Alt Text
Office of Neuroscience Research > Resources and Facilities > WUSTL Neuroscience Publications for the week > Weekly Neuroscience Publications - Archives > WUSTL Neuroscience Publications Archive - December 2012

WUSTL Neuroscience Publications Archive - December 2012

Scopus Weekly Report:

December 20, 2012

December 13, 2012

December 6, 2012

December 2, 2012

 

December 20, 2012  

Xue, J.a , Shan, L.a , Chen, H.a , Li, Y.a , Zhu, H.a , Deng, D.a , Qian, Z.b , Achilefu, S.c , Gu, Y.a
Visual detection of STAT5B gene expression in living cell using the hairpin DNA modified gold nanoparticle beacon
(2013) Biosensors and Bioelectronics, 41 (1), pp. 71-77. 

a Department of Biomedical Engineering, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
b Department of Biomedical Engineering, Nanjing University of Aeronautics and Astronautics, China
c Department of Radiology, School of Medicine, Washington University in St. Louis, MO, United States

Abstract
Signal transducer and activator of transcription 5B (STAT5B) is an important protein in JAK-STAT signaling pathway that is responsible for the metastasis and proliferation of tumor cells. Determination of the STAT5B messenger Ribonucleic Acid (mRNA) relating to the STAT5B expression provides insight into the mechanism of tumor progression. In this study, we designed and used a special hairpin deoxyribonucleic acid (DNA) for human STAT5B mRNA to functionalize gold nanoparticles, which served as a beacon for detecting human STAT5B expression. Up to 90% quenching efficiency was achieved. Upon hybridizing with the target mRNA, the hairpin DNA modified gold nanoparticle beacons (hDAuNP beacons) release the fluorophores attached at 5' end of the oligonucleotide sequence. The fluorescence properties of the beacon before and after the hybridization with the complementary DNA were confirmed in vitro. The stability of hDAuNP beacons against degradation by DNase I and GSH indicated that the prepared beacon is stable inside cells. The detected fluorescence in MCF-7 cancer cells correlates with the specific STAT5B mRNA expression, which is consistent with the result from PCR measurement. Fluorescence microscopy showed that the hDAuNP beacons internalized in cells without using transfection agents, with intracellular distribution in the cytoplasm rather than the nucleus. The results demonstrated that this beacon could directly provide quantitative measurement of the intracellular STAT5B mRNA in living cells. Compared to the previous approaches, this beacon has advantages of higher target to background ratio of detection and an increased resistance to nuclease degradation. The strategy reported in this study is a promising approach for the intracellular measurement of RNA or protein expression in living cells, and has great potential in the study of drug screening and discovery. © 2012 Elsevier B.V.

Author Keywords
Beacon;  Gold nanoparticle;  Hairpin DNA;  Imaging;  STAT5B mRNA;  Visual detection

Document Type: Article
Source: Scopus

 

Feibel, R.M.
Count Sir Luigi Preziosi and His Glaucoma Operation: The Development of Early Glaucoma Filtering Surgery
(2013) Survey of Ophthalmology, 58 (1), pp. 95-101. 

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

Abstract
Count Sir Luigi Preziosi (1888-1965) was a famous ophthalmologist from the island Republic of Malta. He received his ophthalmic training in Rome and the United Kingdom. He practiced ophthalmology in Malta for 45 years and was a professor at the University of Malta. Like many physicians in Malta, he was active in the politics and governance of his country, serving as president of the Senate, president of the National Congress to draft a new constitution, and, finally, as president of the National Assembly of Malta. His most important ophthalmologic contribution was the development of the thermal sclerostomy filtering operation for glaucoma, which he first described in 1924. He referred to this operation initially as electro-cautery puncture and later simply as Preziosi's operation. Many surgeons considered this procedure an advance over the other available filtering operations such as sclerectomy, iridencleisis, and trephination. The operation was then further developed in 1957 by Harold G. Scheie of the University of Pennsylvania. Scheie referred to his procedure as peripheral iridectomy with scleral cautery, and it was a standard filtering operation for glaucoma for many years until the development of trabeculectomy. © 2013 Elsevier Inc.

Author Keywords
Glaucoma filtering surgery;  Peripheral iridectomy with scleral cautery;  Preziosi, Luigi;  Scheie, Harold G;  Thermal sclerostomy

Document Type: Article
Source: Scopus

 

Pineda, J.A.a b , Leonard, J.R.d e , Mazotas, I.G.c , Noetzel, M.b , Limbrick, D.D.d e , Keller, M.S.c , Gill, J.c f g , Doctor, A.a h
Effect of implementation of a paediatric neurocritical care programme on outcomes after severe traumatic brain injury: A retrospective cohort study
(2013) The Lancet Neurology, 12 (1), pp. 45-52. 

a Department of Pediatrics, Division of Critical Care Medicine, Washington University School of Medicine, St Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
c Department of Surgery, Washington University School of Medicine, St Louis, MO, United States
d Department of Neurosurgery, Washington University School of Medicine, St Louis, MO, United States
e Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States
f Department of Political Science, Washington University School of Medicine, St Louis, MO, United States
g Department of Biostatistics, Washington University School of Medicine, St Louis, MO, United States
h Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO, United States

Abstract
Background: Outcomes after traumatic brain injury are worsened by secondary insults; modern intensive-care units address such challenges through use of best-practice pathways. Organisation of intensive-care units has an important role in pathway effectiveness. We aimed to assess the effect of a paediatric neurocritical care programme (PNCP) on outcomes for children with severe traumatic brain injury. Methods: We undertook a retrospective cohort study of 123 paediatric patients with severe traumatic brain injury (Glasgow coma scale scores ≤8, without gunshot or abusive head trauma, cardiac arrest, or Glasgow coma scale scores of 3 with fixed and dilated pupils) admitted to the paediatric intensive-care unit of the St Louis Children's Hospital (St Louis, MO, USA) between July 15, 1999, and Jan 15, 2012. The primary outcome was rate of categorised hospital discharge disposition before and after implementation of a PNCP on Sept 17, 2005. We developed an ordered probit statistical model to assess adjusted outcome as a function of initial injury severity. We assessed care-team behaviour by comparing timing of invasive neuromonitoring and scored intensity of therapies targeting intracranial hypertension. Findings: Characteristics of treated patients (aged 3-219 months) were much the same between treatment periods. Before PNCP implementation, 33 (52%) of 63 patients had unfavourable disposition at hospital discharge (death or admission to an inpatient facility) and 30 (48%) had a favourable disposition (home with or without treatment); after PNCP implementation, 20 (33%) of 60 patients had unfavourable disposition and 40 (67%) had favourable disposition (p=0·01). Seven (11%) patients died before PNCP implementation compared with two (3%) deaths after implementation. The probit model indicated that outcome improved across the spectrum of Glasgow coma scale scores after resuscitation (p=0·02); this improvement progressed with increasing injury severity. Kaplan-Meier analysis suggested that neuromonitoring was started earlier and maintained longer after implementation of the PNCP (p=0·03). Therapeutic intensity scores were increased for the first 3 days of treatment after PNCP implementation (p=0·0298 for day 1, p=0·0292 for day 2, and p=0·0471 for day 3). The probit model suggested that increasing age (p=0·03), paediatric risk of mortality III scores (p=0·0003), and injury severity scores (p=0·02) were reliably associated with increased probability of unfavourable outcomes whereas white race (p=0·01), use of intracranial pressure monitoring (p=0·001), and increasing Glasgow coma scale scores after resuscitation (p=0·04) were associated with increased probability of favourable outcomes. Interpretation: Outcomes for children with traumatic brain injury can be improved by altering the care system in a way that stably implements a cooperative programme of accepted best practice. Funding: St Louis Children's Hospital and the Sean Glanvill Foundations. © 2013 Elsevier Ltd.

Document Type: Article
Source: Scopus

 

Kaul, A., Hussain, I., Gutmann, D.H.
Using genetically engineered mouse models to understand low-grade glioma development and growth in children
(2013) Neuromethods, 77, pp. 203-215. 

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

Abstract
Pilocytic astrocytoma (PA) is the most common brain tumor observed in children. These tumors can form sporadically in children with no underlying genetic disease or in 15-20% of children with neurofibromatosis type 1 (NF1), an inherited cancer predisposition syndrome. Though similar histologically, the genetic basis for PA formation in these two populations are distinct. In the general population, PAs likely arise in response to aberrant BRAF activation, whereas in the context of NF1, they result from bi-allelic inactivation of the NF1 tumor suppressor gene. Since accurate rodent models of sporadic PA are currently under development, Nf1 genetically engineered mouse models have served as tractable systems to study the role of aberrant intracellular signaling, nonneoplastic cells in the tumor microenvironment, and genomic modifiers on gliomagenesis. These small-animal models have also been used as platforms to discover next-generation targeted therapies and to evaluate the efficacy of these potential anticancer treatments prior to clinical trials for NF1-associated astrocytomas. © 2013 Springer Science+Business Media New York.

Author Keywords
Astrocytoma;  Brain tumor;  Genetically engineered mice;  Optic glioma;  Pilocytic astrocytoma

Document Type: Article
Source: Scopus

 

Kelsey, M.a , Politte, D.a , Verner, R.b , Zempel, J.M.c , Nolan, T.a , Babajani-Feremi, A.d , Prior, F.a , Larson-Prior, L.J.a
Determination of neural state classification metrics from the power spectrum of human ECoG
(2012) Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS, art. no. 6346926, pp. 4336-4340. 

a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63110, United States
c Department of Neurology and Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Brain electrical activity exhibits scale-free dynamics that follow power law scaling. Previous works have shown that broadband spectral power exhibits state-dependent scaling with a log frequency exponent that systematically varies with neural state. However, the frequency ranges which best characterize biological state are not consistent across brain location or subject. An adaptive piecewise linear fitting solution was developed to extract features for classification of brain state. Performance was evaluated by comparison to an a posteriori based feature search method. This analysis, using the 1/ characteristics of the human ECoG signal, demonstrates utility in advancing the ability to perform automated brain state discrimination. © 2012 IEEE.

Document Type: Conference Paper
Source: Scopus

 

Gilboa, E.a , La Rosa, P.S.b , Nehorai, A.a
Estimating electrical conductivity tensors of biological tissues using microelectrode arrays
(2012) Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS, art. no. 6346112, pp. 1040-1044. 

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

Abstract
Finding the electrical conductivity of tissue is important for understanding the tissue's structure and functioning. However, the inverse problem of inferring spatial conductivity from data is highly ill-posed and computationally intensive. In this paper, we propose a novel method to solve the inverse problem of inferring tissue conductivity from a set of transmembrane potential and stimuli measurements made by microelectrode arrays (MEA). We propose a parallel optimization algorithm based on a single-step approximation with a parallel alternating optimization routine. This algorithm simplifies the joint tensor field estimation problem into a set of computationally tractable subproblems, allowing the use of efficient standard optimization tools. © 2012 IEEE.

Document Type: Conference Paper
Source: Scopus

 

Holmes, C.D.a , Wronkiewicz, M.b , Somers, T.c , Liu, J.c , Russell, E.c , Kim, D.c , Rhoades, C.c , Dunkley, J.c , Bundy, D.b , Galboa, E.a , Leuthardt, E.d
IPSIHAND BRAVO: An improved EEG-based brain-computer interface for hand motor control rehabilitation
(2012) Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS, art. no. 6346287, pp. 1749-1752. 

a Electrical and Systems Engineering Department, Computer Science Department, Washington University in St. Louis, St. Louis, MO 63130, United States
b Biomedical Engineering Department, Washington University in St. Louis, St. Louis, MO 63130, United States
c School of Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
d Department of Neurosurgery, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Stroke and other nervous system injuries can damage or destroy hand motor control and greatly upset daily activities. Brain computer interfaces (BCIs) represent an emerging technology that can bypass damaged nerves to restore basic motor function and provide more effective rehabilitation. A wireless BCI system was implemented to realize these goals using electroencephalographic brain signals, machine learning techniques, and a custom designed orthosis. The IpsiHand Bravo BCI system is designed to reach a large demographic by using non-traditional brain signals and improving on past BCI system pitfalls. © 2012 IEEE.

Document Type: Conference Paper
Source: Scopus

 

Yablonskiy, D.A.a , Sukstanskii, A.L.a , Luo, J.a , Wang, X.b
Voxel spread function method for correction of magnetic field inhomogeneity effects in quantitative gradient-echo-based MRI
(2012) Magnetic Resonance in Medicine, . Article in Press. 

a Department of Radiology, Washington University in St. Louis, Saint Louis, Missouri, USA
b Department of Physics, Washington University in St. Louis, Saint Louis, Missouri, USA

Abstract
Purpose:: Macroscopic magnetic field inhomogeneities adversely affect different aspects of MRI images. In quantitative MRI when the goal is to quantify biological tissue parameters, they bias and often corrupt such measurements. The goal of this article is to develop a method for correction of macroscopic field inhomogeneities that can be applied to a variety of quantitative gradient-echo-based MRI techniques. Methods:: We have reanalyzed a basic theory of gradient echo MRI signal formation in the presence of background field inhomogeneities and derived equations that allow for correction of magnetic field inhomogeneity effects based on the phase and magnitude of gradient echo data. We verified our theory by mapping effective transverse relaxation rate in computer simulated, phantom, and in vivo human data collected with multigradient echo sequences. Results:: The proposed technique takes into account voxel spread function effects and allowed obtaining virtually free from artifacts effective transverse relaxation rate maps for all simulated, phantom and in vivo data except of the edge areas with very steep field gradients. Conclusion:: The voxel spread function method, allowing quantification of tissue specific effective transverse relaxation rate-related tissue properties, has a potential to breed new MRI biomarkers serving as surrogates for tissue biological properties similar to longitudinal and transverse relaxation rate constants widely used in clinical and research MRI. © 2012 Wiley Periodicals, Inc.

Author Keywords
Gradient echo;  Magnetic field inhomogeneities;  Magnetic susceptibility;  MRI

Document Type: Article in Press
Source: Scopus

 

Wolf, T.J.a b , Rognstad, M.C.a
Changes in cognition following mild stroke

(2012) 
Neuropsychological Rehabilitation, . Article in Press. 

a Programme in Occupational Therapy, Department of Neurology, Washington University School of Medicine, 4444 Forest Park, St. Louis, MO 63108, USA
b Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA

Abstract
The objective of the study was to determine how performance on cognitive assessments administered in the subacute phase of mild stroke change or remain stable over time. A prospective longitudinal cohort pilot study was used to assess the cognitive status of participants with mild stroke (n = 20) at two time points: (1) within 3 weeks post-discharge from the acute care setting following mild stroke, and (2) approximately 6 months post-mild stroke. Participants were given a battery of cognitive assessments at both time points that included the following measures: (1) Short Blessed Test, (2) California Verbal Learning Test (CVLT), (3) Connor's Continuous Performance Task (CPT), and (4) The Delis-Kaplan Executive Function System (DKEFS) Trail Making subtest. The only significant differences between the test administrations was on the CVLT Short Delay Free Recall (p =.027) and Long Delay Free Recall (p =.002) which was likely due to practice effects associated with this measure. The results of the study show that performance on standardised cognitive testing in the early phases of mild stroke remained stable over a 6 month period. These results help justify the necessity and ability to assess cognition immediately post-mild stroke in order to make accurate and appropriate rehabilitation recommendations. © 2012 Copyright Taylor & Francis.

Author Keywords
Cognition;  Executive function;  Neuropsychological tests;  Rehabilitation;  Stroke

Document Type: Article in Press
Source: Scopus

 

Panagopoulos, V.N.a , Trull, T.J.b , Glowinski, A.L.a , Lynskey, M.T.a , Heath, A.C.a , Agrawal, A.a , Henders, A.K.c , Wallace, L.c , Todorov, A.A.a , Madden, P.A.F.a , Moore, E.d , Degenhardt, L.e f , Martin, N.G.c , Montgomery, G.W.c , Nelson, E.C.a
Examining the association of NRXN3 SNPs with borderline personality disorder phenotypes in heroin dependent cases and socio-economically disadvantaged controls
(2012) Drug and Alcohol Dependence, . Article in Press. 

a Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, USA
b Department of Psychological Sciences, University of Missouri, 219 Psychology Building, 200 South 7th Street, Columbia, MO 65211, USA
c Queensland Institute of Medical Research, Royal Brisbane Hospital Post Office, Brisbane, Queensland 4029, Australia
d New South Wales Health, Justice Health and Forensic Mental Health Network, Suite 302, Level 2, Westfield Office Tower, 152 Bunnerong Road, Pagewood, NSW 2036, Australia
e National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW 2052, Australia
f Centre for Health Policy, Programs and Economics, School of Population Health, University of Melbourne, Parkville, VIC 3010, Australia

Abstract
Background: Borderline personality disorder (BPD) and substance use disorders frequently co-occur; their dual presence predicts poor prognosis. The genetic underpinnings of BPD have not been well-characterized and could offer insight into comorbidity. The current report focuses on the association of neurexin 3 (NRXN3) single nucleotide polymorphisms (SNPs) with BPD symptoms in heroin dependent cases and controls. Methods: The sample of the Comorbidity and Trauma Study, a genetic association study of heroin dependence, consists of Australian heroin dependent cases ascertained from opioid replacement therapy clinics and controls ascertained in nearby economically disadvantaged neighborhoods. The assessment included a screening instrument for BPD, used previously in Australian population surveys. Genotypic and BPD phenotypic data were available for 1439 cases and 507 controls. We examined the association of 1430 candidate gene SNPs with BPD phenotypes. Results: One or more NRXN3 SNPs were nominally associated with all BPD phenotypes; however, none met the conservative significance threshold we employed to correct for multiple testing. The most strongly associated SNPs included rs10144398 with identity disturbance (p = 4.9 × 10-5) and rs10151731 with affective instability (p = 8.8 × 10-5). The strongest association with screening positive for BPD was found for the NRXN3 SNP, rs10083466 (p = .0013). Neither the correlation of BPD phenotypes nor the linkage disequilibrium relationships of the SNPs account for the number of observed associations involving NRXN3 SNPs. Conclusions: Our findings provide intriguing preliminary evidence for the association of NRXN3 with BPD phenotypes. The strongest associations were found for traits (i.e., affective instability; identity disturbance) also observed with other disorders. © 2012.

Author Keywords
Borderline personality disorder;  Genetic association study;  Heroin dependence;  NRXN3

Document Type: Article in Press
Source: Scopus

 

Aoun, S.G.a , Bendok, B.R.a , Rahme, R.J.a , Dacey Jr., R.G.b , Batjer, H.H.a
Standardizing the Evaluation of Scientific and Academic Performance in Neurosurgery-Critical Review of the "h" Index and its Variants
(2012) World Neurosurgery, . Article in Press. 

a Department of Neurological Surgery, Feinberg School of Medicine and McGaw Medical Center, Northwestern University, Chicago, Illinois, USA
b Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri, USA

Abstract
Assessing the academic impact and output of scientists and physicians is essential to the academic promotion process and has largely depended on peer review. The inherent subjectivity of peer review, however, has led to an interest to incorporate objective measures into more established methods of academic assessment and promotion. Journal impact factor has been used to add objectivity to the process but this index alone does not capture all aspects of academic impact and achievement. The "h" index and its variants have been designed to compensate for these shortcomings, and have been successfully used in the fields of physics, mathematics, and biology, and more recently in medicine. Leaders in academic neurosurgery should be aware of the advantages offered by each of these indices, as well as of their individual shortcomings, to be able to efficiently use them to refine the peer-review process. This review critically analyzes indices that are currently available to evaluate the academic impact of scientists and physicians. These indices include the total citation count, the total number of papers, the impact factor, as well as the "h" index with eight of its most common variants. The analysis focuses on their use in the field of academic neurosurgery, and discusses means to implement them in current review processes. © 2012 Elsevier Inc. All rights reserved.

Author Keywords
"h" index;  Academic output;  Impact factor;  Neurosurgery;  Peer-review;  Promotion;  Research;  Tenure

Document Type: Article in Press
Source: Scopus

 

Harari, O.a , Wang, J.-C.a , Bucholz, K.a , Edenberg, H.J.b , Heath, A.a , Martin, N.G.c , Pergadia, M.L.a , Montgomery, G.d , Schrage, A.a , Bierut, L.J.a , Madden, P.F.a , Goate, A.M.a
Pathway Analysis of Smoking Quantity in Multiple GWAS Identifies Cholinergic and Sensory Pathways
(2012) PLoS ONE, 7 (12), art. no. e50913, . 

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Biochemistry and Molecular Biology, School of Medicine, Indiana University, Indianapolis, IN, United States
c Genetic Epidemiology, Queensland Institute of Medical Research, Brisbane, Australia
d Molecular Epidemology, Queensland Institute of Medical Research, Brisbane, Australia

Abstract
Cigarette smoking is a common addiction that increases the risk for many diseases, including lung cancer and chronic obstructive pulmonary disease. Genome-wide association studies (GWAS) have successfully identified and validated several susceptibility loci for nicotine consumption and dependence. However, the trait variance explained by these genes is only a small fraction of the estimated genetic risk. Pathway analysis complements single marker methods by including biological knowledge into the evaluation of GWAS, under the assumption that causal variants lie in functionally related genes, enabling the evaluation of a broad range of signals. Our approach to the identification of pathways enriched for multiple genes associated with smoking quantity includes the analysis of two studies and the replication of common findings in a third dataset. This study identified pathways for the cholinergic receptors, which included SNPs known to be genome-wide significant; as well as novel pathways, such as genes involved in the sensory perception of smell, that do not contain any single SNP that achieves that stringent threshold. © 2012 Harari et al.

Document Type: Article
Source: Scopus

 

Wacker, B.K.a , Perfater, J.L.a , Gidday, J.M.a b
Hypoxic preconditioning induces stroke tolerance in mice via a cascading HIF, sphingosine kinase, and CCL2 signaling pathway
(2012) Journal of Neurochemistry, 123 (6), pp. 954-962. 

a Department of Neurosurgery, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, MO 63110, United States
b Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO, United States

Abstract
The induction of ischemic tolerance by preconditioning provides a platform to elucidate endogenous mechanisms of stroke protection. In these studies, we characterize the relationship between hypoxia-inducible factor (HIF), sphingosine kinase 2 (SphK2), and chemokine (C-C motif) ligand 2 (CCL2) in models of hypoxic or pharmacological preconditioning-induced ischemic tolerance. A genetics-based approach using SphK2- and CCL2-null mice showed both SphK2 and CCL2 to be necessary for the induction of ischemic tolerance following preconditioning with hypoxia, the hypoxia-mimetic cobalt chloride, or the sphingosine-1-phosphate (S1P) agonist FTY720. A pharmacological approach confirmed the necessity of HIF signaling for all three preconditioning stimuli, and showed that the SphK/S1P pathway transduces tolerance via the S1P 1 receptor. In addition, our data suggest significant cross-talk between HIF and SphK2-produced S1P signaling, which together act to up-regulate CCL2 expression. Overall, HIF, SphK, S1P, and CCL2 participate in a signaling cascade to induce the gene expression responsible for the stroke-tolerant phenotype established by hypoxic and FTY720 preconditioning. The identification of these common molecular mediators involved in signaling the genomic response to multiple preconditioning stimuli provides several targets for therapeutic manipulation. Signaling the preconditioning genomic response Preconditioning for stroke tolerance with hypoxia, cobalt, and FTY720 requires HIF activity and SphK2-generated S1P signaling via the S1P1 receptor. In turn, cross-talk/feedback between HIF and S1P signaling up-regulates CCL2 expression to induce this epigenetic response. The identification herein of multiple upstream mediators of ischemic tolerance provides several targets of translational relevance for preconditioning in humans. © 2012 International Society for Neurochemistry.

