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

WUSTL Neuroscience Publications Archive - May 2014

Scopus weekly report:

May 5, 2014

May 12, 2014

May 19, 2014

May 26, 2014

 

May 26, 2014

Sanders, DavidW.a , Kaufman, SarahK.a , DeVos, SarahL.a , Sharma, ApurwaM.a , Mirbaha, H.a , Li, A.a , Barker, ScarlettJ.a , Foley, AlexC.c , Thorpe, JulianR.c , Serpell, LouiseC.c , Miller, TimothyM.a , Grinberg, LeaT.b , Seeley, WilliamW.b , Diamond, MarcI.a Distinct Tau Prion Strains Propagate in Cells and Mice and Define Different Tauopathies  (2014) Neuron, . Article in Press.

a Department of Neurology, Washington University in St. Louis, St. Louis, MO 63105, USA

b Department of Neurology and Pathology, University of California, San Francisco, San Francisco, CA 94143, USA

c School of Life Sciences, University of Sussex, Falmer BN1 9QG, UK

Abstract

Prion-like propagation of tau aggregation might underlie the stereotyped progression of neurodegenerative tauopathies. True prions stably maintain unique conformations ("strains") in vivo that link structure to patterns of pathology. We now find that tau meets this criterion. Stably expressed tau repeat domain indefinitely propagates distinct amyloid conformations in a clonal fashion in culture. Reintroduction of tau from these lines into naive cells reestablishes identical clones. We produced two strains in vitro that induce distinct pathologies in vivo as determined by successive inoculations into three generations of transgenic mice. Immunopurified tau from these mice recreates the original strains in culture. We used the cell system to isolate tau strains from 29 patients with 5 different tauopathies, finding that different diseases are associated with different sets of strains. Tau thus demonstrates essential characteristics of a prion. This might explain the phenotypic diversity of tauopathies and could enable more effective diagnosis and therapy. © 2014 Elsevier Inc. All rights reserved.

Document Type: Article in Press

Source: Scopus

 

Tung, T.H.

Nerve Transfers
(2014) Clinics in Plastic Surgery, . Article in Press.

Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8238, St Louis, MO 63110, USA

Abstract

This article provides an update of the current state of motor and sensory nerve transfers for the functional reconstruction of proximal and distal nerve lesions of the upper extremity. General principles, indications, surgical options, and functional outcomes are summarized for conventional transfers used in brachial plexus reconstruction, more recently described distal nerve transfers for isolated nerve injuries in the extremity, and sensory nerve transfers performed both proximally and distally. © 2014 Elsevier Inc. All rights reserved.

Author Keywords

Brachial plexus;  Nerve injury;  Nerve reconstruction;  Nerve repair;  Nerve transfer

Document Type: Article in Press

Source: Scopus

 

Wetherill, L.a , Agrawal, A.b , Kapoor, M.b , Bertelsen, S.b , Bierut, L.J.b , Brooks, A.c , Dick, D.d , Hesselbrock, M.e , Hesselbrock, V.e , Koller, D.L.a , Le, N.b , Nurnberger, J.I.a , Salvatore, J.E.d , Schuckit, M.f , Tischfield, J.A.c , Wang, J.-C.b , Xuei, X.a , Edenberg, H.J.a , Porjesz, B.g , Bucholz, K.b , Goate, A.M.b , Foroud, T.a

Association of substance dependence phenotypes in the COGA sample

(2014) Addiction Biology, . Article in Press.

a Indiana University School of Medicine Indianapolis, IN USA

b Washington University School of Medicine St. Louis, MO USA

c Rutgers University Piscataway, NJ USA

d Virginia Commonwealth University Richmond, VA USA

e University of Connecticut Health Center Farmington, CT USA

f University of California, San Diego La Jolla, CA USA

g SUNY Downstate Medical Center Brooklyn, NY USA

Abstract

Alcohol and drug use disorders are individually heritable (50%). Twin studies indicate that alcohol and substance use disorders share common genetic influences, and therefore may represent a more heritable form of addiction and thus be more powerful for genetic studies. This study utilized data from 2322 subjects from 118 European-American families in the Collaborative Study on the Genetics of Alcoholism sample to conduct genome-wide association analysis of a binary and a continuous index of general substance dependence liability. The binary phenotype (ANYDEP) was based on meeting lifetime criteria for any DSM-IV dependence on alcohol, cannabis, cocaine or opioids. The quantitative trait (QUANTDEP) was constructed from factor analysis based on endorsement across the seven DSM-IV criteria for each of the four substances. Heritability was estimated to be 54% for ANYDEP and 86% for QUANTDEP. One single-nucleotide polymorphism (SNP), rs2952621 in the uncharacterized gene LOC151121 on chromosome 2, was associated with ANYDEP (P=1.8×10-8), with support from surrounding imputed SNPs and replication in an independent sample [Study of Addiction: Genetics and Environment (SAGE); P=0.02]. One SNP, rs2567261 in ARHGAP28 (Rho GTPase-activating protein 28), was associated with QUANTDEP (P=3.8×10-8), and supported by imputed SNPs in the region, but did not replicate in an independent sample (SAGE; P=0.29). The results of this study provide evidence that there are common variants that contribute to the risk for a general liability to substance dependence. © 2014 Society for the Study of Addiction.

Author Keywords

Alcohol dependence;  Cannabis dependence;  Cocaine dependence;  Common genetic liability;  Drug dependence;  Opioid dependence

Document Type: Article in Press

Source: Scopus

 

Zhao, Y.a , Cudkowicz, M.E.b , Shefner, J.M.c , Krivickas, L.b , David, W.S.b , Vriesendorp, F.c , Pestronk, A.d , Caress, J.B.e , Katz, J.f , Simpson, E.g , Rosenfeld, J.h , Pascuzzi, R.i , Glass, J.j , Rezania, K.k , Harmatz, J.S.a , Schoenfeld, D.l , Greenblatt, D.J.a

Systemic pharmacokinetics and cerebrospinal fluid uptake of intravenous ceftriaxone in patients with amyotrophic lateral sclerosis

(2014) Journal of Clinical Pharmacology, . Article in Press.

a Program in Pharmacology and Experimental Therapeutics Tufts University School of Medicine Boston, MA USA

b Neurology Clinical Research Institute Massachusetts General Hospital Harvard Medical School Boston, MA USA

c Department of Neurology State University of New York Upstate Medical University Syracuse, NY USA

d Department of Neurology Washington University in St. Louis St. Louis, MO USA

e Department of Neurology Wake Forest University Winston-Salem, NC USA

f Department of Neurology California Pacific Medical Center San Francisco, CA USA

g Department of Neurology Methodist Neurological Institute Houston, TX USA

h Department of Neurology Neuroscience Institute University of California San Francisco Fresno Fresno, CA USA

i Department of Neurology Indiana University Indianapolis, IN USA

j Department of Neurology Emory University Atlanta, GA USA

k Department of Neurology University of Chicago Chicago, IL USA

l Department of Biostatistics Massachusetts General Hospital Boston, MA USA

Abstract

The cephalosporin antibiotic ceftriaxone was evaluated as a potential therapeutic agent for the treatment of amyotrophic lateral sclerosis (ALS). The pharmacokinetics (PK) of ceftriaxone in plasma and cerebrospinal fluid (CSF) were investigated in 66 participants in a previously reported clinical trial. Their mean age was 51 years, and 65% were male. Participants were randomly assigned to 1 of 3 treatment groups receiving intravenous infusions (mean duration: 25minutes) every 12hours of either: placebo and placebo; 2g ceftriaxone and placebo; or 2g ceftriaxone twice. Mean steady-state plasma PK variables were: volume of distribution, 14L (0.17L/kg); elimination half-life, 8-9h; total clearance, 17-21mL/min (0.22-0.25mL/min/kg). Values were not different between dosage groups. CSF PK analysis, determined through sparse CSF sampling, indicated apparent entry and elimination half-life values of 1.0 and 34hours, respectively. With both dosage regimens, CSF concentrations were maintained above the target threshold of 1.0μM (0.55μg/mL) as determined from in vitro models. The plasma and CSF PK profiles of ceftriaxone were used as a basis for planning the Phase 3 clinical trial of ceftriaxone in ALS. © 2014 The American College of Clinical Pharmacology.

Author Keywords

Amyotrophic lateral sclerosis;  Ceftriaxone;  Cerebrospinal fluid uptake;  HPLC micromethod;  Plasma pharmacokinetics

Document Type: Article in Press

Source: Scopus

 

Craver, C.F.a , Graham, B.b , Rosenbaum, R.S.c d

Remembering Mr B.

 (2014) Cortex, . Article in Press.

a Philosophy-Neuroscience-Psychology Program, Washington University in St. Louis, United States

b J.D. Candidate, Yale Law School, United States

c Department of Psychology and Neuroscience Graduate Diploma Program, York University, Toronto, Canada

d Rotman Research Institute, Baycrest, Toronto, Canada

Abstract

In the accompanying translation and film, Gustav Störring describes the psychological profile of Mr. B. (Franz Breundl), a victim of carbon monoxide poisoning with a nearly complete short-term memory deficit. Störring diagnoses Mr. B. as lacking entirely the capacity to register or retain any information in consciousness for longer than two seconds. Here we introduce these historical documents, describe their historical context, summarize and discuss the central features of the case, and consider the potential significance of the case for contemporary theories of working memory, the self, and personal identity. © 2013 Elsevier Ltd. All rights reserved.

Author Keywords

Amnesia;  Carbon monoxide poisoning;  Memory;  Self;  Working memory

Document Type: Article in Press

Source: Scopus

 

Weston, S.J., Jackson, J.J.

Identification of the healthy neurotic: Personality traits predict smoking after disease onset

(2014) Journal of Research in Personality, . Article in Press.

Washington University in St. Louis, United States

Abstract

Personality traits are known predictors of health behaviors and health status. However, most of this work focuses exclusively on how personality influences health outcomes rather than how personality influences response to disease. Using a large, national study (N = 7051), we investigated whether conscientiousness and neuroticism were associated with smoking behavior after the onset of a disease. After the onset of a major chronic disease, high levels of neuroticism predicted less smoking when paired with high levels of conscientiousness, a combination described as healthy neuroticism. Healthy neuroticism only predicted smoking behavior after the onset of disease, not before, suggesting that the relationship between personality and responses to health problems differs from the relationship between personality and the onset of health problems. © 2014 Elsevier Inc. All rights reserved.

Author Keywords

Conscientiousness;  Disease response;  Healthy neurotic;  Interaction;  Neuroticism;  Smoking

Document Type: Article in Press

Source: Scopus

 

Yano, H.a b c d , Baranov, S.V.e , Baranova, O.V.e , Kim, J.e , Pan, Y.b , Yablonska, S.e , Carlisle, D.L.e , Ferrante, R.J.e , Kim, A.H.c f g , Friedlander, R.M.a h

Inhibition of mitochondrial protein import by mutant huntingtin

(2014) Nature Neuroscience, . Article in Press.

a 1] Department of Neurological Surgery, Neuroapoptosis Laboratory, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

b Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri, USA

c Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA

d Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA

e Department of Neurological Surgery, Neuroapoptosis Laboratory, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

f 1] Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri, USA

g Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, USA

h University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA

 

Abstract

Mitochondrial dysfunction is associated with neuronal loss in Huntington's disease (HD), a neurodegenerative disease caused by an abnormal polyglutamine expansion in huntingtin (Htt). However, the mechanisms linking mutant Htt and mitochondrial dysfunction in HD remain unknown. We identify an interaction between mutant Htt and the TIM23 mitochondrial protein import complex. Remarkably, recombinant mutant Htt directly inhibited mitochondrial protein import in vitro. Furthermore, mitochondria from brain synaptosomes of presymptomatic HD model mice and from mutant Htt-expressing primary neurons exhibited a protein import defect, suggesting that deficient protein import is an early event in HD. The mutant Htt-induced mitochondrial import defect and subsequent neuronal death were attenuated by overexpression of TIM23 complex subunits, demonstrating that deficient mitochondrial protein import causes mutant Htt-induced neuronal death. Collectively, these findings provide evidence for a direct link between mutant Htt, mitochondrial dysfunction and neuronal pathology, with implications for mitochondrial protein import-based therapies in HD.

