possesses a visual system that is strikingly similar to that of primates. To explore the potential for opsin gene duplication and divergence in this species, we sequenced the opsin genes of 11 individuals (19 X-chromosomes) from three South Pacific islands. Our results indicate the uniform presence of two opsins with predicted peak sensitivities of ca. 360 and 553 nm. This result fails to support a causal link between diurnal frugivory and trichromatic vision, although it remains plausible that the diurnal activities of P. samoensis have insufficient antiquity to favor opsin gene renovation.


Author Keywords
Chiroptera;  Euarchontoglires;  Megachiroptera;  Primate evolution;  Pteropodidae


Document Type: Article
Source: Scopus

Krauss, M.J., Cavazos-Rehg, P.A., Plunk, A.D., Bierut, L.J., Grucza, R.A.
Effects of State Cigarette Excise Taxes and Smoke-Free Air Policies on State Per Capita Alcohol Consumption in the United States, 1980 to 2009
Alcoholism: Clinical and Experimental Research, 38 (10), pp. 2630-2638. 


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


Abstract
Background: Increasing state cigarette excise taxes and strengthening smoke-free air (SFA) laws are known to reduce smoking prevalence. Some studies suggest that such policies may also reduce alcohol use, but results for cigarette taxes have been mixed, and associations with smoke-free air policies have been limited to some demographic subgroups. To shed further light on the potential secondary effects of tobacco control policy, we examined whether increases in cigarette taxes and strengthening of SFA laws were associated with reductions of per capita alcohol consumption and whether any reductions were specific to certain beverage types. Methods: State per capita alcohol consumption from 1980 to 2009 was modeled as a function of state price per pack of cigarettes and SFA policy scores while controlling for secular trends and salient state covariates. Both policy measures also accounted for local policies. Total alcohol, beer, wine, and spirits consumption per capita were modeled separately. For each type of beverage, we used a nested models approach to determine whether the 2 policies together were associated with reduced consumption. Results: For total alcohol consumption, and for beer or spirits (but not wine), one or both tobacco policies were associated with reductions in consumption. A 1% increase in cigarette price per pack was associated with a 0.083% decrease in per capita total alcohol consumption (95% confidence interval [CI] 0.0002 to 0.166, p = 0.0495), and a 1-point increase in SFA policy score, measured on a 6-point scale, was associated with a 1.1% decrease in per capita total alcohol consumption (95% CI 0.4 to 1.7, p = 0.001; p < 0.001 for the hypothesis that the 2 policies are jointly associated with reduced alcohol consumption). Conclusions: The public health benefits of increasing cigarette taxes and smoke-free policies may go beyond the reduction of smoking and extend to alcohol consumption, specifically beer and spirits.


Author Keywords
Alcohol Consumption;  Alcohol Sales;  Cigarette Price;  Smoke-Free Air Policy


Document Type: Article
Source: Scopus

Lundin, J.I.a , Ton, T.G.N.b , Lacroix, A.Z.c , Longstreth, W.T.b d , Franklin, G.M.a b , Swanson, P.D.b , Smith-Weller, T.a , Racette, B.A.e , Checkoway, H.c
Formulations of hormone therapy and risk of Parkinson's disease
Movement Disorders, 29 (13), pp. 1631-1636. 


a Department of Environmental and Occupational Health Sciences, University of WashingtonSeattle, WA, United States
b Department of Neurology, University of WashingtonSeattle, WA, United States
c Department of Family and Preventive Medicine, University of California San DiegoLa Jolla, CA, United States
d Department of Epidemiology, University of WashingtonSeattle, WA, United States
e Department of Neurology, Washington UniversitySt. Louis, MO, United States