Author Keywords
bioactive lipids;  chemokines;  neuroprotection;  sphingosine-1-phosphate

Document Type: Article
Source: Scopus

 

Yeung, C.C.S., Mills, J.C., Hassan, A., Kreisel, F.H., Nguyen, T.T., Frater, J.L.
MIST1-a novel marker of plasmacytic differentiation
(2012) Applied Immunohistochemistry and Molecular Morphology, 20 (6), pp. 561-565. 

Department of Pathology and Immunology, Washington University, 660 South Euclid Avenue, St Louis, MO 63110, United States

Abstract
BACKGROUND: Currently available plasma cell markers include CD138 and CD38. However, CD38 is not specific to plasma cells. It is also expressed by many epithelial cells and other hematopoietic cells. In addition, rare CD138-negative PCNs may be exceedingly difficult to diagnose. MIST1 is a transcription factor expressed by mouse and human neoplastic and non-neoplastic plasma cells. Our goals were to compare MIST1 expression to CD38/CD138 in neoplasms with plasmacytic differentiation, assess reactivity in normal samples and nonplasmacytic cell lineages, and to determine whether MIST1 is expressed in CD138-negative PCNs. DESIGN: Eighty-five neoplasms with plasma cell differentiation [marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma (LPL), plasmablastic lymphoma (PB), plasma cell neoplasm (PCN)] and 2 non-neoplastic cases (normal marrow) were tested with MIST1 immunohistochemistry. CD138/38 expression for each case was compared with MIST1 reactivity. RESULTS: Plasma cells were MIST1 positive in all cases interrogated. CD38 and/or CD138 expression was reviewed in all cases and found to be concordant in 46/47 (97.8%) of tested cases, with the exception of 1 case of PB that showed MIST1 positivity and no CD138 expression. All other cell lineages were negative, with the exception of MZL and LPL, in which MIST1 highlighted a subset of the lymphocytes, with plasmacytic differentiation. CONCLUSIONS: MIST1 is a sensitive and specific marker of plasmacytic differentiation. CD138+ plasma cells expressed MIST1 in all tested cases; however, 1 PB showed MIST1 positivity and no CD138 expression, suggesting MIST1 may be useful in certain CD138-negative cases. In MZL and LPL, MIST1 highlights a subset of the lymphocytes in lymphomas with plasmacytic differentiation. Copyright © 2012 by Lippincott Williams & Wilkins.

Author Keywords
immunohistochemistry;  lymphoma;  MIST1;  plasma cell neoplasm;  plasmablastic lymphoma;  plasmacytic differentiation

Document Type: Article
Source: Scopus

 

Johnson, K.J.a b c , Fisher, M.J.d e , Listernick, R.L.f , North, K.N.g , Schorry, E.K.h , Viskochil, D.i , Weinstein, M.j , Rubin, J.B.k , Gutmann, D.H.l
Parent-of-origin in individuals with familial neurofibromatosis type 1 and optic pathway gliomas
(2012) Familial Cancer, 11 (4), pp. 653-656. 

a Brown School, Washington University in St. Louis, St. Louis, MO 63130, United States
b Department of Pediatrics, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
c Public Health Program, George Warren Brown School, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130, United States
d Department of Oncology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, United States
e Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
f Children's Memorial Hospital, Chicago, IL, United States
g University of Sydney, Sydney, Australia
h Cincinnati Children's Hospital, Cincinnati, OH, United States
i University of Utah, Salt Lake City, UT, United States
j Sick Kids, University of Toronto, Toronto, Canada
k Division of Pediatric Hematology-Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
l Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant cancer syndromes worldwide. Individuals with NF1 have a wide variety of clinical features including a strongly increased risk for pediatric brain tumors. The etiology of pediatric brain tumor development in NF1 is largely unknown. Recent studies have highlighted the contribution of parent-oforigin effects to tumorigenesis in sporadic cancers and cancer predisposition syndromes; however, there is limited data on this effect for cancers arising in NF1. To increase our understanding of brain tumor development in NF1, we conducted a multi-center retrospective chart review of 240 individuals with familial NF1 who were diagnosed with a pediatric brain tumor (optic pathway glioma; OPG) to determine whether a parent-of-origin effect exists overall or by the patient's sex. Overall, 50 % of individuals with familial NF1 and an OPG inherited the NF1 gene from their mother. Similarly, by sex, both males and females were as likely to inherit the NF1 gene from their mother as from their father, with 52 % and 48 % of females and males with OPGs inheriting the NF1 gene from their mother. In conclusion, in contrast to findings from other studies of sporadic cancers and cancer predisposition syndromes, our results indicate no parent-of-origin effect overall or by patient sex for OPGs in NF1. © Springer Science+Business Media B.V. 2012.

Author Keywords
Brain tumor;  Neurofibromatosis type 1;  Optic pathway glioma;  Parent-of-origin

Document Type: Article
Source: Scopus

 

Kaul, A.a , Chen, Y.-H.a , Emnett, R.J.a , Dahiya, S.b , Gutmann, D.H.a
Pediatric glioma-associated KIAA1549: BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner
(2012) Genes and Development, 26 (23), pp. 2561-2566. 

a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63108, United States
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63108, United States

Abstract
Tandem duplications involving the BRAF kinase gene have recently been identified as the most frequent genetic alteration in sporadic pediatric glioma, creating a novel fusion protein (f-BRAF) with increased BRAF activity. To define the role of f-BRAF in gliomagenesis, we demonstrate that f-BRAF regulates neural stem cell (NSC), but not astrocyte, proliferation and is sufficient to induce glioma-like lesions in mice. Moreover, f-BRAF-driven NSC proliferation results from tuberin/Rheb-mediated mammalian target of rapamycin (mTOR) hyperactivation, leading to S6-kinase-dependent degradation of p27. Collectively, these results establish mTOR pathway activation as a key growth regulatory mechanism common to both sporadic and familial low-grade gliomas in children. © 2012 by Cold Spring Harbor Laboratory Press.

Author Keywords
Astrocytes;  Neural stem cells;  Pilocytic astrocytoma

Document Type: Article
Source: Scopus

 

Human, T.a , Onuoha, A.b , Diringer, M.b , Dhar, R.b
Response to a bolus of conivaptan in patients with acute hyponatremia after brain injury
(2012) Journal of Critical Care, 27 (6), pp. 745.e1-745.e5. 

a Department of Clinical Pharmacy, Neurology/Neurosurgery Intensive Care Unit, Barnes-Jewish Hospital, Saint Louis, MO, United States
b Department of Neurology (Division of Neurocritical Care), Washington University School of Medicine, Saint Louis, MO 63110, United States

Abstract
Purpose: The aim of the study was to analyze the response to the vasopressin-receptor antagonist conivaptan in a large cohort of brain-injured patients with acute hyponatremia. Materials and Methods: The natremic response (rise in serum sodium) to an initial bolus of conivaptan was retrospectively evaluated in 124 patients over a 3-year period in our neurosciences intensive care unit. Variables associated with this response were identified using linear regression. Results: Median pretreatment sodium was 132 mEq/L, and duration of hyponatremia before dose was 1 day. Median natremic response was +4 mEq/L (interquartile range, 2-7 mEq/L), measured a median of 9 hours (interquartile range, 6-12 hours) after conivaptan administration. This was associated with significant urine output (median, 2.6 L over 12 hours), with degree of aquaresis associated with natremic response (regression coefficient, B = 1.8 change in sodium per liter; 95% confidence interval, 1.3-2.4; P < .001). Seventy-four patients (60%) responded with a rise of at least 4 mEq/L. Response was predicted by higher baseline urine output (B = 0.018 per mL; 0.004-0.032; P = .01) and lack of oral fluid intake (B = 2.06; 0.44-3.68; P = .01) but not tonicity of intravenous fluids or creatinine clearance. Conclusions: Conivaptan given as a bolus can effectively treat acute hyponatremia in brain-injured patients. © 2012 Elsevier Inc.

Author Keywords
Brain injury;  Conivaptan;  Hyponatremia;  SIADH;  Vasopressin

Document Type: Article
Source: Scopus

 

De Bruin, G.a b , Pereira Da Silva, R.a
Stroke complicating traumatic ventricular septal defect
(2012) Journal of Emergency Medicine, 43 (6), pp. 987-988. 

a Department of Internal Medicine, Division of Cardiology, Universidade Federal Do Ceara, Fortaleza, Ceara, Brazil
b Department of Neurology, Washington University, Barnes-Jewish Hospital, 660 South Euclid Avenue, St Louis, MO 63110, United States

Abstract
Background: Traumatic ventricular septal defect (VSD) occurs in approximately 5% of blunt or penetrating cardiac injuries and can result in rare complications. Objectives: To report the serious complication of stroke after a traumatic VSD. Case report: A 27-year-old man with no previous medical history presented to the Emergency Department with aphasia and right hemiparesis after a stab wound to the chest. He underwent emergent evacuation of a pericardial effusion and repair of a right ventricular wall perforation. Head computed tomography revealed left middle cerebral artery infarct. Post-operatively, he was noted to have a cardiac murmur, and echocardiogram revealed a VSD. The VSD was surgically repaired without complication. Conclusion: Stroke can complicate traumatic VSDs.

Author Keywords
embolic;  stab wound;  stroke;  traumatic;  VSD

Document Type: Article
Source: Scopus

 

Karch, C.M., Jeng, A.T., Nowotny, P., Cady, J., Cruchaga, C., Goate, A.M.
Expression of Novel Alzheimer's Disease Risk Genes in Control and Alzheimer's Disease Brain

(2012) PLoS ONE, 7 (11), art. no. e50976, . 

Department of Psychiatry, Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, United States

Abstract
Late onset Alzheimer's disease (LOAD) etiology is influenced by complex interactions between genetic and environmental risk factors. Large-scale genome wide association studies (GWAS) for LOAD have identified 10 novel risk genes: ABCA7, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A6A, MS4A6E, and PICALM. We sought to measure the influence of GWAS single nucleotide polymorphisms (SNPs) and gene expression levels on clinical and pathological measures of AD in brain tissue from the parietal lobe of AD cases and age-matched, cognitively normal controls. We found that ABCA7, CD33, and CR1 expression levels were associated with clinical dementia rating (CDR), with higher expression being associated with more advanced cognitive decline. BIN1 expression levels were associated with disease progression, where higher expression was associated with a delayed age at onset. CD33, CLU, and CR1 expression levels were associated with disease status, where elevated expression levels were associated with AD. Additionally, MS4A6A expression levels were associated with Braak tangle and Braak plaque scores, with elevated expression levels being associated with more advanced brain pathology. We failed to detect an association between GWAS SNPs and gene expression levels in our brain series. The minor allele of rs3764650 in ABCA7 is associated with age at onset and disease duration, and the minor allele of rs670139 in MS4A6E was associated with Braak tangle and Braak plaque score. These findings suggest that expression of some GWAS genes, namely ABCA7, BIN1, CD33, CLU, CR1 and the MS4A family, are altered in AD brains. © 2012 Karch et al.

Document Type: Article
Source: Scopus

 

Liu, Y.a b , York, T.c , Akers, W.a , Sudlow, G.a , Gruev, V.c , Achilefu, S.a b
Complementary fluorescence-polarization microscopy using division-of-focal-plane polarization imaging sensor
(2012) Journal of Biomedical Optics, 17 (11), art. no. 116001, . 

a Washington University, Department of Radiology, St. Louis, MO 63110, United States
b Washington University, Department of Biomedical Engineering, St. Louis, MO 63110, United States
c Washington University, Department of Computer Science and Engineering, St. Louis, MO 63110, United States

Abstract
Fluorescence microscopy offers high sensitivity for disease diagnosis. However, little structural information is revealed by this method, requiring another technique to localize the source of fluorescence. We developed a complementary fluorescence-polarization microscope. We used a division-of-focal-plane charge coupled device polarization sensor to enable real-time video rate polarization imaging without any moving parts. The polarization information provided by the microscope enabled detection of structural element and complements the fluorescence information. Application of this multimodal system for cancer imaging using a tumor selective molecular probe revealed the association of diminished structural integrity of tumor tissue with high fluorescence of the imaging agent compared to surrounding normal tissue. This study demonstrates a new paradigm to improve cancer detection and diagnosis. © 2012 Society of Photo-Optical Instrumentation Engineers (SPIE).

Author Keywords
fluorescence microscopy;  molecular probe;  near infrared;  polarization microscopy;  surgical margin;  tumor imaging

Document Type: Article
Source: Scopus

 

Nie, L., Cai, X., Maslov, K., Garcia-Uribe, A., Anastasio, M.A., Wang, L.V.
Photoacoustic tomography through a whole adult human skull with a photon recycler
(2012) Journal of Biomedical Optics, 17 (11), art. no. 110506, . 

Washington University, Department of Biomedical Engineering, St. Louis, One Brookings Drive, Saint Louis, MO 63110, United States

Abstract
Photoacoustic tomography (PAT) of the human brain is challenging due to the fact that the skull strongly absorbs and scatters light, and attenuates and distorts ultrasound as well. For the first time, we demonstrated the feasibility of PAT through a whole adult human skull. A photon recycler (PR) was built to increase light transmittance through the skull. Both a graphite target and a canine brain were imaged through the skull. Use of the PR was found to improve the photoacoustic signal-to-noise ratio by a factor of 2.4. In addition, subtraction of photoacoustic signals that arise from light absorption within the skull significantly improved the contrast of the target. Our results indicate that PAT can potentially be applied to in vivo human brain imaging. © 2012 Society of Photo-Optical Instrumentation Engineers (SPIE).

Author Keywords
human brain imaging;  optical scattering;  photoacoustic tomography;  skull absorption;  subtraction imaging;  transcranial imaging

Document Type: Article
Source: Scopus

 

Webb, A.B.a e , Taylor, S.R.b , Thoroughman, K.A.c , Doyle III, F.J.d , Herzog, E.D.a
Weakly Circadian Cells Improve Resynchrony
(2012) PLoS Computational Biology, 8 (11), art. no. e1002787, . 

a Department of Biology, Washington University, St. Louis, MO, United States
b Department of Computer Science, Colby College, Waterville, ME, United States
c Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
d Department of Chemical Engineering, University of California Santa Barbara, Santa Barbara, CA, United States
e Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

Abstract
The mammalian suprachiasmatic nuclei (SCN) contain thousands of neurons capable of generating near 24-h rhythms. When isolated from their network, SCN neurons exhibit a range of oscillatory phenotypes: sustained or damping oscillations, or arrhythmic patterns. The implications of this variability are unknown. Experimentally, we found that cells within SCN explants recover from pharmacologically-induced desynchrony by re-establishing rhythmicity and synchrony in waves, independent of their intrinsic circadian period We therefore hypothesized that a cell's location within the network may also critically determine its resynchronization. To test this, we employed a deterministic, mechanistic model of circadian oscillators where we could independently control cell-intrinsic and network-connectivity parameters. We found that small changes in key parameters produced the full range of oscillatory phenotypes seen in biological cells, including similar distributions of period, amplitude and ability to cycle. The model also predicted that weaker oscillators could adjust their phase more readily than stronger oscillators. Using these model cells we explored potential biological consequences of their number and placement within the network. We found that the population synchronized to a higher degree when weak oscillators were at highly connected nodes within the network. A mathematically independent phase-amplitude model reproduced these findings. Thus, small differences in cell-intrinsic parameters contribute to large changes in the oscillatory ability of a cell, but the location of weak oscillators within the network also critically shapes the degree of synchronization for the population. © 2012 Webb et al.

Document Type: Article
Source: Scopus

 

Lee, M.H., Solowski, N., Wineland, A., Okuyemi, O., Nicklaus, J., Kallogjeri, D., Piccirillo, J.F., Burton, H.
Functional connectivity during modulation of tinnitus with orofacial maneuvers
(2012) Otolaryngology - Head and Neck Surgery (United States), 147 (4), pp. 757-762. 

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

Abstract
Objective. To determine changes in cortical neural networks as defined by resting-state functional connectivity magnetic resonance imaging during voluntary modulation of tinnitus with orofacial maneuvers. Study Design. Cross-sectional study. Setting. Academic medical center. Subjects and Methods. Participants were scanned during the maneuver and also at baseline to serve as their own control. The authors chose, a priori, 58 seed regions to evaluate previously described cortical neural networks by computing temporal correlations between all seed region pairs. Seed regions whose correlations significantly differed between rest and maneuver (P < 05, uncorrected) entered into a second-stage analysis of computing the correlation coefficient between the seed region and time courses in each of the remaining brain voxels. A threshold-free cluster enhancement permutation analysis evaluated the distribution of these correlation coefficients after transformation to Fisher z scores and registration to a surface-based reconstruction using Freesurfer. Results. The median age for the 16 subjects was 54 years (range, 27-72 years), and all had subjective, unilateral or bilateral, nonpulsatile tinnitus for 6 months or longer. In 9 subjects who could voluntarily increase the loudness of their tinnitus, there were no significant differences in functional connectivity in any cortical networks. A separate analysis evaluated results from 3 patients who decreased the loudness of their tinnitus. Four subjects were excluded because of excessive motion in the scanner. Conclusion. The absence of significant differences in functional connectivity due to voluntary orofacial maneuvers that increased tinnitus loudness failed to confirm prior reports of altered cerebral blood flows during somatomotor behaviors. © 2012 American Academy of Otolaryngology - Head and Neck Surgery Foundation.

Author Keywords
imaging;  tinnitus

Document Type: Article
Source: Scopus

 

Yazlovitskaya, E.M., Hallahan, D.E.
Molecular targeted drug delivery radiotherapy
(2011) Current Cancer Research, 19, pp. 187-200. 

Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park, Suite 200, St. Louis, MO 63130, United States

Abstract
This chapter discusses prosurvival signal transduction pathways, such as PI3K/Akt and MAPK/ERK signaling, induced by ionizing radiation in the tumor microvasculature. Molecular targeting of these radiation-induced signaling pathways provides a means to enhance tumor control. Preclinical studies show that this approach improves the efficacy of radiotherapy in mouse models of cancer. © Springer Science+Business Media, LLC 2011.

Author Keywords
Molecular targeting;  Radiotherapy;  Signal transduction pathways

Document Type: Article
Source: Scopus

December 13, 2012  

Arsikere, H.a , Leung, G.K.F.a , Lulich, S.M.b , Alwan, A.a
Automatic estimation of the first three subglottal resonances from adults' speech signals with application to speaker height estimation
(2013) Speech Communication, 55 (1), pp. 51-70. 

a Electrical Engineering Department, University of California, Los Angeles, 56-125B Engineering IV Building, Box 951594, Los Angeles, CA 90095, United States
b Department of Psychology, Washington University, Saint Louis, MO 63130, United States

Abstract
Recent research has demonstrated the usefulness of subglottal resonances (SGRs) in speaker normalization. However, existing algorithms for estimating SGRs from speech signals have limited applicability - they are effective with isolated vowels only. This paper proposes a novel algorithm for estimating the first three SGRs (Sg1,Sg2 and Sg3) from continuous adults' speech. While Sg1 and Sg2 are estimated based on the phonological distinction they provide between vowel categories, Sg3 is estimated based on its correlation with Sg2. The RMS estimation errors (approximately 30, 60 and 100 Hz for Sg1,Sg2 and Sg3, respectively) are not only comparable to the standard deviations in the measurements, but also are independent of vowel content and language (English and Spanish). Since SGRs correlate with speaker height while remaining roughly constant for a given speaker (unlike vocal tract parameters), the proposed algorithm is applied to the task of height estimation using speech signals. The proposed height estimation method matches state-of-the-art algorithms in performance (mean absolute error = 5.3 cm), but uses much less training data and a much smaller feature set. Our results, with additional analysis of physiological data, suggest the existence of a limit to the accuracy of speech-based height estimation. © 2012 Elsevier B.V. All rights reserved.

Author Keywords
Automatic estimation;  Bilingual speakers;  Speaker height;  Subglottal resonances

Document Type: Article
Source: Scopus

 

North, C.S.a b c , Hong, B.A.d , Adewuyi, S.A.b , Pollio, D.E.e , Jain, M.K.f , Devereaux, R.g , Quartey, N.A.h , Ashitey, S.i , Lee, W.M.j , Lisker-Melman, M.k
Hepatitis C treatment and SVR: the gap between clinical trials and real-world treatment aspirations
(2012) General Hospital Psychiatry, . Article in Press. 

a The VA North Texas Health Care System, Dallas, TX, USA
b Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA
c Surgery/Division of Emergency Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
e The University of Alabama School of Social Work, Tuscaloosa, AL, USA
f Internal Medicine/Divisions of Infectious Diseases, The University of Texas Southwestern Medical Center, Dallas, TX, USA
g The University of Texas Southwestern Graduate School of Biomedical Sciences, Dallas, TX, USA
h Department of Internal Medicine, Tulane University School of Medicine, New Orleans, LA, USA
i Department of Family Medicine, John Peter Smith Hospital, Fort Worth, TX, USA
j Digestive and Liver Diseases, The University of Texas Southwestern Medical Center, Dallas, TX, USA
k Internal Medicine/Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA

Abstract
Objective: Despite the remarkable improvements in pharmacologic treatment efficacy for hepatitis C (HCV) reported in published clinical trials, published research suggests that, in "real-world" patient care, these medical outcomes may be difficult to achieve. This review was undertaken to summarize recent experience in the treatment of HCV in clinical settings, examining the course of patients through the stages of treatment and barriers to treatment encountered. Method: A comprehensive and representative review of the relevant literature was undertaken to examine HCV treatment experience outside of clinical trials in the last decade. This review found 25 unique studies with data on course of treatment and/or barriers to treatment in samples of patients with HCV not preselected for inclusion in clinical trials. Results: Results were examined separately for samples selected for HCV infection versus HCV/HIV coinfection. Only 19% of HCV-selected and 16% of HCV/HIV-coinfection selected patients were considered treatment eligible and advanced to treatment; even fewer completed treatment (13% and 11%, respectively) or achieved sustained virologic response (3% and 6%, respectively). Psychiatric and medical ineligibilities were the primary treatment barriers. Conclusion: Only by systematically observing and addressing potentially solvable medical and psychosocial barriers to treatment will more patients be enrolled in and complete HCV therapy.

