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Office of Neuroscience Research > Resources and Facilities > WUSTL Neuroscience Publications for the week > Weekly Neuroscience Publications - Archives > WUSTL Neuroscience Publications Archive - August 2014

WUSTL Neuroscience Publications Archive - August 2014

August 2014

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August 26

August 15

August 26, 2014

Patterson, E.S., Waller, L.E., Kroll, K.L.
Geminin loss causes neural tube defects through disrupted progenitor specification and neuronal differentiation
(2014) Developmental Biology, 393 (1), pp. 44-56. 

Department of Developmental Biology, Washington University School of Medicine, 320 McDonnell Sciences Bldg., 8103, 660 S. Euclid Ave., St. Louis, MO 63110, United States

Geminin is a nucleoprotein that can directly bind chromatin regulatory complexes to modulate gene expression during development. Geminin knockout mouse embryos are preimplantation lethal by the 32-cell stage, precluding in vivo study of Geminin's role in neural development. Therefore, here we used a conditional Geminin allele in combination with several Cre-driver lines to define an essential role for Geminin during mammalian neural tube (NT) formation and patterning. Geminin was required in the NT within a critical developmental time window (embryonic day 8.5-10.5), when NT patterning and closure occurs. Geminin excision at these stages resulted in strongly diminished expression of genes that mark and promote dorsal NT identities and decreased differentiation of ventral motor neurons, resulting in completely penetrant NT defects, while excision after embryonic day 10.5 did not result in NT defects. When Geminin was deleted specifically in the spinal NT, both NT defects and axial skeleton defects were observed, but neither defect occurred when Geminin was excised in paraxial mesenchyme, indicating a tissue autonomous requirement for Geminin in developing neuroectoderm. Despite a potential role for Geminin in cell cycle control, we found no evidence of proliferation defects or altered apoptosis. Comparisons of gene expression in the NT of Geminin mutant versus wild-type siblings at embryonic day 10.5 revealed decreased expression of key regulators of neurogenesis, including neurogenic bHLH transcription factors and dorsal interneuron progenitor markers. Together, these data demonstrate a requirement for Geminin for NT patterning and neuronal differentiation during mammalian neurulation in vivo. © 2014 Elsevier Inc.

Author Keywords
Chromatin;  Neural tube defect;  Neuroepithelium;  Neurogenesis

Document Type: Article
Source: Scopus

Kalayjian, R.C.a d , Wu, K.b , Evans, S.b , Clifford, D.B.c , Pallaki, M.d , Currier, J.S.e , Smryzynski, M.b f
Proteinuria is associated with neurocognitive impairment in antiretroviral therapy treated HIV-infected individuals
(2014) Journal of Acquired Immune Deficiency Syndromes, 67 (1), pp. 30-35. 

a Department of Medicine, MetroHealth Medical Center, Cleveland, OH, United States
b Geriatric Research Education and Clinical Centers, Louis Stokes Cleveland Veterans Administration, Cleveland, OH, United States
c Statistical and Data Analysis Center, Harvard School of Public Health, Boston, MA, United States
d Department of Neurology and Neurological Surgery, Washington University of St. Louis, St. Louis, MO, United States
e UCLA CARE Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States
f Department of Epidemiology, Milken Institute School of Public Health, George Washington University, Washington, DC, United States

Background: Proteinuria is a marker of vascular dysfunction that predicted increased cardiovascular mortality and is associated with neurocognitive impairment (NCI) in population-based studies. We examined associations between proteinuria and HIV-Associated NCI. Methods: Multivariable logistic regression was used to examine associations between NCI at the first neurocognitive assessment (baseline) and simultaneous, clinically significant proteinuria [as random spot urine protein-to-creatinine ratios (UP/Cr) 200 mg/g] in a prospective multicenter observational cohort study. Generalized estimating equations were used to examine associations between baseline proteinuria and subsequent NCI among subjects without NCI at baseline. NCI was defined as a Z-score, derived from the combination of normalized scores from the Trailmaking A and B and the Wechsler Adult Intelligence Scale-Revised Digit Symbol tests. Results: A total of 1972 subjects were included in this analysis. Baseline proteinuria was associated with increased odds of NCI [odds ratio (OR): 1.41, 95% confidence interval (CI): 1.08 to 1.85; P = 0.01] and with subsequent NCI among subjects without NCI at baseline (OR: 1.39, 95% CI: 1.01 to 1.93; P = 0.046) in multivariable models adjusted for risk factors and potential confounders. Similar associations were evident when these analyses were limited to visits at which time study subjects maintained plasma HIV RNA levels <200 copies per milliliter. Conclusions: The association between proteinuria and NCI observed in this study adds to a growing body of evidence implicating contributions by vascular disease to NCI in antiretroviral treated individuals. Studies examining interventions that improve vascular function are warranted. © 2014 by Lippincott Williams & Wilkins.

Author Keywords
HIV-Associated neurocognitive disorders;  neurocognitive impairment;  proteinuria;  vascular disease

Document Type: Conference Paper
Source: Scopus

Heath, A.C.a , Waldron, M.C.b , Martin, N.G.c , Nelson, E.C.a , Bucholz, K.K.a , Madden, P.A.F.a
Human Mate Selection and Addiction: a Conceptual Critique
(2014) Behavior Genetics, . Article in Press. 

a Department of Psychiatry 8134, Washington University School of Medicine, Midwest Alcoholism Research Center, 4560 Clayton Avenue, Suite 1000, St Louis, MO 63110, United States
b School of Education, Indiana University at Bloomington, Bloomington, IN, United States
c Queensland Institute of Medical Research, Brisbane, QLD, Australia

The authors review past work on modeling human mate selection, and suggest, using illustrations from existing literature on the impact of alcoholism on relationship formation and dissolution and reproduction, that the challenges of adequately characterizing human mate selection have not yet been overcome. Some paths forwards are suggested. © 2014 Springer Science+Business Media New York.

Author Keywords
Mate selection;  parental separation;  Reproductive timing

Document Type: Article in Press
Source: Scopus

Le Roux, P.a , Menon, D.K.b , Citerio, G.c , Vespa, P.d , Bader, M.K.e , Brophy, G.M.f , Diringer, M.N.g , Stocchetti, N.h , Videtta, W.i , Armonda, R.j , Badjatia, N.k , Böesel, J.l , Chesnut, R.m , Chou, S.n , Claassen, J.o , Czosnyka, M.p , De Georgia, M.q , Figaji, A.r , Fugate, J.s , Helbok, R.t , Horowitz, D.u , Hutchinson, P.v , Kumar, M.w , McNett, M.x , Miller, C.y , Naidech, A.z , Oddo, M.aa , Olson, D.ab , O'Phelan, , Provencio, , Puppo, , Riker, , Robertson, , Schmidt, M.ah , Taccone,
Consensus summary statement of the International Multidisciplinary Consensus Conference on Multimodality Monitoring in Neurocritical Care
(2014) Intensive Care Medicine, . Article in Press. 