Abstract
Hormone therapy (HT) is a class of medications widely prescribed to women in the Western world. Evidence from animal models and in vitro studies suggests that estrogen may protect against nigrostriatal system injury and increase dopamine synthesis, metabolism, and transport. Existing epidemiologic research indicates a possible reduced risk of Parkinson's disease (PD) associated with HT use. The objective of this study was to evaluate PD risk associated with specific HT formulations. Neurologist-confirmed cases and age-matched controls were identified from Group Health Cooperative (GHC) of Washington State. Final analysis included 137 female cases and 227 controls. Hormone therapy use was ascertained from the GHC pharmacy database, further classified as conjugated estrogens, esterified estrogens, and progestin. Ever use of HT formulation demonstrated a suggested elevated risk with esterified estrogen use (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.0-9.8), and no risk associated with conjugated estrogen use (OR, 0.6; 95% CI, 0.6-1.3). Restricting this analysis to prescriptions that included progestin further elevated the risk associated with esterified estrogen use (OR, 6.9; 95% CI, 2.1-22.9); again, no risk was associated with conjugated estrogen use (OR, 1.7; 95% CI, 0.6-5.0). The findings from this study suggest an increase in PD risk associated with esterified estrogen use combined with progestin, and no risk associated with conjugated estrogen with progestin. These findings could have important implications for choice of HT in clinical practice.


Author Keywords
Epidemiology;  Estrogen therapy;  Hormone therapy;  Neurodegenerative disease;  Parkinson's disease


Document Type: Article
Source: Scopus

Luis, E.O.a b , Ortega-Cubero, S.b c , Lamet, I.c , Razquin, C.b , Cruchaga, C.d , Benitez, B.A.d , Lorenzo, E.b , Irigoyen, J.b c , Pastor, M.A.a c e , Pastor, P.b c e
Frontobasal gray matter loss is associated with the TREM2 p.R47H variant
(2014) Neurobiology of Aging, 35 (12), pp. 2681-2690. 


a Neuroimaging Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of NavarraPamplona, Spain
b Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of NavarraPamplona, Spain
c Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of MedicinePamplona, Spain
d Hope Center for Neurological Disorders, Department of Psychiatry, Washington University School of MedicineSt Louis, MO, United States
e Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos IIIMadrid, Spain


Abstract
A rare heterozygous TREM2 variant p.R47H (rs75932628) has been associated with an increased risk for Alzheimer's disease (AD). We aimed to investigate the clinical presentation, neuropsychological profile, and regional pattern of gray matter and white matter loss associated with the TREM2 variant p.R47H, and to establish which regions best differentiate p.R47H carriers from noncarriers in 2 sample sets (Spanish and Alzheimer's Disease Neuroimaging Initiative, ADNI1). This was a cross-sectional study including a total number of 16 TREM2 p.R47H carriers diagnosed with AD or mild cognitive impairment, 75 AD p.R47H noncarriers and 75 cognitively intact TREM2 p.R47H noncarriers. Spanish AD TREM2 p.R47H carriers showed apraxia (9 of 9) and psychiatric symptoms such as personality changes, anxiety, paranoia, or fears more frequently than in AD noncarriers (corrected p = 0.039). For gray matter and white matter volumetric brain magnetic resonance imaging voxelwise analyses, we used statistical parametric mapping (SPM8) based on the General Linear Model. We used 3 different design matrices with a full factorial design. Voxel-based morphometry analyses were performed separately in the 2 sample sets. The absence of interset statistical differences allowed us to perform joint and conjunction analyses. Independent voxel-based morphometry analysis of the Spanish set as well as conjunction and joint analyses revealed substantial gray matter loss in orbitofrontal cortex and anterior cingulate cortex with relative preservation of parietal lobes in AD and/or mild cognitive impairment TREM2 p.R47H carriers, suggesting that TREM2 p.R47H variant is associated with certain clinical and neuroimaging AD features in addition to the increased TREM2 p.R47H atrophy in temporal lobes as described previously. The high frequency of pathologic behavioral symptoms, combined with a preferential frontobasal gray matter cortical loss, suggests that frontobasal and temporal regions could be more susceptible to the deleterious biological effects of the TREM2 variant p.R47H.