Document Type: Article in Press

Source: Scopus

 

Eggebrecht, A.T.a , Ferradal, S.L.b , Robichaux-Viehoever, A.c , Hassanpour, M.S.d , Dehghani, H.e , Snyder, A.Z.c f , Hershey, T.g , Culver, J.P.b d f

Mapping distributed brain function and networks with diffuse optical tomography

(2014) Nature Photonics, . Article in Press.

a Department of Radiology, Washington University School of Medicine, St Louis, Missouri 63110, USA

b Department of Biomedical Engineering, Washington University, St Louis, Missouri 63130, USA

c Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA

d Department of Physics, Washington University School of Medicine, St Louis, Missouri 63130, USA

e School of Computer Science, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

f 1] Department of Radiology, Washington University School of Medicine, St Louis, Missouri 63110, USA

g Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri 63110, USA

Abstract

Mapping of human brain function has revolutionized systems neuroscience. However, traditional functional neuroimaging by positron emission tomography or functional magnetic resonance imaging cannot be used when applications require portability, or are contraindicated because of ionizing radiation (positron emission tomography) or implanted metal (functional magnetic resonance imaging). Optical neuroimaging offers a non-invasive alternative that is radiation free and compatible with implanted metal and electronic devices (for example, pacemakers). However, optical imaging technology has heretofore lacked the combination of spatial resolution and wide field of view sufficient to map distributed brain functions. Here, we present a high-density diffuse optical tomography imaging array that can map higher-order, distributed brain function. The system was tested by imaging four hierarchical language tasks and multiple resting-state networks including the dorsal attention and default mode networks. Finally, we imaged brain function in patients with Parkinson's disease and implanted deep brain stimulators that preclude functional magnetic resonance imaging.

Document Type: Article in Press

Source: Scopus

 

Huettner, J.E.

Vertebrate galectins: Endogenous regulators of ionotropic glutamate receptors?

(2014) Journal of Physiology, 592 (10), pp. 2035-2036.

Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, United States

Document Type: Article

Source: Scopus

 

Rutkove, S.B.a , Geisbush, T.R.a , Mijailovic, A.a , Shklyar, I.a , Pasternak, A.b , Visyak, N.b , Wu, J.S.a , Zaidman, C.c , Darras, B.T.b

Cross-sectional Evaluation of Electrical Impedance Myography and Quantitative Ultrasound for the Assessment of Duchenne Muscular Dystrophy in a Clinical Trial Setting

(2014) Pediatric Neurology, . Article in Press.

a Division of Neuromuscular Diseases, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

b Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts

c Department of Neurology, Washington University in St. Louis, St. Louis, Missouri

Abstract

Background: Electrical impedance myography and quantitative ultrasound are two noninvasive, painless, and effort-independent approaches for assessing neuromuscular disease. Both techniques have potential to serve as useful biomarkers in clinical trials in Duchenne muscular dystrophy. However, their comparative sensitivity to disease status and how they relate to one another are unknown. Methods: We performed a cross-sectional analysis of electrical impedance myography and quantitative ultrasound in 24 healthy boys and 24 with Duchenne muscular dystrophy, aged 2-14 years with trained research assistants performing all measurements. Three upper and three lower extremity muscles were studied unilaterally in each child, and the data averaged for each individual. Results: Both electrical impedance myography and quantitative ultrasound differentiated healthy boys from those with Duchenne muscular dystrophy (P < 0.001 for both). Quantitative ultrasound values correlated with age in Duchenne muscular dystrophy boys (rho = 0.45; P = 0.029), whereas electrical impedance myography did not (rho = -0.31; P = 0.14). However, electrical impedance myography phase correlated with age in healthy boys (rho = 0.51; P = 0.012), whereas quantitative ultrasound did not (rho = -0.021; P = 0.92). In Duchenne muscular dystrophy boys, electrical impedance myography phase correlated with the North Star Ambulatory Assessment (rho = 0.65; P = 0.022); quantitative ultrasound revealed a near-significant association (rho = -0.56; P = 0.060). The two technologies trended toward a moderate correlation with one another in the Duchenne muscular dystrophy cohort but not in the healthy group (rho = -0.40; P = 0.054 and rho = -0.32; P = 0.13, respectively). Conclusions: Electrical impedance myography and quantitative ultrasound are complementary modalities for the assessment of boys with Duchenne muscular dystrophy; further study and application of these two modalities alone or in combination in a longitudinal fashion are warranted. © 2014 Elsevier Inc. All rights reserved.

Author Keywords

biomarker;  Duchenne muscular dystrophy;  electrical impedance myography;  outcome measure;  quantitative ultrasound

Document Type: Article in Press

Source: Scopus

 

Haller, G.a , Li, P.b , Esch, C.b , Hsu, S.c , Goate, A.M.a , Steinbach, J.H.d

Functional characterization improves associations between rare non-synonymous variants in CHRNB4 and smoking behavior

(2014) PLoS ONE, 9 (5), art. no. e96753, .

a Departments of Psychiatry and Genetics, Washington University, St. Louis, MO, United States

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

c Department of Psychiatry, Washington University, St. Louis, MO, United States

d Department of Anesthesiology, Taylor Family Institute for Innovative Psychiatric Research, Washington University, St. Louis, MO, United States

Abstract

Smoking is the leading cause of preventable death worldwide. Accordingly, effort has been devoted to determining the genetic variants that contribute to smoking risk. Genome-wide association studies have identified several variants in nicotinic acetylcholine receptor genes that contribute to nicotine dependence risk. We previously undertook pooled sequencing of the coding regions and flanking sequence of the CHRNA5, CHRNA3, CHRNB4, CHRNA6 and CHRNB3 genes and found that rare missense variants at conserved residues in CHRNB4 are associated with reduced risk of nicotine dependence among African Americans. We identified 10 low frequency (&lt;5%) non-synonymous variants in CHRNB4 and investigated functional effects by co-expression with normal α3 or α4 subunits in human embryonic kidney cells. Voltage-clamp was used to obtain acetylcholine and nicotine concentration-response curves and qRT-PCR, western blots and cell-surface ELISAs were performed to assess expression levels. These results were used to functionally weight genetic variants in a gene-based association test. We find that there is a highly significant correlation between carrier status weighted by either acetylcholine EC50 (β = -0.67, r 2 = 0.017, P = 2×10-4) or by response to low nicotine (β = -0.29, r2 = 0.02, P = 6×10-5) when variants are expressed with the α3 subunit. In contrast, there is no significant association when carrier status is unweighted (β = -0.04, r2 = 0.0009, P = 0.54). These results highlight the value of functional analysis of variants and the advantages to integrating such data into genetic studies. They also suggest that an increased sensitivity to low concentrations of nicotine is protective from the risk of developing nicotine dependence. © 2014 Haller et al.

Document Type: Article

Source: Scopus

 

Lu, X.a , Kim-Han, J.S.b , Harmon, S.b , Sakiyama-Elbert, S.E.a , O'Malley, K.L.b

The Parkinsonian mimetic, 6-OHDA, impairs axonal transport in dopaminergic axons

(2014) Molecular Neurodegeneration, 9 (1), art. no. 17, .

a Department of Biomedical Engineering, Washington University in Saint Louis, Campus Box 1097, 1 Brookings Drive, St. Louis, MO 63130, United States

b Department of Anatomy and Neurobiology, Washington University in Saint Louis, St. Louis, MO 63110, United States

Abstract

6-hydroxydopamine (6-OHDA) is one of the most commonly used toxins for modeling degeneration of dopaminergic (DA) neurons in Parkinson's disease. 6-OHDA also causes axonal degeneration, a process that appears to precede the death of DA neurons. To understand the processes involved in 6-OHDA-mediated axonal degeneration, a microdevice designed to isolate axons fluidically from cell bodies was used in conjunction with green fluorescent protein (GFP)-labeled DA neurons. Results showed that 6-OHDA quickly induced mitochondrial transport dysfunction in both DA and non-DA axons. This appeared to be a general effect on transport function since 6-OHDA also disrupted transport of synaptophysin-tagged vesicles. The effects of 6-OHDA on mitochondrial transport were blocked by the addition of the SOD1-mimetic, Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP), as well as the anti-oxidant N-acetyl-cysteine (NAC) suggesting that free radical species played a role in this process. Temporally, microtubule disruption and autophagy occurred after transport dysfunction yet before DA cell death following 6-OHDA treatment. The results from the study suggest that ROS-mediated transport dysfunction occurs early and plays a significant role in inducing axonal degeneration in response to 6-OHDA treatment. © 2014 Lu et al.; licensee BioMed Central Ltd.

Author Keywords

Microfluidic devices;  Microtubule;  Mitochondria;  Neurodegeneration;  Parkinson's disease

Document Type: Article

Source: Scopus

 

Miller, R.L., Loewy, A.D.

5-HT neurons of the area postrema become c-Fos-activated after increases in plasma sodium levels and transmit interoceptive information to the nucleus accumbens

(2014) American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 306 (9), pp. R663-R673.

Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract

Serotonergic (5-hydroxytryptamine, 5-HT) neurons of the area postrema (AP) represent one neuronal phenotype implicated in the regulation of salt appetite. Tryptophan hydroxylase (Tryp-OH, synthetic enzyme-producing 5-HT) immunoreactive neurons in the AP of rats become c-Fos-activated following conditions in which plasma sodium levels are elevated; these include intraperitoneal injections of hypertonic saline and sodium repletion. Non-Tryp-OH neurons also became c-Fos-activated. Sodium depletion, which induced an increase in plasma osmolality but caused no significant change in the plasma sodium concentration, had no effect on the c-Fos activity in the AP. Epithelial sodium channels are expressed in the Tryp-OH-immunoreactive AP neurons, possibly functioning in the detection of changes in plasma sodium levels. Since little is known about the neural circuitry of these neurons, we tested whether the AP contributes to a central pathway that innervates the reward center of the brain. Stereotaxic injections of pseudorabies virus were made in the nucleus accumbens (NAc), and after 4 days, this viral tracer produced retrograde transneuronal labeling in the Tryp-OH and non-Tryp-OH AP neurons. Both sets of neurons innervate the NAc via a multisynaptic pathway. Besides sensory information regarding plasma sodium levels, the AP→NAc pathway may also transmit other types of chemosensory information, such as those related to metabolic functions, food intake, and immune system to the subcortical structures of the reward system. Because these subcortical regions ultimately project to the medial prefrontal cortex, different types of chemical signals from visceral systems may influence affective functions. © 2014 the American Physiological Society.

 

Author Keywords

Area postrema;  Circumventricular organs;  Epithelial sodium channels;  Nucleus accumbens;  Ventral tegmental area

Document Type: Article

Source: Scopus

 

Guo, Z., Cao, Y.-Q.

Over-expression of TRESK K+ channels reduces the excitability of trigeminal ganglion nociceptors

 (2014) PLoS ONE, 9 (1), art. no. e87029, .