a Brain and Spine Center, Suite 370, Medical Science Building, Lankenau Medical Center, 100 East Lancaster Avenue, Wynnewood, PA 19096, United States
b Neurosciences Critical Care Unit, Division of Anaesthesia, University of Cambridge Consultant, Addenbrooke's HospitalBox 93, Cambridge, CB2 2QQ, United Kingdom
c NeuroIntensive Care Unit, Department of Anesthesia and Critical Care, Ospedale San Gerardo, Via Pergolesi 33, Monza, 20900, Italy
d David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States
e Neuro/Critical Care CNS, Mission Hospital, Mission Viejo, CA 92691, United States
f Virginia Commonwealth University, Medical College of Virginia Campus, 410N. 12th Street, Richmond, VA 23298-0533, United States
g Neurocritical Care Section, Department of Neurology, Washington University, Campus Box 8111, 660 S Euclid Ave, St Louis, MO 63110, United States
h Department of Physiopathology and Transplant, Milan University, Neuro ICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via F Sforza, 35, Milan, 20122, Italy
i ICU Neurocritical Care, Hospital Nacional 'Prof. a. Posadas', El Palomar, Pcia de Buenos Aires, Argentina
j Department of Neurosurgery, MedStar Georgetown University Hospital, Medstar Health, 3800 Reservoir Road NW, Washington, DC 20007, United States
k Department of Neurology, University of Maryland Medical Center, 22 S Greene St, Baltimore, MD 21201, United States
l Department of Neurology, Ruprecht-Karls University, Hospital Heidelberg, Im Neuenheimer Feld 400, Heidelberg, 69120, Germany
m Harborview Medical Center, University of Washington, Mailstop 359766, 325 Ninth Ave, Seattle, WA 98104-2499, United States
n Department of Neurology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, United States
o Neurological Intensive Care Unit, Columbia University College of Physicians and Surgeons, 177 Fort Washington Avenue, Milstein 8 Center room 300, New York, NY 10032, United States
p Department of Neurosurgery, University of Cambridge, Addenbrooke's Hospital, Box 167, Cambridge, CB2 0QQ, United Kingdom
q Neurocritical Care Center, Cerebrovascular Center, University Hospital Case Medical Center, Case Western Reserve University School of Medicine, 11100 Euclid Avenue, Cleveland, OH 44106, United States
r University of Cape Town, 617 Institute for Child Health, Red Cross Children's Hospital, Rondebosch, Cape Town, 7700, South Africa
s Mayo Clinic, Rochester, MN 55905, United States
t Neurocritical Care Unit, Department of Neurology, Innsbruck Medical University, Anichstr.35, Innsbruck, 6020, Austria
u University of Pennsylvania Health System, 3701 Market Street, Philadelphia, PA 19104, United States
v Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's HospitalBox 167, Cambridge, CB2 2QQ, United Kingdom
w Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 3 West Gates, 3400 Spruce Street, Philadelphia, PA 19104, United States
x Nursing Research, The MetroHealth System, 2500 MetroHealth Drive, Cleveland, OH 44109, United States
y Division of Cerebrovascular Diseases and Neurocritical Care, The Ohio State University, 395W. 12th Ave, 7th Floor, Columbus, OH 43210, United States
z Department of Neurology, Northwestern University Feinberg, SOM 710, N Lake Shore Drive, 11th floor, Chicago, IL 60611, United States
aa Department of Intensive Care Medicine, Faculty of Biology and Medicine University of Lausanne, CHUV University Hospital, BH 08-623, Lausanne, 1011, Switzerland
ab Neurology, Neurotherapeutics and Neurosurgery, University of Texas Southwestern, 5323 Harry Hines Blvd, Dallas, TX 75390-8897, United States
ac Department of Neurology, University of Miami, Miller School of Medicine, JMH, 1611 NW 12th Ave, Suite 405, Miami, FL 33136, United States
ad Cerebrovascular Center and Neuroinflammation Research Center, Lerner College of Medicine, Cleveland Clinic, 9500 Euclid Ave, NC30, Cleveland, OH 44195, United States
ae Intensive Care Unit, Hospital de Clinicas, Universidad de la República, Montevideo, Uruguay
af Critical Care Medicine, Maine Medical Center, 22 Bramhall Street, Portland, Maine, 04102-3175, United States
ag Department of Neurosurgery, Center for Neurosurgical Intensive Care, Ben Taub Hospital, Baylor College of Medicine, 1504 Taub Loop, Houston, TX 77030, United States
ah Columbia University College of Physicians and Surgeons, Milstein Hospital 8 Garden South, Suite 331, 177 Fort Washington Avenue, New York, NY, 10032, USA
ai Laboratoire de Recherche Experimentale, Department of Intensive Care, Erasme Hospital, Route de Lennik, 808, Brussels, 1070, Belgium

Neurocritical care depends, in part, on careful patient monitoring but as yet there are little data on what processes are the most important to monitor, how these should be monitored, and whether monitoring these processes is cost-effective and impacts outcome. At the same time, bioinformatics is a rapidly emerging field in critical care but as yet there is little agreement or standardization on what information is important and how it should be displayed and analyzed. The Neurocritical Care Society in collaboration with the European Society of Intensive Care Medicine, the Society for Critical Care Medicine, and the Latin America Brain Injury Consortium organized an international, multidisciplinary consensus conference to begin to address these needs. International experts from neurosurgery, neurocritical care, neurology, critical care, neuroanesthesiology, nursing, pharmacy, and informatics were recruited on the basis of their research, publication record, and expertise. They undertook a systematic literature review to develop recommendations about specific topics on physiologic processes important to the care of patients with disorders that require neurocritical care. This review does not make recommendations about treatment, imaging, and intraoperative monitoring. A multidisciplinary jury, selected for their expertise in clinical investigation and development of practice guidelines, guided this process. The GRADE system was used to develop recommendations based on literature review, discussion, integrating the literature with the participants' collective experience, and critical review by an impartial jury. Emphasis was placed on the principle that recommendations should be based on both data quality and on trade-offs and translation into clinical practice. Strong consideration was given to providing pragmatic guidance and recommendations for bedside neuromonitoring, even in the absence of high quality data. © 2014 Springer-Verlag Berlin Heidelberg and ESICM.

Author Keywords
Bioinformatics;  Biomarkers;  Brain metabolism;  Brain oxygen;  Brain physiology;  Clinical guidelines;  Clinical trials;  Consensus development conference;  Grading of Recommendations Assessment Development and Evaluation (GRADE);  Intracranial pressure;  Microdialysis;  Multimodal monitoring;  Neurocritical care;  Neuromonitoring;  Traumatic brain injury

Document Type: Article in Press
Source: Scopus

Siemers, E.a , Dean, R.A.a , DeMattos, R.B.a , Hutton, M.L.b , Blennow, K.c , Shaw, L.M.d , Holtzman, D.M.e
Anti-Aβ antibody target engagement: commentary regarding Watt et al. Acta Neuropathol 127:803-810 (2014)
(2014) Acta Neuropathologica, . Article in Press. 

a Eli Lilly and Company, Indianapolis, IN, United States
b Eli Lilly and Company, Erl Wood, Surrey, United Kingdom
c Clinical Neurochemistry Lab. Dept. of Neuroscience and Physiology, University of Gothenburg, Mölndal Campus, Gothenburg, Sweden
d Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
e Department of Neurology, Washington University, St. Louis, MO, United States

Document Type: Article in Press
Source: Scopus

Wahlheim, C.N.
Testing can counteract proactive interference by integrating competing information
(2014) Memory & Cognition, . Article in Press. 

Department of Psychology, Washington University, One Brookings Drive, St. Louis, MO 63130, United States

Testing initially learned information before presenting new information has been shown to counteract the deleterious effects of proactive interference by segregating competing sources of information. The present experiments were conducted to demonstrate that testing can also have its effects in part by integrating competing information. Variations of classic A-B, A-D paired-associate learning paradigms were employed that included two lists of word pairs and a cued-recall test. Repeated pairs appeared in both lists (A-B, A-B), control pairs appeared in List 2 only (A-B, C-D), and changed pairs appeared with the same cue in both lists but with different responses (A-B, A-D). The critical manipulation was whether pairs were tested or restudied in an interpolated phase that occurred between Lists 1 and 2. On a final cued-recall test, participants recalled List 2 responses and then indicated when they recollected that responses had earlier changed between lists. The change recollection measure indexed the extent to which competing responses were integrated during List 2. Change was recollected more often for tested than for restudied pairs. Proactive facilitation was obtained in cued recall when change was recollected, whereas proactive interference was obtained when change was not recollected. These results provide evidence that testing counteracted proactive interference in part by making List 1 responses more accessible during List 2, thus promoting integration and increasing later recollection of change. These results have theoretical implications because they show that testing can counteract proactive interference by integrating or segregating competing information. © 2014 Psychonomic Society, Inc.

Author Keywords
Change recollection;  Integration;  Proactive interference;  Reminding;  Testing effects

Document Type: Article in Press
Source: Scopus

Kašcáková, S.a , Hofland, L.J.b , De Bruijn, H.S.c , Ye, Y.d , Achilefu, S.d , Van Der Wansem, K.b , Van Der Ploeg-van Den Heuvel, A.a , Van Koetsveld, P.M.b , Brugts, M.P.e , Van Der Lelij, A.-J.b , Sterenborg, H.J.C.M.a , Ten Hagen, T.L.M.f , Robinson, D.J.c , Van Hagen, M.P.b e
Somatostatin analogues for receptor targeted photodynamic therapy
(2014) PLoS ONE, 9 (8), art. no. e104448, . 

a Center for Optical Diagnostics and Therapy, Department of Radiation Oncology, Erasmus MC, Rotterdam, Netherlands
b Department of Internal Medicine, Erasmus MC, Rotterdam, Netherlands
c Department of Otolaryngology and Head and Neck Surgery, Erasmus MC, Rotterdam, Netherlands
d Department of Radiology, School of Medicine, Washington University, St. Louis, MO, United States
e Department of Immunology, Erasmus Medical Center, Rotterdam, Netherlands
f Department of Surgical Oncology, Erasmus Medical Center, Rotterdam, Netherlands

Photodynamic therapy (PDT) is an established treatment modality, used mainly for anticancer therapy that relies on the interaction of photosensitizer, light and oxygen. For the treatment of pathologies in certain anatomical sites, improved targeting of the photosensitizer is necessary to prevent damage to healthy tissue. We report on a novel dual approach of targeted PDT (vascular and cellular targeting) utilizing the expression of neuropeptide somatostatin receptor (sst2) on tumor and neovascular-endothelial cells. We synthesized two conjugates containing the somatostatin analogue [Tyr3]-octreotate and Chlorin e6 (Ce6): Ce6-K3-[Tyr3]-octreotate (1) and Ce6-[Tyr3]-octreotate-K3-[Tyr3]-octreotate (2). Investigation of the uptake and photodynamic activity of conjugates in-vitro in human erythroleukemic K562 cells showed that conjugation of [Tyr3]-octreotate with Ce6 in conjugate 1 enhances uptake (by a factor 2) in cells over-expressing sst2 compared to wild-type cells. Co-treatment with excess free Octreotide abrogated the phototoxicity of conjugate 1 indicative of a specific sst2-mediated effect. In contrast conjugate 2 showed no receptor-mediated effect due to its high hydrophobicity. When compared with un-conjugated Ce6, the PDT activity of conjugate 1 was lower. However, it showed higher photostability which may compensate for its lower phototoxicity. Intra-vital fluorescence pharmacokinetic studies of conjugate 1 in rat skin-fold observation chambers transplanted with sst2 + AR42J acinar pancreas tumors showed significantly different uptake profiles compared to free Ce6. Co-treatment with free Octreotide significantly reduced conjugate uptake in tumor tissue (by a factor 4) as well as in the chamber neo-vasculature. These results show that conjugate 1 might have potential as an in-vivo sst 2 targeting photosensitizer conjugate.