Author Keywords
Course of treatment;  HCV/HIV coinfection;  Hepatitis C;  Psychosocial barriers to treatment;  Sustained virologic response

Document Type: Article in Press
Source: Scopus

 

Hyun, S.-J.a , Riew, K.D.b , Rhim, S.-C.c
Range of motion loss after cervical laminoplasty: a prospective study with minimum 5-year follow-up data
(2012) Spine Journal, . Article in Press. 

a Department of Neurosurgery, Spine Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, Korea
b Department of Orthopaedic Surgery, Barnes-Jewish Hospital at Washington University, School of Medicine, Suite 1100 WP, 1 Barnes-Jewish Plaza, Campus Box 8233, St. Louis, MO 63110, USA
c Department of Neurosurgery, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-2dong Songpa-Gu, Seoul 138-736, Korea

Abstract
Background context: Although numerous studies have reported on the loss of flexion-extension range of motion (ROM) associated with laminoplasty, few have reported on the time course of this loss of motion for a long-term follow-up period. Purpose: We previously reported our early data on postlaminoplasty cervical ROM. In this article, we describe our minimum 5-year follow-up data to identify the time-dependent change in ROM after cervical laminoplasty. Study design: A prospective cohort study. Patient sample: The procedure was performed in 23 patients. Eighteen patients with a minimum 5-year follow-up were included in the study. Outcome measures: The time-dependent neck ROM changes observed in the neutral, flexion, and extension radiographs were used to measure the radiological outcome. The Japanese Orthopaedic Association classification and a numerical rating scale of axial neck pain and arm pain were used to evaluate clinical outcome. Methods: Twenty-three patients who received unilateral open-door laminoplasties, including miniplate fixation over three levels, were serially evaluated at regular set intervals postoperatively. Eighteen patients with a minimum 5-year follow-up were included in the study. The mean follow-up period was 68.1 months (range, 60-78 months). Nine patients had ossification of posterior longitudinal ligament (OPLL) and nine patients had cervical spondylotic myelopathy (CSM). Enrolled patients were divided into subgroups (OPLL vs. CSM; autofusion vs. nonautofusion) to compare the ROM between the groups. We evaluated the time-dependent neck ROM changes by taking neutral, flexion, and extension radiographs preoperatively and at 1, 3, 6, 9, 12, 18, and 24 months postoperatively. Follow-up radiographs were taken annually after a 2-year follow-up. Results: The preoperative and 1-, 3-, 6-, 12-, 24-, 36-, 48-, and 60-month postoperative ROM figures were 39.9±11.2°, 35.0±9.2°, 33.0±11.0°, 30.1±10.4°, 25.8±13.1°, 24.7±10.0°, 23.8±6.5°, 24.6±8.3°, and 23.6±9.4°, respectively, and at the most recent follow-up, ROM was 24.5±10.1°. Thus, the mean ROM decreased by 15.4±8.4° (38.5%) by the last follow-up (p<.0001). In the OPLL group, we observed a more limited cervical ROM than in the CSM group (47.2% vs. 72.7%). As expected, in the laminar autofusion group, the ROM decreased significantly (55.6% decrease), whereas in the nonautofusion group, the ROM decreased less significantly (13.4% decrease) at the last follow-up. Postoperative axial pain did not correlate with the cervical ROM. Conclusions: These results suggest that the loss of cervical ROM after laminoplasty is time-dependent, and patients with OPLL and laminar autofusion had less ROM. Postlaminoplasty ROM reduction can recover after several years, unless laminar autofusion occurs. © 2012 Elsevier Inc. All rights reserved.

Author Keywords
Cervical spine;  Laminoplasty;  Ossification of the posterior longitudinal ligament;  Range of motion;  Spondylosis

Document Type: Article in Press
Source: Scopus

 

Galanek, J.D.
The Cultural Construction of Mental Illness in Prison: A Perfect Storm of Pathology
(2012) Culture, Medicine and Psychiatry, pp. 1-31. Article in Press. 

Brown School of Social Work, Washington University in St Louis, St. Louis, United States

Abstract
Large numbers of individuals in U.S. prisons meet DSM criteria for severe psychiatric disorder. These individuals also have co-occurring personality and substance abuse disorders, medical conditions, and histories of exposure to social pathologies. Based on nine months of ethnographic fieldwork in a U.S. prison, focusing on staff narratives, I utilize interpretivist and constructivist perspectives to analyze how mental health clinicians construct psychiatric disorder among inmates. Discrete categorization of disorders may be confounded by the clinical co-morbidities of inmates and the prison context. Incarcerated individuals' responses to the institutional context substantially inform mental health staffs' illness construction and the prison itself is identified as an etiological agent for disordered behaviors. In addition, diagnostic processes are found to be indeterminate, contested, and shaped by interactions with staff. Analysis of illness construction reveals that what is at stake for clinicians is not only provision of appropriate treatment, but also mandates for the safety and security of the institution. Enmeshed in these mandates, prison mental health becomes a particular local form of psychiatric knowledge. This paper contributes to anthropological approaches to mental disorder by demonstrating how local contexts mediate psychiatric knowledge and contribute to the limited ethnographic record of prisons. © 2012 Springer Science+Business Media New York.

Author Keywords
Co-occurring disorders;  Illness construction;  Medical anthropology;  Mental illness;  Prison

Document Type: Article in Press
Source: Scopus

 

Amin, N.a , Hottenga, J.-J.b , Hansell, N.K.c , Janssens, A.C.J.d , de Moor, M.H.b , Madden, P.A.e , Zorkoltseva, I.V.f , Penninx, B.W.g h i , Terracciano, A.j , Uda, M.k , Tanaka, T.j , Esko, T.l , Realo, A.l , Ferrucci, L.j , Luciano, M.m , Davies, G.m , Metspalu, A.l , Abecasis, G.R.n , Deary, I.J.m , Raikkonen, K.o , Bierut, L.J.e , Costa, P.T.j , Saviouk, V.b , Zhu, G.c , Kirichenko, A.V.f , Isaacs, A.a , Aulchenko, Y.S.a , Willemsen, G.b , Heath, A.C.e , Pergadia, M.L.e , Medland, S.E.c , Axenovich, T.I.f , de Geus, E.b , Montgomery, G.W.c , Wright, M.J.c , Oostra, B.A.p q , Martin, N.G.c , Boomsma, D.I.b , van Duijn, C.M.p r
Refining genome-wide linkage intervals using a meta-analysis of genome-wide association studies identifies loci influencing personality dimensions
(2012) European Journal of Human Genetics, . Article in Press. 

a Unit of Genetic Epidemiology, Department of Epidemiology and Biostatistics, Erasmus University Medical Center, Rotterdam, The Netherlands
b Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands
c Queensland Institute of Medical Research, Brisbane, QLD, Australia
d Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
e Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA
f Institute of Cytology and Genetics, Russian Academy of Science, Novosibirsk, Russia
g 1] Department of Psychiatry, University Medical Center Groningen, Groningen, The Netherlands
h Departments of Clinical Psychology and Psychiatry, Leiden University, Leiden, The Netherlands
i Department of Psychiatry, EMGO+ Institute, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, Amsterdam, The Netherlands
j National Institute on Aging, NIH, Baltimore, MD, USA
k Istituto di Neurogenetica e Neurofarmacologia, CNR, Monserrato, Cagliari, Italy
l Estonian Genome Project, University of Tartu and Estonian Biocentre, Tartu, Estonia
m Department of Psychology, Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK
n Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA
o Department of Psychology, University of Helsinki, Helsinki, Finland
p 1] Unit of Genetic Epidemiology, Department of Epidemiology and Biostatistics, Erasmus University Medical Center, Rotterdam, The Netherlands
q Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
r Centre of Medical Systems Biology, Leiden, Netherlands Consortium on Health Aging and National Genomics Initiative, the Hague, The Netherlands

Abstract
Personality traits are complex phenotypes related to psychosomatic health. Individually, various gene finding methods have not achieved much success in finding genetic variants associated with personality traits. We performed a meta-analysis of four genome-wide linkage scans (N=6149 subjects) of five basic personality traits assessed with the NEO Five-Factor Inventory. We compared the significant regions from the meta-analysis of linkage scans with the results of a meta-analysis of genome-wide association studies (GWAS) (N
17 000). We found significant evidence of linkage of neuroticism to chromosome 3p14 (rs1490265, LOD=4.67) and to chromosome 19q13 (rs628604, LOD=3.55); of extraversion to 14q32 (ATGG002, LOD=3.3); and of agreeableness to 3p25 (rs709160, LOD=3.67) and to two adjacent regions on chromosome 15, including 15q13 (rs970408, LOD=4.07) and 15q14 (rs1055356, LOD=3.52) in the individual scans. In the meta-analysis, we found strong evidence of linkage of extraversion to 4q34, 9q34, 10q24 and 11q22, openness to 2p25, 3q26, 9p21, 11q24, 15q26 and 19q13 and agreeableness to 4q34 and 19p13. Significant evidence of association in the GWAS was detected between openness and rs677035 at 11q24 (P-value=2.6 × 10 -06, KCNJ1). The findings of our linkage meta-analysis and those of the GWAS suggest that 11q24 is a susceptible locus for openness, with KCNJ1 as the possible candidate gene.European Journal of Human Genetics advance online publication, 5 December 2012; doi:10.1038/ejhg.2012.263.

Document Type: Article in Press
Source: Scopus

 

Saccone, S.F.
Applying In Silico Integrative Genomics to Genetic Studies of Human Disease
(2012) International Review of Neurobiology, 103, pp. 133-156. 

Department of Psychiatry, Washington University, Saint Louis, MO, United States

Abstract
As genome-wide association studies using common single nucleotide polymorphism microarrays transition to whole-genome sequencing and the study of rare variants, new approaches will be required to viably interpret the results given the surge in data. A common strategy is to focus on biological hypotheses derived from sources of functional evidence ranging from the nucleotide to the biochemical process level. The accelerated development of biotechnology has led to numerous sources of functional evidence in the form of public databases and tools. Here, we review current methods and tools for integrating genomic data, particularly from the public domain, into genetic studies of human disease. © 2012 Elsevier Inc.

Author Keywords
Bioinformatics;  Genome-wide association study;  Integrative genomics;  Nicotine dependence;  Psychiatric genetics;  Software;  Whole-genome sequencing

Document Type: Article
Source: Scopus

 

Kipfmueller, F.a , Wyen, H.b , Borgman, M.A.c , Spinella, P.C.d , Wirth, S.e , Maegele, M.f g
Epidemiology, Risk Stratification and Outcome of Severe Pediatric Trauma [Epidemiologie, Risikostratifizierung und Behandlungsergebnisse nach schwerem kindlichen Trauma]
(2012) Klinische Pädiatrie, . Article in Press. 

a Abteilung Neonatologie, Zentrum für Kinderheilkunde, Universität Bonn
b Klinik für Unfallchirurgie, Hand- und Rekonstruktive Chirurgie, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt
c Brooke Army Medical Center, MCHE-DP/PICU, Ft. Sam Houston, United States
d Department of Pediatrics, St. Louis Children ´s Hospital, Washington University School of Medicine, St. Louis, United States
e Helios Klinikum Wuppertal, Zentrum für Kinder- und Jugendmedizin, Universität Witten-Herdecke, Wuppertal
f Klinik für Unfallchirurgie, Orthopädie und Sporttraumatologie, Klinikum Köln-Merheim, Universität Witten-Herdecke, Köln
g IFOM, Institut für Forschung in der Operativen Medizin, Universitat Witten-Herdecke, Köln

Abstract
Accidents and trauma are the leading cause of hospital admissions and major contributors to mortality in children and adolescents. There are age-specific injury patterns and differences in the clinical presentation of pediatric trauma and treatment both at the scene and in the emergency department can be observed. In general, pediatric trauma-scores to appreciate injury severity are adapted from the adult population. The most important factor to increase mortality in the severely injured pediatric population is the extent of a concomitant traumatic brain injury (TBI). In addition, the acute trauma-associated coagulopathy, which is triggered multifactorial, is an independent prognostic marker for mortality in severe trauma. The complexity of all currently available trauma-scores for the pediatric population is one reason why these scores are not unequivocal recommended for the early use in pediatric trauma care. The pediatric BIG-Score was developed to allow an early prognostic stratification for pediatric trauma patients and includes with base excess (BE), INR (International Normalized Ratio) and GCS (Glasgow Coma Scale) relevant prognostic factors for poor outcome. Early risk stratification is crucial in pediatric trauma due to mortality rates ranging between 9% and 15% and with 50% of all fatalities to occur within the first 24 h of hospital admission. © Georg Thieme Verlag KG Stuttgart.

Author Keywords
outcome;  pediatric trauma;  prognosis;  risk stratification

Document Type: Article in Press
Source: Scopus

 

Hanson, P.I., Cashikar, A.
Multivesicular body morphogenesis

(2012) Annual Review of Cell and Developmental Biology, 28, pp. 337-362. 

Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Multivesicular bodies (MVBs) are unique organelles in the endocytic pathway that contain vesicles in their lumen. Sorting and incorporation of material into such vesicles is a critical cellular process that has been intensely studied following discovery of the ESCRT (endosomal sorting complex required for transport) machinery just more than a decade ago. In this review, we summarize current understanding of the cellular functions of MVBs and how the ESCRT machinery contributes to MVB morphogenesis. We also highlight the importance of MVBs and ESCRTs in human health. We identify critical areas in which further mechanistic and spatiotemporal studies in living cells will advance this exciting area of research. Copyright © 2012 by Annual Reviews. All rights reserved.

Author Keywords
cytokinesis;  ESCRT machinery;  exosome;  late endosome;  membrane scission;  viral budding

Document Type: Review
Source: Scopus

 

Duncan, R.P.a , Earhart, G.M.a b c
Should one measure balance or gait to best predict falls among people with Parkinson disease?
(2012) Parkinson's Disease, art. no. 923493, . 

a Program in Physical Therapy, Washington University in St. Louis School of Medicine, Campus Box 8502, 4444 Forest Park Boulevard, St. Louis, MO 63108, United States
b Department of Anatomy and Neurobiology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
c Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States

Abstract
Introduction. We aimed to determine whether gait velocity is as useful as a balance test, a self-report measure of freezing of gait (FOG), and/or a measure of motor symptom severity for predicting falls among people with Parkinson Disease (PD). Methods. Fifty-six individuals with idiopathic PD completed a baseline assessment consisting of these measures: (1) MDS-UPDRS III, (2) Mini-BESTest, (3) gait velocity (forward, backward, dual task, and fast), and (4) FOGQ. Retrospective fall history was collected at baseline and six months later. Participants were considered fallers if they had two or more falls in the surveillance period. Ability of the tests to discriminate between fallers and nonfallers was determined using ROC curves followed by pairwise statistical noninferiority comparisons (P =.05) of the area under the ROC curve (AUC) for each test. Results. At six months, 22 (n = 21) of the sample were fallers. Fallers differed significantly from nonfallers on the MDS-UPDRS III, Mini-BESTest, backward gait velocity, and FOGQ. The Mini-BESTest had the highest AUC and was superior to all gait velocity measures at identifying fallers. Conclusion. A single measure of gait velocity, even in a challenging condition, may not be as effective as the Mini-BESTest in identifying fallers among people with PD. © 2012 Ryan P. Duncan and Gammon M. Earhart.

Document Type: Article
Source: Scopus

 

Knobloch, M.a b , Braun, S.M.G.a b , Zurkirchen, L.b , von Schoultz, C.b , Zamboni, N.c , Araúzo-Bravo, M.J.d , Kovacs, W.J.b , Karalay, O.b , Suter, U.b , Machado, R.A.C.a b , Roccio, M.e , Lutolf, M.P.e , Semenkovich, C.F.f , Jessberger, S.a b
Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis
(2012) Nature, . Article in Press. 

a 1] Brain Research Institute, Faculty of Medicine, University of Zurich, 8057 Zurich, Switzerland
b Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland
c Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
d Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, 48149 Muenster, Germany
e Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
f Washington University School of Medicine, Division of Endocrinology, Metabolism and Lipid Research, St. Louis, Missouri 63110, USA

Abstract
Mechanisms controlling the proliferative activity of neural stem and progenitor cells (NSPCs) have a pivotal role to ensure life-long neurogenesis in the mammalian brain. How metabolic programs are coupled with NSPC activity remains unknown. Here we show that fatty acid synthase (Fasn), the key enzyme of de novo lipogenesis, is highly active in adult NSPCs and that conditional deletion of Fasn in mouse NSPCs impairs adult neurogenesis. The rate of de novo lipid synthesis and subsequent proliferation of NSPCs is regulated by Spot14, a gene previously implicated in lipid metabolism, that we found to be selectively expressed in low proliferating adult NSPCs. Spot14 reduces the availability of malonyl-CoA, which is an essential substrate for Fasn to fuel lipogenesis. Thus, we identify here a functional coupling between the regulation of lipid metabolism and adult NSPC proliferation.

Document Type: Article in Press
Source: Scopus

 

Sinha, P.a , Desai, S.C.a , Ha, D.H.b , Chicoine, M.R.c , Haughey, B.H.a
Extracranial radial forearm free flap closure of refractory cerebrospinal fluid leaks: A novel hybrid transantral-endoscopic approach
(2012) Neurosurgery, 71 (SUPPL.2), pp. ons219-ons225. 

a Department of Otolaryngology - Head and Neck Surgery, Washington University, School of Medicine, 600 S Euclid Ave, St. Louis, MO 63110, United States
b Department of Otolaryngology - Head and Neck Surgery, Magan Medical Clinic, Corvina, CA, United States
c Department of Neurosurgery, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
BACKGROUND:: Although rare, recalcitrant cerebrospinal fluid (CSF) leak after skull base tumor resection or major head trauma is a difficult therapeutic challenge, often complicated by lack of local vascularized tissue in a scarred, radiated field. Craniotomy with a free tissue transfer has been described for CSF leak repair from these complicated skull base defects. OBJECTIVE:: We present our experience with a novel extracranial approach to manage refractory CSF leaks with a radial forearm free flap set in through a transantral and ethmoid sinus approach. METHODS:: Five patients with recalcitrant CSF leaks in the anterior skull base underwent radial forearm free tissue transfer via a hybrid transantral-endoscopic approach. RESULTS:: There were 4 female patients and 1 male patient. Average age was 58 years (range, 30-72 years). Four patients had previous neurosurgical anterior skull base tumor resections, and 1 patient had significant head trauma leading to a recalcitrant CSF leak. All 5 patients had undergone multiple prior endoscopic and/or open repairs. All 5 patients had successful resolution of their leak after undergoing radial forearm free tissue transfer. Two of 5 patients required a second minor endoscopic procedure. No patients required a craniotomy. CONCLUSION:: An extracranial transantral-endoscopic approach for the inset of radial forearm free flap is a safe treatment technique that precludes the need for a craniotomy and promotes effective repair of CSF leaks refractory to traditional endoscopic procedures. © 2012 by the Congress of Neurological Surgeons.

Author Keywords
Cerebrospinal fluid rhinorrhea;  Free tissue transfer flaps;  Iatrogenic;  Postcraniotomy;  Posttraumatic

Document Type: Article
Source: Scopus

 

Ray, W.Z.a , Murphy, R.K.J.a , Dorward, I.G.a , Lusis, E.A.a , Blackburn, S.L.b , Stewart, T.a
Impact of lateral mass anatomic variation on ideal polyaxial screw head mobility: Technical considerations
(2012) British Journal of Neurosurgery, 26 (6), pp. 864-867. 

a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Department of Interventional Neuroradiology, Mallinkrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective. To assess optimal angulation characteristics of lateral mass screws for subaxial (C3 to C6) fixation of the cervical spine in the neutral position. Background. In the typical Magerl or Anderson placement technique, the screw trajectory is ideally parallel to the facet joint. For the rod and screw to align properly, the screw head must rotate enough to become perpendicular to the rod. If the optimal angle for the screw head is limited by the screw design, abnormal torsional forces will be generated at the rod/screw interface inducing kyphosis. In this paper, we examined the spinal anatomy in patients with normal CTs to determine the necessary range of motion between tulip head and screw to prevent forced persuasion and abnormal cervical spine alignment. Methods. We examined subaxial radiographs of 292 vertebrae from C3 to C6 in 73 normal subjects. Computed tomography (CT) scans of the cervical spine with multiplanar reconstructions were evaluated in the axial and sagittal planes. A planned screw entry angle of 30° based upon the midpoint of the lateral mass was used in the axial plane, and parallel to the facet joint in the sagittal plane. The screw head angle (SHA) was then calculated from this 3D measured angle. Results. The measured SHA ranged from 27 to 60°. The average SHA was 43.8°. The average SHA was not significantly different between the levels measured with consistent range and standard deviation. Seventy-six percent (223/292) of levels measured required a SHA >40°, and 12% (36/292) required a SHA >50°. Conclusion. The authors recommend using cervical instrumentation systems that allow for at least 55\of freedom of the polyaxial head to prevent abnormal segmental forces. In systems with lesser angulation, technique modifications must be applied to prevent translational forces. © 2012 The Neurosurgical Foundation.

Author Keywords
Anatomy;  Cervical spine;  Computerized tomography;  Lateral mass screw

Document Type: Article
Source: Scopus

 

Gillespie, N.A.a b , Gehrman, P.c , Byrne, E.M.b , Kendler, K.S.b d , Heath, A.C.e , Martin, N.G.b
Modeling the direction of causation between cross-sectional measures of disrupted sleep, anxiety and depression in a sample of male and female Australian twins
(2012) Journal of Sleep Research, 21 (6), pp. 675-683. 

a Queensland Institute of Medical Research, Brisbane, Qld, Australia
b Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, United States
c Behavioral Sleep Medicine Program, Department of Psychiatry and Penn Sleep Center, University of Pennsylvania, PA, United States
d Department of Human Genetics, Virginia Commonwealth University, VA, United States
e Department of Psychology, Washington University in St Louis, St Louis, MI, United States

Abstract
The direction of causation between measures of disrupted sleep, anxiety and depression is not well understood. Under certain conditions, cross-sectional analysis based on genetically informative data can provide important information about the direction of causation between variables. Two community-based samples of 7235 Australian twins aged 18-87years were mailed an extensive questionnaire that covered a wide range of personality and behavioral measures. Included were self-report measures of disrupted sleep, as well as symptoms of anxiety and depression. Among all females, modeling the direction of causation did not support the hypothesis of sleep having a direct causal impact on risk of anxiety or depression. Among older females, we found evidence that both anxiety and depression interact reciprocally with disrupted sleep, whereas among younger women both anxiety and depression appear to have a causal impact on sleep. Results for males were equivocal. The nosological implications of our findings are discussed. © 2012 European Sleep Research Society.

Author Keywords
Anxiety;  Depression;  Direction of causation;  Disrupted sleep;  Environment;  Genes;  Twins

Document Type: Article
Source: Scopus

 

Kushnir, V., Sayuk, G.S., Gyawali, C.P.
Multiple rapid swallow responses segregate achalasia subtypes on high-resolution manometry
(2012) Neurogastroenterology and Motility, 24 (12), pp. 1069-e561. 

Division of Gastroenterology, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Background Multiple rapid swallows (MRS) inhibit esophageal peristalsis and lower esophageal sphincter (LES) tone; a rebound excitatory response then results in an exaggerated peristaltic sequence. Multiple rapid swallows responses are dependent on intact inhibitory and excitatory neural function and could vary by subtype in achalasia spectrum disorders. Methods Consecutive subjects with incomplete LES relaxation on high-resolution manometry (HRM) (Sierra Scientific, Los Angeles, CA, USA) in the absence of mechanical obstruction were prospectively identified. Achalasia spectrum disorders were classified and HRM plots reviewed according to Chicago criteria. Esophageal peristaltic performance and LES function were assessed after 10 wet swallows and MRS (five 2mL water swallows 2-3 s apart). Findings were compared with 18 healthy controls (28.5±0.6years, 44% women). Key Results A total of 46 subjects (57.1±2.1years, 52.2% women) met inclusion criteria. There was complete failure of peristalsis with MRS in all subjects with achalasia subtypes 1 and 2. In contrast, 80% of achalasia subtype 3 and incomplete LES relaxation (EGJ outflow obstruction) with preserved esophageal body peristalsis had a contractile response to MRS (P<0.001 compared with subtypes 1 and 2); controls demonstrated 94.4% peristalsis. Percent decrease in LES residual pressure during MRS (compared to wet swallows) segregated achalasia subtypes; those with aperistalsis (subtypes 1 and 2) had a lesser decline (22.6%) compared to those with retained esophageal body peristalsis (40.5%) and controls (51.3%, P<0.001 across groups). Conclusions & Inferences Multiple rapid swallow responses segregate achalasia spectrum disorders into two patterns differentiated by presence or absence of esophageal body contraction response to wet swallows. These findings support subtyping of achalasia, with pathophysiologic implications. © 2012 Blackwell Publishing Ltd.