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

Abstract

TWIK-related spinal cord K+ (TRESK) channel is abundantly expressed in trigeminal ganglion (TG) and dorsal root ganglion neurons and is one of the major background K+ channels in primary afferent neurons. Mutations in TRESK channels are associated with familial and sporadic migraine. In rats, both chronic nerve injury and inflammation alter the expression level of TRESK mRNA. Functional studies indicate that reduction of endogenous TRESK channel activity results in hyper-excitation of primary afferent neurons, suggesting that TRESK is a potential target for the development of new analgesics. However, whether and how enhancing TRESK channel activity would decrease the excitability of primary afferent neurons has not been directly tested. Here, we over-expressed TRESK subunits in cultured mouse TG neurons by lipofectamine-mediated transfection and investigated how this altered the membrane properties and the excitability of the small-diameter TG population. To account for the heterogeneity of neurons, we further divided small TG neurons into two groups, based on their ability to bind to fluorescently-labeled isolectin B (IB4). The transfected TG neurons showed a 2-fold increase in the level of TRESK proteins. This was accompanied by a significant increase in the fraction of lamotrigine-sensitive persistent K+ currents as well as the size of total background K+ currents. Consequently, both IB4-positive and IB4-negative TG neurons over-expressing TRESK subunits exhibited a lower input resistance and a 2-fold increase in the current threshold for action potential initiation. IB4-negative TG neurons over-expressing TRESK subunits also showed a significant reduction of the spike frequency in response to supra-threshold stimuli. Importantly, an increase in TRESK channel activity effectively inhibited capsaicin-evoked spikes in TG neurons. Taken together, our results suggest that potent and specific TRESK channel openers likely would reduce the excitability of primary afferent neurons and therefore are potential therapeutics for the treatment of migraine and other chronic pain symptoms. © 2014 Guo, Cao.

 

Document Type: Article

Source: Scopus

 

Dulle, J.E.a b , Stein, K.C.a , True, H.L.a

Regulation of the Hsp104 middle domain activity is critical for yeast prion propagation

(2014) PLoS ONE, 9 (1), art. no. e87521, .

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

b Department of Ophthalmology, University of Michigan, Ann Arbor, MI, United States

Abstract

Molecular chaperones play a significant role in preventing protein misfolding and aggregation. Indeed, some protein conformational disorders have been linked to changes in the chaperone network. Curiously, in yeast, chaperones also play a role in promoting prion maintenance and propagation. While many amyloidogenic proteins are associated with disease in mammals, yeast prion proteins, and their ability to undergo conformational conversion into a prion state, are proposed to play a functional role in yeast biology. The chaperone Hsp104, a AAA+ ATPase, is essential for yeast prion propagation. Hsp104 fragments large prion aggregates to generate a population of smaller oligomers that can more readily convert soluble monomer and be transmitted to daughter cells. Here, we show that the middle (M) domain of Hsp104, and its mobility, plays an integral part in prion propagation. We generated and characterized mutations in the M-domain of Hsp104 that are predicted to stabilize either a repressed or de-repressed conformation of the M-domain (by analogy to ClpB in bacteria). We show that the predicted stabilization of the repressed conformation inhibits general chaperone activity. Mutation to the de-repressed conformation, however, has differential effects on ATP hydrolysis and disaggregation, suggesting that the M-domain is involved in coupling these two activities. Interestingly, we show that changes in the Mdomain differentially affect the propagation of different variants of the [PSI+] and [RNQ+] prions, which indicates that some prion variants are more sensitive to changes in the M-domain mobility than others. Thus, we provide evidence that regulation of the M-domain of Hsp104 is critical for efficient prion propagation. This shows the importance of elucidating the function of the M-domain in order to understand the role of Hsp104 in the propagation of different prions and prion variants. © 2014 Dulle et al.

 

Document Type: Article

Source: Scopus

 

Curfman, D.a , Connor, L.T.b c , Moy, H.P.d , Heitsch, L.d , Panagos, P.a d d , Lee, J.-M.a c , Tan, D.K.d , Ford, A.L.a

Accuracy of emergency medical services-reported last known normal times in patients suspected with acute stroke

(2014) Stroke, 45 (5), pp. 1275-1279.

a Department of Neurology, Washington University School of Medicine, 600 South Euclid Avenue, Box 8111, St. Louis, MO 63110, United States

b Program in Occupational Therapy, Washington University School of Medicine, MO, United States

c Department of Radiology, Washington University School of Medicine, MO, United States

d Department of Emergency Medicine, Washington University School of Medicine, MO, United States

Abstract

BACKGROUND AND PURPOSE-: The last known normal (LKN) time is a critical determinant of IV tissue-type plasminogen activator (IV tPA) eligibility; however, the accuracy of emergency medical services (EMS)-reported LKN times is unknown. We determined the congruence between neurologist-determined and EMS-reported LKN times and identified predictors of incongruent LKN times. METHODS-: We prospectively collected EMS-reported LKN times for patients brought into the emergency department with suspected acute stroke and calculated the absolute difference between the neurologist-determined and EMS-reported LKN times (|ΔLKN|). We determined the rate of inappropriate IV tPA use if EMS-reported times had been used in place of neurologist-determined times. Univariate and multivariable linear regression assessed for any predictors of prolonged |ΔLKN|. RESULTS-: Of 251 patients, mean and median |ΔLKN| were 28 and 0 minutes, respectively. |ΔLKN| was <15 minutes in 91% of the entire cohort and <15 minutes in 80% of patients with a diagnosis of stroke (n=86). Of patients who received IV tPA, none would have been incorrectly excluded from IV tPA if the EMS LKN time had been used. Conversely, of patients who did not receive IV tPA, 6% would have been incorrectly included for IV tPA consideration had the EMS time been used. In patients with wake-up stroke symptoms, EMS underestimated LKN times: mean neurologist LKN time-EMS LKN time =208 minutes. The presence of wake-up stroke symptoms (P<0.0001) and older age (P=0.019) were independent predictors of prolonged |ΔLKN|. CONCLUSIONS-: EMS-reported LKN times were largely congruent with neurologist-determined times. Focused EMS training regarding wake-up stroke symptoms may further improve accuracy. © 2014 American Heart Association, Inc.

Author Keywords

Emergency Medical Services;  Last known normal time;  Stroke

Document Type: Article

Source: Scopus

 

Shin, S.a , Walz, K.A.a , Archambault, A.S.a , Sim, J.b , Bollman, B.P.a , Koenigsknecht-Talboo, J.a , Cross, A.H.a c , Holtzman, D.M.a b c , Wu, G.F.a c d

Apolipoprotein E mediation of neuro-inflammation in a murine model of multiple sclerosis

 (2014) Journal of Neuroimmunology, 271 (1-2), pp. 8-17.

a Department of Neurology, Washington University in St. Louis School of Medicine, Box 8111, 660 S. Euclid Avenue, St. Louis, MO 63110, United States

b Department of Developmental Biology, Washington University in St. Louis School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States

c Hope Center for Neurological Disorders, Washington University in St. Louis School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States

d Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States

Abstract

Apolipoprotein E (ApoE) functions as a ligand in receptor-mediated endocytosis of lipoprotein particles and has been demonstrated to play a role in antigen presentation. To explore the contribution of ApoE during autoimmune central nervous system (CNS) demyelination, we examined the clinical, cellular immune function, and pathologic consequences of experimental autoimmune encephalomyelitis (EAE) induction in ApoE knockout (ApoE-/-) mice. We observed reduced clinical severity of EAE in ApoE-/- mice in comparison to WT mice that was concomitant with an early reduction of dendritic cells (DCs) followed by a reduction of additional innate cells in the spinal cord at the peak of disease without any differences in axonal damage. While T cell priming was enhanced in ApoE-/- mice, reduced severity of EAE was also observed in ApoE-/- recipients of encephalitogenic wild type T cells. Expression of ApoE during EAE was elevated within the CNS of wild type mice, particularly by innate cells such as DCs. Overall, ApoE promotes clinical EAE, likely by mediation of inflammation localized within the CNS. © 2014 Elsevier B.V.

Author Keywords

Antigen presentation;  Apolipoprotein E;  Dendritic cells;  EAE

Document Type: Article

Source: Scopus

 

De Alwis, D.a , Lynskey, M.T.b , Reiersen, A.M.a , Agrawal, A.a

Attention-deficit/hyperactivity disorder subtypes and substance use and use disorders in NESARC

(2014) Addictive Behaviors, 39 (8), pp. 1278-1285.

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

b Kings College, Addictions Department, London, United Kingdom

Abstract

Background: Attention-deficit/hyperactivity disorder (ADHD) is associated with substance use and substance use disorders (SUD). However, relatively little is known about the relationship between DSM-IV ADHD subtypes and substance use or DSM-IV abuse/dependence in epidemiological samples. Methods: Data were obtained from the National Epidemiologic Survey of Alcohol and Related Conditions (NESARC, N. = 33,588). Respondents reported on ADHD symptoms (DSM-IV) for the period of time when they were 17. years or younger. Lifetime use and DSM-IV abuse/dependence of alcohol, nicotine, cannabis, cocaine, sedatives, stimulants and heroin/opiates were compared across those with ADHD symptoms but no diagnosis (ADHDsx; N. = 17,009), the Combined (ADHD-C; N. = 361), Predominantly Inattentive (ADHD-I; N. = 325), and the Predominantly Hyperactive-Impulsive (ADHD-HI; N. = 279) ADHD subtypes. Taking a more dimensional approach, inattentive and hyperactive-impulsive symptom counts and their associations with substance use and misuse were also examined. Results: After adjustments for conduct disorder, major depressive disorder, any anxiety disorder and other socio-demographic covariates, substance use and SUD were associated with ADHDsx, ADHD-C, ADHD-I and ADHD-HI. Overall, substance use and SUD were more weakly associated with the ADHDsx group compared to the three ADHD diagnostic groups.Statistically significant differences were not evident across the three diagnostic groups. Hyperactive-impulsive symptoms were more consistently associated with substance use and SUD compared to inattentive symptoms. Conclusions: ADHD subtypes are consistently associated with substance use and SUD. The relatively stronger association of hyperactive/impulsive symptoms with substance use and abuse/dependence is consistent with the extant literature noting impulsivity as a precursor of substance use and SUD. © 2014 Elsevier Ltd.