Document Type: Article
Source: Scopus

Hulbert, M.L., Ford, A.L.
Understanding sickle cell brain drain
(2014) Blood, 124 (6), pp. 830-831. 

Washington University School of Medicine, United States

In this issue of Blood, Helton et al highlight the neuroradiological findings of children enrolled in the Strokes With Transfusions Changing to Hydroxyurea (SWiTCH) trial.1 This study, which screened 161 children with sickle cell anemia (SCA) receiving chronic transfusion therapy for prevention of recurrent strokes, is the largest SCA cohort followed prospectively with magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) published to date, giving additional insights into the relationships between strokes and cerebral vasculopathy in SCA. © 2014 by The American Society of Hematology.

Document Type: Article
Source: Scopus

Gutmann, D.H.
Eliminating barriers to personalized medicine: Learning from neurofibromatosis type 1
(2014) Neurology, 83 (5), pp. 463-471. 

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

With the emergence of high-throughput discovery platforms, robust preclinical small-animal models, and efficient clinical trial pipelines, it is becoming possible to envision a time when the treatment of human neurologic diseases will become personalized. The emergence of precision medicine will require the identification of subgroups of patients most likely to respond to specific biologically based therapies. This stratification only becomes possible when the determinants that contribute to disease heterogeneity become more fully elucidated. This review discusses the defining factors that underlie disease heterogeneity relevant to the potential for individualized brain tumor (optic pathway glioma) treatments arising in the common single-gene cancer predisposition syndrome, neurofibromatosis type 1 (NF1). In this regard, NF1 is posited as a model genetic condition to establish a workable paradigm for actualizing precision therapeutics for other neurologic disorders. © 2014 American Academy of Neurology.

Document Type: Article
Source: Scopus

Monsell, S.E.a , Mock, C.a , Hassenstab, J.b , Roe, C.M.b , Cairns, N.J.b , Morris, J.C.b , Kukull, W.a
Neuropsychological changes in asymptomatic persons with Alzheimer disease neuropathology
(2014) Neurology, 83 (5), pp. 434-440. 

a National Alzheimer's Coordinating Center, University of Washington, Seattle, United States
b Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Objective: To determine whether asymptomatic persons with Alzheimer disease (AD) neuropathologic change differ in the trajectory of their cognitive performance compared to asymptomatic persons without AD neuropathologic change. Methods: Longitudinal performance on standard neuropsychological tests was examined in participants who died within 2 years of their last cognitive assessment and who were never diagnosed with mild cognitive impairment or dementia (Clinical Dementia Rating global score of 0 at all assessments). Using cognitive and neuropathologic data collected between 2005 and 2013 from the 34 National Institute on Aging-sponsored Alzheimer's Disease Centers, cognitive trajectories were compared for persons with and without evidence of AD neuropathologic change. We evaluated rates of decline in 4 domains (episodic memory, language, attention/working memory, executive function). The significance of the differences (b) in rates of decline was tested using linear regression, adjusting for age, education, sex, and other neuropathologic lesions. Results: Participants who had low to high levels of AD neuropathologic change (n 5131) showed a greater rate of decline on the attention/working memory domain score (b 5 20.11; 95% confidence interval 5 20.19, 20.02; p 5 0.02) when compared to 80 participants who died without evidence of AD neuropathologic change. Conclusions: Clinically normal individuals who come to autopsy with AD neuropathologic change exhibit subtle evidence of declining cognitive trajectories for attention/working memory. © 2014 American Academy of Neurology.

Document Type: Article
Source: Scopus

Cross, A.H.a , Wingerchuk, D.M.b , Weinshenker, B.G.c
Active and progressive: A new duality of MS classification
(2014) Neurology, 83 (3), pp. 206-207. 

a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurology, Mayo Clinic, Scottsdale, AZ, United States
c Department of Neurology, Mayo Clinic, Rochester, MN, United States

Document Type: Editorial
Source: Scopus

Ryman, D.C.a , Acosta-Baena, N.g , Aisen, P.S.e , Bird, T.i , Danek, A.d , Fox, N.C.o , Goate, A.c , Frommelt, P.r , Ghetti, B.r , Langbaum, J.B.S.j , Lopera, F.g , Martins, R.l , Masters, C.L.f , Mayeux, R.P.n , McDade, E.h , Moreno, S.g , Reiman, E.M.j , Ringman, J.M.m , Salloway, S.p , Schofield, P.R.k , Sperling, R.q , Tariot, P.N.j , Xiong, C.b , Morris, J.C.a , Bateman, R.J.a
Symptom onset in autosomal dominant Alzheimer disease: A systematic review and meta-analysis
(2014) Neurology, 83 (3), pp. 253-260. 

a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
d Neurologische Klinik Ludwig-Maximilians-Universität Munich, German Center for Neurodegenerative Diseases, Munich, Germany
e Department of Neurosciences, University of California San Diego, United States
f Mental Health Research Institute, University of Melbourne, Australia
g Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia
h Department of Neurology, University of Pittsburgh, PA, United States
i Department of Neurology, University of Washington, Seattle, United States
j Banner Alzheimer's Institute, Phoenix, AZ, United States
k Neuroscience Research Australia, University of New South Wales, Sydney, Australia
l Edith Cowan University, WA, United States
m Easton Center for Alzheimer's Disease Research, UCLA, Los Angeles, CA, United States
n Department of Neurology, Columbia University, New York, NY, United States
o Queen Square Institute of Neurology, University College London, United Kingdom
p Department of Neurology, Warren Alpert Medical School, Brown University, Providence, RI, United States
q Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Boston, United States

Objective: To identify factors influencing age at symptom onset and disease course in autosomal dominant Alzheimer disease (ADAD), and develop evidence-based criteria for predicting symptom onset in ADAD. Methods: We have collected individual-level data on ages at symptom onset and death from 387 ADAD pedigrees, compiled from 137 peer-reviewed publications, the Dominantly Inherited Alzheimer Network (DIAN) database, and 2 large kindreds of Colombian (PSEN1 E280A) and Volga German (PSEN2 N141I) ancestry. Our combined dataset includes 3,275 individuals, of whom 1,307 were affected by ADAD with known age at symptom onset. We assessed the relative contributions of several factors in influencing age at onset, including parental age at onset, age at onset by mutation type and family, and APOE genotype and sex. We additionally performed survival analysis using data on symptom onset collected from 183 ADAD mutation carriers followed longitudinally in the DIAN Study. Results: We report summary statistics on age at onset and disease course for 174 ADAD mutations, and discover strong and highly significant (p &lt; 10-16, r2 &gt; 0.38) correlations between individual age at symptom onset and predicted values based on parental age at onset and mean ages at onset by mutation type and family, which persist after controlling for APOE genotype and sex. Conclusions: Significant proportions of the observed variance in age at symptom onset in ADAD can be explained by family history and mutation type, providing empirical support for use of these data to estimate onset in clinical research. © 2014 American Academy of Neurology.