Author Keywords
Achalasia;  High-resolution manometry;  Multiple rapid swallows

Document Type: Article
Source: Scopus

 

Filas, B.A.a b , Oltean, A.a , Majidi, S.a , Bayly, P.V.a c , Beebe, D.C.b , Taber, L.A.a c
Regional differences in actomyosin contraction shape the primary vesicles in the embryonic chicken brain
(2012) Physical Biology, 9 (6), art. no. 066007, . 

a Department of Biomedical Engineering, Washington University, St Louis, MO 63130, United States
b Department of Ophthalmology and Visual Sciences, Washington University, School of Medicine, St Louis, MO 63110, United States
c Department of Mechanical Engineering and Materials Science, Washington University, St Louis, MO 63130, United States

Abstract
In the early embryo, the brain initially forms as a relatively straight, cylindrical epithelial tube composed of neural stem cells. The brain tube then divides into three primary vesicles (forebrain, midbrain, hindbrain), as well as a series of bulges (rhombomeres) in the hindbrain. The boundaries between these subdivisions have been well studied as regions of differential gene expression, but the morphogenetic mechanisms that generate these constrictions are not well understood. Here, we show that regional variations in actomyosin-based contractility play a major role in vesicle formation in the embryonic chicken brain. In particular, boundaries did not form in brains exposed to the nonmuscle myosin II inhibitor blebbistatin, whereas increasing contractile force using calyculin or ATP deepened boundaries considerably. Tissue staining showed that contraction likely occurs at the inner part of the wall, as F-actin and phosphorylated myosin are concentrated at the apical side. However, relatively little actin and myosin was found in rhombomere boundaries. To determine the specific physical mechanisms that drive vesicle formation, we developed a finite-element model for the brain tube. Regional apical contraction was simulated in the model, with contractile anisotropy and strength estimated from contractile protein distributions and measurements of cell shapes. The model shows that a combination of circumferential contraction in the boundary regions and relatively isotropic contraction between boundaries can generate realistic morphologies for the primary vesicles. In contrast, rhombomere formation likely involves longitudinal contraction between boundaries. Further simulations suggest that these different mechanisms are dictated by regional differences in initial morphology and the need to withstand cerebrospinal fluid pressure. This study provides a new understanding of early brain morphogenesis. © 2012 IOP Publishing Ltd.

Document Type: Article
Source: Scopus

 

Lin, Z.a b , Perez, P.b , Sun, Z.c , Liu, J.-J.b , Shin, J.H.b , Hyrc, K.L.d , Samways, D.e , Egan, T.e , Holley, M.C.f , Bao, J.b
Reprogramming of single-cell-derived mesenchymal stem cells into hair cell-like cells
(2012) Otology and Neurotology, 33 (9), pp. 1648-1655. 

a Model Animal Research Center of Nanjing University, Nanjing, China
b Department of Otolaryngology, Washington University, School of Medicine, Wuxi, China
c Department of Surgery, Third Affiliated Hospital, Nantong University, Wuxi, China
d Department of Neurology, Washington University, School of Medicine, 1402 S. Grand Boulevard, St. Louis, MO, United States
e Department of Pharmacological and Physiological Science, Saint Louis University, School of Medicine, 1402 S. Grand Boulevard, St. Louis, MO, United States
f Department of Biomedical Science, Addison Building, Western Bank, Sheffield, United Kingdom

Abstract
HYPOTHESIS: Adult mesenchymal stem cells (MSCs) can be converted into hair cell-like cells by transdetermination. BACKGROUND: Given the fundamental role sensory hair cells play in sound detection and the irreversibility of their loss in mammals, much research has focused on developing methods to generate new hair cells as a means of treating permanent hearing loss. Although MSCs can differentiate into multiple cell lineages, no efficient means of reprogramming them into sensory hair cells exists. Earlier work has shown that the transcription factor Atoh1 is necessary for early development of hair cells, but it is not clear whether Atoh1 can be used to convert MSCs into hair cells. METHODS: Clonal MSC cell lines were established and reprogrammed into hair cell-like cells by a combination of protein transfer, adenoviral based gene transfer, and co-culture with neurons. During transdetermination, inner ear molecular markers were analyzed using reverse transcriptase-polymerase chain reaction, and cell structures were examined using immunocytochemistry. RESULTS: Atoh1 overexpression in MSCs failed to convert MSCs into hair cell-like cells, suggesting that the ability of Atoh1 to induce hair cell differentiation is context dependent. Because Atoh1 overexpression successfully transforms VOT-E36 cells into hair cell-like cells, we modified the cell context of MSCs by performing a total protein transfer from VOT-E36 cells before overexpressing Atoh1. The modified MSCs were transformed into hair cell-like cells and attracted contacts from spiral ganglion neurons in a co-culture model. CONCLUSION: We established a new procedure, consisting of VOT-E36 protein transfer, Atoh1 overexpression, and co-culture with spiral ganglion neurons, which can transform MSCs into hair cell-like cells. © 2012 Otology & Neurotology, Inc.

Author Keywords
Adult stem cells;  Differentiation;  Hearing loss;  Sensory neurons

Document Type: Article
Source: Scopus

 

Maddox, G.B.a , Naveh-Benjamin, M.b , Old, S.c , Kilb, A.d
The role of attention in the associative binding of emotionally arousing words

(2012) Psychonomic Bulletin and Review, 19 (6), pp. 1128-1134. 

a Department of Psychology, Washington University, St. Louis, MO, United States
b Department of Psychological Sciences, University of Missouri, Columbia, 106 McAlester Hall, Columbia, MO, 65211, United States
c Missouri Southern State University, Joplin, MO, United States
d Plymouth State University, Plymouth, NH, United States

Abstract
In the present study, we examined the role of attention in modulating the memory benefit of emotional arousal for same-valence word pair associations. To assess the role of attention either at encoding or at retrieval, participants studied lists of positive, neutral, and negative words pairs under full attention, divided attention at encoding, or divided attention at retrieval, and then were tested on the single words and on the associations between words. Consistent with past studies, memory accuracy was higher for emotional items than for neutral items, and no memory difference was observed across emotional arousal conditions for associations when encoding occurred under full attention. In contrast, memory accuracy was higher for emotionally arousing items and associations relative to neutral items when encoding occurred under divided attention. Finally, dividing attention at retrieval revealed similar effects across emotion conditions, suggesting that retrieval of emotional stimuli relative to neutral stimuli, unlike encoding, does not benefit from automatic processing. The discussion emphasizes the role of automatic processing during encoding in producing the benefit of emotionally enhanced memory, as well as the extent to which controlled attention is responsible for eliminating or reversing (relative to neutral materials) emotionally enhanced memory for associations. Additionally, the implications of the divided-attention-at-retrieval manipulation include consideration of the way in which emotional items may be consciously processed during encoding. © 2012 Psychonomic Society, Inc.

Author Keywords
Associative memory;  Divided attention;  Emotion;  Episodic memory

Document Type: Article
Source: Scopus

 

Hynes, M.J., Maurer, J.A.
Photoinduced monolayer patterning for the creation of complex protein patterns
(2012) Langmuir, 28 (47), pp. 16237-16242. 

Department of Chemistry, Center for Materials Innovation, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
This work investigates self-assembled monolayers that were formed from a glycol-terminated thiol monomer and were patterned using photoinduced monolayer desorption. Utilizing direct-write photolithography provided a facile means to generate complex protein patterns containing gradients and punctate regions. The ablated glycol monolayers were characterized using scanning probe microscopy, which allowed us to observe differences in the nanomechanical properties between the patterned and nonpatterned regions of the substrate. The patterned regions on the surface adsorbed proteins, and this process was monitored quantitatively using surface plasmon resonance imaging (SPRi). Moreover, the concentration of the protein could be controlled accurately by simply setting the gray level in the 8-bit image. Adsorbed protein was probed using a commercially available antibody binding assay, which showed significant enhancement over the background. The ability to produce complex protein patterns will contribute greatly to creating in vitro models that more accurately mimic an in vivo environment. © 2012 American Chemical Society.

Document Type: Article
Source: Scopus

 

Cheema, A.a , Katta, J.b , Velez, A.P.b c , Medveczky, M.d , Medveczky, P.G.d e , Quilitz, R.a , Blue, B.J.f , Vincent, A.L.b c , Sandin, R.L.g h i , Greene, J.N.a c i
Encephalitis and inherited HHV-6: Encephalitis case report
(2012) Infectious Diseases in Clinical Practice, 20 (6), pp. 419-421. 

a Division of Infectious Diseases, H. Lee Moffitt Cancer Center, Research Institute, 12902 Magnolia Dr, FOB-3, Tampa, FL 33612-9497, United States
b Division of Infectious Diseases and International Medicine, University of South Florida College of Medicine, United States
c Department of Internal Medicine, University of South Florida College of Medicine, United States
d Department of Molecular Medicine, University of South Florida College of Medicine, United States
e Molecular Oncology Program, H. Lee Moffitt Cancer Center, Research Institute, Tampa, FL, United States
f Washington University, St. Louis, MO, United States
g Clinical Microbiology and Virology Laboratories, H. Lee Moffitt Cancer Center, Research Institute, United States
h Department of Pathology, University of South Florida College of Medicine, Tampa, FL, United States
i Department of Oncologic Sciences, University of South Florida College of Medicine, Tampa, FL, United States

Abstract
After resolution of primary infection, human herpesvirus 6 (HHV-6) remains latent in the host and may reactivate during immunosuppression, inducing end-organ diseases. This case report describes a 56-year-old male with chronic myelomonocytic leukemia who received an allogeneic stem cell transplantation and developed chronic HHV-6 DNA in the serum. The patient was diagnosed with encephalitis. Although the patient stabilized on antiviral therapy, the viral load did not diminish. Semiquantitative polymerase chain reaction revealed that the stem cell donor cells contained germ line transmitted inherited HHV-6 (iHHV-6). Patients with iHHV-6 contain significant levels of HHV-6 DNA in the serum and cerebrospinal fluid regardless of health status due to normal cell lysis. Recently, with lymphocytes derived from iHHV-6 patients, the virus has been shown to reactivate and form new virus. Therefore, active HHV-6 infection in these cases is possible but impossible to determine from existing assays. Therefore, physicians must rely on clinical judgment to determine if the therapy would be beneficial. To complicate matters, some HHV-6 strains are resistant to foscarnet and ganciclovir. This report underscores the need for considering the diagnosis of iHHV-6 in patients harboring unusually high HHV-6 DNA levels and the need for better diagnostic tests to distinguish latent iHHV-6 from reactivated virus. The search for effective anti-HHV-6 drugs continues. Copyright © 2012 by Lippincott Williams & Wilkins.

Author Keywords
allogeneic stem cell transplantation;  antiviral drug resistance;  ciHHV-6;  encephalitis;  germ line integration;  HHV-6;  human herpesvirus 6;  iHHV-6

Document Type: Article
Source: Scopus

 

Bangert, A.S., Balota, D.A.
Keep up the pace: Declines in simple repetitive timing differentiate healthy aging from the earliest stages of Alzheimer's disease
(2012) Journal of the International Neuropsychological Society, 18 (6), pp. 1052-1063. 

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

Abstract
Abstract The current study examined whether healthy older adults (OA) and individuals at the earliest stages of dementia of the Alzheimer's type (DAT) differ from younger adults (YA) and from each other on a simple, extended continuous tapping task using intervals (500 ms, 1000 ms, and 1500 ms) thought to differentially engage attentional control systems. OA groups sped up their tapping at the slowest target rate compared to the YA; this pattern was magnified in the early stage DAT groups. Performance variability appeared especially sensitive to DAT-related changes, as reliable differences between healthy OA and very mild DAT individuals emerged for multiple tap rates. These differences are proposed to result from breakdowns in attentional control that disrupt error-correction processes and the ability to resolve discrepancies between internally-generated temporal expectancies and the external temporal demands of the repetitive timing task. (JINS, 2012, 18, 1-12) Copyright © The International Neuropsychological Society 2012.

Author Keywords
Aging;  Alzheimer type dementia;  Attention;  Dementia;  Sensory motor performance;  Time perception

Document Type: Article
Source: Scopus

 

Wang, L.a , Fagan, A.M.b , Shah, A.R.b , Beg, M.F.c , Csernansky, J.G.a , Morris, J.C.b , Holtzman, D.M.b
Cerebrospinal fluid proteins predict longitudinal hippocampal degeneration in early-stage dementia of the Alzheimer type
(2012) Alzheimer Disease and Associated Disorders, 26 (4), pp. 314-321. 

a Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Abbott Hall 1322, Lake Shore Dr, Chicago, IL 60611, United States
b Washington University School of Medicine, St. Louis, MO, United States
c Simon Frasier University, Chicago, Vancouver, BC, Canada

Abstract
Objective: Biomarkers are needed to improve the sensitivity and accuracy of diagnosis, and also prognosis, in individuals with early Alzheimer disease (AD). Measures of brain structure and disease-related proteins in the cerebrospinal fluid (CSF) have been proposed as biomarkers, yet relatively little is known about the relationships between such measures. The present study was conducted to assess the relationship between CSF Aβ and tau protein levels and longitudinal measures of hippocampal structure in individuals with and without very mild dementia of the Alzheimer type. Design: A single CSF sample and longitudinal magnetic resonance scans were collected. The CSF samples were assayed for tau, phosphorylated tau181 (p-tau181), Aβ1-42, and Aβ1-40 using an enzyme-linked immunosorbent assay. Large-deformation diffeomorphic metric mapping was used to generate hippocampal surfaces, and a composite hippocampal surface (previously constructed from 86 healthy participants) was used as a structural reference. Patients or other participants: Thirteen participants with very mild AD (Clinical Dementia Rating, CDR 0.5) and 11 cognitively normal participants (CDR 0). Intervention: None. Main outcome measures: Initial and rate-of-change measures of total hippocampal volume and displacement of the hippocampal surface within zones overlying the CA1, subiculum, and CA2-4+DG cellular subfields, and their correlations with initial CSF measures. Results: Lower CSF β1-42 levels and higher tau/β1-42 and p-tau181/β1-42 ratios were strongly correlated with decreases in hippocampal volume and measures of progressive inward deformations of the CA1 subfield in participants with early AD, but not in cognitively normal participants. Conclusions: Despite the small sample size, we found that β1-42 related and tau-related CSF measures were associated with hippocampal degeneration in individuals with clinically diagnosed early AD and may reflect an association with a common underlying disease mechanism.© 2012 by Lippincott Williams & Wilkins.

Author Keywords
β-amyloid;  biomarkers;  hippocampal subfields;  magnetic resonance imaging (MRI);  p-tau;  tau

Document Type: Article
Source: Scopus

 

Pyc, M.A.a , Rawson, K.A.b
Are judgments of learning made after correct responses during retrieval practice sensitive to lag and criterion level effects?
(2012) Memory and Cognition, 40 (6), pp. 976-988. 

a Department of Psychology, Washington University in St Louis, Box 1125, St Louis, MO 63130, United States
b Department of Psychology, Kent State University, P.O. Box 5190, Kent, OH 44242, United States

Abstract
Although successful retrieval practice is beneficial for memory, various factors (e. g., lag and criterion level) moderate this benefit. Accordingly, the efficacy of retrieval practice depends on how students use retrieval practice during learning, which in turn depends on accurate metacognitive monitoring. The present experiments evaluated the extent to which judgments of learning (JOLs) made after correct responses are sensitive to factors (i. e., lag and criterion level) that moderate retrieval practice effects, as well as which cues influence JOLs under these conditions. Participants completed retrieval practice for word pairs with either short or long lags between practice trials until items were correctly recalled 1, 3, 6, or 9 times. After the criterion trial for an item, participants judged the likelihood of recalling that item on the final test 1 week later. JOLs showed correct directional sensitivity to criterion level, with both final test performance and JOLs increasing as criterion level increased. However, JOLs showed incorrect directional sensitivity to lag, with greater performance but lower JOLs for longer versus shorter lags. Additionally, results indicated that retrieval fluency and metacognitive beliefs about criterion level-but not lag-influenced JOLs. © 2012 Psychonomic Society, Inc.

Author Keywords
Memory;  Metamemory;  Recall

Document Type: Article
Source: Scopus

December 6, 2012  

Jack, A.I.a , Dawson, A.J.a , Begany, K.L.a , Leckie, R.L.a , Barry, K.P.a , Ciccia, A.H.b , Snyder, A.Z.c
FMRI reveals reciprocal inhibition between social and physical cognitive domains
(2013) NeuroImage, 66, pp. 385-401. 

a Department of Cognitive Science, Case Western Reserve University, Cleveland, OH, United States
b Department of Psychological Sciences, Case Western Reserve University, Cleveland, OH, United States
c Department of Radiology, Washington University in St Louis Medical School, St Louis, MO, United States

Abstract
Two lines of evidence indicate that there exists a reciprocal inhibitory relationship between opposed brain networks. First, most attention-demanding cognitive tasks activate a stereotypical set of brain areas, known as the task-positive network and simultaneously deactivate a different set of brain regions, commonly referred to as the task negative or default mode network. Second, functional connectivity analyses show that these same opposed networks are anti-correlated in the resting state. We hypothesize that these reciprocally inhibitory effects reflect two incompatible cognitive modes, each of which may be directed towards understanding the external world. Thus, engaging one mode activates one set of regions and suppresses activity in the other. We test this hypothesis by identifying two types of problem-solving task which, on the basis of prior work, have been consistently associated with the task positive and task negative regions: tasks requiring social cognition, i.e., reasoning about the mental states of other persons, and tasks requiring physical cognition, i.e., reasoning about the causal/mechanical properties of inanimate objects. Social and mechanical reasoning tasks were presented to neurologically normal participants during fMRI. Each task type was presented using both text and video clips. Regardless of presentation modality, we observed clear evidence of reciprocal suppression: social tasks deactivated regions associated with mechanical reasoning and mechanical tasks deactivated regions associated with social reasoning. These findings are not explained by self-referential processes, task engagement, mental simulation, mental time travel or external vs. internal attention, all factors previously hypothesized to explain default mode network activity. Analyses of resting state data revealed a close match between the regions our tasks identified as reciprocally inhibitory and regions of maximal anti-correlation in the resting state. These results indicate the reciprocal inhibition is not attributable to constraints inherent in the tasks, but is neural in origin. Hence, there is a physiological constraint on our ability to simultaneously engage two distinct cognitive modes. Further work is needed to more precisely characterize these opposing cognitive domains. © 2012 Elsevier Inc.

Author Keywords
Anti-correlated networks;  Default network;  Dual-process theory;  FMRI;  Task negative;  Task-positive

Document Type: Article
Source: Scopus

 

Heitsch, L.E.a , Panagos, P.D.b
Treating the Elderly Stroke Patient. Complications, Controversies, and Best Care Metrics
(2013) Clinics in Geriatric Medicine, 29 (1), pp. 231-255. 

a Division of Emergency Medicine, Washington University School of Medicine, 660 S Euclid, CB 8072, St Louis, MO 63110, United States
b Division of Emergency Medicine and Department of Neurology, Washington University School of Medicine, 660 S Euclid, CB 8072, St Louis, MO 63110, United States

Abstract
Acute stroke is a devastating disease that affects almost 800,000 Americans annually. Worldwide, the incidence of stroke is rapidly increasing. Although stroke can affect all age groups, patients over age 80 are at much higher risk for ischemic stroke. Despite this, there are disparities in thrombolytic treatment rates, and as well as outcomes, between elderly stroke patients and their younger counterparts. This article discusses what is currently known about the elderly stroke patient for a greater understanding of the disease burden, research limitations and potential treatment options. © 2013 Elsevier Inc.

Author Keywords
Acute ischemic stroke;  Elderly stroke;  Emergency care/treatment;  Intra-arterial;  Thrombolysis;  TPA

Document Type: Review
Source: Scopus

 

Clayton, E.H.a , Engelbach, J.A.b , Garbow, J.R.b , Bayly, P.V.a c
Characterization of murine glioma by magnetic resonance elastography: Preliminary results
(2013) Conference Proceedings of the Society for Experimental Mechanics Series, 5, pp. 93-98. 

a Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, Saint Louis, MO, United States
b Department of Radiology, Washington University in St. Louis, Saint Louis, MO, United States
c Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO, United States

Abstract
Magnetic resonance elastography (MRE) is a non-invasive imaging technique that permits quantitative measurement of the mechanical properties of biological tissue. In MRE, coherent tissue displacements are induced by a mechanical actuator and images are collected in synchrony with these mechanical motions. Components of displacement in any direction can be measured by applying the motion-encoding gradients along that direction. The mechanical properties of tissue are derived by fitting measured displacement data to the equations governing wave propagation. A number of groups have explored the diagnostic value of MRE in the clinical setting, driven largely by the empirically observed relationship between tissue health and stiffness. The investigation of MRI methods as biomarkers of tumor progression and early therapeutic response remains an extremely active and important area of research. In this regard, MRE has considerable potential for staging cancer and monitoring the effects of therapy. We seek to demonstrate the utility of MRE for cancer staging by tracking the viscoelastic properties of brain tumor in a mouse model of high-grade glioma. Brain tissue viscoelasticity cannot be probed in vivo by any other known imaging technique, yet is suspected to contain valuable information about tissue health. Preliminary results indicate elastographic sensitivity to the presence of brain tumors in the living mouse. © The Society for Experimental Mechanics, Inc. 2013.

Author Keywords
Brain;  Material;  Mechanical properties;  MR imaging;  Non invasive;  Tumor

Document Type: Conference Paper
Source: Scopus

 

Connesson, N.a , Clayton, E.H.b , Bayly, P.V.b , Pierron, F.c
The effects of noise and spatial sampling on identification of material parameters by magnetic resonance elastography
(2013) Conference Proceedings of the Society for Experimental Mechanics Series, 5, pp. 161-168. 

a Laboratoire Sols-Solides-Structures (3SR), Université de Grenoble (INPG-UJE), BP 53, 38041 Grenoble Cedex 9, France
b Department of Mechanical Engineering and Materials Science, Washington University, St. Louis, Campus Box 1185, One Brookings Drive, St. Louis, MO 63130, United States
c Laboratoire de Mécanique et Procédés de Fabrication (LMPF), Arts et Métiers ParisTech., rue St Dominique, 51006 Châlons-en-Champagne Cedex, France

Abstract
In-vivo measurement of the mechanical properties of soft tissues is challenging but may provide invaluable data in biomechanics and medicine. Different experimental techniques are currently used to measure 3D strain or displacements fields under static or dynamic loading. Different analysis methods have also been developed to extract the materials mechanical properties from these data (finite element model + cost function, local fitting of the propagation equation, etc). The main difficulty of these extractions consists in dealing with the experimental noise and spatial derivatives required during the processing. The aim of this communication is to provide an insight into the Optimized Virtual Field Method (OVFM, Avril et al. Comput Mech 34:439-452, 2004) abilities to identify mechanical properties while analyzing noisy data. MRE data over harmonically loaded soft materials has been simulated. The effect of noise and spatial sampling has then been studied while identifying locally a viscoelastic model with the OVFM. This noise effect study provided an a priori criterion to estimate the local identification quality. The results also helped to underline and estimate identification biases induced by the noise and spatial subsampling. A viscoelastic model has then been identified over a real experimental data set, providing 3D mechanical parameters maps. © The Society for Experimental Mechanics, Inc. 2013.