Author Keywords
Alzheimer;  Genetics;  MRI;  Mutation;  Neuroimaging;  TREM2;  Variant;  Voxel-based morphometry


Document Type: Article
Source: Scopus

Padakanti, P.K.a , Zhang, X.a , Jin, H.a , Cui, J.a , Wang, R.a , Li, J.a , Flores, H.P.b , Parsons, S.M.c , Perlmutter, J.S.a b , Tu, Z.a
In Vitro and In Vivo Characterization of Two C-11-Labeled PET Tracers for Vesicular Acetylcholine Transporter
(2014) Molecular Imaging and Biology, 16 (6), pp. 773-780. Cited 1 time.


a Department of Radiology, Washington University School of Medicine, 510 South Kingshighway BlvdSt. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, 510 South Kingshighway BlvdSt. Louis, MO, United States
c Department of Chemistry and Biochemistry, University of CaliforniaSanta Barbara, CA, United States


Abstract
Purpose: The vesicular acetylcholine transporter (VAChT) is a specific biomarker for imaging presynaptic cholinergic neurons. Herein, two potent and selective 11C-labeled VAChT inhibitors were evaluated in rodents and nonhuman primates for imaging VAChT in vivo.

Procedures: For both (−)-[11C]2 and (−)-[11C]6, biodistribution, autoradiography, and metabolism studies were performed in male Sprague Dawley rats. Positron emission tomography (PET) brain studies with (−)-[11C]2 were performed in adult male cynomolgus macaques; 2 h dynamic data was acquired, and the regions of interest were drawn by co-registration of the PET images with the MRI.

Results: The resolved enantiomers (−)-2 and (−)-6 were very potent and selective for VAChT in vitro (Ki &lt; 5 nM for VAChT with &gt;35-fold selectivity for VAChT vs. σ receptors); both radioligands, (−)-[11C]2 and (−)-[11C]6, demonstrated high accumulation in the VAChT-enriched striatum of rats. (−)-[11C]2 had a higher striatum to cerebellum ratio of 2.4-fold at 60 min; at 30 min, striatal uptake reached 0.550 ± 0.086 %ID/g. Uptake was also specific and selective; following pretreatment with (±)-2, striatal uptake of (−)-[11C]2 in rats at 30 min decreased by 50 %, while pretreatment with a potent sigma ligand had no significant effect on striatal uptake in rats. In addition, (−)-[11C]2 displayed favorable in vivo stability in rat blood and brain. PET studies of (−)-[11C]2 in nonhuman primates indicate that it readily crosses the blood-brain barrier (BBB) and provides clear visualization of the striatum; striatal uptake reaches the maximum at 60 min, at which time the target to nontarget ratio reached ~2-fold.

Conclusions: The radioligand (−)-[11C]2 has high potential to be a suitable PET radioligand for imaging VAChT in the brain of living subjects.


Author Keywords
Alzheimer’s disease;  PET imaging;  Radiotracer;  VAChT;  Vesamicol


Document Type: Article
Source: Scopus

Marrus, N.a , Underwood-Riordan, H.b , Randall, F.a , Zhang, Y.a , Constantino, J.N.a
Lack of effect of risperidone on core autistic symptoms: Data from a longitudinal study
(2014) Journal of Child and Adolescent Psychopharmacology, 24 (9), pp. 513-518. 


a Division of Child and Adolescent Psychiatry, Department of Psychiatry, Washington UniversitySt. Louis, MO, United States
b Department of Educational Psychology, Research, and Evaluation, College of Education, University of MissouriSt. Louis, MO, United States


Abstract
Objective: The purpose of this study was to investigate the course of autistic symptoms, using a quantitative measure of core autistic traits, among risperidone-treated children who participated in a 10 year life course longitudinal study. Methods: Parents completed surveys of intervention history, as well as serial symptom severity measurements using the Social Responsiveness Scale (SRS), on their autism spectrum disorder (ASD)-affected children. Fifty participants (out of a total of 184 with full intervention histories) were reported to have been treated with risperidone during the course of the study. Serial SRS scores during risperidone treatment were available for a majority of children whose parents reported a positive effect from risperidone. Results: Two thirds of risperidone-treated children (n = 33) were reported by parents to have improved by taking the medication, with the principal effects described being that children were calmer, better focused, and less aggressive. SRS scores of children reported to have responded positively to risperidone did not improve over time. Conclusions: Risperidone's beneficial effect on aggression and other elements of adaptive functioning were not necessarily accompanied by reduction in core ASD symptoms, as serially assessed by the same caregivers who reported improvement in their children. These results reflect the distinction between reduction in core symptom burden and improvement in adaptive functioning. Given the cumulative risks of atypical neuroleptics, the findings underscore the importance of periodic reevaluation of medication benefit for children with ASD receiving neuroleptic treatment.