Document Type: Article
Source: Scopus

Baker, L.M.a , Laidlaw, D.H.b , Conturo, T.E.d , Hogan, J.c , Zhao, Y.c , Luo, X.c , Correia, S.e , Cabeen, R.b , Lane, E.M.f , Heaps, J.M.a , Bolzenius, J.a , Salminen, L.E.a , Akbudak, E.d , McMichael, A.R.d , Usher, C.a , Behrman, A.a , Paul, R.H.a
White matter changes with age utilizing quantitative diffusion MRI
(2014) Neurology, 83 (3), pp. 247-252. 

a University of Missouri-St. Louis, Brown University, Providence, RI, United States
b Computer Science Department, Brown University, Providence, RI, United States
c Department for Biostatistics, Center for Statistical Sciences, Brown University, Providence, RI, United States
d Washington University School of Medicine, Mallinckrodt Institute of Radiology, St. Louis, MO, Italy
e Division of Biology and Medicine, Brown Medical School, Providence, RI, United States
f Vanderbilt University Medical Center, Nashville, TN, United States

Objective: To investigate the relationship between older age and mean cerebral white matter fiber bundle lengths (FBLs) in specific white matter tracts in the brain using quantified diffusion MRI. Methods: Sixty-three healthy adults older than 50 years underwent diffusion tensor imaging. Tractography tracings of cerebral white matter fiber bundles were derived from the diffusion tensor imaging data. Results: Results revealed significantly shorter FBLs in the anterior thalamic radiation for every 1-year increase over the age of 50 years. Conclusions: We investigated the effects of age on FBL in specific white matter tracts in the brains of healthy older individuals utilizing quantified diffusion MRI. The results revealed a significant inverse relationship between age and FBL. Longitudinal studies of FBL across a lifespan are needed to examine the specific changes to the integrity of white matter. © 2014 American Academy of Neurology.

Document Type: Article
Source: Scopus

Lenze, E.J.a , Hershey, T.a , Newcomer, J.W.b , Karp, J.F.c , Blumberger, D.d , Anger, J.a , Doré, P.a , Dixon, D.a
Antiglucocorticoid therapy for older adults with anxiety and co-occurring cognitive dysfunction: Results from a pilot study with mifepristone
(2014) International Journal of Geriatric Psychiatry, 29 (9), pp. 962-969. 

a School of Medicine, Washington University, St Louis, MO, United States
b Florida Atlantic University, Boca Raton, FL, United States
c School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
d Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada

Objectives In older adults with anxiety disorders, chronically elevated cortisol may contribute to cognitive impairment and elevated anxiety. We conducted a pilot study with mifepristone, a glucocorticoid receptor antagonist, as a potential treatment for late-life anxiety disorders and co-occurring cognitive dysfunction. Methods Fifteen individuals 60 years and older with an anxiety disorder plus cognitive dysfunction participated in the 12-week study. In the first week, participants were randomly assigned to mifepristone 300 mg daily or placebo. In the subsequent 3 weeks, all participants received mifepristone 300 mg. Mifepristone was then discontinued, and the participants were reassessed 8 weeks later. We examined the following: (1) cognitive changes; (2) worry symptom severity; (3) safety and tolerability; and (4) salivary cortisol before, during, and after mifepristone exposure. Results Overall safety, tolerability, and high retention supported the feasibility of this research. Participants with higher baseline cortisol levels (peak cortisol >6.0 ng/ml, n = 5) showed improvements in memory, executive function, and worry severity after 3-4 weeks of mifepristone with persistent memory and worry improvements 8 weeks after mifepristone discontinuation. Individuals with low-to-normal baseline cortisol (n = 8) showed little to no improvement. As expected, cortisol levels rose during mifepristone exposure and returned to pretreatment levels 8 weeks after mifepristone discontinuation. In the first week of treatment, there were no differences between placebo-treated and mifepristone-treated participants. Conclusion The results of this pilot study warrant further testing of antiglucocorticoid agents in late-life anxiety disorders with co-occurring cognitive dysfunction. Mifepristone is hypothesized to have benefits in patients with evidence of glucocorticoid excess. Directions for further study are discussed. Copyright © 2014 John Wiley & Sons, Ltd.

Author Keywords
anxiety;  glucocorticoid;  memory;  mifepristone;  older adults;  stress

Document Type: Article
Source: Scopus

Friess, S.H.a , Sutton, R.M.b , French, B.c , Bhalala, U.d , Maltese, M.R.b , Naim, M.Y.b , Bratinov, G.b , Arciniegas Rodriguez, S.b , Weiland, T.R.b , Garuccio, M.b , Nadkarni, V.M.b , Becker, L.B.e , Berg, R.A.b
Hemodynamic directed CPR improves cerebral perfusion pressure and brain tissue oxygenation
(2014) Resuscitation, 85 (9), pp. 1298-1303. 

a St. Louis Children's Hospital, Washington University in St. Louis School of Medicine, Department of Pediatrics, 660 S. Euclid Avenue, St. Louis, MO 63110, United States
b The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Department of Anesthesiology and Critical Care Medicine, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, United States
c University of Pennsylvania Perelman School of Medicine, Department of Biostatistics and Epidemiology, 423 Guardian Drive, Philadelphia, PA 19104, United States
d Bloomberg Children's Center, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Department of Anesthesiology and Critical Care Medicine, 1800 Orleans Street, Baltimore, MD 21287, United States
e The Hospital of the University of Pennsylvania, University of Pennsylvania Perelman School of Medicine, Department of Emergency Medicine, 3400 Spruce Street, Philadelphia, PA 19104, United States

Aim: Advances in cardiopulmonary resuscitation (CPR) have focused on the generation and maintenance of adequate myocardial blood flow to optimize the return of spontaneous circulation and survival. Much of the morbidity associated with cardiac arrest survivors can be attributed to global brain hypoxic ischemic injury. The objective of this study was to compare cerebral physiological variables using a hemodynamic directed resuscitation strategy versus an absolute depth-guided approach in a porcine model of ventricular fibrillation (VF) cardiac arrest. Methods: Intracranial pressure and brain tissue oxygen tension probes were placed in the frontal cortex prior to induction of VF in 21 female 3-month-old swine. After 7. min of VF, animals were randomized to receive one of three resuscitation strategies: (1) hemodynamic directed care (CPP-20): chest compressions (CCs) with depth titrated to a target systolic blood pressure of 100. mmHg and titration of vasopressors to maintain coronary perfusion pressure (CPP) >20. mmHg; (2) depth 33. mm (D33): target CC depth of 33. mm with standard American Heart Association (AHA) epinephrine dosing; or (3) depth 51. mm (D51): target CC depth of 51. mm with standard AHA epinephrine dosing. Results: Cerebral perfusion pressures (CerePP) were significantly higher in the CPP-20 group compared to both D33 (p<. 0.01) and D51 (p= 0.046), and higher in survivors compared to non-survivors irrespective of treatment group (p<. 0.01). Brain tissue oxygen tension was also higher in the CPP-20 group compared to both D33 (p<. 0.01) and D51 (p= 0.013), and higher in survivors compared to non-survivors irrespective of treatment group (p<. 0.01). Subjects with a CPP >20. mmHg were 2.7 times more likely to have a CerePP >30. mmHg (p<. 0.001). Conclusions: Hemodynamic directed resuscitation strategy targeting coronary perfusion pressure >20. mmHg following VF arrest was associated with higher cerebral perfusion pressures and brain tissue oxygen tensions during CPR. © 2014 Elsevier Ireland Ltd.

Author Keywords
Brain tissue oxygen tension;  Cardiopulmonary resuscitation;  Cerebral perfusion pressure;  Coronary perfusion pressure;  Intracranial pressure;  Ventricular fibrillation

Document Type: Article
Source: Scopus

Blanchard, H.a , Taha, A.Y.a , Cheon, Y.a , Kim, H.-W.a b , Turk, J.c , Rapoport, S.I.a
iPLA2β knockout mouse, a genetic model for progressive human motor disorders, develops age-related neuropathology
(2014) Neurochemical Research, 39 (8), pp. 1522-1532. 

a Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, United States
b College of Life Sciences, Sejong University, 98 Gunja-dong, Gwangjin-Gu, Seoul 143-747, South Korea
c Division of Endocrinology, Medicine Department Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, United States

Calcium-independent phospholipase A2 group VIa (iPLA 2β) preferentially releases docosahexaenoic acid (DHA) from the sn-2 position of phospholipids. Mutations of its gene, PLA2G6, are found in patients with several progressive motor disorders, including Parkinson disease. At 4 months, PLA2G6 knockout mice (iPLA2β-/-) show minimal neuropathology but altered brain DHA metabolism. By 1 year, they develop motor disturbances, cerebellar neuronal loss, and striatal α-synuclein accumulation. We hypothesized that older iPLA2β-/- mice also would exhibit inflammatory and other neuropathological changes. Real-time polymerase chain reaction and Western blotting were performed on whole brain homogenate from 15 to 20-month old male iPLA2β -/- or wild-type (WT) mice. These older iPLA2β -/- mice compared with WT showed molecular evidence of microglial (CD-11b, iNOS) and astrocytic (glial fibrillary acidic protein) activation, disturbed expression of enzymes involved in arachidonic acid metabolism, loss of neuroprotective brain derived neurotrophic factor, and accumulation of cytokine TNF-α messenger ribonucleic acid, consistent with neuroinflammatory pathology. There was no evidence of synaptic loss, of reduced expression of dopamine active reuptake transporter, or of accumulation of the Parkinson disease markers Parkin or Pink1. iPLA2γ expression was unchanged. iPLA2β deficient mice show evidence of neuroinflammation and associated neuropathology with motor dysfunction in later life. These pathological biomarkers could be used to assess efficacy of dietary intervention, antioxidants or other therapies on disease progression in this mouse model of progressive human motor diseases associated with a PLA2G6 mutation. © 2014 Springer Science+Business Media.