Author Keywords

ADHD subtypes;  Substance use;  Substance use disorders

Document Type: Article

Source: Scopus

 

Leonard, J.R.a , Jaffe, D.M.b , Kuppermann, N.c q , Olsen, C.S.d , Leonard, J.C.b , Nigrovic, L.E.e , Powell, E.f , Stankovic, C.g , Mahajan, P.g , Donoghue, A.h , Brown, K.i , Reeves, S.D.j , Hoyle Jr., J.D.k , Borgialli, D.l , Anders, J.m , Rebella, G.n , Adelgais, K.o , Lillis, K.p , Kim, E.q , Teshome, G.r , Rogers, A.J.s , Babcock, L.t , Holubkov, R.d , Dean, J.M.d

Cervical spine injury patterns in children

 (2014) Pediatrics, 133 (5), pp. e1179-e1188.

a Department of Neurosurgery, Division of Pediatric Neurosurgery, Washington University in St Louis School of Medicine, St Louis, MO, United States

b Department of Pediatrics, Division of Emergency Medicine, Washington University in St Louis School of Medicine, One Children's Place, St Louis, MO 63110, United States

c Departments of Emergency Medicine and Pediatrics, University of California, Davis School of Medicine, Sacramento, CA, United States

d Data Coordinating Center, University of Utah School of Medicine, Salt Lake City, UT, United States

e Boston Children's Hospital, Boston, MA, United States

f Chicago Memorial/Northwestern, Chicago, IL, United States

g Children's Hospital of Michigan, Detroit, MI, United States

h Children's Hospital of Philadelphia, Philadelphia, PA, United States

i Children's National Medical Center, Washington, DC, United States

j Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States

k DeVos Children's Hospital/Spectrum Health, Grand Rapids, MI, United States

l Hurley Medical Center, Flint, MI, United States

m Johns Hopkins Medical Center, Baltimore, MD, United States

n Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI, United States

o Primary Children's Medical Center, Salt Lake City, UT, United States

p State University of New York, Buffalo, Buffalo, NY, United States

q UC Davis Medical Center, Sacramento, CA, United States

r University of Maryland, Baltimore, MD, United States

s University of Michigan, Ann Arbor, MI, United States

t University of Rochester Medical Center, Rochester, NY, United States

Abstract

BACKGROUND AND OBJECTIVE: Pediatric cervical spine injuries (CSIs) are rare and differ from adult CSIs. Our objective was to describe CSIs in a large, representative cohort of children. METHODS: We conducted a 5-year retrospective review of children,16 years old with CSIs at 17 Pediatric Emergency Care Applied Research Network hospitals. Investigators reviewed imaging reports and consultations to assign CSI type. We described cohort characteristics using means and frequencies and used Fisher's exact test to compare differences between 3 age groups: <2 years, 2 to 7 years, and 8 to 15 years. We used logistic regression to explore the relationship between injury level and age and mechanism of injury and between neurologic outcome and cord involvement, injury level, age, and comorbid injuries. RESULTS: A total of 540 children with CSIs were included in the study. CSI level was associated with both age and mechanism of injury. For children <2 and 2 to 7 years old, motor vehicle crash (MVC) was the most common injury mechanism (56%, 37%). Children in these age groups more commonly injured the axial (occiput-C2) region (74%, 78%). In children 8 to 15 years old, sports accounted for as many injuries as MVCs (23%, 23%), and 53% of injuries were subaxial (C3-7). CSIs often necessitated surgical intervention (axial, 39%; subaxial, 30%) and often resulted in neurologic deficits (21%) and death (7%). Neurologic outcome was associated with cord involvement, injury level, age, and comorbid injuries. CONCLUSIONS: We demonstrated a high degree of variability of CSI patterns, treatments and outcomes in children. The rarity, variation, and morbidity of pediatric CSIs make prompt recognition and treatment critical. Copyright © 2014 by the American Academy of Pediatrics.

Author Keywords

Cervical spine injury;  Children

Document Type: Article

Source: Scopus

 

Pepino, M.Y., Bradley, D., Eagon, J.C., Sullivan, S., Abumrad, N.A., Klein, S.

Changes in taste perception and eating behavior after bariatric surgery-induced weight loss in women

(2014) Obesity, 22 (5), pp. E13-E20.

Center for Human Nutrition, Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States

Objective Roux-en-Y gastric bypass (RYGB) surgery causes greater weight loss than laparoscopic adjustable gastric banding (LAGB). We tested the hypothesis that RYGB has weight loss-independent effects on taste perception, which influence eating behavior and contribute to the greater weight loss. Methods Subjects were studied before and after ∼20% weight loss induced by RYGB (n = 17) or LAGB (n = 10). The following have been evaluated: taste sensitivity for sweet, salty and savory stimuli, sucrose and monosodium glutamate (MSG) preferences, sweetness palatability, eating behavior, and expression of taste-related genes in biopsies of fungiform papillae. Results Weight loss induced by both procedures caused the same decrease in: preferred sucrose concentration (-12 ± 10%), perceived sweetness of sucrose (-7 ± 5%), cravings for sweets and fast-foods (-22 ± 5%), influence of emotions (-27 ± 5%), and external food cues (-30 ± 4%) on eating behavior, and expression of α-gustducin in fungiform papillae (all P values <0.05). RYGB, but not LAGB, shifted sweetness palatability from pleasant to unpleasant when repetitively tasting sucrose (P = 0.05). Neither procedure affected taste detection thresholds nor MSG preferences. Conclusions LAGB and RYGB cause similar alterations in eating behaviors, when weight loss is matched. These changes in eating behavior were not associated with changes in taste sensitivity, suggesting other, as yet unknown, mechanisms are involved. Copyright © 2013 The Obesity Society.

Document Type: Article
Source: Scopus

 

 

May 19, 2014

Schuermeyer, J.a , Salomonsen-Sautel, S.a , Price, R.K.b , Balan, S.b , Thurstone, C.a c , Min, S.-J.d , Sakai, J.T.a Temporal trends in marijuana attitudes, availability and use in Colorado compared to non-medical marijuana states: 2003-11 (2014) Drug and Alcohol Dependence, . Article in Press.

a Department of Psychiatry, University of Colorado Anschutz Medical Campus, Aurora, CO, United States

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

c Denver Health and Hospital Authority, Denver, Colorado, United States

d Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States

Abstract

Background: In 2009, policy changes were accompanied by a rapid increase in the number of medical marijuana cardholders in Colorado. Little published epidemiological work has tracked changes in the state around this time. Methods: Using the National Survey on Drug Use and Health, we tested for temporal changes in marijuana attitudes and marijuana-use-related outcomes in Colorado (2003-11) and differences within-year between Colorado and thirty-four non-medical-marijuana states (NMMS). Using regression analyses, we further tested whether patterns seen in Colorado prior to (2006-8) and during (2009-11) marijuana commercialization differed from patterns in NMMS while controlling for demographics. Results: Within Colorado those reporting "great-risk" to using marijuana 1-2 times/week dropped significantly in all age groups studied between 2007-8 and 2010-11 (e.g. from 45% to 31% among those 26 years and older; p = 0.0006). By 2010-11 past-year marijuana abuse/dependence had become more prevalent in Colorado for 12-17 year olds (5% in Colorado, 3% in NMMS; p = 0.03) and 18-25 year olds (9% vs. 5%; p = 0.02). Regressions demonstrated significantly greater reductions in perceived risk (12-17 year olds, p = 0.005; those 26 years and older, p = 0.01), and trend for difference in changes in availability among those 26 years and older and marijuana abuse/dependence among 12-17 year olds in Colorado compared to NMMS in more recent years (2009-11 vs. 2006-8). Conclusions: Our results show that commercialization of marijuana in Colorado has been associated with lower risk perception. Evidence is suggestive for marijuana abuse/dependence. Analyses including subsequent years 2012+ once available, will help determine whether such changes represent momentary vs. sustained effects. © 2014 Elsevier Ireland Ltd. All rights reserved.

Author Keywords

Cannabis;  Decriminalization;  Legalized marijuana;  Marijuana policy;  Medical marijuana

Document Type: Article in Press

Source: Scopus

 

Reynolds, L.C.a b , Inder, T.E.c d e , Neil, J.J.e f , Pineda, R.G.c g , Rogers, C.E.a b

Maternal obesity and increased risk for autism and developmental delay among very preterm infants

(2014) Journal of Perinatology, . Article in Press.

a 1] Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA

b Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA

c 1] Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA

d Department of Neurology, Washington University School of Medicine, St Louis, MO, USA

e Department of Radiology, Washington University School of Medicine, St Louis, MO, USA

f 1] Department of Neurology, Washington University School of Medicine, St Louis, MO, USA

g Program in Occupational Therapy, Washington University School of Medicine, St Louis, MO, USA

Abstract

Objective:Thirty-five percent of women of child-bearing age are obese, and there is evidence that maternal obesity may increase the risk for adverse neurodevelopmental outcome. However, research regarding obesity and neurodevelopment among children born preterm is limited. This study aimed to determine associations between maternal obesity and neurodevelopment in very preterm children at age 2 years.Study Design:Maternal/infant dyads (n=62) born ≤30 weeks gestation were enrolled in a prospective cohort study at a level-III neonatal intensive care unit. Mothers were classified as obese or non-obese based on pre-pregnancy body mass index. Infants underwent magnetic resonance imaging at term equivalent and developmental testing at age 2. Maternal obesity was investigated for associations with neurodevelopment. Result:Maternal obesity was associated with positive screen for autism (odds ratio=9.88, P=0.002) and lower composite language scores (β=-9.36, (confidence interval=-15.11, -3.61), P=0.002). Conclusion:Maternal obesity was associated with adverse neurodevelopmental outcome at age 2 in this cohort of very preterm children. This study requires replication, but may support targeted surveillance of infants born to women with maternal obesity.Journal of Perinatology advance online publication, 8 May 2014; doi:10.1038/jp.2014.80.

Document Type: Article in Press

Source: Scopus

 

Church, J.A.a , Schlaggar, B.L.b c d e

Pediatric Tourette syndrome: Insights from recent neuroimaging studies

(2014) Journal of Obsessive-Compulsive and Related Disorders, . Article in Press.

a Department of Psychology, University of Texas at Austin, 108 E. Dean Keeton, Stop A8000, Austin, TX 78712, United States

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

c Department of Radiology, 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

e Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract

Tourette syndrome has been examined using many different neuroimaging techniques. There has been a recent surge of neuroimaging research papers related to Tourette syndrome that are exploring many different aspects of the disorder and its comorbidities. This brief review focuses on recent MRI-based imaging studies of pediatric Tourette syndrome, including anatomical, functional, resting state, and diffusion tensor MRI techniques. Consistencies across studies are explored, and particularly important issues involved in acquiring data from this special population are discussed. © 2014 Elsevier Ltd. All rights reserved.

Author Keywords

Anatomy;  Development;  DTI;  fMRI;  MRI;  Tourette;  VBM

Document Type: Article in Press

Source: Scopus

 

Blennow, K.a , Dubois, B.b , Fagan, A.M.c , Lewczuk, P.d , de Leon, M.J.e f , Hampel, H.b

Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer's disease

(2014) Alzheimer's and Dementia, . Article in Press.

a Department of Neuroscience and Physiology, Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, University of Gothenburg, Mölndal, Sweden

b Institute for Memory and Alzheimer's Disease, Institute of Neurology, Pitié-Salpêtrière Hospital Group, Pierre and Marie Curie University, Paris, France

c Department of Neurology, Washington University School of Medicine, St Louis, MO, USA

d Universitätsklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany

e Department of Psychiatry, New York University School of Medicine, New York, NY, USA

f Centre for Brain Health, New York University School of Medicine, New York, NY, USA

Abstract

Several potential disease-modifying drugs for Alzheimer's disease (AD) have failed to show any effect on disease progression in clinical trials, conceivably because the AD subjects are already too advanced to derive clinical benefit from treatment and because diagnosis based on clinical criteria alone introduces a high misdiagnosis rate. Thus, well-validated biomarkers for early detection and accurate diagnosis are crucial. Low cerebrospinal fluid (CSF) concentrations of the amyloid-β (Aβ1-42) peptide, in combination with high total tau and phosphorylated tau, are sensitive and specific biomarkers highly predictive of progression to AD dementia in patients with mild cognitive impairment. However, interlaboratory variations in the results seen with currently available immunoassays are of concern. Recent worldwide standardization efforts and quality control programs include standard operating procedures for both preanalytical (e.g., lumbar puncture and sample handling) and analytical (e.g., preparation of calibration curve) procedures. Efforts are also ongoing to develop highly reproducible assays on fully automated instruments. These global standardization and harmonization measures will provide the basis for the generalized international application of CSF biomarkers for both clinical trials and routine clinical diagnosis of AD. © 2014 The Alzheimer's Association.