Document Type: Article
Source: Scopus

Wojahn, R.D., Foeger, N.C., Gelberman, R.H., Calfee, R.P.
Long-term outcomes following a single corticosteroid injection for trigger finger
(2014) Journal of Bone and Joint Surgery - American Volume, 96 (22), pp. 1849-1854. 


Department of Orthopaedic Surgery, Washington University Orthopedics, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8233Saint Louis, MO, United States


Abstract
Background: The outcomes of corticosteroid injection for trigger finger are well documented only with short-term followup. The purpose of this investigation was to determine the long-term effectiveness of a single injection and to examine predictors of success up to ten years after injection.

Methods: This case series analyzed 366 first-time corticosteroid injections in flexor tendon sheaths from January 2000 to December 2007 with a minimum follow-up duration of five years. Two hundred and forty patients (66%) were female, 161 patients (44%) had multiple trigger fingers, and eighty-eight patients (24%) had diabetes at the time of injection. The primary outcome of treatment failure was defined as subsequent injection or surgical trigger finger release of the affected digit. Medical records were reviewed, and any patients without documented failure or a return office visit in 2012 to 2013 were contacted by telephone regarding symptom recurrence and the need for additional treatment. Kaplan-Meier analyses with log-rank test and Cox regression analysis assessed the effect of baseline patient and disease characteristics on injection success.

Results: Forty-five percent of patients demonstrated long-term treatment success after a single injection. In the final regression model, the interaction of sex and the number of trigger fingers was the single predictor of treatment success. Exploring this association revealed a ten-year success rate of 56% for female patients presenting for the first time with a trigger finger compared with 35% inmale patients presenting for the first time with a trigger finger, 39% in female patients with multiple trigger fingers, and 37% in male patients with multiple trigger fingers. Eighty-four percent of treatment failures occurred within the first two years following injection. Patient age, symptom type, and undifferentiated diabetes status were not predictive of treatment success.

Conclusions: Female patients presenting with their first trigger finger have the highest rate of long-term treatment success after a single corticosteroid injection. Patients who continue to experience symptom relief two years after injection are likely to maintain long-term success.

Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Document Type: Article
Source: Scopus

Grucza, R.A.a , Plunk, A.D.a , Krauss, M.J.a , Cavazos-Rehg, P.A.a , Deak, J.a , Gebhardt, K.a , Chaloupka, F.J.b , Bierut, L.J.a
Probing the smoking-suicide association: Do smoking policy interventions affect suicide risk?
(2014) Nicotine and Tobacco Research, 16 (11), pp. 1487-1494. 


a Department of Psychiatry, Washington University School of MedicineSt. Louis, MO, United States
b Department of Economics and Health Policy Center, University of Illinois at ChicagoChicago, IL, United States


Abstract
Introduction: Smokers exhibit elevated risk for suicide, but it is unknown whether smoking interventions reduce suicide risk. We examined whether state-level policy interventions-increases in cigarette excise taxes and strengthening of smoke-free air laws-corresponded to a reduction in suicide risk during the 1990s and the early 2000s. We also examined whether the magnitude of such reductions correlated with individuals' predicted probability of smoking, which would be expected if the associations stemmed from changes in smoking behavior. Methods: We paired individual-level data on suicide deaths from the U.S. Multiple Cause of Death files, years 1990-2004, with living population data from the same period. These were linked with state data on cigarette excise taxes and smoke-free air policies. Utilizing a quasiexperimental analytical approach, we estimated the association between changes in policy and suicide risk. To examine whether associations correlated with individuals' probability of smoking, we used external survey data to derive a predicted probability of smoking function from demographic variables, which was then used to stratify the population by predicted smoking prevalence. Results: Cigarette excise taxes, smoke-free air policies, and an index combining the two policies all exhibited protective associations with suicide. The associations were strongest in segments of the population where predicted smoking prevalence was the highest and weaker in segments of the population where predicted smoking prevalence was the lowest, suggesting that the protective associations were related to changes in smoking behavior. Conclusion: These results provide support for the proposition that population interventions for smoking could reduce risk for suicide.