Author Keywords
Arachidonic and docosahexaenoic acid;  Brain;  Motor disturbances;  Neuropathology;  Parkinson disease

Document Type: Article
Source: Scopus

Van Stavern, G.P.
Metabolic, hereditary, traumatic, and neoplastic optic neuropathies
(2014) CONTINUUM Lifelong Learning in Neurology, 20 (4), pp. 877-906. 

Departments of Ophthalmology and Visual Sciences and Neurology, Washington University, 600 S. Euclid Avenue, St. Louis, MO 63110, United States

Purpose of Review: Toxic, nutritional, hereditary, traumatic, and neoplastic optic neuropathies result in significant disability due to visual dysfunction. Many of these conditions are treatable. Early diagnosis may allow for intervention to stabilize or improve vision and prevent unnecessary testing. These conditions have overlapping clinical features, and careful assessment of the visual system allows for accurate diagnosis and management. Recent Findings: Newer treatment strategies are available for optic neuropathies previously thought untreatable, such as some hereditary optic neuropathies. Many conditions that previously were felt to represent distinct diseases can be linked by a common pattern of mitochondrial dysfunction. Summary: The optic nerve is susceptible to a wide variety of pathologic processes. The correct diagnosis depends on a thorough history and detailed evaluation of the visual system. Certain optic neuropathies selectively affect the papillomacular bundle, and particular attention to this location can considerably narrow the differential diagnosis and subsequent workup. © 2014, American Academy of Neurology.

Document Type: Review
Source: Scopus

Peelle, J.E.
Methodological challenges and solutions in auditory functional magnetic resonance imaging
(2014) Frontiers in Neuroscience, (8 JUL), art. no. Article 253, . 

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

Functional magnetic resonance imaging (fMRI) studies involve substantial acoustic noise. This review covers the difficulties posed by such noise for auditory neuroscience, as well as a number of possible solutions that have emerged. Acoustic noise can affect the processing of auditory stimuli by making them inaudible or unintelligible, and can result in reduced sensitivity to auditory activation in auditory cortex. Equally importantly, acoustic noise may also lead to increased listening effort, meaning that even when auditory stimuli are perceived, neural processing may differ from when the same stimuli are presented in quiet. These and other challenges have motivated a number of approaches for collecting auditory fMRI data. Although using a continuous echoplanar imaging (EPI) sequence provides high quality imaging data, these data may also be contaminated by background acoustic noise. Traditional sparse imaging has the advantage of avoiding acoustic noise during stimulus presentation, but at a cost of reduced temporal resolution. Recently, three classes of techniques have been developed to circumvent these limitations. The first is Interleaved Silent Steady State (ISSS) imaging, a variation of sparse imaging that involves collecting multiple volumes following a silent period while maintaining steady-state longitudinal magnetization. The second involves active noise control to limit the impact of acoustic scanner noise. Finally, novel MRI sequences that reduce the amount of acoustic noise produced during fMRI make the use of continuous scanning a more practical option. Together these advances provide unprecedented opportunities for researchers to collect high-quality data of hemodynamic responses to auditory stimuli using fMRI.

Author Keywords
Auditory cortex;  Auditory perception;  Executive function;  Hearing;  Music;  Speech

Document Type: Article
Source: Scopus

Blackburn, S.L.a , Kadkhodayan, Y.b , Ray, W.Z.c , Zipfel, G.J.c , Cross III, D.T.d , Moran, C.J.d , Derdeyn, C.P.d
Onyx is associated with poor venous penetration in the treatment of spinal dural arteriovenous fistulas
(2014) Journal of NeuroInterventional Surgery, 6 (7), pp. 536-540. 

a Department of Neurosurgery, University of Florida, P O Box 100265, Gainesville, FL 32610-0265, United States
b Interventional Neuroradiology, Abbott Northwestern Hospital, Minneapolis, MN, United States
c Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
d Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States

Background and purpose: The use of Onyx has become the mainstream for the treatment of cranial dural arteriovenous fistulas (AVFs) and arteriovenous malformations, but the reported success for type I spinal dural arteriovenous fistulas (sDAVFs) remains limited. We review our experience with Onyx and report its limitations in the treatment of spinal AVFs. Materials and methods: We retrospectively reviewed the Interventional Neuroradiology Procedure database at Washington University for cases of sDAVF embolization. Radiology reports were reviewed for fistula classification, treatment technique, and initial and follow-up results. Angiographic images were reviewed to confirm diagnosis, treatment, and penetration of embolisate into the draining vein. Results: With the use of Onyx, sDAVFs were obliterated in six of seven patients at the time of treatment. Follow-up angiography confirmed sDAVF obliteration in two patients, and recurrence in two cases. Two patients had no follow-up. One patient not cured at the time of treatment was treated surgically. Of the nine total treatments, Onyx successfully crossed the nidus into the draining vein in only four cases. Successful venous embolization was facilitated with positioning of the microcatheter to less than 5 mm from the nidus in three of the four cases. The use of n-butyl cyanoacrylate (NBCA) resulted in venous penetration in eight of 10 cases, and short term follow-up cure in seven of 10 patients. Conclusions: Our experience with Onyx for type I sDAVF embolization has been tempered by difficulty in achieving venous penetration and, consequently, a high rate of recurrence. For management of these fistulas, we favor NBCA or surgical treatment.

Document Type: Article
Source: Scopus

Lyall, K.a b , Constantino, J.N.c , Weisskopf, M.G.d e , Roberts, A.L.f , Ascherio, A.a d g , Santangelo, S.L.d h
Parental social responsiveness and risk of autism spectrum disorder in offspring
(2014) JAMA Psychiatry, 71 (8), pp. 936-942. 

a Department of Nutrition, Harvard School of Public Health, 655 Huntington Ave, Boston, MA 02115, United States
b Department of Public Health Sciences, University of California, Davis, CA, United States
c Department of Psychiatry, Washington University, St Louis, MO, United States
d Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States
e Department of Environmental Health, Harvard School of Public Health, Boston, MA, United States
f Department of Social and Behavioral Sciences, Harvard School of Public Health, Boston, MA, United States
g Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
h Department of Psychiatry, Maine Medical Center, Maine Medical Center Research Institute, Portland, United States

IMPORTANCE Although autism spectrum disorder (ASD) is known to be heritable, patterns of inheritance of subclinical autistic traits in nonclinical samples are poorly understood. OBJECTIVE To examine the familiality of Social Responsiveness Scale (SRS) scores of individuals with and without ASD. DESIGN, SETTING, AND PARTICIPANTS We performed a nested case-control study (pilot study: July 1, 2007, through June 30, 2009; full-scale study: September 15, 2008, through September 14, 2012) within a population-based longitudinal cohort. Participants were drawn from the Nurses' Health Study II, a cohort of 116 430 female nurses recruited in 1989. Case participants were index children with reported ASD; control participants were frequency matched by year of birth of case participants among those not reporting ASD. Of 3161 eligible participants, 2144 nurses (67.8%) returned SRS forms for a child and at least 1 parent and were included in these analyses. EXPOSURE The SRS scores, as reported by nurse mothers and their spouses, were examined in association with risk of ASD using crude and adjusted logistic regression analyses. The SRS scores of the children were examined in association with SRS scores of the parents using crude and adjusted linear regression analyses stratified by case status. MAIN OUTCOMES AND MEASURES Autism spectrum disorder, assessed by maternal report, validated in a subgroup with the Autism Diagnostic Interview-Revised. RESULTS A total of 1649 individuals were included in these analyses, including 256 ASD case participants, 1393 control participants, 1233 mothers, and 1614 fathers. Risk of ASD was increased by 85.0%among children whose parents had concordantly elevated SRS scores (odds ratio [OR], 1.85; 95%CI, 1.08-3.16) and by 52.0% when the score of either parent was elevated (OR, 1.52; 95%CI, 1.11-2.06). Elevated scores of the father significantly increased the risk of ASD in the child (OR, 1.94; 95%CI, 1.38-2.71), but no association was seen with elevated scores of the mother. Elevated parent scores significantly increased child scores in controls, corresponding to an increase in 23 points (P < .001). CONCLUSIONS AND RELEVANCE These findings support the role of additive genetic influences in concentrating inherited ASD susceptibility in successive generations and the potential role of preferential mating, and suggest that typical variation in parental social functioning can produce clinically significant differences in offspring social traits. Copyright © 2014 American Medical Association. All rights reserved.

Document Type: Article
Source: Scopus

Custer, P.L., Kent, T.L.
Pitfalls of ophthalmic radiographic imaging
(2014) Current Opinion in Ophthalmology, 25 (5), pp. 432-435. 

Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, MO, United States

Purpose of Review: Ophthalmologists are dependent on computed tomography (CT) and MRI to aid in the diagnosis and management of patients with orbital and visual conditions. Pitfalls in the imaging process can lead to inefficient care or patient harm. This review summarizes these problems and provides methods to reduce imaging errors. Recent Findings: There has been exponential growth in the number of radiographic scans performed, resulting in increased awareness of the risks from medical radiation. Strategies to minimize radiation exposure include reducing the need for sequential scans, using appropriate technology, and substituting MRI for CT. Contrast administration can be associated with systemic reactions, renal disease, and thyroid dysfunction. Scan interpretation errors are reduced by the ophthalmologist reviewing the study and communication with the radiologist. Summary: Medical radiation exposure can be reduced by initially ordering the appropriate scan and substituting MRI for CT when possible. MRI is contraindicated in patients with certain implants and metallic foreign bodies. Noncontrast studies are adequate to evaluate many conditions and some patients should not receive contrast. Imaging errors can be reduced by the ophthalmologist personally reviewing the orbital scans and correlating the results with the clinical findings. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Author Keywords
computed tomography;  iodinated contrast;  magnetic resonance

Document Type: Review
Source: Scopus

Mac Donald, C.L.a b , Johnson, A.M.a , Wierzechowski, L.c , Kassner, E.c , Stewart, T.c , Nelson, E.C.d , Werner, N.J.a , Zonies, D.c , Oh, J.c e , Fang, R.c f , Brody, D.L.a
Prospectively assessed clinical outcomes in concussive blast vs nonblast traumatic brain injury among evacuated US military personnel
(2014) JAMA Neurology, 71 (8), pp. 994-1002. 

a Department of Neurology, Washington University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110, United States
b Department of Neurological Surgery, University of Washington, Seattle, WA, United States
c Landstuhl Regional Medical Center, Landstuhl, Germany
d Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
e Department of Trauma, Critical Care, and Acute Care Surgery, Walter Reed National Military Medical Center, Baltimore, MD, United States
f US Air Force Center for Sustainment of Trauma and Readiness Skills, R. Adams Cowley Shock Trauma Center, University of Maryland, Baltimore, MD, United States

IMPORTANCE: Blast injury has been identified as the signature injury in the conflicts in Iraq and Afghanistan. However it remains to be determined whether fundamental differencesmay exist between blast-related traumatic brain injury (TBI) and TBI due to other mechanisms. OBJECTIVES: To determine similarities and differences between clinical outcomes in US military personnel with blast-related vs. non-blast-related concussive TBI and to identify the specific domains of impairment that best correlate with overall disability. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study involving active duty US Military personnel evacuated from Iraq or Afghanistan to Landstuhl Regional Medical Center, in Landstuhl, Germany. Four groups of participants were enrolled from 2010 to 2013: (1) blast plus impact complex TBI (n=53), (2) non-blast related TBI with injury due to other mechanisms (n=29), (3) blast-exposed controls evacuated for other medical reasons (n=27) (4) non-blast-exposed controls evacuated for other medical reasons (n=69). All patients with TBI met Department of Defense criteria for concussive (mild) TBI. The study participants were evaluated 6-12 months after injury at Washington University in St Louis. In total, 255 subjects were enrolled in the study, and 183 participated in follow-up evaluations, 5 of whom were disqualified. MAIN OUTCOMES AND MEASURES: In-person clinical examinations included evaluation for overall disability, a standardized neurological exam, headache questionnaires, neuropsychological test battery, combat exposure and alcohol use surveys, and structured interview evaluations for post-traumatic stress disorder (PTSD) and depression. RESULTS: Global outcomes, headache severity, neuropsychological performance, and surprisingly even PTSD severity and depression were indistinguishable between the two TBI groups, independent of mechanism of injury. Both TBI groups had higher rates of moderate to severe overall disability than the respective control groups: 41/53 (77%) of blast plus impact TBI and 23/29 (79%) of nonblast TBI vs. 16/27 (59%) of blast-exposed controls and 28/69 (41%) of non-blast-exposed controls. In addition, blast-exposed controls had worse headaches and more severe PTSD than non-blast-exposed controls. Self-reported combat exposure intensity was higher in the blast plus impact TBI group than in nonblast TBI group and was higher in blast-exposed controls than in non-blast-exposed controls. However, combat exposure intensity did not correlate with PTSD severity in the TBI groups, but a modest positive correlation was observed in the controls. Overall outcomes were most strongly correlated with depression, headache severity, and number of abnormalities on neuropsychological testing. However a substantial fraction of the variance in overall outcome was not explained by any of the assessed measures. CONCLUSIONS AND RELEVANCE: One potential interpretation of these results is that TBI itself, independent of injury mechanism and combat exposure intensity, is a primary driver of adverse outcomes. Many other important factors may be as yet unmeasured, and adverse outcomes following war-time injuries are difficult to fully explain. TRIAL REGISTRATION: Identifier: NCT01313130. Copyright 2014 American Medical Association. All rights reserved.

Document Type: Article
Source: Scopus

Mike, A., Jackson, J.J., Oltmanns, T.F.
The conscientious retiree: The relationship between conscientiousness, retirement, and volunteering
(2014) Journal of Research in Personality, 52, pp. 68-77. 

Washington University in St. Louis, United States

The current study examined the relationship between conscientiousness, work status, and volunteering utilizing two large samples, the St. Louis Personality and Aging Network (SPAN) and the Health and Retirement Study (HRS). It was hypothesized that conscientious adults who were retired would be more likely to volunteer because, after retirement, they gain a substantial amount of free time, while losing an outlet for their industrious and achievement-striving tendencies. Cross-sectional and longitudinal analyses revealed that conscientious, retired individuals were more likely to volunteer than conscientious, working individuals. Further analyses revealed that facets of conscientiousness provide differential information from the general trait. These findings indicate that volunteering during retirement fills an important niche for high-striving, conscientious individuals. © 2014 Elsevier Inc.

Author Keywords
Conscientiousness;  Facets;  Retirement;  Social investment;  Volunteering;  Work status

Document Type: Article
Source: Scopus

Dale, A.M.a , Gardner, B.T.a , Zeringue, A.a b , Werner, R.c , Franzblau, A.c , Evanoff, B.a
The effectiveness of post-offer pre-placement nerve conduction screening for carpal tunnel syndrome
(2014) Journal of Occupational and Environmental Medicine, 56 (8), pp. 840-847. 

a Department of General Medical Sciences, Washington University School of Medicine, Campus B. 8005, 660 S Euclid Ave, St Louis, MO 63110, United States
b School of Public Health, St Louis University, St Louis, MO, United States
c Department of Environmental and Health Sciences, University of Michigan School of Public Health, Ann Arbor, United States

Objective: We evaluated post-offer pre-placement (POPP) nerve conduction studies (NCS) for carpal tunnel syndrome (CTS), testing diagnostic yield and cost-effectiveness. Methods: A total of 1027 newly hired workers underwent baseline NCS and were followed for an average of 3.7 years for diagnosed CTS. Measures of diagnostic yield included sensitivity, specificity, and positive predictive value (PPV). Cost-effectiveness of POPP screening was evaluated using a range of inputs. RESULTS:: Abnormal NCS was strongly associated with future CTS with univariate hazard ratios ranging from 2.95 to 11.25, depending on test parameters used. Nevertheless, PPV was poor, 6.4% to 18.5%. Cost-effectiveness of POPP varied with CTS case costs, screening costs, and NCS thresholds. Conclusions: Although abnormal NCS at hire increases risk of future CTS, the PPV is low, and POPP screening is not cost-effective to employers in most scenarios tested. Copyright © 2014 by American College of Occupational and Environmental Medicine.