Author Keywords
Elastography;  Inverse method;  Noise effect;  Virtual field method

Document Type: Conference Paper
Source: Scopus

Source: Scopus

 

Bank, L.M.a b i j , Bianchi, L.M.a b i , Ebisu, F.a i k , Lerman-Sinkoff, D.a c l , Smiley, E.C.a , Shen, Y.-C.a , Ramamurthy, P.a c , Thompson, D.L.a c m , Roth, T.M.a n , Beck, C.R.a d o , Flynn, M.a p , Teller, R.S.a q , Feng, L.a r , Nicholas Llewellyn, G.a d s , Holmes, B.b , Sharples, C.b , Coutinho-Budd, J.b t , Linn, S.A.a d , Chervenak, A.P.a d , Dolan, D.F.a d , Benson, J.e , Kanicki, A.e , Martin, C.A.e , Altschuler, R.e , Koch, A.E.f , Jewett, E.M.g u , Germiller, J.A.a h , Barald, K.F.a b d v
Macrophage migration inhibitory factor acts as a neurotrophin in the developing inner ear
(2012) Development (Cambridge), 139 (24), pp. 4666-4674. 

a Department of Cell and Developmental Biology, University of Michigan Medical School, 3728 BSRB 109, Zina Pitcher Place, Ann Arbor, MI 48109-2200, United States
b Neuroscience Department, Oberlin College, Science Center A243, 119 Woodland Avenue, Oberlin, OH 44074, United States
c Department of Biomedical Engineering, College of Engineering, University of Michigan, 2200 Bonisteel Boulevard, Ann Arbor, MI 48109-2099, United States
d University of Michigan Medical School, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, United States
e Department of Otolaryngology, 9200B, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0600, United States
f Department of Internal Medicine Division of Rheumatology, University of Michigan Medical School, 4045 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, United States
g Department of Computational Medicine and Bioinformatics, 2017 Palmer Commons Building, 100 Washtenaw Avenue, Ann Arbor, MI 48109-2218, United States
h Division of Pediatric Otolaryngology, The Children's Hospital of Philadelphia Department of Otorhinolaryngology, University of Pennsylvania Wood Center, First Floor 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, United States
i Department of Biology, Eastern Michigan University, 316 Mark Jefferson Hall, Ypsilanti, MI 48197, United States
j Department of Otolaryngology, Head and Neck Surgery Kyoto University Hospital/Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
k Washington University St Louis, MSTP Box 8226, 660 S. Euclid Avenue, St Louis, MO 63110-1093, United States
l Department of Chemistry, Eastern Michigan University, Mark Jefferson Hall, Ypsilanti, MI 48197, United States
m Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue #5183, Ann Arbor, MI 48109-2216, United States
n Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, 604B, Houston, TX 77030, United States
o The Ohio State University College of Medicine, 370 West 9th Avenue, Columbus, OH 43210, United States
p Department of Bioengineering, University of Utah, 20 S 2030 E, Salt Lake City, UT 84112, United States
q Michigan State University College of Osteopathic Medicine, C110 East Fee Hall, East Lansing, MI 48824, United States
r Molecular Microbiology Immunology Department, HMR 504, and Institute for Emerging Pathogens and Immune Disease, Keck School of Medicine USC, 2011 Zonal Avenue, Los Angeles, CA 90033, United States
s Department of Neurology, Washington University in St Louis, 4566 Scott Avenue, Box 8111, St Louis, MO 63110, United States
t New England Hematology and Oncology, Vernon Cancer Center, 2014 Washington Street, Newton, MA 02462, United States
u Department of Neuroscience, University of North Carolina, UNC Chapel Hill, 115 Mason Farm Rd., Neurosci. Res. Bldg, Chapel Hill, NC 27599, United States
v Department of Biology, 339 Herrin Labs Stanford University, 371 Serra Mall, Stanford, CA 94305-5020, United States

Abstract
This study is the first to demonstrate that macrophage migration inhibitory factor (MIF), an immune system 'inflammatory' cytokine that is released by the developing otocyst, plays a role in regulating early innervation of the mouse and chick inner ear. We demonstrate that MIF is a major bioactive component of the previously uncharacterized otocyst-derived factor, which directs initial neurite outgrowth from the statoacoustic ganglion (SAG) to the developing inner ear. Recombinant MIF acts as a neurotrophin in promoting both SAG directional neurite outgrowth and neuronal survival and is expressed in both the developing and mature inner ear of chick and mouse. A MIF receptor, CD74, is found on both embryonic SAG neurons and adult mouse spiral ganglion neurons. Mif knockout mice are hearing impaired and demonstrate altered innervation to the organ of Corti, as well as fewer sensory hair cells. Furthermore, mouse embryonic stem cells become neuron-like when exposed to picomolar levels of MIF, suggesting the general importance of this cytokine in neural development. © 2012. Published by The Company of Biologists Ltd.

Author Keywords
Directional neurite outgrowth;  Neurodevelopment;  Neuroimmuno axis;  Neurotrophin

Document Type: Article
Source: Scopus

 

Roediger III, H.L., Pyc, M.A.
Applying cognitive psychology to education: Complexities and prospects
(2012) Journal of Applied Research in Memory and Cognition, 1 (4), pp. 263-265. 

Washington University, St. Louis, United States

Author Keywords
Education;  Research;  Techniques to improve education

Document Type: Editorial
Source: Scopus

 

Holmes, B.B., Diamond, M.I.
Cellular mechanisms of protein aggregate propagation
(2012) Current Opinion in Neurology, 25 (6), pp. 721-726. 

Department of Neurology, Washington University in St Louis, 660 South Euclid Avenue, St Louis, MO 63110, United States

Abstract
PURPOSE OF REVIEW: New research on the mechanisms of neurodegeneration highlights parallels between prion disease pathogenesis and other, more common disorders not typically thought to be infectious. This involves propagation of protein misfolding from cell to cell by templated conformational change. This review focuses on the cell biology that underlies propagation of protein aggregation between cells, including a discussion of protein biochemistry and relevant mouse models. RECENT FINDINGS: Like the prion protein, several other proteins exhibit self-propagating fibrillar conformations in vitro. Multiple cellular studies have now implicated endocytic mechanisms in the uptake of aggregates into cells. Aggregates that enter cells somehow escape endocytic vesicles to contact cytosolic protein. The mechanism of release of protein monomers and aggregates from cells is not well understood. Animal models have confirmed that brain lysates and purified protein can accelerate brain pathology in a manner similar to prions. SUMMARY: Aggregate flux in and out of cells likely contributes to the progression of neuropathology in neurodegenerative diseases. A better understanding of these mechanisms is emerging and can help explain local spread of protein aggregation and the role of neural networks in disease. This will also inform new therapeutic strategies aimed at blocking this process. © 2012 Wolters Kluwer Health / Lippincott Williams & Wilkins.

Author Keywords
cell-cell propagation;  networks;  neurodegeneration;  prion;  templated conformational change

Document Type: Review
Source: Scopus

 

Battaglia, D.a , Lin, Y.-W.b , Brogna, C.a , Crinò, A.c , Grasso, V.d , Mozzi, A.F.e , Russo, L.d , Spera, S.c , Colombo, C.d , Ricci, S.f , Nichols, C.G.b , Mercuri, E.a , Barbetti, F.d g
Glyburide ameliorates motor coordination and glucose homeostasis in a child with diabetes associated with the KCNJ11/S225T, del226-232 mutation
(2012) Pediatric Diabetes, 13 (8), pp. 656-660. 

a Child Neurology Unit, Department of Pediatrics, Sacro Cuore Catholic University, 00168 Rome, Italy
b Department of Cell Biology and Physiology, Center for the Investigation of Membrane Exitability Diseases, Washington University School of Medicine, St Louis, 63110, United States
c Autoimmune Endocrine Diseases Unit, Endocrinology Department, Bambino Gesù Children's Hospital, Research Institute Palidoro, Rome, 00050, Italy
d Laboratory of Mendelian Diabetes, Bambino Gesù Children's Hospital, Research Institute, University of Tor Vergata, Rome, 00134, Italy
e Department of Laboratory Medicine, University of Tor Vergata, Rome, 00134, Italy
f Department of Neuroscience, Clinical Psychology Unit, Bambino Gesù Children's Hospital Research Institute, Rome, 00164, Italy
g Department of Internal Medicine, University of Tor Vergata, Rome, 00134, Italy

Abstract
Gain-of-function mutations of KCNJ11 can cause permanent neonatal diabetes mellitus, but only rarely after 6months of age. Specific uncommon mutations KCNJ11give rise to a syndrome defined as developmental delay, epilepsy, and neonatal diabetes (DEND), or - more frequently - to a milder sub-type lacking epilepsy, denoted as intermediate-DEND (iDEND). Our aim was to consider a possible monogenic etiology in a 12-yr-old boy with early onset diabetes and mild neurological features. We studied a subject diagnosed with diabetes at 21months of age, and negative to type 1 diabetes autoantibodies testing. He had learning difficulties during primary school, and a single episode of seizures at the age of 10 yr. We performed direct DNA sequencing of the KCNJ11 gene with subsequent functional study of mutated channels in COSm6 cells. The patient's clinical response to oral glyburide (Glyb) was assessed. Motor coordination was evaluated before and after 6 and 12months of Glyb therapy. Sequencing of the KCNJ11 gene detected the novel, spontaneous mutation S225T, combined with deletion of amino acids 226-232. In vitro studies revealed that the mutation results in a K ATP channel with reduced sensitivity to the inhibitory action of ATP. Glyb improved diabetes control (hemoglobin A1c on insulin: 52mmol/mol/6.9%; on Glyb: 36mmol/mol/5.4%) and also performance on motor coordination tests that were impaired before the switch of therapy. We conclude that KCNJ11/S225T, del226-232 mutation caused a mild iDEND form in our patient. KCNJ11 should be considered as the etiology of diabetes even beyond the neonatal period if present in combination with negative autoantibody testing and even mild neurological symptoms. © 2012 John Wiley &amp; Sons A/S.

Author Keywords
Developmental delay;  Glyburide;  Infancy onset diabetes;  KCNJ11;  Mutation

Document Type: Article
Source: Scopus

 

Sheybani, A.a , Harocopos, G.J.a b , Rao, P.K.a
Immunohistochemical study of epiretinal membranes in patients with uveitis
(2012) Journal of Ophthalmic Inflammation and Infection, 2 (4), pp. 243-248. 

a Department of Ophthalmology and Visual Sciences, School of Medicine, Washington University in St. Louis, CB 8096, 660 S. Euclid, St. Louis, MO, 63110, United States
b Department of Pathology and Immunology, School of Medicine, CB 8096, 660 S. Euclid, St. Louis, MO, 63110, United States

Abstract
Background: The purpose of this study is to report two cases of idiopathic uveitis with secondary epiretinal membrane (ERM) formation in order to describe histologic and immunohistochemical features that may help distinguish uveitic from idiopathic ERMs. Methods: The study utilized a clinical case series and histopathological and immunohistochemical findings. Results: There was no identifiable etiology of inflammation in either case. Histology and immunohistochemistry demonstrated a mixture of abundant inflammatory cells, including lymphocytes, histiocytes, plasma cells, and occasional eosinophils, among a stromal matrix composed of glial elements and condensed vitreous, but no retinal pigment epithelium (RPE) was present. The relative proportions of the various inflammatory cell types were assessed with immunohistochemistry, and among the lymphocyte population, T cells predominated over B cells. In one of the cases, there was an abundance of histiocytes, consistent with granulomatous uveitis, which was later confirmed on histology of the enucleated globe. Conclusions: Idiopathic ERM formation is thought to be secondary to glial cell migration that may require some involvement of RPE cells. The absence of RPE and abundance of inflammatory cells may be used to identify ERMs as secondary to uveitis. © 2012 The Author(s).

Author Keywords
Cytokines;  Epiretinal membrane;  Histology;  Immunohistochemistry;  Inflammation;  Surgery;  Uveitis

Document Type: Article
Source: Scopus

 

Roediger III, H.L., Pyc, M.A.
Inexpensive techniques to improve education: Applying cognitive psychology to enhance educational practice

(2012) Journal of Applied Research in Memory and Cognition, 1 (4), pp. 242-248. 

Washington University, St. Louis, MO, United States

Abstract
The need to improve the educational system has never been greater. People in congress and business argue for expensive technological applications to improve education despite a lack of empirical evidence for their efficacy. We argue that one inexpensive avenue for improving education has been largely ignored. Cognitive and educational psychologists have identified strategies that greatly improve learning and retention of information, and yet these techniques are not generally applied in education nor taught in education schools. In fact, teachers often use instructional practices known to be wrong (i.e., massing rather than interleaving examples to explain a topic). We identify three general principles that are inexpensive to implement and have been shown in both laboratory and field experiments to improve learning: (1) distribution (spacing and interleaving) of practice in learning facts and skills; (2) retrieval practice (via self testing) for durable learning; and (3) explanatory questioning (elaborative interrogation and self-explanation) as a study strategy. We describe each technique, provide supporting evidence, and discuss classroom applications. Each principle can be applied to most subject matters from kindergarten to higher education. Applying findings from cognitive psychology to classroom instruction is no panacea for educational problems, but it represents one helpful and inexpensive strategy. © 2012 Society for Applied Research in Memory and Cognition.

Author Keywords
Inexpensive techniques to improve education

Document Type: Article
Source: Scopus

 

Musiek, E.S., Holtzman, D.M.
Origins of Alzheimer's disease: Reconciling cerebrospinal fluid biomarker and neuropathology data regarding the temporal sequence of amyloid-beta and tau involvement
(2012) Current Opinion in Neurology, 25 (6), pp. 715-720. 

Department of Neurology, Hope Center for Neurologic Diseases, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States

Abstract
PURPOSE OF REVIEW: This review aims to address the temporal sequencing of involvement of amyloid-beta (Aβ) and tau in the pathogenesis of Alzheimer's disease and reconcile apparently conflicting neuropathologic and biomarker data. RECENT FINDINGS: Although neuropathologic studies show that limbic system tau disease occurs ubiquitously in middle-aged individuals before the appearance of amyloid plaques, biomarker studies in living individuals suggest that Aβ disease is the initiating event in Alzheimer's disease and precedes cerebrospinal fluid tau changes. Evidence from neuropathologic, biomarker, genetic and cellular/mouse studies shows that tau accumulation in limbic regions occurs slowly with age and does not induce widespread neurodegeneration, but that Aβ interacts with tau in some way to accelerate neurofibrillary disease and induce neurodegeneration. SUMMARY: Aβ aggregation is the key initial trigger of Alzheimer's disease pathologic changes and interacts with tau to exacerbate age-related tauopathy and induce neurodegeneration. © 2012 Wolters Kluwer Health / Lippincott Williams & Wilkins.

Author Keywords
Aβ;  amyloid;  biomarkers;  neurofibrillary tangle;  tau

Document Type: Review
Source: Scopus

 

Jaeger, A., Selmeczy, D., O'Connor, A.R., Diaz, M., Dobbins, I.G.
Prefrontal cortex contributions to controlled memory judgment: fMRI evidence from adolescents and young adults
(2012) Neuropsychologia, 50 (14), pp. 3745-3756. Article in Press. 

Department of Psychology, Washington University in St Louis, Brookings Drive, Campus box 1125, St. Louis, MO 63130-4899, USA

Abstract
Cortical regions supporting cognitive control and memory judgment are structurally immature in adolescents. Here we studied adolescents (13-15 y.o.) and young adults (20-22 y.o.) using a recognition memory paradigm that modulates cognitive control demands through cues that probabilistically forecast memory probe status. Behaviorally, adolescence was associated with quicker responding in the presence of invalid cues compared to young adulthood. fMRI data demonstrated that while both groups increasingly activated posterior dorsolateral prefrontal (dlPFC), midline, and lateral parietal regions for invalidly compared to validly cued trials, this differential invalid cueing response ended sooner in adolescents, consistent with their quicker responding on invalidly cued trials. Critically, dlPFC also demonstrated reversed brain-behavior associations across the groups. Increased mean dlPFC activation during invalid cueing was linked to improved performance in young adults, whereas increases within adolescents were linked to impaired performance. Resting state connectivity analysis revealed greater connectivity between dlPFC and episodic retrieval linked regions in young adults relative to adolescents. These data demonstrate that the functional interpretation of dlPFC activation hinges on its physical maturation and suggest that the pattern of behavioral and neural response in adolescents reflects different functional integration of cognitive control and memory systems. © 2012 Elsevier Ltd.

Author Keywords
Adolescence;  Cueing;  Development;  Memory;  Recognition

Document Type: Article in Press
Source: Scopus

 

Pan, T.a , Erickson, B.J.b , Marcus, D.S.c
Whitepapers on imaging infrastructure for research part three: Security and privacy
(2012) Journal of Digital Imaging, 25 (6), pp. 692-702. 

a Center for Comprehensive Informatics, Emory University, 201 Dowman Drive, Atlanta, GA 30322, United States
b Department of Radiology, Mayo Clinic-Rochester, 200 First Street SW, Rochester, MN 55905, United States
c Department of Radiology, Washington University, School of Medicine, 4525 Scott Ave., St. Louis, MO 63110, United States

Document Type: Article
Source: Scopus

 

Etzel, J.A., Cole, M.W., Braver, T.S.
Looking outside the searchlight
(2012) Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics), 7263 LNAI, pp. 26-33. 

Cognitive Control and Psychopathalogy Lab., Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, United States

Abstract
Searchlight analysis (information mapping) with pattern classifiers is a popular method of multivariate fMRI analysis often interpreted as localizing informative voxel clusters. Applicability and utility of this method is limited, however, by its dependency on searchlight radius, the assumption that information is present at all spatial scales, and its susceptibility to overfitting. These problems are demonstrated in a dataset in which, contrary to common expectation, voxels identified as informative do not clearly contain more information than those not so identified. © 2012 Springer-Verlag.

Author Keywords
fMRI;  information mapping;  MVPA;  searchlight analysis

Document Type: Conference Paper
Source: Scopus

 

Pineda, J.A.a b , Leonard, J.R.d e , Mazotas, I.G.c , Noetzel, M.b , Limbrick, D.D.d e , Keller, M.S.c , Gill, J.c f g , Doctor, A.a h
Effect of implementation of a paediatric neurocritical care programme on outcomes after severe traumatic brain injury: a retrospective cohort study
(2012) The Lancet Neurology, . Article in Press. 

a Department of Pediatrics, Division of Critical Care Medicine, Washington University School of Medicine, St Louis, MO, USA
b Department of Neurology, Washington University School of Medicine, St Louis, MO, USA
c Department of Surgery, Washington University School of Medicine, St Louis, MO, USA
d Department of Neurosurgery, Washington University School of Medicine, St Louis, MO, USA
e Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA
f Department of Political Science, Washington University School of Medicine, St Louis, MO, USA
g Department of Biostatistics, Washington University School of Medicine, St Louis, MO, USA
h Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO, USA

Abstract
Background: Outcomes after traumatic brain injury are worsened by secondary insults; modern intensive-care units address such challenges through use of best-practice pathways. Organisation of intensive-care units has an important role in pathway effectiveness. We aimed to assess the effect of a paediatric neurocritical care programme (PNCP) on outcomes for children with severe traumatic brain injury. Methods: We undertook a retrospective cohort study of 123 paediatric patients with severe traumatic brain injury (Glasgow coma scale scores ≤8, without gunshot or abusive head trauma, cardiac arrest, or Glasgow coma scale scores of 3 with fixed and dilated pupils) admitted to the paediatric intensive-care unit of the St Louis Children's Hospital (St Louis, MO, USA) between July 15, 1999, and Jan 15, 2012. The primary outcome was rate of categorised hospital discharge disposition before and after implementation of a PNCP on Sept 17, 2005. We developed an ordered probit statistical model to assess adjusted outcome as a function of initial injury severity. We assessed care-team behaviour by comparing timing of invasive neuromonitoring and scored intensity of therapies targeting intracranial hypertension. Findings: Characteristics of treated patients (aged 3-219 months) were much the same between treatment periods. Before PNCP implementation, 33 (52%) of 63 patients had unfavourable disposition at hospital discharge (death or admission to an inpatient facility) and 30 (48%) had a favourable disposition (home with or without treatment); after PNCP implementation, 20 (33%) of 60 patients had unfavourable disposition and 40 (67%) had favourable disposition (p=0·01). Seven (11%) patients died before PNCP implementation compared with two (3%) deaths after implementation. The probit model indicated that outcome improved across the spectrum of Glasgow coma scale scores after resuscitation (p=0·02); this improvement progressed with increasing injury severity. Kaplan-Meier analysis suggested that neuromonitoring was started earlier and maintained longer after implementation of the PNCP (p=0·03). Therapeutic intensity scores were increased for the first 3 days of treatment after PNCP implementation (p=0·0298 for day 1, p=0·0292 for day 2, and p=0·0471 for day 3). The probit model suggested that increasing age (p=0·03), paediatric risk of mortality III scores (p=0·0003), and injury severity scores (p=0·02) were reliably associated with increased probability of unfavourable outcomes whereas white race (p=0·01), use of intracranial pressure monitoring (p=0·001), and increasing Glasgow coma scale scores after resuscitation (p=0·04) were associated with increased probability of favourable outcomes. Interpretation: Outcomes for children with traumatic brain injury can be improved by altering the care system in a way that stably implements a cooperative programme of accepted best practice. Funding: St Louis Children's Hospital and the Sean Glanvill Foundations. © 2012 Elsevier Ltd. All rights reserved.

Document Type: Article in Press
Source: Scopus

 

Barch, D.M.
Introduction to Special Issue on the Neurobiology of Depression
(2012) Neurobiology of Disease, . Article in Press. 

Washington University in St. Louis, USA

Document Type: Article in Press
Source: Scopus

 

Tripodi, S.J.a , Pettus-Davis, C.b
Histories of childhood victimization and subsequent mental health problems, substance use, and sexual victimization for a sample of incarcerated women in the US
(2012) International Journal of Law and Psychiatry, . Article in Press. 

a Florida State University, College of Social Work, 296 Champions Way, University Center C, Tallahassee, FL 32306, United States
b Washington University in St. Louis, Brown School, Campus Box 1196, Goldfarb Hall, Room 241, One Brookings Drive, St. Louis, MO 63130, United States

Abstract
Women are entering US prisons at nearly double the rate of men and are the fastest growing prison population. Current extant literature focuses on the prevalence of the incarceration of women, but few studies exist that emphasize the different trajectories to prison. For example, women prisoners have greater experiences of prior victimization, more reports of mental illness, and higher rates of illicit substance use. The purpose of this study was to understand the prevalence of childhood victimization and its association with adult mental health problems, substance abuse disorders, and further sexual victimization. The research team interviewed a random sample of 125 women prisoners soon to be released from prison to gather information on their childhood physical and sexual victimization, mental health and substance abuse problems as an adult, and sexual victimization in the year preceding incarceration. Results indicate that women prisoners in this sample, who were both physically and sexually victimized as children, were more likely to be hospitalized as an adult for a psychological or emotional problem. Women who were sexually victimized or both physically and sexually victimized were more likely to attempt suicide. Women who experienced physical victimization as children and women who were both physically and sexually victimized were more likely to have a substance use disorder and women who were sexually abused as children or both physically and sexually victimized were more likely to be sexually abused in the year preceding prison. This article ends with a discussion about prisons' role in providing treatment for women prisoners and basing this treatment on women's trajectories to prison, which disproportionately include childhood victimization and subsequent mental health and substance use problems. © 2012 Elsevier Ltd. All rights reserved.