Author Keywords

β-Amyloid;  Alzheimer's disease;  Biomarkers;  Cerebrospinal fluid;  Mild cognitive impairment;  Tau protein

Document Type: Article in Press

Source: Scopus

 

Harari, O.a , Cruchaga, C.a g , Kauwe, J.S.K.i , Ainscough, B.J.h , Bales, K.j , Pickering, E.H.j , Bertelsen, S.a , Fagan, A.M.b f g , Holtzman, D.M.b e f g , Morris, J.C.b c f g , Goate, A.M.a b d f g

Phosphorylated tau-Aβ42 ratio as a continuous trait for biomarker discovery for early-stage Alzheimer's disease in multiplex immunoassay panels of cerebrospinal fluid

(2014) Biological Psychiatry, 75 (9), pp. 723-731. Cited 1 time.

a Department of Psychiatry, Washington University School of Medicine, 425 S. Euclid Avenue, St. Louis, MO 63110, 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 Genetics, Washington University School of Medicine, St. Louis, MO, United States

e Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States

f Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States

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

h Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, United States

i Department of Biology, Brigham Young University, Provo, UT, United States

j Neuroscience Research Unit, Worldwide Research and Development, Pfizer, Inc., Groton, CT, United States

Abstract

Background Identification of the physiologic changes that occur during the early stages of Alzheimer's disease (AD) may provide critical insights for the diagnosis, prognosis, and treatment of disease. Cerebrospinal fluid (CSF) biomarkers are a rich source of information that reflect the brain proteome. Methods A novel approach was applied to screen a panel of ~190 CSF analytes quantified by multiplex immunoassay, and common associations were detected in the Knight Alzheimer's Disease Research Center (N = 311) and the Alzheimer's Disease Neuroimaging Initiative (N = 293) cohorts. Rather than case-control status, the ratio of CSF levels of tau phosphorylated at threonine 181 (ptau181) and Aβ42 was used as a continuous trait in these analyses. Results The ptau181-Aβ42 ratio has more statistical power than traditional modeling approaches, and the levels of CSF heart-type fatty acid binding protein (FABP) and 12 other correlated analytes increase as AD progresses. These results were validated using the traditional case-control status model. Stratification of the dataset demonstrated that increases in these analytes occur very early in the disease course and were apparent even in nondemented individuals with AD pathology (low ptau181, low Aβ42) compared with elderly control subjects with no pathology (low ptau181, high Aβ42). The FABP-Aβ42 ratio demonstrates a similar hazard ratio for disease conversion to ptau181-Aβ42 even though the overlap in classification is incomplete suggesting that FABP contributes independent information as a predictor of AD. Conclusions Our results indicate that the approach presented here can be used to identify novel biomarkers for AD correctly and that CSF heart FABP levels start to increase at very early stages of AD. © 2014 Society of Biological Psychiatry.

Author Keywords

Alzheimer's disease;  biomarkers;  brain proteome - Rules Based Medicine Discovery Multi-Analyte Profile 1.0;  cerebrospinal fluid (CSF);  heart-type fatty acid binding protein

Document Type: Article

Source: Scopus

 

Luby, J.L.

Toward mapping altered trajectories of brain development in depression

(2014) American Journal of Psychiatry, 171 (5), pp. 489-491.

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

Document Type: Review

Source: Scopus

 

Shin, S.a , Walz, K.A.a , Archambault, A.S.a , Sim, J.b , Bollman, B.P.a , Koenigsknecht-Talboo, J.a , Cross, A.H.a c , Holtzman, D.M.a b c , Wu, G.F.a c d

Apolipoprotein E mediation of neuro-inflammation in a murine model of multiple sclerosis

(2014) Journal of Neuroimmunology, . Article in Press.

a Department of Neurology, Washington University in St. Louis School of Medicine, Box 8111, 660 S. Euclid Avenue, St. Louis, MO 63110, United States

b Department of Developmental Biology, Washington University in St. Louis School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States

c Hope Center for Neurological Disorders, Washington University in St. Louis School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States

d Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States

Abstract

Apolipoprotein E (ApoE) functions as a ligand in receptor-mediated endocytosis of lipoprotein particles and has been demonstrated to play a role in antigen presentation. To explore the contribution of ApoE during autoimmune central nervous system (CNS) demyelination, we examined the clinical, cellular immune function, and pathologic consequences of experimental autoimmune encephalomyelitis (EAE) induction in ApoE knockout (ApoE-/-) mice. We observed reduced clinical severity of EAE in ApoE-/- mice in comparison to WT mice that was concomitant with an early reduction of dendritic cells (DCs) followed by a reduction of additional innate cells in the spinal cord at the peak of disease without any differences in axonal damage. While T cell priming was enhanced in ApoE-/- mice, reduced severity of EAE was also observed in ApoE-/- recipients of encephalitogenic wild type T cells. Expression of ApoE during EAE was elevated within the CNS of wild type mice, particularly by innate cells such as DCs. Overall, ApoE promotes clinical EAE, likely by mediation of inflammation localized within the CNS. © 2014 Elsevier B.V. All rights reserved.

Author Keywords

Antigen presentation;  Apolipoprotein E;  Dendritic cells;  EAE

Document Type: Article in Press

Source: Scopus

 

Imai, S.-i.a , Guarente, L.b c d

NAD+ and sirtuins in aging and disease

(2014) Trends in Cell Biology, . Article in Press.

a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA

b Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

c Glenn Laboratory for the Science of Aging, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

d Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

Abstract

Nicotinamide adenine dinucleotide (NAD+) is a classical coenzyme mediating many redox reactions. NAD+ also plays an important role in the regulation of NAD+-consuming enzymes, including sirtuins, poly-ADP-ribose polymerases (PARPs), and CD38/157 ectoenzymes. NAD+ biosynthesis, particularly mediated by nicotinamide phosphoribosyltransferase (NAMPT), and SIRT1 function together to regulate metabolism and circadian rhythm. NAD+ levels decline during the aging process and may be an Achilles' heel, causing defects in nuclear and mitochondrial functions and resulting in many age-associated pathologies. Restoring NAD+ by supplementing NAD+ intermediates can dramatically ameliorate these age-associated functional defects, counteracting many diseases of aging, including neurodegenerative diseases. Thus, the combination of sirtuin activation and NAD+ intermediate supplementation may be an effective antiaging intervention, providing hope to aging societies worldwide. © 2014 Elsevier Ltd. All rights reserved.

Author Keywords

NAD+;  nicotinamide mononucleotide;  nicotinamide phosphoribosyltransferase;  nicotinamide riboside;  poly-ADP-ribose polymerases;  sirtuins

Document Type: Article in Press

Source: Scopus

 

Genin, G.M.

Nanoscopic injury with macroscopic consequences: Tau proteins as mediators of diffuse axonal injury

(2014) Biophysical Journal, 106 (8), pp. 1551-1552.

Department of Mechanical Engineering and Materials Science, Washington University School of Medicine, St. Louis, MO, United States

Document Type: Note

Source: Scopus

 

Saez, P.A.a b e , Bender, H.A.c , Barr, W.B.a , Mindt, M.R.b c , Morrison, C.E.a , Hassenstab, J.d , Rodriguez, M.a , Vazquez, B.a

The impact of education and acculturation on nonverbal neuropsychological test performance among latino/a patients with epilepsy

(2014) Applied Neuropsychology:Adult, 21 (2), pp. 108-119.

a NYU Langone Medical Center, School of Medicine, New York University, New York, NY, United States

b Psy., Fordham University, Bronx, NY, United States

c Neurology and Psychiatry, Mount Sinai School of Medicine, New York, NY, United States

d Neurology and Psychology, Washington University, School of Medicine, St. Louis, Missouri, United States

e NYU Langone Medical Center, Comprehensive Epilepsy Center, Department of Neurology, 223 East 34th Street, New York, NY 10016, United States

Abstract

The present study examined the relationship between various sociocultural factors (e.g., acculturation, education), neurological variables (e.g., epilepsy duration and seizure frequency) and nonverbal neuropsychological (NP) test performance in a sample of 305 Latino/a and Non-Latino/a White adults with and without epilepsy. All participants completed nonverbal NP measures of visuospatial skills, memory, executive functioning, and psychomotor speed. An acculturation scale was administered to Spanish-speaking epilepsy patients and controls. Education was strongly correlated with performance on all but one of the nonverbal measures across the entire sample. Among Spanish-speaking Latino/a patients with epilepsy, level of acculturation to U.S. culture was associated with a measure of behavioral inflexibility (p <.05) and with a composite measure of nonverbal NP test performance (p <.05). Finally, the results of hierarchical regression models showed that sociocultural factors accounted for a greater proportion of variance in nonverbal NP test performance than did neurological factors. These results provide further evidence that sociocultural factors are strong predictors of NP test performance in clinical populations, even on nonverbal tests. Assessment of acculturation may be as critical as assessment of disease factors in interpreting cognitive performance in Latino/a individuals. © 2014 Copyright Taylor & Francis Group, LLC.

Author Keywords

cross-cultural;  Hispanic Americans;  tests

Document Type: Article

Source: Scopus

 

Frauscher, B.a , Jennum, P.b , Ju, Y.-E.S.c , Postuma, R.B.d , Arnulf, I.e , De Cock, V.C.f , Dauvilliers, Y.f , Fantini, M.L.g h , Ferini-Strambi, L.i , Gabelia, D.a , Iranzo, A.j , Leu-Semenescu, S.e , Mitterling, T.a , Miyamoto, M.k , Miyamoto, T.l , Montplaisir, J.Y.m , Oertel, W.n , Pelletier, A.o , Prunetti, P.p , Puligheddu, M.q , Santamaria, J.j , Sonka, K.r , Unger, M.n s , Wolfson, C.o , Zucconi, M.i , Terzaghi, M.i p , Högl, B.a , Mayer, G.t , Manni, R.p

Comorbidity and medication in REM sleep behavior disorder: A multicenter case-control study

(2014) Neurology, 82 (12), pp. 1076-1079.

a Department of Neurology, Innsbruck Medical University, Austria

b Danish Center for Sleep Medicine, University of Copenhagen, Denmark

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

d Department of Neurology, McGill University, Montreal General Hospital, Canada

e Unité des Pathologies du Sommeil, Hôpital Pitié-Salpêtrière, Marie Curie University, Paris, France

f Sleep Unit, Department of Neurology, Hôpital Gui de Chauliac, Montpellier, Montpellier, France

g Sleep Disorders Center, Department of Neurosciences, University of Turin, Italy

h UFR Medecine, EA 7280, University Clermont 1, France

i Sleep Disorders Center, Università Vita-Salute San Raffaele, Milan, Italy

j Neurology Service, Hospital Clinic de Barcelona, IDIBAPS, Spain

k Department of Neurology, Dokkyo Medical University, School of Medicine, Tochigi, Japan

l Department of Neurology, Dokkyo Medical University Koshigaya Hospital, Saitama, Japan

m Centre D'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Coeur de Montréal, Canada

n Philipps-Universität, Marburg, Germany

o Neuroepidemiology Research Unit, Research Institute of the McGill University Health Centre, Montreal, Canada

p Unit of Sleep Medicine, National Institute of Neurology IRCCS, C. Mondino Foundation, Pavia, Italy

q Sleep Center, Department of Cardiovascular and Neurological Sciences, University of Cagliari, Italy

r Department of Neurology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic

s Department of Neurology, Saarland University, Homburg/Saar, Germany

t Hephata Klinik, Schwalmstadt-Treysa, Germany

Abstract

Objective: This controlled study investigated associations between comorbidity and medication in patients with polysomnographically confirmed idiopathic REM sleep behavior disorder (iRBD), using a large multicenter clinic-based cohort. Methods: Data of a self-administered questionnaire on comorbidity and medication use of 318 patients with iRBD and 318 matched controls were analyzed. Comparisons between cases and controls were made using logistic regression analysis. Results: Patients with iRBD were more likely to report depression (odds ratio [OR] 2.0, 95% confidence interval [CI] 1.3-2.9) and concomitant antidepressant use (OR 2.2, 95% CI 1.4-3.6). Subanalysis of antidepressant agents revealed that the increased use of antidepressants in iRBD was due to selective serotoninergic reuptake inhibitors (OR 3.6, 95% CI 1.8-7.0) and not due to other antidepressant classes. Patients with iRBD reported more lifetime antidepressant use than comorbid depression (antidepressant use: OR 1.9, 95%CI 1.1-3.3; depression: OR 1.6, 95%CI 1.0-2.5). Patients with iRBD reported more ischemic heart disease (OR 1.9, 95% CI 1.1-3.1). This association did not change substantially when adjusting for cardiovascular risk factors (OR 2.3, 95% CI 1.3-3.9). The use of inhaled glucocorticoids was higher in patients with iRBD compared to controls (OR 5.3, 95% CI 1.8-15.8), likely reflecting the higher smoking rate in iRBD (smoking: OR 15.3, 95%CI 2.0-118.8; nonsmoking: OR 2.4, 95%CI 0.4-13.2) and consequent pulmonary disease. Conclusions: This large study confirms the association between comorbid depression and antidepressant use in iRBD. In addition, there was an unexpected association of iRBD with ischemic heart disease that was not explained by cardiovascular risk factors. © 2014 American Academy of Neurology.