Document Type: Article
Source: Scopus


August 15, 2014

Moritz, G.L.a , Melin, A.D.b , Yu, F.T.Y.c , Bernard, H.d , Ong, P.S.e , Dominy, N.J.a f
Niche convergence suggests functionality of the nocturnal fovea
(2014) Frontiers in Integrative Neuroscience, 8 (JUL), art. no. 61, . 

a Department of Biological Sciences, The Class of 1978 Life Sciences Center, Dartmouth College, Hanover, NH, United States
b Department of Anthropology, Washington University, St. Louis, MO, United States
c Research and Education Division, Zoology and Entomology, Kota Kinabalu, Malaysia
d Institute for Tropical Biology and Conservation, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
e Institute of Biology, University of the Philippines Diliman, Quezon City, Philippines
f Department of Anthropology, Dartmouth College, Hanover, NH, United States

The fovea is a declivity of the retinal surface associated with maximum visual acuity. Foveae are widespread across vertebrates, but among mammals they are restricted to haplorhine primates (tarsiers, monkeys, apes, and humans), which are primarily diurnal. Thus primates have long contributed to the view that foveae are functional adaptations to diurnality. The foveae of tarsiers, which are nocturnal, are widely interpreted as vestigial traits and therefore evidence of a diurnal ancestry. This enduring premise is central to adaptive hypotheses on the origins of anthropoid primates; however, the question of whether tarsier foveae are functionless anachronisms or nocturnal adaptations remains open. To explore this question, we compared the diets of tarsiers (Tarsius) and scops owls (Otus), taxa united by numerous anatomical homoplasies, including foveate vision. A functional interpretation of these homoplasies predicts dietary convergence. We tested this prediction by analyzing stable isotope ratios that integrate dietary information. In Borneo and the Philippines, the stable carbon isotope compositions of Tarsius and Otus were indistinguishable, whereas the stable nitrogen isotope composition of Otus was marginally higher than that of Tarsius. Our results indicate that species in both genera consumed mainly ground-dwelling prey. Taken together, our findings support a functional interpretation of the many homoplasies shared by tarsiers and scops owls, including a retinal fovea. We suggest that the fovea might function similarly in tarsiers and scops owls by calibrating the auditory localization pathway. The integration of auditory localization and visual fixation during prey detection and acquisition might be critical at low light levels. © 2014 Moritz, Melin, Tuh Yit Yu, Bernard, Ong and Dominy.

Author Keywords
Diet;  Fovea centralis;  Otus lempiji;  Otus megalotis;  Stable isotopes;  Tarsius bancanus;  Tarsius syrichta;  Visual predation

Document Type: Article
Source: Scopus

Cai, Z.a , Ouyang, Q.b g , Zeng, D.a , Nguyen, K.N.f , Modi, J.a , Wang, L.b , White, A.G.a , Rogers, B.E.f , Xie, X.-Q.b c , Anderson, C.J.a d e
64Cu-labeled somatostatin analogues conjugated with cross-bridged phosphonate-based chelators via strain-promoted click chemistry for PET imaging: In silico through in vivo studies
(2014) Journal of Medicinal Chemistry, 57 (14), pp. 6019-6029. 

a Department of Radiology, Pittsburgh, PA 15219, United States
b Department of Pharmaceutical Sciences, Computational Chemical Genomics Screening Center, School of Pharmacy, Pittsburgh, PA 15219, United States
c Drug Discovery Institute, Pittsburgh, PA 15219, United States
d Department of Pharmacology and Chemical Biology, Pittsburgh, PA 15219, United States
e Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15219, United States
f Department of Radiation Oncology, Washington University in St. Louis, St. Louis, Mo 63130, United States
g College of Pharmacy Third, Military Medical University, Chongqing 400038, China

Somatostatin receptor subtype 2 (sstr2) is a G-protein-coupled receptor (GPCR) that is overexpressed in neuroendocrine tumors. The homology model of sstr2 was built and was used to aid the design of new somatostatin analogues modified with phosphonate-containing cross-bridged chelators for evaluation of using them as PET imaging radiopharmaceuticals. The new generation chelators were conjugated to Tyr3-octreotate (Y3-TATE) through bioorthogonal, strain-promoted alkyne azide cycloaddition (SPAAC) to form CB-TE1A1P-DBCO-Y3- TATE (AP) and CB-TE1K1P-PEG4-DBCO-Y3-TATE (KP) in improved yields compared to standard direct conjugation methods of amide bond formation. Consistent with docking studies, the clicked bioconjugates showed high binding affinities to sstr2, with Kd values ranging from 0.6 to 2.3 nM. Selected isomers of the clicked products were used in biodistribution and PET/CT imaging. Introduction of the bulky dibenzocyclooctyne group in AP decreased clearance rates from circulation. However, the additional carboxylate group and PEG linker from the KP conjugate significantly improved labeling conditions and in vivo stability of the copper complex and ameliorated the slower pharmacokinetics of the clicked somatostatin analogues. © 2014 American Chemical Society.

Document Type: Article
Source: Scopus

Thoroughman, K.A.a , Hruschka, A.b , Widder, P.c
Engineering virtual studio: KEEN modules to foster entrepreneurial mindset in an integrative, first/second year online course
(2014) ASEE Annual Conference and Exposition, Conference Proceedings, . 

a School of Engineering and Applied Science, Washington University, St. Louis, United States
b Washington University, St. Louis, United States
c Biomedical Engineering Department, Washington University, St. Louis, United States

Engineering is a field that interacts with its surroundings by applying science to practical problems. In developing future engineers, teaching the technical fundamentals is only part of the task; engineering programs must also develop engineers that are able to apply those skills into the real world. Example problems are sometimes shown in classes, but lack the interactivity necessary to instill the skill in students. Introducing students to entrepreneurship directly promotes creativity and marketplace connection while indirectly instilling connection to real world problems and promoting scholarly and pre-professional identity within engineering. Here we introduce foundations to an entrepreneurial mindset to freshmen and sophomores via online modules, which we developed and piloted this academic year. We have previously built a one-credit, online, pass/fail course, Engineering Virtual Studio (EVS), that builds understanding across foundational coursework and into real-world relevance through discussions with peers and upperclassman mentors. Our new Entrepreneurial KEEN Modules integrate into EVS investigations into market and society driven problems, to which students explore solutions in consultation with campus and local experts, all in an integrative context. This instills a mindset of problem establishment and problem solving as cornerstones to foster real-world relevance, motivation, and goals for students beginning as early as possible in their undergraduate study. This entrepreneurial foundation helps provide context and relevance to foundational material, and fosters independence and personally relevant vantage points on coursework and the whole of the major. Here we report on our work-in-progress and initial formative assessment of performance and motivation of students in the entrepreneurial modules. © American Society for Engineering Education, 2014.

Document Type: Conference Paper
Source: Scopus

Pachman, D.R.a , Watson, J.C.b , Lustberg, M.B.c , Wagner-Johnston, N.D.d , Chan, A.e , Broadfield, L.f , Cheung, Y.T.e , Steer, C.g , Storey, D.J.h , Chandwani, K.D.i , Paice, J.j , Jean-Pierre, P.k , Oh, J.l , Kamath, J.m , Fallon, M.n , Strik, H.o , Koeppen, S.p , Loprinzi, C.L.a
Management options for established chemotherapy-induced peripheral neuropathy
(2014) Supportive Care in Cancer, 22 (8), pp. 2281-2295. 

a Division of Medical Oncology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, United States
b Department of Neurology, Mayo Clinic, Rochester, MN, United States
c Division of Medical Oncology, Arthur G. James Cancer Hospital, Ohio State University, Columbus, OH, United States
d Division of Medical Oncology, Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States
e Department of Pharmacy, National University of Singapore, Singapore, Singapore
f Department of Pharmacy, Cancer Care Nova Scotia, Halifax, NS, Canada
g Border Medical Oncology, Wodonga, VIC, Australia
h Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, United Kingdom
i Department of Radiation Oncology, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY, United States
j Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
k Department of Psychology, Neurocognitive Translational Research Lab., University of Notre Dame, Notre Dame, IN, United States
l Center for Lasting Effects of Cancer Treatment, Department of General Internal Medicine, MD Anderson Cancer Center, Houston, TX, United States
m Department of Psychiatry, University of Connecticut Health Center, Farmington, CT, United States
n University of Edinburgh, Edinburgh, United Kingdom
o Department of Neurology, University of Marburg, Baldinger Strasse, Marburg, Germany
p Department of Neurology, University of Duisburg-Essen, Essen, Germany

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating condition associated with a variety of chemotherapeutic agents. Clinicians are cognizant of the negative impact of CIPN on cancer treatment outcomes and patients' psychosocial functioning and quality of life. In an attempt to alleviate this problem, clinicians and patients try various therapeutic interventions, despite limited evidence to support efficacy of these treatments. The rationale for such use is mostly based on the evidence for the treatment options in non-CIPN peripheral neuropathy syndromes, as this area is more robustly studied than is CIPN treatment. In this manuscript, we examine the existing evidence for both CIPN and non-CIPN treatments and develop a summary of the best available evidence with the aim of developing a practical approach to the treatment of CIPN, based on available literature and clinical practice experience. © 2014 Springer-Verlag.