Document Type: Article
Source: Scopus

Topjian, A.A.a b , Stuart, A.a , Pabalan, A.A.a , Clair, A.a , Kilbaugh, T.J.a b , Abend, N.S.c d , Berg, R.A.a b , Heuer, G.G.e f , Storm, P.B., Jr.e f , Huh, J.W.a b , Friess, S.H.g
Risk Factors Associated with Infections and Need for Permanent Cerebrospinal Fluid Diversion in Pediatric Intensive Care Patients with Externalized Ventricular Drains
(2014) Neurocritical Care, 21 (2), pp. 294-299. 


a Department of Anesthesia and Critical Care Medicine, Children’s Hospital of PhiladelphiaPhiladelphia, PA, United States
b Department of Anesthesia and Critical Care Medicine, University of PennsylvaniaPhiladelphia, PA, United States
c Division of Neurology, Children’s Hospital of PhiladelphiaPhiladelphia, PA, United States
d Departments of Neurology and Pediatrics, University of PennsylvaniaPhiladelphia, PA, United States
e Division of Neurosurgery, Children’s Hospital of PhiladelphiaPhiladelphia, PA, United States
f Department of Neurosurgery, University of PennsylvaniaPhiladelphia, PA, United States
g Department of Pediatrics, Washington University School of Medicine in St. Louis, Campus Box 8028, 5th Floor MPRB, 660 S. Euclid AvenueSt. Louis, MO, United States


Abstract
Background: Externalized ventricular drains (EVDs) are commonly used in pediatric intensive care units (PICU) but few data are available regarding infection rates, infection risks, or factors associated with conversion to permanent cerebrospinal fluid (CSF) diversion.

Methods: Retrospective observational study of patients managed with EVDs admitted to a tertiary care PICU from January 2005 to December 2009.

Results: Three hundred eighty patients were identified. Neurologic diagnostic groups were externalization of existing shunt in 196 patients (52 %), brain tumor in 122 patients (32 %), intracranial hemorrhage in 23 patients (6 %), traumatic brain injury in 17 patients (5 %), meningitis in 9 patients (2 %), or other in 13 patients (3 %). Six percent of all patients (24/380) had new infections associated with EVD management for an infection rate of 8.6 per 1,000 catheter days. The median time to positive cultures was 7 days (interquartile range 4.75, 9) after EVD placement. Patients with EVD infections had significantly longer EVD duration 6 versus 11.5 days (p = 0.0001), and higher maximum EVD outputs 1.9 versus 1.5 mL/kg/h (p = 0.0017). Need for permanent CSF diversion was associated with higher maximum EVD drainage (1.3 vs. 1.6 mL/kg/h p < 0.0001), longer EVD duration (5 vs. 4 days, p < 0.005), and younger age (4.5 vs. 8 years, p < 0.02) but not intracranial hypertension (72 vs. 82 % of patients, p = 0.4).

Conclusions: In our large pediatric cohort, EVD infections were associated with longer EVD duration and higher maximum EVD output. Permanent CSF diversion was more likely in patients with higher maximum EVD drainage, longer EVD duration, and younger age.


Author Keywords
Externalized ventricular drain;  Neurocritical care;  Pediatric;  Pediatric intensive care unit;  Ventricular catheter infection;  Ventriculoperitoneal shunt


Document Type: Article
Source: Scopus

Padakanti, P.K.a , Zhang, X.a , Li, J.a , Parsons, S.M.b , Perlmutter, J.S.a c , Tu, Z.a
Syntheses and Radiosyntheses of Two Carbon-11 Labeled Potent and Selective Radioligands for Imaging Vesicular Acetylcholine Transporter
(2014) Molecular Imaging and Biology, 16 (6), pp. 765-772. Cited 1 time.


a Department of Radiology, Washington University School of Medicine, 510 South Kingshighway BlvdSt. Louis, MO, United States
b Department of Chemistry and Biochemistry, University of CaliforniaSanta Barbara, CA, United States
c Department of Neurology, Washington University School of Medicine, 510 South Kingshighway BlvdSt. Louis, MO, United States


Abstract
Purpose: The vesicular acetylcholine transporter (VAChT) is a specific biomarker for imaging presynaptic cholinergic neurons. The syntheses and C-11 labeling of two potent enantiopure VAChT inhibitors are reported here.