Author Keywords
Mental health;  Prisoners;  Substance abuse;  Victimization;  Women offenders

Document Type: Article in Press
Source: Scopus

 

Lee, P.H.a b c d e , Perlis, R.H.a c d e f , Jung, J.-Y.g , Byrne, E.M.h i , Rueckert, E.c d e , Siburian, R.a , Haddad, S.a , Mayerfeld, C.E.a , Heath, A.C.j , Pergadia, M.L.j , Madden, P.A.F.j , Boomsma, D.I.k , Penninx, B.W.l , Sklar, P.m , Martin, N.G.h , Wray, N.R.i , Purcell, S.M.a b c d e m , Smoller, J.W.a c d e f
Multi-locus genome-wide association analysis supports the role of glutamatergic synaptic transmission in the etiology of major depressive disorder
(2012) Translational Psychiatry, 2, art. no. e184, . 

a Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, United States
b Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, United States
c Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, United States
d Department of Psychiatry, Harvard Medical School, Boston, MA, United States
e Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States
f Psychiatric Genetics Program in Mood and Anxiety Disorders, Massachusetts General Hospital, Boston, MA, United States
g Center for Biomedical Informatics, Harvard Medical School, Boston, MA, United States
h Genetic Epidemiology, Queensland Institute of Medical Research, Brisbane, QLD, Australia
i University of Queensland, Brisbane St Lucia, QLD, Australia
j Department of Psychiatry, Washington University, St Louis, MO, United States
k Department of Biological Psychology, VU University, Amsterdam, Netherlands
l Department of Psychiatry, VU University Medical Center, Amsterdam, Netherlands
m Division of Psychiatric Genomics, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, United States

Abstract
Major depressive disorder (MDD) is a common psychiatric illness characterized by low mood and loss of interest in pleasurable activities. Despite years of effort, recent genome-wide association studies (GWAS) have identified few susceptibility variants or genes that are robustly associated with MDD. Standard single-SNP (single nucleotide polymorphism)-based GWAS analysis typically has limited power to deal with the extensive heterogeneity and substantial polygenic contribution of individually weak genetic effects underlying the pathogenesis of MDD. Here, we report an alternative, gene-set-based association analysis of MDD in an effort to identify groups of biologically related genetic variants that are involved in the same molecular function or cellular processes and exhibit a significant level of aggregated association with MDD. In particular, we used a text-mining-based data analysis to prioritize candidate gene sets implicated in MDD and conducted a multi-locus association analysis to look for enriched signals of nominally associated MDD susceptibility loci within each of the gene sets. Our primary analysis is based on the meta-analysis of three large MDD GWAS data sets (total N=4346 cases and 4430 controls). After correction for multiple testing, we found that genes involved in glutamatergic synaptic neurotransmission were significantly associated with MDD (set-based association P=6.9 × 10 -4). This result is consistent with previous studies that support a role of the glutamatergic system in synaptic plasticity and MDD and support the potential utility of targeting glutamatergic neurotransmission in the treatment of MDD. © 2012 Macmillan Publishers Limited All rights reserved.

Author Keywords
Genome-wide association study;  glutamatergic synaptic neurotransmission;  major depressive disorder;  pathway analysis

Document Type: Article
Source: Scopus

 

Goodman, J.K., Malkoc, S.A.
Choosing here and now versus there and later: The moderating role of psychological distance on assortment size preferences
(2012) Journal of Consumer Research, 39 (4), pp. 751-768. 

Olin Business School, Washington University in St. Louis, St. Louis, MO63130, United States

Abstract
Consumers prefer larger assortments, despite the negative consequences associated with choosing from these sets. This article examines the role of psychological distance (temporal and geographical) in consumers' assortment size decisions and rectifies contradicting hypotheses produced by construal level theory. Six studies demonstrate that while consumers prefer larger assortments when the choice takes place in the here and now, they are more likely to prefer small assortments when choices pertain to distant locations and times. This decrease in preference for large assortments is due to psychological distance increasing the similarity of the options in a category, making them appear more substitutable. This effect of psychological distance reverses when consumers consider desirability/feasibility trade-off information inherent in the assortment size decision. These findings point to important outcomes of psychological distance, resolving opposing predictions of construal level theory, and identify boundary conditions for the well-established notion that consumers are attracted to large assortments.

Document Type: Article
Source: Scopus

 

Kerchner, G.A.a , Racine, C.A.b , Hale, S.c , Wilheim, R.d , Laluz, V.d , Miller, B.L.d , Kramer, J.H.d
Cognitive Processing Speed in Older Adults: Relationship with White Matter Integrity
(2012) PLoS ONE, 7 (11), art. no. e50425, . 

a Stanford Center for Memory Disorders, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, United States
b Departments of Neurological Surgery and Radiation Oncology, University of California, San Francisco, CA, United States
c Cognitive Development Laboratory, Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
d Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, United States

Abstract
Cognitive processing slows with age. We sought to determine the importance of white matter integrity, assessed by diffusion tensor imaging (DTI), at influencing cognitive processing speed among normal older adults, assessed using a novel battery of computerized, non-verbal, choice reaction time tasks. We studied 131 cognitively normal adults aged 55-87 using a cross-sectional design. Each participant underwent our test battery, as well as MRI with DTI. We carried out cross-subject comparisons using tract-based spatial statistics. As expected, reaction time slowed significantly with age. In diffuse areas of frontal and parietal white matter, especially the anterior corpus callosum, fractional anisotropy values correlated negatively with reaction time. The genu and body of the corpus callosum, superior longitudinal fasciculus, and inferior fronto-occipital fasciculus were among the areas most involved. This relationship was not explained by gray or white matter atrophy or by white matter lesion volume. In a statistical mediation analysis, loss of white matter integrity mediated the relationship between age and cognitive processing speed. © 2012 Kerchner et al.

Document Type: Article
Source: Scopus

 

Sun, J.a i , Xu, J.a , Cairns, N.J.b c , Perlmutter, J.S.a b d e f , Mach, R.H.a g h
Dopamine D 1, D 2, D 3 Receptors, Vesicular Monoamine Transporter Type-2 (VMAT2) and Dopamine Transporter (DAT) Densities in Aged Human Brain
(2012) PLoS ONE, 7 (11), art. no. e49483, . 

a Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
f Department of Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
g Department of Cell Biology amd Physiology, Washington University School of Medicine, St. Louis, MO, United States
h Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, United States
i Neurosurgery Department, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China

Abstract
The dopamine D 1, D 2, D 3 receptors, vesicular monoamine transporter type-2 (VMAT2), and dopamine transporter (DAT) densities were measured in 11 aged human brains (aged 77-107.8, mean: 91 years) by quantitative autoradiography. The density of D 1 receptors, VMAT2, and DAT was measured using [ 3H]SCH23390, [ 3H]dihydrotetrabenazine, and [ 3H]WIN35428, respectively. The density of D 2 and D 3 receptors was calculated using the D 3-preferring radioligand, [ 3H]WC-10 and the D 2-preferring radioligand [ 3H]raclopride using a mathematical model developed previously by our group. Dopamine D 1, D 2, and D 3 receptors are extensively distributed throughout striatum; the highest density of D 3 receptors occurred in the nucleus accumbens (NAc). The density of the DAT is 10-20-fold lower than that of VMAT2 in striatal regions. Dopamine D 3 receptor density exceeded D 2 receptor densities in extrastriatal regions, and thalamus contained a high level of D 3 receptors with negligible D 2 receptors. The density of dopamine D 1 linearly correlated with D 3 receptor density in the thalamus. The density of the DAT was negligible in the extrastriatal regions whereas the VMAT2 was expressed in moderate density. D 3 receptor and VMAT2 densities were in similar level between the aged human and aged rhesus brain samples, whereas aged human brain samples had lower range of densities of D 1 and D 2 receptors and DAT compared with the aged rhesus monkey brain. The differential density of D 3 and D 2 receptors in human brain will be useful in the interpretation of PET imaging studies in human subjects with existing radiotracers, and assist in the validation of newer PET radiotracers having a higher selectivity for dopamine D 2 or D 3 receptors. © 2012 Sun et al.

Document Type: Article
Source: Scopus

 

Graf, E.R.a d , Valakh, V.d , Wright, C.M.a , Wu, C.b , Liu, Z.c , Zhang, Y.Q.c , DiAntonio, A.d
RIM promotes calcium channel accumulation at active zones of the Drosophila neuromuscular junction

(2012) Journal of Neuroscience, 32 (47), pp. 16586-16596. 

a Department of Biology and Neuroscience Program, Amherst College, Amherst, MA 01002, United States
b Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, United States
c Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
d Department of Developmental Biology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Synaptic communication requires the controlled release of synaptic vesicles from presynaptic axon terminals. Release efficacy is regulated by the many proteins that comprise the presynaptic release apparatus, including Ca 2+ channels and proteins that influence Ca 2+ channel accumulation at release sites. Here we identify Drosophila RIM (Rab3 interacting molecule) and demonstrate that it localizes to active zones at the larval neuromuscular junction. In Drosophila RIM mutants, there is a large decrease in evoked synaptic transmission because of a significant reduction in both the clustering of Ca 2+ channels and the size of the readily releasable pool of synaptic vesicles at active zones. Hence, RIM plays an evolutionarily conserved role in regulating synaptic calcium channel localization and readily releasable pool size. Because RIM has traditionally been studied as an effector of Rab3 function, we investigate whether RIM is involved in the newly identified function of Rab3 in the distribution of presynaptic release machinery components across release sites. Bruchpilot (Brp), an essential component of the active zone cytomatrix T bar, is unaffected by RIM disruption, indicating that Brp localization and distribution across active zones does not require wild-type RIM. In addition, larvae containing mutations in both RIM and rab3 have reduced Ca 2+ channel levels and a Brp distribution that is very similar to that of the rab3 single mutant, indicating that RIM functions to regulate Ca 2+ channel accumulation but is not a Rab3 effector for release machinery distribution across release sites. © 2012 the authors.

Document Type: Article
Source: Scopus

 

Kwasnieski, J.C.a , Mogno, I.a , Myers, C.A.b , Corbo, J.C.b , Cohen, B.A.a
Complex effects of nucleotide variants in a mammalian cis-regulatory element
(2012) Proceedings of the National Academy of Sciences of the United States of America, 109 (47), pp. 19498-19503. 

a Center for Genome Sciences and Systems Biology, Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MO 63108, United States
b Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States

Abstract
Cis-regulatory elements (CREs) control gene expression by recruiting transcription factors (TFs) and other DNA binding proteins. We aim to understand how individual nucleotides contribute to the function of CREs. Here we introduce CRE analysis by sequencing (CRE-seq), a high-throughput method for producing and testing large numbers of reporter genes in mammalian cells. We used CRE-seq to assay >1,000 single and double nucleotide mutations in a 52-bp CRE in the Rhodopsin promoter that drives strong and specific expression in mammalian photoreceptors. We find that this particular CRE is remarkably complex. The majority (86%) of single nucleotide substitutions in this sequence exert significant effects on regulatory activity. Although changes in the affinity of known TF binding sites explain some of these expression changes, wepresent evidence for complex phenomena, including binding site turnover and TF competition. Analysis of double mutants revealed complex, nucleotide-specific interactions between residues in different TF binding sites. We conclude that some mammalian CREs are finely tuned by evolution and function through complex, nonadditive interactions between bound TFs. CRE-seq will be an important tool to uncover the rules that govern these interactions.

Author Keywords
CRX;  Gene regulation;  Genomics;  Retina;  Systems biology

Document Type: Article
Source: Scopus

 

Stemler, K.M.a , Crock, L.W.e , Lai, H.H.d , Mills, J.C.b c , Gereau IV, R.W.e , Mysorekar, I.U.a b
Protamine Sulfate Induced Bladder Injury Protects from Distention Induced Bladder Pain
(2012) Journal of Urology, . Article in Press. 

a Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
c Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
d Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
e Department of Anesthesiology, Washington University Pain Center, St. Louis, Missouri

Abstract
Purpose: Bladder pain is a debilitating symptom of many urological conditions. There is no generally effective treatment. Abnormal urothelial turnover is common to multiple disease states but the specific components of urothelial injury and the resulting molecular signals that lead to bladder pain are unknown. We examined mouse models of bladder injury induced by uropathogenic Escherichia coli, protamine sulfate (Sigma®) and bacterial lipopolysaccharide to identify cellular and molecular correlates underlying pain sensitization in response to the stimuli. Materials and Methods: C57BL/6 female mice (Jackson Laboratory, Bar Harbor, Maine) were given intravesicular protamine sulfate, lipopolysaccharide or uropathogenic E. coli. The impact of each on nociception was determined by measuring the evoked visceromotor response to bladder distention 24 hours after inoculation. Levels of pyuria and tissue inflammation were examined by urinary cytology and tissue histology. Quantitative polymerase chain reaction and gene expression analysis were used to identify injury profiles associated with nociception. Results: Protamine sulfate treatment was significantly analgesic upon bladder distention. Protamine treated bladders did not show pyuria or extensive tissue damage. Protamine injury was associated with a global decrease in the expression of inflammation associated genes. In contrast, uropathogenic E. coli injury significantly increased the nociceptive response to bladder distention. Lipopolysaccharide treatment did not affect nociception. Finally, injury induced expression of inflammation associated genes correlated with nociceptive responses. Conclusions: Protamine treatment of the bladder is analgesic and tissue protective, and it suppresses the inflammatory cytokine expression normally associated with nociception. Also, the injury modalities that result in differential tissue response patterns provide an innovative method for identifying mediators of visceral pain. © 2013 American Urological Association Education and Research, Inc.

Author Keywords
inflammation;  nociception;  pain;  protamines;  urinary bladder

Document Type: Article in Press
Source: Scopus

 

Xu, M.a g , Liu, K.a , Swaroop, M.a , Porter, F.D.b , Sidhu, R.c , Finkes, S.c , Ory, D.S.c , Marugan, J.J.a , Xiao, J.a , Southall, N.a , Pavan, W.J.d , Davidson, C.e , Walkley, S.U.e , Remaley, A.T.f , Baxa, U.h , Sun, W.a , McKew, J.C.a , Austin, C.P.a , Zheng, W.a
δ-tocopherol reduces lipid accumulation in Niemann-Pick type C1 and Wolman cholesterol storage disorders
(2012) Journal of Biological Chemistry, 287 (47), pp. 39349-39360. 

a National Center for Advancing Translational Sciences, National Institutes of Health, MSC 3370, 9800 Medical Center Dr., Bethesda, MD 20892-3370, United States
b Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, MD 20892, United States
c Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO, United States
d Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, United States
e Sidney Weisner Laboratory of Genetic Neurological Disease, Rose F. Kennedy Center, Albert Einstein College of Medicine, Bronx, NY 10461, United States
f Laboratory of Lipoprotein Metabolism, NHLBI, National Institutes of Health, Bethesda, MD 20892, United States
g Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
h Electron Microscopy Laboratory, NCI, National Institutes of Health, Bethesda, MD 20892, United States

Abstract
Niemann-Pick disease type C (NPC) and Wolman disease are two members of a family of storage disorders caused by mutations of genes encoding lysosomal proteins. Deficiency in function of either the NPC1 or NPC2 protein in NPC disease or lysosomal acid lipase in Wolman disease results in defective cellular cholesterol trafficking. Lysosomal accumulation of cholesterol and enlarged lysosomes are shared phenotypic characteristics of both NPC and Wolman cells. Utilizing a phenotypic screen of an approved drug collection, we found that δ-tocopherol effectively reduced lysosomal cholesterol accumulation, decreased lysosomal volume, increased cholesterol efflux, and alleviated pathological phenotypes in both NPC1 and Wolman fibroblasts. Reduction of these abnormalities may be mediated by a δ-tocopherol-induced intracellular Ca 2+ response and subsequent enhancement of lysosomal exocytosis. Consistent with a general mechanism for reduction of lysosomal lipid accumulation, we also found that δ-tocopherol reduces pathological phenotypes in patient fibroblasts from other lysosomal storage diseases, including NPC2, Batten (ceroid lipofuscinosis, neuronal 2, CLN2), Fabry, Farber, Niemann-Pick disease type A, Sanfilippo type B (mucopolysaccharidosis type IIIB, MPSIIIB), and Tay-Sachs. Our data suggest that regulated exocytosis may represent a potential therapeutic target for reduction of lysosomal storage in this class of diseases.

Document Type: Article
Source: Scopus

 

Peelle, J.E.
The hemispheric lateralization of speech processing depends on what "speech" is: A hierarchical perspective
(2012) Frontiers in Human Neuroscience, (NOVEMBER 2012), . 

Department of Otolaryngology, Washington University In St. Louis, St. Louis, MO, United States

Abstract
A recurring question in neuroimaging studies of spoken language is whether speech is processed largely bilaterally, or whether the left hemisphere plays a more dominant role (cf., Hickok and Poeppel, 2007; Rauschecker and Scott, 2009). Although questions regarding underly- ing mechanisms are certainly of interest, the discussion unfortunately gets side- tracked due to the imprecise use of the word "speech": by being more explicit about the type of cognitive and linguis- tic processing to which we are referring it may be possible to reconcile many of the disagreements present in the literature. © 2012 Peelle.

Document Type: Article
Source: Scopus

 

Bracamontes, J.R., Li, P., Akk, G., Steinbach, J.H.
A neurosteroid potentiation site can be moved among GABA A receptor subunits
(2012) Journal of Physiology, 590 (22), pp. 5739-5747. 

Department of Anesthesiology and the Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St Louis, MO 63110, United States

Abstract
Endogenous neurosteroids are among the most potent and efficacious potentiators of activation of GABA A receptors. It has been proposed that a conserved glutamine residue in the first membrane-spanning region (TM1 region) of the α subunits is required for binding of potentiating neurosteroids. Mutations of this residue can reduce or remove the ability of steroids to potentiate function. However, it is not known whether potentiation requires that a steroid interact with the α subunit, or not. To examine this question we mutated the homologous residue in the β2 and γ2L subunits to glutamine, and found that these mutations could not confer potentiation by allopregnanolone (3α5αP) when expressed in receptors containing ineffective α1 subunits. However, potentiation is restored when the entire TM1 region from the α1 subunit is transferred to the β2 or γ2L subunit. Mutations in the TM1 region that affect potentiation when made in the α1 subunit have similar effects when made in transferred TM1 region. Further, the effects of 3α5αP on single-channel kinetics are similar for wild-type receptors and receptors with moved TM1 regions. These results support the idea that steroids bind in the transmembrane regions of the receptor. The observations are consistent with previous work indicating that neurosteroid potentiation is mediated by an action that affects the receptor as a whole, rather than an individual subunit or pair of subunits, and in addition demonstrate that the mechanism is independent of the nature of the subunit that interacts with steroid. © 2012 The Authors. The Journal of Physiology © 2012 The Physiological Society.

Document Type: Article
Source: Scopus

 

Prather, H.a , Spitznagle, T.b , Hunt, D.c
Benefits of exercise during pregnancy
(2012) PM and R, 4 (11), pp. 845-850. 

a Physical Medicine and Rehabilitation, Department of Orthopaedic Surgery, Washington University School of Medicine, One Barnes Plaza, Suite 11300, St Louis, MO 63110, United States
b Program in Physical Therapy, Washington University School of Medicine, St Louis, MO, United States
c Physical Medicine and Rehabilitation, Department of Orthopaedic Surgery, Washington University School of Medicine, St Louis, MO, United States

Abstract
There is a direct link between healthy mothers and healthy infants. Exercise and appropriate nutrition are important contributors to maternal physical and psychological health. The benefits and potential risks of exercise during pregnancy have gained even more attention, with a number of studies having been published after the 2002 American College of Obstetrics and Gynecologists guidelines. A review of the literature was conducted by using PubMed, Scopus, and Embase to assess the literature regarding the benefits of exercise during pregnancy. The search revealed 219 publications, which the authors then narrowed to 125 publications. The purpose of this review is to briefly summarize the known benefits of exercise to the mother, fetus, and newborn. © 2012 American Academy of Physical Medicine and Rehabilitation.

Document Type: Article
Source: Scopus

 

McCutcheon, V.V.a , Grant, J.D.a , Heath, A.C.a , Bucholz, K.K.a , Sartor, C.E.b , Nelson, E.C.a , Madden, P.A.F.a , Martin, N.G.c
Environmental influences predominate in remission from alcohol use disorder in young adult twins
(2012) Psychological Medicine, 42 (11), pp. 2421-2431. 

a Midwest Alcoholism Research Center, Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Ave., Campus Box 8134, St Louis, MO 63110, United States
b Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
c Department of Epidemiology and Public Health, Queensland Institute for Medical Research, Brisbane, Australia

Abstract
Background Familial influences on remission from alcohol use disorder (AUD) have been studied using family history of AUD rather than family history of remission. The current study used a remission phenotype in a twin sample to examine the relative contributions of genetic and environmental influences to remission. Method The sample comprised 6183 twins with an average age of 30 years from the Australian Twin Registry. Lifetime history of alcohol abuse and dependence symptoms and symptom recency were assessed with a structured telephone interview. AUD was defined broadly and narrowly as history of two or more or three or more abuse or dependence symptoms. Remission was defined as absence of symptoms at time of interview among individuals with lifetime AUD. Standard bivariate genetic analyses were conducted to derive estimates of genetic and environmental influences on AUD and remission. Results Environmental influences alone accounted for remission in males and for 89% of influences on remission in females, with 11% due to genetic influences shared with AUD, which decreased the likelihood of remission. For women, more than 80% of influences on remission were distinct from influences on AUD, and environmental influences were from individual experiences only. For men, just over 50% of influences on remission were distinct from those on AUD, and the influence of environments shared with the co-twin were substantial. The results for the broad and narrow phenotypes were similar. Conclusions The current study establishes young adult remission as a phenotype distinct from AUD and highlights the importance of environmental influences on remission. © 2012 Cambridge University Press.

Author Keywords
Alcohol dependence;  alcohol use disorder;  remission;  twins

Document Type: Article
Source: Scopus

 

Panagos, P.D.
Implications of early and accurate imaging for suspected transient ischemic attack
(2012) American Journal of Emergency Medicine, 30 (9), p. 2075. 

Department of Emergency Medicine, Washington University, St Louis, MO, 63110, United States

Document Type: Letter
Source: Scopus

 

Rubin, E.H., Zorumski, C.F.
More about the future of psychiatry education: In reply to Walaszek and Reardon
(2012) Academic Medicine, 87 (11), pp. 1455-1456. 

Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MI, United States

Document Type: Letter
Source: Scopus

 

Niewoehner, P.M.a , Henderson, R.R.b , Dalchow, J.c , Beardsley, T.L.a , Stern, R.A.d , Carr, D.B.e
Predicting road test performance in adults with cognitive or visual impairment referred to a veterans affairs medical center driving clinic
(2012) Journal of the American Geriatrics Society, 60 (11), pp. 2070-2074. 

a Veterans Affairs Medical Center, 1 Jefferson Barracks Drive, 117/JB, St. Louis, MO 63125, United States
b Southern Illinois University, Edwardsville, IL, United States
c Sanford Health, University of South, Dakota Medical Center, Sioux Falls, SD, United States
d Alzheimer's Disease Center, School of Medicine, Boston University, Boston, MA, United States
e Division of Geriatrics and Nutritional Science, Rehabilitation Institute of St. Louis, Washington University, St. Louis, MO, United States

Abstract
Objectives To develop a screening battery for office-based clinicians that would assist with the prediction of impaired driving performance and deciding who should proceed to road testing in a sample of adults with cognitive or visual deficits. Design Prospective observational study. Setting Driving evaluation clinic at a Veterans Affairs Medical Center (VAMC) in St. Louis, Missouri. Participants Seventy-seven individuals aged 23 to 91 with diagnoses of cognitive or visual impairment or both referred to an occupational therapy based driving clinic by VAMC providers because of concerns regarding driving safety. Measurements Predictor variables included tests of visual and cognitive functioning and activities of daily living. The major outcome was pass or fail on a standardized performance-based on-road driving test. Results Thirty percent of the referrals failed the road test. The best predictors of driving performance were the Trail-Making Test Part A and the Mazes Test from the Neuropsychological Assessment Battery. Conclusion Measures of visual search, psychomotor speed, and executive functioning accurately predicted road test performance in a significant number of participants. These brief tests may assist clinicians in deciding who should proceed with a road test in a driver rehabilitation clinic or perhaps to whom it should be recommended to cease driving. © 2012, The American Geriatrics Society.