Document Type: Article

Source: Scopus

 

Powers, W.J.a , Clarke, W.R.b , Grubb Jr., R.L.c d , Videen, T.O.d e , Adams Jr., H.P.f , Derdeyn, C.P.c d e

Lower stroke risk with lower blood pressure in hemodynamic cerebral ischemia

(2014) Neurology, 82 (12), pp. 1027-1032. Cited 1 time.

a Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, United States

b Clinical Trials Statistics and Data Management Center, University of Iowa College of Public Health, Iowa City, United States

c Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States

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

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

f Department of Neurology, University of Iowa Carver School of Medicine, Iowa City, United States

Abstract

Objective: To determine whether strict blood pressure (BP) control is the best medical management for patients with symptomatic carotid artery occlusion and hemodynamic cerebral ischemia. Methods: In this prospective observational cohort study, we analyzed data from91 participants in the nonsurgical group of the Carotid Occlusion Surgery Study (COSS) who had recent symptomatic internal carotid artery occlusion and hemodynamic cerebral ischemia manifested by ipsilateral increased oxygen extraction fraction. The target BP goal in COSS was ≤130/85 mm Hg. We compared the occurrence of ipsilateral ischemic stroke during follow-up in the 41 participants with mean BP ≤130/85 mm Hg to the remaining 50 with higher BP. Results: Of 16 total ipsilateral ischemic strokes that occurred during follow-up, 3 occurred in the 41 participants with mean follow-up BP of >130/85 mm Hg, compared to 13 in the remaining 50 participants with mean follow-up BP .130/85 mm Hg (hazard ratio 3.742, 95% confidence interval 1.065-13.152, log-rank p 5 0.027). Conclusion: BPs ≤130/85 mm Hg were associated with lower subsequent stroke risk in these patients. Classification of evidence: This study provides Class III evidence that control of hypertension ≤130/85 mm Hg is associated with a reduced risk of subsequent ipsilateral ischemic stroke in patients with recently symptomatic carotid occlusion and hemodynamic cerebral ischemia (increased oxygen extraction fraction). © 2014 American Academy of Neurology.

Document Type: Article

Source: Scopus

 

Paciorkowski, A.R.a b , Weisenberg, J.c , Kelley, J.B.d , Spencer, A.e , Tuttle, E.b , Ghoneim, D.b , Thio, L.L.c , Christian, S.L.f , Dobyns, W.B.f g , Paschal, B.M.e h

Autosomal recessive mutations in nuclear transport factor KPNA7 are associated with infantile spasms and cerebellar malformation

(2014) European Journal of Human Genetics, 22 (5), pp. 589-593. Cited 1 time.

a Departments of Neurology, Pediatrics and Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, United States

b Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY, United States

c Departments of Neurology and Pediatrics, Pediatric Epilepsy Center, Washington University, St Louis, MO, United States

d Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

e Center for Cell Signaling, University of Virginia, Charlottesville, VA, United States

f Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, United States

g Departments of Pediatrics and Neurology, University of Washington, Seattle, WA, United States

h Departments of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, United States

 Abstract

Nuclear import receptors of the KPNA family recognize the nuclear localization signal in proteins and together with importin-β mediate translocation into the nucleus. Accordingly, KPNA family members have a highly conserved architecture with domains that contact the nuclear localization signal and bind to importin-β. Here, we describe autosomal recessive mutations in KPNA7 found by whole exome sequencing in a sibling pair with severe developmental disability, infantile spasms, subsequent intractable epilepsy consistent with Lennox-Gastaut syndrome, partial agenesis of the corpus callosum, and cerebellar vermis hypoplasia. The mutations mapped to exon 7 in KPNA7 result in two amino-acid substitutions, Pro339Ala and Glu344Gln. On the basis of the crystal structure of the paralog KPNA2 bound to a bipartite nuclear localization signal from the retinoblastoma protein, the amino-acid substitutions in the affected subjects were predicted to occur within the seventh armadillo repeat that forms one of the two nuclear localization signal-binding sites in KPNA family members. Glu344 is conserved in all seven KPNA proteins, and we found that the Glu354Gln mutation in KPNA2 is sufficient to reduce binding to the retinoblastoma nuclear localization signal to approximately one-half that of wild-type protein. Our data show that compound heterozygous mutations in KPNA7 are associated with a human neurodevelopmental disease, and provide the first example of a human disease associated with mutation of a nuclear transport receptor. © 2014 Macmillan Publishers Limited All rights reserved.

Author Keywords

cerebellar vermis hypoplasia;  importins;  infantile spasms;  KPNA7;  Lennox Gastaut syndrome;  whole exome sequencing

Document Type: Article

Source: Scopus

 

Cavalli, V., Holtzman, D.

B-RAF unlocks axon regeneration

(2014) Journal of Experimental Medicine, 211 (5), p. 746.

Washington University School of Medicine, Saint Louis, United States

Document Type: Note

Source: Scopus

 

Lacouture, M.E.a , Elizabeth Davis, M.a , Elzinga, G.b , Butowski, N.c , Tran, D.d , Villano, J.L.e , Dimeglio, L.f , Davies, A.M.f , Wong, E.T.b

Characterization and management of dermatologic adverse events with the NovoTTF-100A system, a novel anti-mitotic electric field device for the treatment of recurrent glioblastoma

(2014) Seminars in Oncology, 41 (SUPPL. 4), pp. S1-S14.

a Rockefeller Outpatient Pavilion, Memorial Sloan-Kettering Cancer Center, 160 E 53rd St, New York, NY 10022, United States

b Beth Israel Deaconess Medical Center, New York, NY, United States

c University of California, San Francisco, CA, United States

d Washington University, St Louis, MO, United States

e University of Kentucky, Louisville, KY, United States

f Novocure, Portsmouth, NH, United States

Abstract

The NovoTTF-100A System (NovoTTF™ Therapy, Novocure Inc.) is a device that delivers alternating electric fields (TTFields) to tumor cells and interferes with mitosis. It is approved for use as monotherapy for the treatment of recurrent glioblastoma (rGB). TTFields are delivered through insulated transducer arrays applied onto the shaved scalp and connected to a battery-operated field generator. The occurrence of dermatologic adverse events (dAEs) is primarily due to the continuous contact between the array-related components and the scalp for periods of 3-4 days (together with other risk factors). These dAEs may include allergic and irritant dermatitis, mechanical lesions, ulcers, and skin infection. The incidence of dAEs in the phase III trial (n = 116) was 16% (2% grade 2, 0% grade 3/4); the post-marketing surveillance program (n = 570) revealed 156 (21.8%) dAEs with some patients reporting more than one event. Prophylactic strategies for dAEs include proper shaving and cleansing of the scalp and array relocation. Treatment-based strategies are AE-specific and include topical or oral antibiotics, topical corticosteroids, and isolation of affected skin areas from adhesives and pressure. The addition of skin care strategies to the NovoTTF-100A System use will maximize adherence to therapy while maintaining quality of life, all of which contribute to the therapeutic benefit of NovoTTF Therapy in rGB. © 2014 Elsevier Inc.

Document Type: Article

Source: Scopus

 

Kraus, C.L.a , Tychsen, L.a b , Lueder, G.T.a b , Culican, S.M.a b

Comparison of the effectiveness and safety of transscleral cyclophotocoagulation and endoscopic cyclophotocoagulation in pediatric glaucoma

(2014) Journal of Pediatric Ophthalmology and Strabismus, 51 (2), pp. 120-127.

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

b St. Louis Children's Hospital, St. Louis, MO, United States

Abstract

Purpose: Among the options for surgical management of pediatric glaucoma, destruction of the ciliary body reduces aqueous production and, consequently, intraocular pressure (IOP). Compared to more invasive filtering and shunt procedures, cyclodestruction is an attractive option for control of IOP in pediatric glaucomas. Methods: The relative reduction in IOP, duration of effect, and comparable safety and efficacy of transscleral cyclophotocoagulation (TSCP) and endoscopic cyclophotocoagulation (ECP) in pediatric patients with glaucoma was studied in this retrospective chart review. Results: A reduction in IOP of 28.6% and 33.2% with TSCP and ECP, respectively, was found. Eyes treated with ECP underwent an average of 3.24 cyclodestructive procedures; eyes treated with TSCP underwent an average of 2.29 cyclodestructive treatments. These differences were not statistically significant. A final success rate of 67.6% after TSCP and 62% after ECP failed to significantly differ between the two groups. Consequently, two-thirds of the patients were able to avoid penetrating surgery and the associated risks after one or more cyclodestructive procedures. Conclusions: TSCP and ECP are safe, effective, and comparable treatments for pediatric glaucomas. The results suggest that TSCP and ECP may be considered first-line therapy to achieve control of IOP in all forms of pediatric glaucoma. © SLACK Incorporated.

Document Type: Article

Source: Scopus

 

Greene, D.J.a b , Laumann, T.O.c , Dubis, J.W.c , Ihnen, S.K.c , Neta, M.c , Power, J.D.c , Pruett Jr., J.R.a , Black, K.J.a b c d , Schlaggar, B.L.b c d e

Developmental changes in the organization of functional connections between the basal ganglia and cerebral cortex

(2014) Journal of Neuroscience, 34 (17), pp. 5842-5854.

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States

b Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States

c Department of Neurology, 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

e Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract

The basal ganglia (BG) comprise a set of subcortical nuclei with sensorimotor, cognitive, and limbic subdivisions, indicative of functional organization. BG dysfunction in several developmental disorders suggests the importance of the healthy maturation of these structures. However, few studies have investigated the development of BG functional organization. Using resting-state functional connectivity MRI (rs-fcMRI), we compared human child and adult functional connectivity of the BG with rs-fcMRI-defined cortical systems. Because children move more than adults, customized preprocessing, including volume censoring, was used to minimize motion-induced rs-fcMRI artifact. Our results demonstrated functional organization in the adult BG consistent with subdivisions previously identified in anatomical tracing studies. Group comparisons revealed a developmental shift in bilateral posterior putamen/pallidum clusters from preferential connectivity with the somatomotor "face" system in childhood to preferential connectivity with control/attention systems (frontoparietal, ventral attention) in adulthood. This shift was due to a decline in the functional connectivity of these clusters with the somatomotor face system over development, and no change with control/attention systems. Applying multivariate pattern analysis, we were able to reliably classify individuals as children or adults based on BG-cortical system functional connectivity. Interrogation of the features driving this classification revealed, in addition to the somatomotor face system, contributions by the orbitofrontal, auditory, and somatomotor hand systems. These results demonstrate that BG-cortical functional connectivity evolves over development, and may lend insight into developmental disorders that involve BG dysfunction, particularly those involving motor systems (e.g., Tourette syndrome). © 2014 the authors.