Procedures: Two VAChT inhibitors, (±)-2 and (±)-6, were successfully synthesized. A chiral HPLC column was used to resolve the enantiomers from each corresponding racemic mixture for in vitro characterization. The radiosyntheses of (−)-[11C]2 and (−)-[11C]6 from the corresponding desmethyl phenol precursor was accomplished using [11C]methyl iodide or [11C]methyl triflate, respectively.

Results: The synthesis of (−)-[11C]2 was accomplished with 40–50 % radiochemical yield (decay-corrected), SA &gt; 480 GBq/μmol (EOB), and radiochemical purity &gt;99 %. Synthesis of (−)-[11C]6 was accomplished with 5–10 % yield, SA &gt; 140 GBq/μmol (EOB), and radiochemical purity &gt;97 %. The radiosynthesis and dose formulation of each tracer was completed in 55–60 min.

Conclusions: Two potent enantiopure VAChT ligands were synthesized and 11C-labeled with good radiochemical yield and specific activity.


Author Keywords
Alzheimer’s disease;  PET imaging;  Radiotracer;  VAChT;  Vesamicol


Document Type: Article
Source: Scopus

Musiek, E.S.
Tau-chopping enzyme adds fuel to the neurodegeneration fire
(2014) Science Translational Medicine, 6 (262), . 


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


Document Type: Note
Source: Scopus

Ramsey, A.T., Montgomery, K.
Technology-Based Interventions in Social Work Practice: A Systematic Review of Mental Health Interventions
(2014) Social Work in Health Care, 53 (9), pp. 883-899. 


Center for Mental Health Services Research, Brown School of Social Work, Washington University in St. LouisSt. Louis, MO, United States


Abstract
Despite concerns around the use of technology-based interventions, they are increasingly being employed by social workers as a direct practice methodology to address the mental health needs of vulnerable clients. Researchers have highlighted the importance of using innovative technologies within social work practice, yet little has been done to summarize the evidence and collectively assess findings. In this systematic review, we describe accounts of technology-based mental health interventions delivered by social workers over the past 10 years. Results highlight the impacts of these tools and summarize advantages and disadvantages to utilizing technologies as a method for delivering or facilitating interventions.


Author Keywords
access to care;  interventions;  mental health;  social work practice;  technology


Document Type: Article
Source: Scopus

Gleason, M.E.J.a , Weinstein, Y.b , Balsis, S.c , Oltmanns, T.F.d
The enduring impact of maladaptive personality traits on relationship quality and health in later life
Journal of Personality, 82 (6), pp. 493-501. Cited 1 time.


a University of TexasAustin, United States
b University of Massachusetts-Lowell, United States
c Texas A and M University, United States
d Washington UniversitySt. Louis, United States


Abstract
Over the past 5 years, the St. Louis Personality and Aging Network (SPAN) has been collecting data on personality in later life with an emphasis on maladaptive personality, social integration, and health outcomes in a representative sample of 1,630 adults aged 55-64 living in the St. Louis area. This program has confirmed the importance of considering both the normal range of personality and in particular the role of maladaptive traits in order to understand individuals' relationships, life events, and health outcomes. In the current article, we discuss the explanatory benefits of considering maladaptive traits or traits associated with personality disorders when discussing the role of personality in social and health outcomes, with an emphasis on adults in middle to later life, and integrate these findings into the greater literature.