Author Keywords
automobile driving;  driving safety;  psychometric testing;  road testing

Document Type: Article
Source: Scopus

 

Wong, E.S.W.a , Morgenstern, D.b , Mofiz, E.c , Gombert, S.a , Morris, K.M.a , Temple-Smith, P.d , Renfree, M.B.e , Whittington, C.M.a , King, G.F.b , Warren, W.C.f , Papenfuss, A.T.c g , Belov, K.a h
Proteomics and deep sequencing comparison of seasonally active venom glands in the platypus reveals novel venom peptides and distinct expression profiles

(2012) Molecular and Cellular Proteomics, 11 (11), pp. 1354-1364. 

a Faculty of Veterinary Science, University of Sydney, Camperdown, NSW 2006, Australia
b Department of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD 4072, Australia
c Bioinformatics Division, Walter and Eliza Hall Institute for Medical Research, Parkville, VIC 3050, Australia
d Department of Obstetrics and Gynaecology, Monash University, VIC 3800, Australia
e Department of Zoology, University of Melbourne, VIC 3010, Australia
f Genome Institute, Washington University School of Medicine, Forest Park Parkway, St. Louis, MO 63108, United States
g Department of Mathematics and Statistics, University of Melbourne, VIC 3010, Australia
h Faculty of Veterinary Science, University of Sydney, RMC Gunn B19, Sydney, NSW 2006, Australia

Abstract
The platypus is a venomous monotreme. Male platypuses possess a spur on their hind legs that is connected to glands in the pelvic region. They produce venom only during the breeding season, presumably to fight off conspecifics. We have taken advantage of this unique seasonal production of venom to compare the transcriptomes of in- and out-of-season venom glands, in conjunction with proteomic analysis, to identify previously undiscovered venom genes. Comparison of the venom glands revealed distinct gene expression profiles that are consistent with changes in venom gland morphology and venom volumes in and out of the breeding season. Venom proteins were identified through shot-gun sequenced venom proteomes of three animals using RNA-seq-derived transcripts for peptide-spectral matching. 5,157 genes were expressed in the venom glands, 1,821 genes were up-regulated in the in-season gland, and 10 proteins were identified in the venom. New classes of platypus-venom proteins identified included antimicrobials, amide oxidase, serpin protease inhibitor, proteins associated with the mammalian stress response pathway, cytokines, and other immune molecules. Five putative toxins have only been identified in platypus venom: growth differentiation factor 15, nucleobindin-2, CD55, a CXC-chemokine, and corticotropin-releasing factor-binding protein. These novel venom proteins have potential biomedical and therapeutic applications and provide insights into venom evolution. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

Document Type: Article
Source: Scopus

 

Chen, L.a , Hu, L.a , Dong, J.-Y.a , Ye, Q.a , Hua, N.a , Wong, M.b , Zeng, L.-H.a b
Rapamycin has paradoxical effects on S6 phosphorylation in rats with and without seizures
(2012) Epilepsia, 53 (11), pp. 2026-2033. 

a School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang 310015, China
b Department of Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Purpose: Accumulating data have demonstrated that seizures induced by kainate (KA) or pilocarpine activate the mammalian target of rapamycin (mTOR) pathway and that mTOR inhibitor rapamycin can inhibit mTOR activation, which subsequently has potential antiepileptic effects. However, a preliminary study showed a paradoxical exacerbation of increased mTOR pathway activity reflected by S6 phosphorylation when rapamycin was administrated within a short period before KA injection. In the present study, we examined this paradoxical effect of rapamycin in more detail, both in normal rats and KA-injected animals. Methods: Normal rats or KA-treated rats pretreated with rapamycin at different time intervals were sacrificed at various time points (1, 3, 6, 10, 15, and 24 h) after rapamycin administration or seizure onset for western blotting analysis. Phosphorylation of mTOR signaling target of Akt, mTOR, Rictor, Raptor, S6K, and S6 were analyzed. Seizure activity was monitored behaviorally and graded according to a modified Racine scale (n = 6 for each time point). Neuronal cell death was detected by Fluoro-Jade B staining. Key Findings: In normal rats, we found that rapamycin showed the expected dose-dependent inhibition of S6 phosphorylation 3-24 h after injection, whereas a paradoxical elevation of S6 phosphorylation was observed 1 h after rapamycin. Similarly, pretreatment with rapamycin over 10 h before KA inhibited the KA seizure-induced mTOR activation. In contrast, rapamycin administered 1-6 h before KA caused a paradoxical increase in the KA seizure-induced mTOR activation. Rats pretreated with rapamycin 1 h prior to KA exhibited an increase in severity and duration of seizures and more neuronal cell death as compared to vehicle-treated groups. In contrast, rapamycin pretreated 10 h prior to KA had no effect on the seizures and decreased neuronal cell death. The paradoxical effect of rapamycin on S6 phosphorylation was correlated with upstream mTOR signaling and was reversed by pretreatment of perifosine, an Akt inhibitor. Significance: These data indicate the complexity of S6 regulation and its effect on epilepsy. Paradoxical effects of rapamycin need to be considered in clinical applications, such as for potential treatment for epilepsy and other neurologic disorders. © 2012 International League Against Epilepsy.

Author Keywords
Kainate;  mTOR signaling pathway;  Paradoxical effect;  Rapamycin;  S6 phosphorylation

Document Type: Article
Source: Scopus

 

Weiner, N.W.a , Toglia, J.b , Berg, C.c
Weekly calendar planning activity (WCPA): A performance-based assessment of executive function piloted with at-risk adolescents
(2012) American Journal of Occupational Therapy, 66 (6), pp. 699-708. 

a CarePartners Health Services and Carolina Pediatric Therapy, Asheville, NC, United States
b Graduate Occupational Therapy Program, Mercy College, Dobbs Ferry, NY, United States
c Program in Occupational Therapy, Washington University in St. Louis, 4444 Forest Park Avenue, St. Louis, MO 63108, United States

Abstract
OBJECTIVE. We piloted the Weekly Calendar Planning Activity (WCPA), a performance-based measure of executive function (EF), to establish a baseline for at-risk adolescents. METHOD. Participants were 113 youths ages 16-21 who were enrolled at a charter school for youth returning to high school after dropping out. We administered the WCPA and collected demographic information. RESULTS. On average, participants spent 15.9 min on the WCPA, made 7.9 errors, and followed 4.0 of 5 possible rules. No ceiling effect was observed in overall accuracy. Participants used a mean of 3.1 strategies (standard deviation 5 1.9) while completing the WCPA. Participants who used more strategies spent more time planning and completing the task and were more accurate. CONCLUSION. The WCPA may be useful to occupational therapists as a performance measure of EF. This assessment allows evaluation of complex task performance, strategy use, self-evaluation of performance, and error patterns, which can be used in developing intervention strategies.

Author Keywords
Activities of daily living;  Adolescent development;  Executive function;  Task performance and analysis

Document Type: Article
Source: Scopus

 

Shin, J.a g , Padmanabhan, A.b c , De Groh, E.D.b c , Lee, J.-S.a h , Haidar, S.d , Dahlberg, S.a , Guo, F.a , He, S.a , Wolman, M.A.b c , Granato, M.b c , Lawson, N.D.e , Wolfe, S.A.e , Kim, S.-H.f , Solnica-Krezel, L.g , Kanki, J.P.a , Ligon, K.L.d , Epstein, J.A.b c , Look, A.T.a
Zebrafish neurofibromatosis type 1 genes have redundant functions in tumorigenesis and embryonic development
(2012) DMM Disease Models and Mechanisms, 5 (6), pp. 881-894. 

a Department of Pediatric Oncology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, United States
b Department of Cell and Developmental Biology, Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, United States
c Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
d Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, United States
e Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 06105, United States
f Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States
g Department of Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
h Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, South Korea

Abstract
Neurofibromatosis type 1 (NF1) is a common, dominantly inherited genetic disorder that results from mutations in the neurofibromin 1 (NF1) gene. Affected individuals demonstrate abnormalities in neural-crest-derived tissues that include hyperpigmented skin lesions and benign peripheral nerve sheath tumors. NF1 patients also have a predisposition to malignancies including juvenile myelomonocytic leukemia (JMML), optic glioma, glioblastoma, schwannoma and malignant peripheral nerve sheath tumors (MPNSTs). In an effort to better define the molecular and cellular determinants of NF1 disease pathogenesis in vivo, we employed targeted mutagenesis strategies to generate zebrafish harboring stable germline mutations in nf1a and nf1b, orthologues of NF1. Animals homozygous for loss-of-function alleles of nf1a or nf1b alone are phenotypically normal and viable. Homozygous loss of both alleles in combination generates larval phenotypes that resemble aspects of the human disease and results in larval lethality between 7 and 10 days post fertilization. nf1-null larvae demonstrate significant central and peripheral nervous system defects. These include aberrant proliferation and differentiation of oligodendrocyte progenitor cells (OPCs), dysmorphic myelin sheaths and hyperplasia of Schwann cells. Loss of nf1 contributes to tumorigenesis as demonstrated by an accelerated onset and increased penetrance of high-grade gliomas and MPNSTs in adult nf1a +/-; nf1b -/-; p53 e7/e7 animals. nf1-null larvae also demonstrate significant motor and learning defects. Importantly, we identify and quantitatively analyze a novel melanophore phenotype in nf1-null larvae, providing the first animal model of the pathognomonic pigmentation lesions of NF1. Together, these findings support a role for nf1a and nf1b as potent tumor suppressor genes that also function in the development of both central and peripheral glial cells as well as melanophores in zebrafish. © 2012. Published by The Company of Biologists Ltd.

Document Type: Article
Source: Scopus

 

Gattis, M.N.a , Sacco, P.b , Cunningham-Williams, R.M.c
Substance use and mental health disorders among heterosexual identified men and women who have same-sex partners or same-sex attraction: Results from the national epidemiological survey on alcohol and related conditions
(2012) Archives of Sexual Behavior, 41 (5), pp. 1185-1197. 

a School of Social Work, University of Wisconsin-Madison, 1350 University Ave., Madison, WI 53706-1510, United States
b School of Social Work, University of Maryland-Baltimore, Baltimore, MD, United States
c George Warren Brown School of Social Work, Washington University, St. Louis, MO, United States

Abstract
This study examined sexual orientation discordance, a mismatch between self-reported sexual identity and sexual behavior or sexual attraction, by describing the characteristics, substance use disorders, andmental health risks of heterosexual identified individuals who endorsed this pattern of sexual identification, behavior, and attraction. Using data from the National Epidemiological Survey on Alcohol and Related Conditions (NESARC), we created three groups based on participants' reported sexual identity and either their sexual behavior or sexual attraction: heterosexual concordant, homosexual concordant, and heterosexual discordant. Bivariate models assessed the relationship of discordant status and demographic correlates, lifetime substance use disorders, and mental health diagnoses. Logistic regression models tested associations between both behavior discordance and attraction discordance and the likelihood of having lifetime disorders of substance use, major depression, and generalized anxiety. Results of this study provided evidence of varying levels of substance use andmental health disorder risk by gender, discordance status, and discordance type. Behavioral discordance was associated with increased risk of mental health and substance use disorder among women (compared to heterosexual concordance). Findings among men were less consistent with heightened risk of alcohol and inhalant use only. Attraction discordance was notably different from behavioral discordance. The odds of substance use and mental health disorders were the same or lower compared with both the heterosexual and homosexual concordance groups. Future research should begin to test theoretical explanations for these differences. © Springer Science+Business Media, LLC 2012.

Author Keywords
Epidemiology;  Men who have sex with men;  Mental health;  Sexual identity;  Sexual orientation;  Substance abuse

Document Type: Review
Source: Scopus

December 2, 2012   

Karch, C.M., Jeng, A.T., Goate, A.M.
Calcium phosphatase calcineurin influences tau metabolism
(2013) Neurobiology of Aging, 34 (2), pp. 374-386. 

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

Abstract
Alzheimer's disease (AD) is characterized by neuronal loss and the accumulation of β-amyloid plaques and neurofibrillary tangles in the brain. Cerebrospinal fluid (CSF) levels of β-amyloid and tau/phospho-tau181 (ptau181) are also associated with AD. We have previously demonstrated that a single nucleotide polymorphism in calcineurin is associated with CSF ptau181 levels and AD progression. In this study, we demonstrate that calcineurin protein levels are inversely correlated with dementia severity and Braak tangle stage in AD brains, and calcineurin activity is globally reduced in AD brains. We then sought to model the observed changes in CSF tau by measuring extracellular tau in cultured cells. SH-SY5Y cells treated with calcineurin inhibitors produced reduced calcineurin activity and a corresponding increase in extracellular ptau181. These findings are consistent with our observations in AD patients, who have elevated CSF ptau181 and reduced calcineurin activity in brain extracts. Thus, we have identified a gene that contributes to AD pathology and has functional consequences on tau metabolism in cultured cells. © 2013 Elsevier Inc.

Author Keywords
Alzheimer's disease;  Calcineurin; Tau;  Phosphorylation

Document Type: Article
Source: Scopus

 

Barch, D.M.a b c , Gaffrey, M.S.a , Botteron, K.N.a c , Belden, A.C.a , Luby, J.L.a
Functional brain activation to emotionally valenced faces in school-aged children with a history of preschool-onset major depression
(2012) Biological Psychiatry, 72 (12), pp. 1035-1042. 

a Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
b Department of Psychology, Washington University in St. Louis, Saint Louis, MO, United States
c Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Background: Recent research has demonstrated that clinical depression can emerge as early as the preschool period. Here, we examine brain function in children with a history of preschool-onset depression (PO-MDD) in comparison with healthy children. Methods: Participants were medication naïve school-aged children (ages 7-11) with PO-MDD (n = 22) or no psychiatric history (n = 16) followed longitudinally as part of the Preschool Depression Study. We used functional magnetic resonance imaging measures of blood oxygen level-dependent signal to examine functional brain activity in response to emotionally valenced faces (sad, fearful, angry, happy, neutral) following a negative mood induction provided to all children. Results: In categorical group comparisons, children with PO-MDD demonstrated increased activity in parietal cortex in response to sad faces but no differences in brain activity in a priori regions of interest (e.g., amygdala). However, in dimensional analyses, the severity of depression symptoms at the baseline preschool assessment predicted increased responses to sad faces in amygdala, hippocampal, parietal, and orbital frontal regions. Conclusions: School-aged children with a history of PO-MDD showed patterns of functional brain responses to emotionally evocative stimuli similar to patterns found in adults and adolescents with major depression. These patterns were most strongly related to the severity of depression during the preschool period, suggesting that the magnitude of early symptoms may be particularly important for understanding altered brain function. These findings suggest that an early episode of depression before age 6 may be associated with enduring brain change or may represent a biomarker that was present even before the preschool episode. © 2012 Society of Biological Psychiatry.

Author Keywords
Amygdala;  childhood;  emotional processing;  fMRI;  limbic system;  major depression

Document Type: Article
Source: Scopus

 

Benedikt, J.a , Inyushin, M.a , Kucheryavykh, Y.V.b , Rivera, Y.a , Kucheryavykh, L.Y.b , Nichols, C.G.c , Eaton, M.J.b , Skatchkov, S.N.a b
Intracellular polyamines enhance astrocytic coupling
(2012) NeuroReport, 23 (17), pp. 1021-1025. 

a Department of Physiology, Universidad Central Del Caribe, School of Medicine, P.O. Box 60327, Bayamón, 00960-6032, Puerto Rico
b Department of Biochemistry, Universidad Central Del Caribe, School of Medicine, Bayamón, Puerto Rico
c Department of Cell Biology2, Washington University, School of Medicine, St Louis, MO, United States

Abstract
Spermine (SPM) and spermidine, endogenous polyamines with the ability to modulate various ion channels and receptors in the brain, exert neuroprotective, antidepressant, antioxidant, and other effects in vivo such as increasing longevity. These polyamines are preferably accumulated in astrocytes, and we hypothesized that SPM increases glial intercellular communication by interacting with glial gap junctions. The results obtained in situ, using Lucifer yellow propagation in the astrocytic syncitium of 21-25-day-old rat CA1 hippocampal slices, showed reduced coupling when astrocytes were dialyzed with standard intracellular solutions without SPM. However, there was a robust increase in the spreading of Lucifer yellow through gap junctions to neighboring astrocytes when the cells were patched with intracellular solutions containing 1 mM SPM, a physiological concentration in glia. Lucifer yellow propagation was inhibited by gap junction blockers. Our findings show that the glial syncitium propagates SPM through gap junctions and further indicate a new role of polyamines in the regulation of the astroglial network under both normal and pathological conditions. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Author Keywords
astrocyte coupling;  dye propagation;  gap junction channels;  polyamines;  spermine

Document Type: Article
Source: Scopus

 

Reiman, E.M.a b f g i , Quiroz, Y.T.h j s , Fleisher, A.S.a g l s , Chen, K.c g i j , Velez-Pardo, C.j m s , Jimenez-Del-Rio, M.j m , Fagan, A.M.k m , Shah, A.R.k m , Alvarez, S.m n , Arbelaez, A.m n , Giraldo, M.j m , Acosta-Baena, N.j m , Sperling, R.A.o q , Dickerson, B.q , Stern, C.E.h p q , Tirado, V.j m , Munoz, C.j m , Reiman, R.A.f , Huentelman, M.J.f g m , Alexander, G.E.d e g , Langbaum, J.B.S.g m , Kosik, K.S.m r , Tariot, P.N.g m , Lopera, F.j m
Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: A case-control study
(2012) The Lancet Neurology, 11 (12), pp. 1048-1056. 

a Banner Alzheimer's Institute, Phoenix, AZ, United States
b Department of Psychiatry, University of Arizona, Phoenix, Tucson, AZ, United States
c Department of Radiology, University of Arizona, Phoenix, Tucson, AZ, United States
d Department of Psychology, University of Arizona, Phoenix, Tucson, AZ, United States
e McKnight Brain Institute, University of Arizona, Phoenix, Tucson, AZ, United States
f Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, United States
g Arizona Alzheimer's Consortium, Phoenix, AZ, United States
h Center for Memory and Brain, Psychology Department, Boston University, Boston, MA, United States
i Department of Mathematics, Arizona State University, Tempe, AZ, United States
j University of Antioquia, Medellin, Colombia
k Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
l Department of Neurology, University of California, San Diego, CA, United States
m Hospital Pablo Tobón Uribe, Medellin, Colombia
n Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
o Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
p Department of Radiology, Massachusetts General Hospital, Boston, MA, United States
q Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, United States
r Neuroscience Research Institute, University of California, Santa Barbara, CA, United States
s Alzheimer's Prevention Initiative, United States

Abstract
Background: We have previously characterised functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's disease. To gain further knowledge on the preclinical phase of Alzheimer's disease, we sought to characterise structural and functional MRI, CSF, and plasma biomarkers in a cohort of young adults carrying a high-penetrance autosomal dominant mutation that causes early-onset Alzheimer's disease. Methods: Between January and August, 2010, 18-26-year-old presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the Colombian Alzheimer's Prevention Initiative Registry in Medellín Antioquia, Colombia, had structural MRI, functional MRI during associative memory encoding and novel viewing and control tasks, and cognitive assessments. Consenting participants also had lumbar punctures and venepunctures. Outcome measures were task-dependent hippocampal or parahippocampal activations and precuneus or posterior cingulate deactivations, regional grey matter reductions, CSF Aβ 1-42, total tau and phospho-tau 181 concentrations, and plasma Aβ 1-42 concentrations and Aβ 1-42:Aβ 1-40 ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to Alzheimer's disease. Cognitive and fluid biomarkers were compared using Mann-Whitney tests. Findings: 44 participants were included: 20 PSEN1 E280A mutation carriers and 24 non-carriers. The carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) e{open}4 carriers. Compared with non-carriers, carriers had greater right hippocampal and parahippocampal activation (p=0·001 and p&lt;0·014, respectively, after correction for multiple comparisons), less precuneus and posterior cingulate deactivation (all p&lt;0·010 after correction), and less grey matter in several parietal regions (all p&lt;0·002 uncorrected and corrected p=0·009 in the right parietal search region). In the 20 participants (ten PSEN1 E280A mutation carriers and ten non-carriers) who had lumbar punctures and venepunctures, mutation carriers had higher CSF Aβ 1-42 concentrations (p=0·008) and plasma Aβ 1-42 concentrations (p=0·01) than non-carriers. Interpretation: Young adults at genetic risk for autosomal dominant Alzheimer's disease have functional and structural MRI findings and CSF and plasma biomarker findings consistent with Aβ 1-42 overproduction. Although the extent to which the underlying brain changes are either neurodegenerative or developmental remain to be determined, this study shows the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant Alzheimer's disease. Funding: Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the State of Arizona. © 2012 Elsevier Ltd.

Document Type: Article
Source: Scopus

 

Nissen, S.a , Liang, S.a , Shehktman, T.a b , Kelsoe, J.R.a b c , Kelsoe, J.R.d , Greenwood, T.A.d , Nievergelt, C.M.d , McKinney, R.d , Shilling, P.D.d , Smith, E.N.d , Schork, N.J.e , Bloss, C.S.e , Nurnberger, J.I.f , Edenberg, H.J.f , Foroud, T.f , Koller, D.L.f , Gershon, E.S.g , Liu, C.g , Badner, J.A.g , Scheftner, W.A.h , Lawson, W.B.i , Nwulia, E.A.i , Hipolito, M.i , Coryell, W.j , Rice, J.k , Byerley, W.l , McMahon, F.J.m , Berrettini, W.H.n , Potash, J.B.o , Zandi, P.P.o , Mahon, P.B.o , McInnis, M.G.p , Zöllner, S.p , Zhang, P.p , Craig, D.W.q , Szelinger, S.q , Barrett, T.B.r , Schulze, T.G.s
Evidence for association of bipolar disorder to haplotypes in the 22q12.3 region near the genes stargazin, ift27 and parvalbumin
(2012) American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, 159 B (8), pp. 941-950. 

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

Abstract
We have previously reported genome-wide significant linkage of bipolar disorder to a region on 22q12.3 near the marker D22S278. Towards identifying the susceptibility gene, we have conducted a fine-mapping association study of the region in two independent family samples, an independent case-control sample and a genome-wide association dataset. Two hundred SNPs were first examined in a 5Mb region surrounding the D22S278 marker in a sample of 169 families and analyzed using PLINK. The peak of association was a haplotype near the genes stargazin (CACNG2), intraflagellar transport protein homolog 27 (IFT27) and parvalbumin (PVALB; P=4.69×10 -4). This peak overlapped a significant haplotype in a family based association study of a second independent sample of 294 families (P=1.42×10 -5). Analysis of the combined family sample yielded statistically significant evidence of association to a rare three SNP haplotype in the gene IFT27 (P=8.89×10 -6). Twelve SNPs comprising these haplotypes were genotyped in an independent sample of 574 bipolar I cases and 550 controls. Statistically significant association was found for a haplotype window that overlapped the region from the first two family samples (P=3.43×10 -4). However, analyses of the two family samples using the program LAMP, found no evidence for association in this region, but did yield significant evidence for association to a haplotype 3' of CACNG2 (P=1.76×10 -6). Furthermore, no evidence for association was found in a large genome-wide association dataset. The replication of association to overlapping haplotypes in three independent datasets suggests the presence of a bipolar disorder susceptibility gene in this region. © 2012 Wiley Periodicals, Inc.