Author Keywords

Basal ganglia;  Development;  Functional connectivity;  Resting state

Document Type: Article

Source: Scopus

 

Loukola, A.a , Wedenoja, J.a , Keskitalo-Vuokko, K.a , Broms, U.a b , Korhonen, T.a b , Ripatti, S.b c d , Sarin, A.-P.b c , Pitkäniemi, J.a , He, L.a , Häppölä, A.a , Heikkilä, K.a , Chou, Y.-L.e , Pergadia, M.L.e , Heath, A.C.e , Montgomery, G.W.f , Martin, N.G.f , Madden, P.A.F.e , Kaprio, J.a b c

Genome-wide association study on detailed profiles of smoking behavior and nicotine dependence in a twin sample

(2014) Molecular Psychiatry, 19 (5), pp. 615-624. Cited 1 time. 

a Department of Public Health, Hjelt Institute, University of Helsinki, PO Box 41, Helsinki FI-00014, Finland

b National Institute for Health and Welfare, Helsinki, Finland

c Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland

d Wellcome Trust Sanger Institute, Cambridge, United Kingdom

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

f Queensland Institute of Medical Research, Brisbane, QLD, Australia 

Abstract

Smoking is a major risk factor for several somatic diseases and is also emerging as a causal factor for neuropsychiatric disorders. Genome-wide association (GWA) and candidate gene studies for smoking behavior and nicotine dependence (ND) have disclosed too few predisposing variants to account for the high estimated heritability. Previous large-scale GWA studies have had very limited phenotypic definitions of relevance to smoking-related behavior, which has likely impeded the discovery of genetic effects. We performed GWA analyses on 1114 adult twins ascertained for ever smoking from the population-based Finnish Twin Cohort study. The availability of 17 smoking-related phenotypes allowed us to comprehensively portray the dimensions of smoking behavior, clustered into the domains of smoking initiation, amount smoked and ND. Our results highlight a locus on 16p12.3, with several single-nucleotide polymorphisms (SNPs) in the vicinity of CLEC19A showing association (P<1 × 10-6) with smoking quantity. Interestingly, CLEC19A is located close to a previously reported attention-deficit hyperactivity disorder (ADHD) linkage locus and an evident link between ADHD and smoking has been established. Intriguing preliminary association (P<1 × 10-5) was detected between DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) ND diagnosis and several SNPs in ERBB4, coding for a Neuregulin receptor, on 2q33. The association between ERBB4 and DSM-IV ND diagnosis was replicated in an independent Australian sample. Recently, a significant increase in ErbB4 and Neuregulin 3 (Nrg3) expression was revealed following chronic nicotine exposure and withdrawal in mice and an association between NRG3 SNPs and smoking cessation success was detected in a clinical trial. ERBB4 has previously been associated with schizophrenia; further, it is located within an established schizophrenia linkage locus and within a linkage locus for a smoker phenotype identified in this sample. In conclusion, we disclose novel tentative evidence for the involvement of ERBB4 in ND, suggesting the involvement of the Neuregulin/ErbB signalling pathway in addictions and providing a plausible link between the high co-morbidity of schizophrenia and ND. 

Author Keywords

ADHD;  genome-wide association analysis;  nicotine dependence;  schizophrenia;  smoking behavior;  smoking quantity 

Document Type: Article

Source: Scopus

 

Jesuraj, N.J.a , Marquardt, L.M.a , Kwasa, J.A.a , Sakiyama-Elbert, S.E.a b

Glial cell line-derived neurotrophic factor promotes increased phenotypic marker expression in femoral sensory and motor-derived Schwann cell cultures

(2014) Experimental Neurology, 257, pp. 10-18.

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

b Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract

Schwann cells (SCs) secrete growth factors and extracellular matrix molecules that promote neuronal survival and help guide axons during regeneration. Transplantation of SCs is a promising strategy for enhancing peripheral nerve regeneration. However, we and others have shown that after long-term in vitro expansion, SCs revert to a de-differentiated state similar to the phenotype observed after injury. In vivo, glial cell-line derived neurotrophic factor (GDNF) may guide the differentiation of SCs to remyelinate regenerating axons. Therefore, we hypothesized that exogenous GDNF may guide the differentiation of SCs into their native phenotypes in vitro through stimulation of GDNF family receptor (GFR)α-1. When activated in SCs, GFRα-1 promotes phosphorylation of Fyn, a Src family tyrosine kinase responsible for mediating downstream signaling for differentiation and proliferation. In this study, SCs harvested from the sensory and motor branches of rat femoral nerve were expanded in vitro and then cultured with 50 or 100. ng/mL of GDNF. The exogenous GDNF promoted differentiation of sensory and motor-derived SCs back to their native phenotypes, as demonstrated by decreased proliferation after 7. days and increased expression of S100Ββ and phenotype-specific markers. Furthermore, inhibiting Fyn with Src family kinase inhibitors, PP2 and SU6656, and siRNA-mediated knockdown of Fyn reduced GDNF-stimulated differentiation of sensory and motor-derived SCs. These results demonstrate that activating Fyn is necessary for GDNF-stimulated differentiation of femoral nerve-derived SCs into their native phenotypes in vitro. Therefore GDNF could be incorporated into SC-based therapies to promote differentiation of SCs into their native phenotype to improve functional nerve regeneration. © 2014 Elsevier Inc.

Author Keywords

Cell transplantation;  Differentiation;  Fyn;  Nerve regeneration;  Peripheral nerve

Document Type: Article

Source: Scopus

 

Monroe, H.A., Sinks, B.C.

Hyperacusis as a symptom of superior semicircular canal dehiscence

(2014) Seminars in Hearing, 35 (2), pp. 145-156. 

Department of Otolaryngology, Head and Neck Surgery, Washington University School of Medicine, Campus Box 8115, 660 S. Euclid Avenue, St. Louis, MO 63110, United States

Abstract

This article provides a brief overview of how symptoms of hyperacusis and autophony can occur as a result of a dehiscence in the superior semicircular canal. Hyperacusis is a word typically used to describe hypersensitivity to external acoustic stimuli. In the case of superior semicircular canal dehiscence (SSCD), the patient is sensitive not only to loud sounds in their environment but also to the abnormally amplified internal sounds of their body. Superior semicircular canal dehiscence is diagnosed through a combination of case history, audiometric findings, vestibular evoked myogenic potential thresholds, and high-resolution computer-assisted tomography scans. Patients may initially present with auditory or vestibular symptoms or in some cases, both. The anatomy and physiology associated with SSCD will be briefly discussed along with symptoms and treatment options. The presentation of symptoms differs between individuals. Case studies will be utilized to bring all of these elements together. © 2014 by Thieme Medical Publishers, Inc.

  Author Keywords

air-bone gap;  bone conduction;  hyperacusis;  Superior semicircular canal dehiscence;  vestibular evoked myogenic potentials

Document Type: Review

 

Source: Scopus

 

May 12, 2014

Blennow, K.a , Dubois, B.b , Fagan, A.M.c , Lewczuk, P.d , de Leon, M.J.e f , Hampel, H.b

Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer's disease

(2014) Alzheimer's and Dementia, . Article in Press. 

a Department of Neuroscience and Physiology, Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, University of Gothenburg, Mölndal, Sweden

b Institute for Memory and Alzheimer's Disease, Institute of Neurology, Pitié-Salpêtrière Hospital Group, Pierre and Marie Curie University, Paris, France

c Department of Neurology, Washington University School of Medicine, St Louis, MO, USA

d Universitätsklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany

e Department of Psychiatry, New York University School of Medicine, New York, NY, USA

f Centre for Brain Health, New York University School of Medicine, New York, NY, USA

Abstract

Several potential disease-modifying drugs for Alzheimer's disease (AD) have failed to show any effect on disease progression in clinical trials, conceivably because the AD subjects are already too advanced to derive clinical benefit from treatment and because diagnosis based on clinical criteria alone introduces a high misdiagnosis rate. Thus, well-validated biomarkers for early detection and accurate diagnosis are crucial. Low cerebrospinal fluid (CSF) concentrations of the amyloid-β (Aβ1-42) peptide, in combination with high total tau and phosphorylated tau, are sensitive and specific biomarkers highly predictive of progression to AD dementia in patients with mild cognitive impairment. However, interlaboratory variations in the results seen with currently available immunoassays are of concern. Recent worldwide standardization efforts and quality control programs include standard operating procedures for both preanalytical (e.g., lumbar puncture and sample handling) and analytical (e.g., preparation of calibration curve) procedures. Efforts are also ongoing to develop highly reproducible assays on fully automated instruments. These global standardization and harmonization measures will provide the basis for the generalized international application of CSF biomarkers for both clinical trials and routine clinical diagnosis of AD. © 2014 The Alzheimer's Association.

 

Author Keywords

β-Amyloid;  Alzheimer's disease;  Biomarkers;  Cerebrospinal fluid;  Mild cognitive impairment;  Tau protein

 

Document Type: Article in Press

Source: Scopus

 

Fan, J.a , Zhang, X.a , Li, J.a , Jin, H.a , Padakanti, P.K.a , Jones, L.A.a , Flores, H.P.b , Su, Y.b , Perlmutter, J.S.a b , Tu, Z.a

Radiosyntheses and in vivo evaluation of carbon-11 PET tracers for PDE10A in the brain of rodent and nonhuman primate

(2014) Bioorganic and Medicinal Chemistry, 22 (9), pp. 2648-2654.

a Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, United States

b Department of Neurology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, United States

Abstract

The radiosyntheses and in vivo evaluation of four carbon-11 labeled quinoline group-containing radioligands are reported here. Radiolabeling of [11C]1-4 was achieved by alkylation of their corresponding desmethyl precursors with [11C]CH3I. Preliminary biodistribution evaluation in Sprague-Dawley rats demonstrated that [11C]1 and [ 11C]2 had high striatal accumulation (at peak time) for [ 11C]1 and [11C]2 were 6.0-fold and 4.5-fold at 60 min, respectively. Following MP-10 pretreatment, striatal uptake in rats of [ 11C]1 and [11C]2 was reduced, suggesting that the tracers bind specifically to PDE10A. MicroPET studies of [11C]1 and [ 11C]2 in nonhuman primates (NHP) also showed good tracer retention in the striatum with rapid clearance from non-target brain regions. Striatal uptake (SUV) of [11C]1 reached 1.8 at 30 min with a 3.5-fold striatum:cerebellum ratio. In addition, HPLC analysis of solvent extracts from NHP plasma samples suggested that [11C]1 had a very favorable metabolic stability. Our preclinical investigations suggest that [ 11C]1 is a promising candidate for quantification of PDE10A in vivo using PET. © 2014 Elsevier Ltd. All rights reserved.