Document Type: Article
Source: Scopus

Cole, M.W.a b , Repovš, G.c , Anticevic, A.d
The frontoparietal control system: A central role in mental health
(2014) Neuroscientist, 20 (6), pp. 652-664. 


a Center for Molecular and Behavioral Neuroscience, Rutgers University, Aidekman Research Center, 197 University AvenueNewark, NJ, United States
b Psychology Department, Washington UniversitySt. Louis, MO, United States
c Department of Psychology, University of LjubljanaLjubljana, Slovenia
d Department of Psychiatry, Psychology, Abraham Ribicoff Research Facilities, Yale UniversityNew Haven, CT, United States


Abstract
Recent findings suggest the existence of a frontoparietal control system consisting of flexible hubs that regulate distributed systems (e.g., visual, limbic, motor) according to current task goals. A growing number of studies are reporting alterations of this control system across a striking range of mental diseases. We suggest this may reflect a critical role for the control system in promoting and maintaining mental health. Specifically, we propose that this system implements feedback control to regulate symptoms as they arise (e.g., excessive anxiety reduced via regulation of amygdala), such that an intact control system is protective against a variety of mental illnesses. Consistent with this possibility, recent results indicate that several major mental illnesses involve altered brain-wide connectivity of the control system, likely altering its ability to regulate symptoms. These results suggest that this "immune system of the mind" may be an especially important target for future basic and clinical research.


Author Keywords
brain networks;  cognitive control;  executive functions;  prefrontal cortex;  psychiatric disease


Document Type: Review
Source: Scopus

Roediger, H.L.
The science of successful learning
(2014) Educational Leadership, 72 (2), pp. 42-46. 


Washington UniversitySt. Louis, MO, United States


Document Type: Article
Source: Scopus

Plotkin, S.R.a , Albers, A.C.b , Babovic-Vuksanovic, D.c , Blakeley, J.O.d , Breakefield, X.O.e , Dunn, C.M.b , Evans, D.G.f , Fisher, M.J.g , Friedman, J.M.h , Giovannini, M.i , Gutmann, D.H.b , Kalamarides, M.j , Mcclatchey, A.I.k , Messiaen, L.l , Morrison, H.m , Parkinson, D.B.n , Stemmer-Rachamimov, A.O.k , Van Raamsdonk, C.D.h , Riccardi, V.M.o , Rosser, T.p , Schindeler, A.q , Smith, M.J.f , Stevenson, D.A.r , Ullrich, N.J.s , van der Vaart, T.t , Weiss, B.u , Widemann, B.C.v , Zhu, Y.w , Bakker, A.C.x , Lloyd, A.C.y
Update from the 2013 international neurofibromatosis conference
American Journal of Medical Genetics, Part A, 164 (12), pp. 2969-2978. 


a Department of Neurology and Cancer Center, Massachusetts General Hospital, Harvard Medical SchoolBoston, MA, United States
b Department of Neurology, Washington University School of MedicineSt. Louis, MO, United States
c Department of Medical Genetics, Mayo ClinicRochester, MN, United States
d Department of Neurology, Johns Hopkins UniversityBaltimore, MD, United States
e Neuroscience Center, Center for Molecular Imaging and Department of Neurology, Massachusetts General Hospital/Harvard Medical SchoolBoston, MA, United States
f Center for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre, University of ManchesterManchester, United Kingdom
g Division of Oncology, Children's Hospital of PhiladelphiaPhiladelphia, PA, United States
h Department of Medical Genetics, University of British ColumbiaVancouver, Canada
i Center for Neural Tumor Research, House Research InstituteLos Angeles, CA, United States
j Department of Neurosurgery, Hopital Pitié-SalpêtriéreParis, France
k Department of Pathology, Massachusetts General Hospital, Harvard Medical SchoolBoston, MA, United States
l Department of Genetics, University of Alabama at BirminghamBirmingham, AL, United States
m Leibniz Institute for Age ResearchJena, Germany
n Centre for Biomedical Research, University of Plymouth, Peninsula College of Medicine and DentistryPlymouth, United Kingdom
o The Neurofibromatosis InstituteLa Crescenta, CA, United States
p Department of Neurology, Children's Hospital, Los Angeles, University of Southern CaliforniaLos Angeles, CA, United States
q Kids' Research Institute, The Children's Hospital at Westmead, University of SydneyWestmead, Australia
r Division of Medical Genetics, Department of Pediatrics, University of UtahSalt Lake City, UT, United States
s Departments of Neurology and Pediatric Oncology, Boston Children's Hospital, Harvard Medical SchoolBoston, MA, United States
t ENCORE - NF1 CenterErasmus MC, Rotterdam, Netherlands
u Division of Hematology/Oncology, Cincinnati Children's Hospital Medical CenterCincinnati, OH, United States
v Pediatric Oncology Branch, National Cancer InstituteBethesda, MD, United States
w Gilbert Neurofibromatosis Institute, Children's National Medical CenterWashington, DC, United States
x Children's Tumor FoundationNew York, NY, United States
y MRC Laboratory for Molecular Cell Biology, University College LondonLondon, United Kingdom