Author Keywords
Chemotherapy-induced peripheral neuropathy;  CIPN;  Neuropathy

Document Type: Review
Source: Scopus

Raikar, S.S.a , Halloran, D.R.b , Elliot, M.c , McHugh, M.d , Patel, S.e , Gauvain, K.M.d f
Outcomes of pediatric low-grade gliomas treated with radiation therapy: A single-institution study
(2014) Journal of Pediatric Hematology/Oncology, 36 (6), pp. e366-e370. 

a Department of Pediatrics, Division of Pediatric Hematology/Oncology, Emory University School of Medicine, Atlanta, GA, United States
b Department of Pediatrics, Saint Louis University School of Medicine, Saint Louis, MO, United States
c Division of Biostatistics, Saint Louis University School of Public Health, Saint Louis, MO, United States
d Department of Medicine, Division of Oncology, Saint Louis, MO, United States
e Department of Pediatrics, Division of Pediatric Hematology/Oncology, Washington University School of Medicine, Saint Louis, MO, United States
f Department of Medicine, Henry Ford Health System, Detroit, MI, United States

Radiation therapy is often considered the treatment of choice for low-grade gliomas. However, given the long-term effects of radiation on the developing brain, the appropriate use of radiation therapy in pediatric patients remains controversial. The purpose of this study was to evaluate progression-free survival (PFS) of pediatric low-grade glioma patients treated with radiation therapy. Data were obtained through a retrospective chart review of patients treated between 1991 and 2008 from a single tertiary care center in the midwest. The study population consisted of 17 patients, of whom 8 (47%) had tumor recurrence after radiation therapy. The median follow-up time was 8.2 years, with a range of 2.3 to 17.2 years. The median age at diagnosis was 5.4 years, and the median age at radiation therapy was 9.4 years. The 3- and the 10-year PFS were 69%±11.7% and 46%±13.3%, respectively. A significant difference in PFS was seen when comparing brainstem tumors with hypothalamic/optic pathway tumors (P=0.019). Differences in PFS based on the age at diagnosis, the extent of initial surgery, and indication for radiation therapy were not significant. A larger multicenter study is needed to better assess PFS in these patients. Copyright © 2014 by Lippincott Williams & Wilkins.

Author Keywords
pediatric low-grade gliomas;  radiation therapy low-grade astrocytoma

Document Type: Article
Source: Scopus

Presnall, N.a , Webster-Stratton, C.H.b , Constantino, J.N.a
Parent training: Equivalent improvement in externalizing behavior for children with and without familial risk
(2014) Journal of the American Academy of Child and Adolescent Psychiatry, 53 (8), pp. 859-868. 

a Washington University, St. Louis, United States
b University of Washington, United States

Objective The Incredible Years Series intervention has demonstrated efficacy for decreasing conduct disorder (CD) symptomatology in clinically affected youth in multiple randomized controlled trials. Because children with family psychiatric histories of antisocial behavior are at markedly increased risk for enduring symptoms of antisocial behavior (compared with their counterparts with a negative family history), the authors examined whether intervention effects across studies would prevail in that subgroup or would be relatively restricted to children without genetic risk. Method A reanalysis was conducted of 5 randomized controlled trials of Incredible Years involving 280 clinically affected children 3 to 8 years of age for whom a family psychiatric history of externalizing behavior in first- and second-degree relatives was ascertained from at least 1 parent. Results Incredible Years equally benefitted children with CD with and without family psychiatric histories of externalizing behavior. Family psychiatric history of externalizing behavior and parental depressive symptomatology predicted greater severity of CD symptomatology at baseline. Conclusion The beneficial effects of IY are evident in children with CD, irrespective of whether their conditions are more or less attributable to inherited susceptibility to enduring antisocial syndromes. A next phase of research should address whether earlier implementation of group-based education for parents of young children at increased familial risk for antisocial behavior syndromes - before the development of disruptive patterns of behavior - would result in even more pronounced effects and thereby constitute a cost-effective, targeted, preventive intervention for CD. © 2014 American Academy of Child and Adolescent Psychiatry.

Author Keywords
antisocial;  behavioral;  children;  Incredible Years;  maltreatment

Document Type: Article
Source: Scopus

Mashour, G.A.a , Avidan, M.S.b
Postoperative delirium: Disconnecting the network?
(2014) Anesthesiology, 121 (2), pp. 214-216. 

a Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, United States
b Department of Anesthesiology and Cardiothoracic Intensive Care, Washington University School of Medicine, St. Louis, MO, United States

Document Type: Editorial
Source: Scopus

Cavazos-Rehg, P.A.a , Breslau, N.b , Hatsukami, D.c , Krauss, M.J.a , Spitznagel, E.L.d , Grucza, R.A.a , Salyer, P.a , Hartz, S.M.a , Bierut, L.J.a
Smoking cessation is associated with lower rates of mood/anxiety and alcohol use disorders
(2014) Psychological Medicine, 44 (12), pp. 2523-2535. Cited 2 times.

a Department of Psychiatry, Washington University, School of Medicine, 660 South Euclid, St Louis, MO 63110, United States
b Department of Epidemiology and Biostatistics, College of Human Medicine, Michigan State University, East Lansing, MI, United States
c Department of Psychiatry, University of Minnesota, Minneapolis, MN, United States
d Department of Mathematics, Washington University in St Louis, St Louis, MO, United States

Background The psychological outcomes that accompany smoking cessation are not yet conclusive but positive outcomes could help to persuade quitting. Method We used data from the longitudinal National Epidemiological Study of Alcohol and Related Conditions. Logistic regression was used to examine associations between cigarette smoking reduction and Wave 2 status of addiction/mental health disorder among daily smokers at Wave 1, stratified by status of the diagnosis of interest at Wave 1. We adjusted for differences in baseline covariates between smokers with different levels of smoking reduction between Wave 1 and Wave 2 using propensity score regression adjustment. Results After adjusting for propensity scores and other mental health/addiction co-morbidities at Wave 2, among daily smokers who had current or lifetime history diagnosis of the outcome of interest at Wave 1, quitting by Wave 2 predicted a decreased risk of mood/anxiety disorder [adjusted odds ratio (aOR) 0.6, 95% confidence interval (CI) 0.4-0.9] and alcohol disorder (aOR 0.7, 95% CI 0.5-0.99) at Wave 2. Among daily smokers with no lifetime history diagnosis of the outcome of interest at Wave 1, quitting smoking by Wave 2 predicted a decreased risk of drug use disorder at Wave 2 (aOR 0.3, 95% CI 0.1-0.9). Conclusions There is no support in our data for the concern that smoking cessation would result in smokers' increased risk of some mental disorders. To the contrary, our data suggest that smoking cessation is associated with risk reduction for mood/anxiety or alcohol use disorder, even among smokers who have had a pre-existing disorder. © Cambridge University Press 2014.

Author Keywords
Cessation;  longitudinal data;  mental health;  psychiatry;  smoking;  substance use disorders

Document Type: Article
Source: Scopus

Gropler, R.J.
Trying to prevent diabetic cardiovascular autonomic neuropathy: More questions than answers
(2014) Journal of Nuclear Cardiology, 21 (4), pp. 842-844. 

Division of Radiological Sciences, Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway, St. Louis, MO 63110, United States

Document Type: Editorial
Source: Scopus

Wu-Fienberg, Y.a , Moore, A.M.a , Marquardt, L.M.a b , Newton, P.a , Johnson, P.J.a , Mackinnon, S.E.a , Sakiyama-Elbert, S.E.a b , Wood, M.D.a
Viral transduction of primary Schwann cells using a Cre-lox system to regulate GDNF expression
(2014) Biotechnology and Bioengineering, 111 (9), pp. 1886-1894. 

a Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, Campus Box 8238, 660 South Euclid Avenue, St. Louis, MO 63110, United States
b Department of Biomedical Engineering, Washington University, St. Louis, MO, United States

Glial cell-line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor known to enhance motor nerve regeneration following its delivery. However, recent studies have determined that extended GDNF delivery to regenerating axons can entrap motor axons at the site of GDNF delivery. This entrapment leads to reduced motor axons available to reinnervate muscle. To address this issue, we designed a cell-based GDNF expression system that can temporally regulate protein expression using an inducible gene excision mechanism to prevent entrapment at the site of expression. To design this system for regulation of GDNF expression, we transduced two lentiviral vectors, one containing a constitutively active GDNF transgene flanked by two loxP sites, and the other containing a tetracycline-inducible cre transgene along with its constitutively active transactivator, into Schwann cells (SCs). These SCs over-express GDNF, but expression can be suppressed through the administration of tetracycline family antibiotics, such as doxycycline. The engineered SCs produced significantly more GDNF as compared to untransduced controls, as measured by enzyme-linked immunosorbent assay (ELISA). Following doxycycline treatment, these SCs produced significantly lower levels of GDNF and induced less neurite extension as compared to untreated SCs. Engineered SCs treated with doxycycline showed a marked increase in Cre recombinase expression, as visualized by immunohistochemistry (IHC), providing evidence of a mechanism for the observed changes in GDNF expression levels and biological activity. This cell-based GDNF expression system could have potential for future in vivo studies to provide a temporally controlled GDNF source to promote axon growth. Biotechnol. Bioeng. 2014;111: 1886-1894. © 2014 Wiley Periodicals, Inc.

Author Keywords
Candy-store effect;  Cre-lox;  Drug delivery;  Glial cell line derived neurotrophic factor;  Lentivirus;  Peripheral nerve

Document Type: Article
Source: Scopus