Author Keywords
Bipolar disorder;  Chromosome 22;  Genetic association;  Stargazin

Document Type: Article
Source: Scopus

 

Anticevic, A.a b c , Cole, M.W.d , Murray, J.D.e f , Corlett, P.R.a c , Wang, X.-J.e f i , Krystal, J.H.a b c g h
The role of default network deactivation in cognition and disease

(2012) Trends in Cognitive Sciences, 16 (12), pp. 584-592. 

a Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, United States
b National Inst. on Alcohol Abuse and Alcoholism (NIAAA), Center for the Translational Neuroscience of Alcoholism (CTNA), Yale University, New Haven, CT 06519, United States
c Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Department of Psychiatry, Yale University, New Haven, CT 06519, United States
d Department of Psychology, Washington University in St. Louis, St. Louis, MO, 63130, United States
e Department of Physics, Yale University, New Haven, CT 06520, United States
f Department of Neurobiology, Kavli Institute of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, United States
g Psychiatry Services, Department of Psychiatry, Yale-New Haven Hospital, New Haven, CT 06510, United States
h Clinical Neuroscience Division, Veterans Affairs (VA) National Center for Post-Traumatic Stress Disorder (PTSD), VA Connecticut Healthcare System, West Haven, CT 06516, United States
i Center for Neural Science, New York University, 4 Washington Place, New York, NY 10003, United States

Abstract
A considerable body of evidence has accumulated over recent years on the functions of the default-mode network (DMN) - a set of brain regions whose activity is high when the mind is not engaged in specific behavioral tasks and low during focused attention on the external environment. In this review, we focus on DMN suppression and its functional role in health and disease, summarizing evidence that spans several disciplines, including cognitive neuroscience, pharmacological neuroimaging, clinical neuroscience, and theoretical neuroscience. Collectively, this research highlights the functional relevance of DMN suppression for goal-directed cognition, possibly by reducing goal-irrelevant functions supported by the DMN (e.g., mind-wandering), and illustrates the functional significance of DMN suppression deficits in severe mental illness. © 2012 Elsevier Ltd.

Author Keywords
Cognition;  Computational modeling;  Default-mode network;  Schizophrenia;  Suppression

Document Type: Review
Source: Scopus

 

Mon, T.a , L'Ecuyer, S.b , Farber, N.B.a , White, A.J.c , Baszis, K.W.c , Hearn, J.K.a , Spiegel, T.E.a , French, A.R.c , Kitcharoensakkul, M.c
The use of electroconvulsive therapy in a patient with juvenile systemic lupus erythematosus and catatonia
(2012) Lupus, 21 (14), pp. 1575-1581. 

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Ranken Jordan-A Pediatric Specialty Hospital, Maryland Heights, MO, United States
c Department of Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Catatonia is a rare manifestation in patients with systemic lupus erythematosus (SLE). As catatonia can be associated with both psychiatric and organic conditions, this could create a diagnostic dilemma once this occurs in SLE patients. The report describes a 15-year-old female with SLE who developed catatonia three days after the diagnosis of SLE was made. Her catatonia was refractory to the treatment with immunosuppressive therapy, which included pulse methylprednisolone, intravenous cyclophosphamide, rituximab, intravenous immunoglobulin (IVIG) and plasmapheresis. Given her persistent catatonia, electroconvulsive therapy (ECT) was initiated three months after the onset of her symptoms. After the third ECT treatment, her mental status dramatically improved and returned nearly to baseline while she was continued on the immunosuppression. This is the first report of a successful ECT therapy in catatonic lupus in children. © 2012 The Author(s).

Author Keywords
catatonia;  ECT;  neuropsychiatric lupus

Document Type: Article
Source: Scopus

 

Sakai, E.Y., Carpenter, B.D., Rieger, R.E.
"what's wrong with grandma?": Depictions of alzheimer's disease in children's storybooks
(2012) American Journal of Alzheimer's Disease and other Dementias, 27 (8), pp. 584-591. 

Washington University, Campus Box 1125, St Louis, MO 63130, United States

Abstract
Alzheimer's disease (AD) affects the entire family system, including young children. Yet there are few resources to help children understand AD. Storybooks are used to educate children about other diseases and may be useful in AD as well. In this study, we examined the depiction of AD in 33 English-language children's storybooks written specifically about AD. As a group, storybooks present AD as a brain disease, but provide little information about the diagnostic process or treatments. Clinical presentations are diverse among characters with AD, and no single book presents a comprehensive depiction of the cognitive, behavioral, affective, and functional symptoms of the disease. In fact, the prevalence of some symptoms in this "population" of storybook characters diverges substantially from epidemiological reports. Books designed to familiarize children about AD should be comprehensive and accurate. Current resources, while useful, could be improved to ensure health literacy about AD in young children. © The Author(s) 2012.

Author Keywords
Alzheimer's disease;  books;  children;  dementia;  epidemiology

Document Type: Article
Source: Scopus

 

McCusker, E.C.a c , Bagnéris, C.a , Naylor, C.E.a , Cole, A.R.a , D'Avanzo, N.b d , Nichols, C.G.b , Wallace, B.A.a
Structure of a bacterial voltage-gated sodium channel pore reveals mechanisms of opening and closing
(2012) Nature Communications, 3, art. no. 1102, . 

a Department of Crystallography, Institute of Structural and Molecular Biology, University of London, Malet Street, London WC1E 7HX, United Kingdom
b Department of Cell Biology and Physiology, Center for Investigation of Membrane, Excitability Diseases, Washington University School of Medicine, St Louis, MO 63110, United States
c Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158-2517, United States
d Department of Physiology and GEPROM, Université de Montréal, Montréal, QC H3C 3J7, Canada

Abstract
Voltage-gated sodium channels are vital membrane proteins essential for electrical signalling; in humans, they are key targets for the development of pharmaceutical drugs. Here we report the crystal structure of an open-channel conformation of NavMs, the bacterial channel pore from the marine bacterium Magnetococcus sp. (strain MC-1). It differs from the recently published crystal structure of a closed form of a related bacterial sodium channel (NavAb) by having its internal cavity accessible to the cytoplasmic surface as a result of a bend/rotation about a central residue in the carboxy-terminal transmembrane segment. This produces an open activation gate of sufficient diameter to allow hydrated sodium ions to pass through. Comparison of the open and closed structures provides new insight into the features of the functional states present in the activation cycles of sodium channels and the mechanism of channel opening and closing. © 2012 Macmillan Publishers Limited. All rights reserved.

Document Type: Article
Source: Scopus

 

Liu, S.a b , Gu, Y.c , DeAngelis, G.C.d , Angelaki, D.E.a b
Choice-related activity and correlated noise in subcortical vestibular neurons
(2012) Nature Neuroscience, . Article in Press. 

a 1] Department of Neurobiology, Washington University School of Medicine, St. Louis, Missouri, USA
b Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA
c Department of Neurobiology, Washington University School of Medicine, St. Louis, Missouri, USA
d Department of Brain and Cognitive Sciences, University of Rochester, Rochester, New York, USA

Abstract
Functional links between neuronal activity and perception are studied by examining trial-by-trial correlations (choice probabilities) between neural responses and perceptual decisions. We addressed fundamental issues regarding the nature and origin of choice probabilities by recording from subcortical (brainstem and cerebellar) neurons in rhesus monkeys during a vestibular heading discrimination task. Subcortical neurons showed robust choice probabilities that exceeded those seen in cortex (area MSTd) under identical conditions. The greater choice probabilities of subcortical neurons could be predicted by a stronger dependence of correlated noise on tuning similarity, as revealed by population decoding. Significant choice probabilities were observed almost exclusively for neurons that responded selectively to translation, whereas neurons that represented net gravito-inertial acceleration did not show choice probabilities. These findings suggest that the emergence of choice probabilities in the vestibular system depends on a critical signal transformation that occurs in subcortical pathways to distinguish translation from orientation relative to gravity.

Document Type: Article in Press
Source: Scopus

 

Quayle, S.N.a , Lee, J.Y.c d , Cheung, L.W.T.e , Ding, L.f g , Wiedemeyer, R.a , Dewan, R.W.a , Huang-Hobbs, E.a , Zhuang, L.a , Wilson, R.K.f g , Ligon, K.L.a b , Mills, G.B.e , Cantley, L.C.c d , Chin, L.a h
Somatic Mutations of PIK3R1 Promote Gliomagenesis
(2012) PLoS ONE, 7 (11), art. no. e49466, . 

a Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
b Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, United States
c Division of Signal Transduction, Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, United States
d Department of Systems Biology, Harvard Medical School, Boston, MA, United States
e Department of Systems Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
f The Genome Institute, Washington University School of Medicine, St Louis, MO, United States
g Department of Genetics, Washington University School of Medicine, St Louis, MO, United States
h Department of Genomic Medicine and Institute for Applied Cancer Science, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States

Abstract
The phosphoinositide 3-kinase (PI3K) pathway is targeted for frequent alteration in glioblastoma (GBM) and is one of the core GBM pathways defined by The Cancer Genome Atlas. Somatic mutations of PIK3R1 are observed in multiple tumor types, but the tumorigenic activity of these mutations has not been demonstrated in GBM. We show here that somatic mutations in the iSH2 domain of PIK3R1 act as oncogenic driver events. Specifically, introduction of a subset of the mutations identified in human GBM, in the nSH2 and iSH2 domains, increases signaling through the PI3K pathway and promotes tumorigenesis of primary normal human astrocytes in an orthotopic xenograft model. Furthermore, we show that cells that are dependent on mutant P85α-mediated PI3K signaling exhibit increased sensitivity to a small molecule inhibitor of AKT. Together, these results suggest that GBM patients whose tumors carry mutant PIK3R1 alleles may benefit from treatment with inhibitors of AKT. © 2012 Quayle et al.

Document Type: Article
Source: Scopus

 

Luzzo, K.M.a , Wang, Q.b , Purcell, S.H.a , Chi, M.a , Jimenez, P.T.a , Grindler, N.a , Schedl, T.c , Moley, K.H.a
High Fat Diet Induced Developmental Defects in the Mouse: Oocyte Meiotic Aneuploidy and Fetal Growth Retardation/Brain Defects
(2012) PLoS ONE, 7 (11), art. no. e49217, . 

a Washington University School of Medicine, Department of Obstetrics and Gynecology, St. Louis, MO, United States
b State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
c Washington University School of Medicine, Department of Genetics, St. Louis, MO, United States

Abstract
Background: Maternal obesity is associated with poor outcomes across the reproductive spectrum including infertility, increased time to pregnancy, early pregnancy loss, fetal loss, congenital abnormalities and neonatal conditions. Furthermore, the proportion of reproductive-aged woman that are obese in the population is increasing sharply. From current studies it is not clear if the origin of the reproductive complications is attributable to problems that arise in the oocyte or the uterine environment. Methodology/Principal Findings: We examined the developmental basis of the reproductive phenotypes in obese animals by employing a high fat diet mouse model of obesity. We analyzed very early embryonic and fetal phenotypes, which can be parsed into three abnormal developmental processes that occur in obese mothers. The first is oocyte meiotic aneuploidy that then leads to early embryonic loss. The second is an abnormal process distinct from meiotic aneuploidy that also leads to early embryonic loss. The third is fetal growth retardation and brain developmental abnormalities, which based on embryo transfer experiments are not due to the obese uterine environment but instead must be from a defect that arises prior to the blastocyst stage. Conclusions/Significance: Our results suggest that reproductive complications in obese females are, at least in part, from oocyte maternal effects. This conclusion is consistent with IVF studies where the increased pregnancy failure rate in obese women returns to the normal rate if donor oocytes are used instead of autologous oocytes. We postulate that preconceptional weight gain adversely affects pregnancy outcomes and fetal development. In light of our findings, preconceptional counseling may be indicated as the preferable, earlier target for intervention in obese women desiring pregnancy and healthy outcomes. © 2012 Luzzo et al.


Document Type: Article
Source: Scopus

 

Peterson, D.S.a , Plotnik, M.b c d e f , Hausdorff, J.M.b g h , Earhart, G.M.a i j
Evidence for a relationship between bilateral coordination during complex gait tasks and freezing of gait in Parkinson's disease
(2012) Parkinsonism and Related Disorders, 18 (9), pp. 1022-1026. 

a Washington University in St. Louis, St. Louis, MO, United States
b Laboratory for Gait and Neurodynamics, Movement Disorders Unit, Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
c Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
d Gonda Brain Research Center, Bar Ilan University, Ramat Gan, Israel
e Advanced Technologies Center, Rehabilitation Hospital, Sheba Medical Center, Tel Hashomer, Israel
f Department of Neurological Rehabilitation, Sheba Medical Center, Tel Hashomer, Israel
g Department of Physical Therapy, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
h Department of Medicine, Harvard Medical School, Boston, MA, United States
i Department of Anatomy and Neurobiology, Washington University in St. Louis, St. Louis, MO, United States
j Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: Freezing of gait is a debilitating and common gait disturbance observed in individuals with Parkinson's disease (PD). Although the underlying mechanisms of freezing remain unclear, bilateral coordination of steps, measured as a phase coordination index, has been suggested to be related to freezing. Phase coordination index has not, however, been measured during tasks associated with freezing such as turning and backward walking. Understanding how bilateral coordination changes during tasks associated with freezing may improve our understanding of the causes of freezing. Methods: Twelve individuals with PD who freeze (freezers), 19 individuals with PD who do not freeze (non-freezers), and 10 healthy, age-matched older adults participated. General motor disease severity and freezing severity were assessed. Phase coordination index was calculated for all subjects during forward walking, backward walking, continuous turning in small radius circles, and turning in large radius circles. Results: Freezers and non-freezers had similar disease duration and general motor severity. Stepping coordination (measured as phase coordination index) was significantly worse in freezers compared to non-freezers and controls. Turning and backward walking, tasks related to freezing, resulted in worse coordination with respect to forward walking. Coordination was associated with severity of freezing scores such that worse coordination was correlated with more severe freezing. Conclusions: These results provide evidence that stepping coordination is related to freezing in people with PD. Identifying variables associated with freezing may provide insights into factors underlying this symptom, and may inform rehabilitative interventions to reduce its occurrence in PD. © 2012 Elsevier Ltd.

Author Keywords
Coordination;  Freezing;  Gait;  Parkinson disease;  Turning

Document Type: Article
Source: Scopus

 

Windsor, L.C.a , Murugan, V.b
From the Individual to the Community: Perspectives About Substance Abuse Services

 

(2012) Journal of Social Work Practice in the Addictions, 12 (4), pp. 412-433. 

a School of Social Work, Rutgers: The State University of New Jersey, 360 Martin Luther King Jr. Blvd., 4th Floor, Newark, NJ 07102, United States
b School of Social Work, Washington University, St. Louis, MO, United States

Abstract
This article argues that substance abuse interventions in distressed African American communities must be culturally tailored and must incorporate a framework targeting changes in both individual behavior and the community. This study employed concept mapping in conjunction with community-based participatory research principles to involve 100 community members, substance users, and service providers to examine the role of alcohol and other drugs in distressed African American communities. Findings reveal the way participants understand the role of drugs and alcohol in their community and their perceptions of substance abuse services. The article describes a collaborative approach to engage the community in addressing substance abuse. © 2012 Copyright Taylor & Francis Group, LLC.

Author Keywords
African American;  community-based intervention;  community-based participatory research;  concept mapping;  culturally tailored interventions;  substance abuse treatment

Document Type: Article
Source: Scopus

 

Tien, A.-C.a , Tsai, H.-H.a , Molofsky, A.V.a , McMahon, M.b , Foo, L.C.c , Kaul, A.d , Dougherty, J.D.e f , Heintz, N.e , Gutmann, D.H.d , Barres, B.A.c , Rowitch, D.H.a
Regulated temporal-spatial astrocyte precursor cell proliferation involves BRAF signalling in mammalian spinal cord
(2012) Journal of Cell Science, 125 (14), pp. 2477-2487. 

a Departments of Pediatrics and Neurosurgery, Eli and Edythe Broad Center of Regeneration Medicine, Stem Cell Research and Howard Hughes Medical Inst., University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, United States
b Helen Diller Family Comprehensive Cancer Center, University of California, 1450 Third Street, San Francisco, CA 94158, United States
c Department of Neurobiology, Stanford University, Palo Alto, CA 94305, United States
d Department of Neurology, Washington University, School of Medicine, St Louis, MO 63110, United States
e Rockefeller University, 1230 York Ave., New York, NY 10065, United States
f Department of Genetics and Department of Psychiatry, Washington University, School of Medicine, St Louis, MO 63110, United States

Abstract
Expansion of astrocyte populations in the central nervous system is characteristic of evolutionarily more complex organisms. However, regulation of mammalian astrocyte precursor proliferation during development remains poorly understood. Here, we used Aldh1L1-GFP to identify two morphologically distinct types of proliferative astrocyte precursors: radial glia (RG) in the ventricular zone and a second cell type we call an 'intermediate astrocyte precursor' (IAP) located in the mantle region of the spinal cord. Astrogenic RG and IAP cells proliferated in a progressive ventral-to-dorsal fashion in a tight window from embryonic day 13.5 until postnatal day 3, which correlated precisely with the pattern of active ERK signalling. Conditional loss of BRAF function using BLBP-cre resulted in a 20% decrease in astrocyte production, whereas expression of activated BRAFV600E resulted in astrocyte hyperproliferation. Interestingly, BRAFV600E mitogenic effects in astrocytes were restricted, in part, by the function of p16INK4A-p19ARF, which limited the temporal epoch for proliferation. Together, these findings suggest that astrocyte precursor proliferation involves distinct RG and IAP cells; is subjected to temporal and spatial control; and depends in part on BRAF signalling at early stages of mammalian spinal cord development. © 2012.

Author Keywords
Aldh1L1;  Astrocyte precursor;  BRAF;  Glioma;  Mouse;  RAS signalling;  Spinal cord development

Document Type: Article
Source: Scopus

 

Estrada-Martínez, L.M.a , Caldwell, C.H.c , Bauermeister, J.A.d , Zimmerman, M.A.b
Stressors in Multiple Life-Domains and the Risk for Externalizing and Internalizing Behaviors Among African Americans During Emerging Adulthood
(2012) Journal of Youth and Adolescence, 41 (12), pp. 1600-1612. 

a George Warren Brown School of Social Work, Washington University in St. Louis, One Brookings Drive, Campus Box 1196, St. Louis, MO 63130, United States
b Health Behavior and Health Education, University of Michigan School of Public Health, 2846 SPH I, 1415 Washington Heights, Ann Arbor, MI 48109-2029, United States
c Health Behavior and Health Education, University of Michigan School of Public Health, 3822 SPH I, 1415 Washington Heights, Ann Arbor, MI 48109-2029, United States
d Health Behavior and Health Education, University of Michigan School of Public Health, 3790A SPH I, 1415 Washington Heights, Ann Arbor, MI 48109-2029, United States

Abstract
Behavioral and mental health outcomes have been associated with experiencing high levels of stress. Yet, little is known about the link between the nature of stressors, their accumulation over time, and the risk for externalizing and internalizing outcomes. Compared to the general population, African Americans are exposed to a disproportionate number of stressors beginning earlier in life. Incorporating Agnew's General Strain Theory into the study of stress, this study examined whether different kinds of stressors are equally salient in the risk for violent behaviors and depressive symptoms among African Americans transitioning into young adulthood. It further examined the effects of the accumulation of stressors in different life domains and their effect on risks. This study utilized data from an African American subsample of an ongoing longitudinal study that followed 604 adolescents (53 % females) from 9th grade into adulthood. Multilevel growth curve models were used to examine how changes in stressors across multiple life domains related to violent behaviors and depressive symptoms. We found that continued exposure to perceived daily stress and racial discrimination stress increased the risk for violent behaviors during young adulthood, and exhibited a nonlinear relationship between the accumulation of stressors and risk for violence. Moreover, we found that exposure to perceived daily stress, financial stress, neighborhood stress, and racial discrimination stress increased the risk of depressive symptoms and led to a linear relationship between the accumulation of stressors and risk for depressive symptoms. Findings suggest identifiable stressors that can persist over time to influence risks at young adulthood. © 2012 Springer Science+Business Media, LLC.

Author Keywords
African Americans;  Depression;  Emerging adulthood;  Stressors;  Violence

Document Type: Article
Source: Scopus

 

Jain, R.a b , Javidan-Nejad, C.c , Alexander-Brett, J.a , Horani, A.d , Cabellon, M.C.a , Walter, M.J.a , Brody, S.L.a
Sensory functions of motile cilia and implication for bronchiectasis
(2012) Frontiers in Bioscience, S4 (3), pp. 1088-1098. 

a Department of Medicine, Washington University, School of Medicine, Box 8052, 660 S. Euclid Ave., St. Louis, MO 63110, United States
b Department of Medicine, University of Texas, Southwestern Medical Center, Dallas, TX 75390, United States
c Department of Radiology, Washington University, School of Medicine, St. Louis, MO 63110, United States
d Department of Pediatrics, Washington University, School of Medicine, St. Louis, MO 63110, United States

Abstract
Cilia are specialized organelles that extend from the cell surface into the local environment. Cilia of the airway epithelia are motile to provide mucociliary clearance. On other cells, solitary cilia are specialized to detect chemical or mechanosensory signals. Sensory proteins in motile cilia have recently been identified that detect fluid flow, bitter taste and sex hormones. The relationship of these sensory functions in motile cilia to disease is now being revealed. An example are the polycystin-1 and polycystin-2 proteins that function as a flow sensor in kidney cilia and are mutated in autosomal dominant polycystic kidney disease (ADPKD). These polycystins are also expressed in motile cilia, potentially operating as sensors in the lung. Computed tomography studies from patients with ADPKD reveal evidence of bronchiectasis, suggesting polycystins are important in lung function. The motile cilia expression of this proteincomplex, as well as sensory channel TRPV4, bitter taste and sex hormones receptors, indicate that the cilia is wired to interpret environmental cues. Defective signaling of sensory proteins may result in a ciliopathy that includes lung disease.

Author Keywords
ADPKD;  Bronchiectasis;  Cilia;  Review;  Sensory;  Signaling

Document Type: Article
Source: Scopus

 

Clayton, E.H.a , Bayly, P.V.b
Brain response to extracranial acoustic loads: Shear wave propagation characterized by vector fields
(2011) ASME 2011 International Mechanical Engineering Congress and Exposition, IMECE 2011, 2, pp. 25-29. 

a Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130, United States
b Mechanical Engineering and Materials Science and Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Traumatic brain injuries (TBI) due to blast are common in modern combat situations, and often lead to permanent cognitive impairment. Despite the prevalence and severity of blast-induced TBI, the condition remains poorly understood. Computer simulations of blast and blast injury mechanics offer enormous potential; however, computer models require accurate descriptions of tissue mechanics and boundary conditions in vivo. To gain insight into the mechanisms of blast injury, we applied direct (light) oscillatory pressure loading to the skulls of human volunteers, and measured displacement and strain fields using the methodology of magnetic resonance elastography (MRE). MRE is a non-invasive imaging modality that provides quantitative spatial maps of tissue stiffness. MRE is performed by inducing micron-amplitude propagating shear waves into tissue and imaging the resulting harmonic motion with standard clinical MRI hardware. Shear waves are initiated by an MR-compatible actuator and detected by a specialized "motion-sensitive" MRI pulse sequence (software). Motion sensitized MR images provide displacement field data which can be inverted to estimate material stiffness by invoking a restricted form of Navier's equation. Clinical interest in MRE has largely been driven by the empirical relationship between tissue stiffness and health. However, the "raw" MRE data (3-D displacement measurements) themselves can elucidate loading paths, anatomic boundaries and the dynamic response of the intact human head. In this study, we use the MRE imaging technique to measure in vivo displacement fields of brain motion as the cranium is exposed to acoustic frequency pressure excitation (45, 60, 80 Hz) and we calculate the resulting shear-strain fields (2-D).We estimate the Poynting vector (energy flux) field to illuminate the directions of internal wave propagation, and to identify the energy absorbing and reflecting regions within the brain. Copyright © 2011 by ASME.

Document Type: Conference Paper
Source: Scopus