Author Keywords
Merlin;  Neurofibromatosis 1;  Neurofibromatosis 2;  Neurofibromin;  NF1;  NF2;  Preclinical models;  Schwannomatosis;  SMARCB1;  Tumor suppressor


Document Type: Article
Source: Scopus

Dasanayake, I.S.a , Li, J.-S.b
Constrained charge-balanced minimum-power controls for spiking neuron oscillators
(2014) Systems and Control Letters, . Article in Press. 


a Department of Chemical Engineering, University of California Santa Barbara, Santa Barbara, CA 93106, USA
b Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA


Abstract
In this paper, we study the optimal control of phase models for spiking neuron oscillators. We focus on the design of minimum-power current stimuli that elicit spikes of neurons at specified times, subject to the charge-balance constraint. Such charge-balanced controls, in practice, are used to suppress undesirable side effects occurred due to the accumulation of electric charge resulting from the applied external stimuli. We derive charge-balanced minimum-power controls for a general phase model using the maximum principle, where the cases with unbounded and bounded control amplitude are examined. The latter is of fundamental importance because phase models are valid under weak forcing. The developed optimal control strategies are applied to both mathematically ideal and experimentally observed phase models to demonstrate their applicability, including the widely studied Hodgkin-Huxley model.


Author Keywords
Maximum principle;  Optimal control;  Phase models;  Phase response curve (PRC);  Spiking neurons


Document Type: Article in Press
Source: Scopus

Ducharme, S.a , Albaugh, M.D.b , Hudziak, J.J.b , Botteron, K.N.c , Nguyen, T.-V.a , Truong, C.a , Evans, A.C.a , Karama, S.a d
Anxious/depressed symptoms are linked to right ventromedial prefrontal cortical thickness maturation in healthy children and young adults
(2013) Cerebral Cortex, 24 (11), pp. 2941-2950. Cited 3 times.


a McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill UniversityMontreal, QC, Canada
b Vermont Center for Children, Youth, and Families, University of VermontBurlington, VT, United States
c Mallinckrodt Institute of Radiology, Washington University, School of MedicineSt. Louis, MO, United States
d Department of Psychiatry, Douglas Mental Health University Institute, McGill UniversityMontreal, QC, Canada


Abstract
The relationship between anxious/depressed traits and neuromaturation remains largely unstudied. Characterizing this relationship during healthy neurodevelopment is critical to understanding processes associated with the emergence of child/adolescent onset mood/anxiety disorders. In this study, mixed-effects models were used to determine longitudinal cortical thickness correlates of Child Behavior Checklist (CBCL) and Young Adult Self Report Anxious/Depressed scores in healthy children. Analyses included 341 subjects from 4.9 to 22.3 year-old with repeated MRI at up to 3 time points, at 2-year intervals (586 MRI scans). There was a significant "CBCL Anxious/Depressed by Age" interaction on cortical thickness in the right ventromedial prefrontal cortex (vmPFC), including the medial orbito-frontal, gyrus rectus, and subgenual anterior cingulate areas. Anxious/Depressed scores were negatively associated with thickness at younger ages (<9 years), but positively associated with thickness at older ages (15-22 years), with the shift in polarity occurring around age 12. This was secondary to a slower rate of vmPFC cortical thinning in subjects with higher scores. In young adults (18-22 years), Anxious/Depressed scores were also positively associated with precuneus/posterior cingulate cortical thickness. Potential neurobiological mechanisms underlying this maturation pattern are proposed. These results demonstrate the dynamic impact of age on relations between vmPFC and negative affect in the developing brain.


Author Keywords
anxiety;  brain development;  Child Behavior Checklist;  depression;  magnetic resonance imaging


Document Type: Article
Source: Scopus