 

Author Keywords

Carbon-11;  CNS;  MP-10;  PDE10A;  PET imaging

 

Document Type: Article

Source: Scopus

 

Liu, J.a , Ren, L.b , Womer, F.Y.c , Wang, J.d , Fan, G.b , Jiang, W.e , Blumberg, H.P.a , Tang, Y.e , Xu, K.b , Wang, F.a b

Alterations in amplitude of low frequency fluctuation in treatment-naïve major depressive disorder measured with resting-state fMRI

(2014) Human Brain Mapping, . Article in Press.

a Department of Psychiatry Yale University School of Medicine New Haven, Connecticut

b Department of Radiology The First Affiliated Hospital of China Medical University Shenyang, Liaoning People's Republic of China

c Department of Psychiatry Washington University School of Medicine St. Louis, Missouri

d Center for Cognition and Brain Disorders and the Affiliated Hospital, Hangzhou Normal University Hangzhou, Zhejiang People's Republic of China

e Department of Psychiatry The First Affiliated Hospital of China Medical University Shenyang, Liaoning People's Republic of China

Abstract

There are limited resting-state functional magnetic resonance imaging (fMRI) studies in major depressive disorder (MDD). Of these studies, functional connectivity analyses are mostly used. However, a new method based on the magnitude of low frequency fluctuation (LFF) during resting-state fMRI may provide important insight into MDD. In this study, we examined the amplitude of LFF (ALFF) within the whole brain during resting-state fMRI in 30 treatment-naïve MDD subjects and 30 healthy control (HC) subjects. When compared with HC, MDD subjects showed increased ALFF in the frontal cortex (including the bilateral ventral/dorsal anterior cingulate cortex, orbitofrontal cortex, premotor cortex, ventral prefrontal cortex, left dorsal lateral frontal cortex, left superior frontal cortex), basal ganglia (including the right putamen and left caudate nucleus), left insular cortex, right anterior entorhinal cortex and left inferior parietal cortex, together with decreased ALFF in the bilateral occipital cortex, cerebellum hemisphere, and right superior temporal cortex. These findings may relate to characteristics of MDD, such as excessive self-referential processing and deficits in cognitive control of emotional processing, which may contribute to the persistent and recurrent nature of the disorder. © 2014 Wiley Periodicals, Inc.

 

Author Keywords

Amplitude of low-frequency fluctuation;  Cerebellum;  Depression;  Prefrontal cortex;  Resting-state fMRI

 

Document Type: Article in Press

Source: Scopus

 

 

Bear, K.A.a b , Solomon, B.D.a c d , Antonini, S.e , Arnhold, I.J.P.f , França, M.M.f , Gerkes, E.H.g , Grange, D.K.h , Hadley, D.W.a , Jääskeläinen, J.i , Paulo, S.S.e , Rump, P.g , Stratakis, C.A.j , Thompson, E.M.k l , Willis, M.m , Winder, T.L.n , Jorge, A.L.o , Roessler, E.a , Muenke, M.a

Pathogenic mutations in GLI2 cause a specific phenotype that is distinct from holoprosencephaly

(2014) Journal of Medical Genetics, . Article in Press.

a Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA

b Department of Pediatrics, Tripler Army Medical Center, Honolulu, Hawaii, USA

c Division of Medical Genomics, Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia, USA

d Department of Pediatrics, Inova Children's Hospital, Inova Health System, Falls Church, Virginia, USA

e Department of Pediatrics, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil

f Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42, Disciplina de Endocrinologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

g Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

h Washington University Schl Mdcn, St. Louis, Missouri, USA

i Department of Pediatrics, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland

j Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

k SA Pathology, South Australian Clinical Genetics Service, Women's and Children's Hospital, Adelaide, South Australia, Australia

l Department of Paediatrics, University of Adelaide, Adelaide, South Australia, Australia

m Department of Pediatrics, Clinical Genetics, Naval Medical Center, San Diego, California, USA

n Prevention Genetics, Marshfield, Wisconsin, USA

o Unidade de Endocrinologia Genética, LIM/25, Disciplina de Endocrinologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

Abstract

Background Mutations in GLI2 have been associated with holoprosencephaly (HPE), a neuroanatomic anomaly resulting from incomplete cleavage of the developing forebrain, and an HPE-like phenotype involving pituitary anomalies and polydactyly. Objective To characterise the genotypic and phenotypic findings in individuals with GLI2 variants and clarify clinical findings in individuals with loss-of-function mutations. Methods Through the National Institutes of Health and collaborating centres, ~400 individuals with HPE spectrum disorders, endocrine disorders or craniofacial anomalies were screened for GLI2 mutations. Results were combined with all published cases. We compared the clinical and molecular features of individuals with truncating mutations to individuals with variants of unknown significance (defined as not resulting in protein truncation, reported in normal controls and/or deemed unlikely to be pathogenic by functional prediction software). Results 112 individuals with variants in GLI2 were identified, with 43 having truncating mutations. Individuals with truncating mutations were more likely to have both pituitary anomalies and polydactyly versus those with variants of unknown significance (p<0.0001 by Fisher's exact test); only 1 of 43 had frank HPE. These individuals were more likely to have recognised penetrance (polydactyly or pituitary anomalies or both) than those without truncating mutations (p=0.0036 by Fisher's exact test). A common facial phenotype was seen in individuals (with midface hypoplasia, cleft lip/palate and hypotelorism) with truncating mutations. Conclusions Individuals with truncating mutations in GLI2 typically present with pituitary anomalies, polydactyly and subtle facial features rather than HPE. This will be helpful in screening populations for GLI2 mutations and for counselling affected patients. © 2014 by the BMJ Publishing Group Ltd.

 

Document Type: Article in Press

Source: Scopus

 

Chen, Y.-H., Gutmann, D.H.

The molecular and cell biology of pediatric low-grade gliomas

(2014) Oncogene, 33 (16), pp. 2019-2026. Cited 1 time.

Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St Louis, MO 63110, United States

 

Abstract

Pilocytic astrocytoma (PA) is the most common glial cell tumor arising in children. Sporadic cases are associated with KIAA1549:BRAF fusion rearrangements, while 15-20% of children develop PA in the context of the neurofibromatosis 1 (NF1) inherited tumor predisposition syndrome. The unique predilection of these tumors to form within the optic pathway and brainstem (NF1-PA) and cerebellum (sporadic PA) raises the possibility that gliomagenesis requires more than biallelic inactivation of the NF1 tumor suppressor gene or expression of the KIAA1549:BRAF transcript. Several etiologic explanations include differential susceptibilities of preneoplastic neuroglial cell types in different brain regions to these glioma-causing genetic changes, contributions from non-neoplastic cells and signals in the tumor microenvironment, and genomic modifiers that confer glioma risk. As clinically-faithful rodent models of sporadic PA are currently under development, Nf1 genetically-engineered mouse (GEM) models have served as tractable systems to study the role of the cell of origin, deregulated intracellular signaling, non-neoplastic cells in the tumor microenvironment and genomic modifiers in gliomagenesis. In this report, we highlight advances in Nf1-GEM modeling and review new experimental evidence that supports the emerging concept that Nf1- and KIAA1549:BRAF-induced gliomas arise from specific cell types in particular brain locations. © 2014 Macmillan Publishers Limited.

 

 

Author Keywords

astrocyte;  brain tumor;  genetically-engineered mice;  glioma;  neural stem cell;  pilocytic astrocytoma

 

Document Type: Review

Source: Scopus

 

Musiek, E.

Stopping seizures after brain injury

(2014) Science Translational Medicine, 6 (232), art. no. 232ec69, .

 

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

 

Document Type: Note

Source: Scopus

 

Bai, H.a , Yang, X.b , Temuribagena , Guilana , Suyalatua , Narisu, N.c , Wu, H.a , Chen, Y.a , Liu, Y.d , Wu, Q.b

A rare novel mutation in TECTA causes autosomal dominant nonsyndromic hearing loss in a Mongolian family

(2014) BMC Medical Genetics, 15 (1), art. no. 34, .

 

a Inner Mongolia University for the Nationalities, Tongliao, Inner 028000, Mongolia

b BGI-Shenzhen, Shenzhen, Guangdong 518083, China

c Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States

d Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract

Background: The genetic basis of autosomal dominant nonsyndromic hearing loss is complex. Genetic factors are responsible for approximately 50% of cases with congenital hearing loss. However, no previous studies have documented the clinical phenotype and genetic basis of autosomal dominant nonsyndromic hearing loss in Mongolians.Methods: In this study, we performed exon capture sequencing of a Mongolian family with hereditary hearing loss and identified a novel mutation in TECTA gene, which encodes α -tectorin, a major component of the inner ear extracellular matrix that contacts the specialized sensory hair cells.Results: The novel G → T missense mutation at nucleotide 6016 results in a substitution of amino acid aspartate at 2006 with tyrosine (Asp2006Tyr) in a highly conserved zona pellucida (ZP) domain of α-tectorin. The mutation is not found in control subjects from the same family with normal hearing and a genotype-phenotype correlation is observed.Conclusion: A novel missense mutation c.6016 G > T (p.Asp2006Tyr) of TECTA gene is a characteristic TECTA-related mutation which causes autosomal dominant nonsyndromic hearing loss. Our result indicated that mutation in TECTA gene is responsible for the hearing loss in this Mongolian family. © 2014 Bai et al.; licensee BioMed Central Ltd.

 

Author Keywords

Autosomal dominant nonsyndromic hearing loss;  Mongolian family;  TECTA gene

 

Document Type: Article

Source: Scopus

 

Chung, Y.S.a , Barch, D.a b , Strube, M.a

A meta-analysis of mentalizing impairments in adults with schizophrenia and autism spectrum disorder

(2014) Schizophrenia Bulletin, 40 (3), pp. 602-616. Cited 2 times.

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

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

Abstract

Mentalizing has been examined both in autism spectrum disorder (ASD) and schizophrenia (SCZ) primarily by either cognitive-linguistic (referred to as verbal) or emotion recognition from eyes (referred to as visual) mentalizing tasks. Each type of task is thought to measure different aspects of mentalizing. Differences in clinical features and developmental courses of each disorder may predict distinct patterns of mentalizing performance across dis orders on each type of task. To test this, a meta-analysis was conducted using 37 studies that assessed mentalizing either verbally or visually in adults with SCZ or ASD. We found that the estimated effect sizes of impairments in verbal and visual mentalizing tasks for both clinical groups were statistically large and at a similar level (overall Hedges' g = 0.73-1.05). For each disorder, adults with SCZ showed a trend towards larger impairments on verbal (overall Hedges' g = 0.99) than on visual mentalizing task (overall Hedges' g = 0.73; Qbet = 3.45, p =.06, df =1). Adults with ASD did not show different levels of impairment on the verbal versus visual tasks (Qbet = 0.08, p =.78, df =1). These results suggest that both clinical groups share, at least in part, some common cognitive processing deficits associated with mentalizing impairments. © The Author 2013. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.

 

Author Keywords

autism/social cognition;  mentalizing;  schizophrenia

 Document Type: Article

Source: Scopus

 

Moore, A.M.a , Novak, C.B.b

Advances in nerve transfer surgery

(2014) Journal of Hand Therapy, 27 (2), pp. 96-105.

a Division of Plastic and Reconstructive Surgery, Washington University, School of Medicine, St. Louis, MO, United States

b Hand and Upper Extremity Program, Division of Plastic and Reconstructive Surgery, University of Toronto, Toronto, ON, Canada

Abstract

Peripheral nerve injuries are devastating injuries and can result in physical impairments, poor functional outcomes and high levels of disability. Advances in our understanding of peripheral nerve regeneration and nerve topography have lead to the development of nerve transfers to restore function. Over the past two decades, nerve transfers have been performed and modified. With the advancements in surgical management and recognition of importance of cortical plasticity, motor-reeducation and perioperative rehabilitation, nerve transfers are producing improved functional outcomes in patients with nerve injuries. This manuscript explores the recent literature as it relates to current nerve transfer techniques and advances in post-operative rehabilitation protocols, with a focus on indications, techniques and outcomes. © 2014 Hanley & Belfus, an imprint of Elsevier Inc. All rights reserved.

 

Document Type: Article

Source: Scopus 

 

Wheatley, C.J.a , Carr, D.B.b , Marottoli, R.A.c

Consensus statements on driving for persons with dementia

(2014) Occupational Therapy in Health Care, 28 (2), pp. 132-139. Cited 1 time. 

a Driver Rehabilitation Specialist, Outpatient Rehabilitation Department, MedStar Good Samaritan Hospital, 5601 Loch Raven Blvd, Baltimore, MD 21239, United States

b Division of Geriatrics and Nutritional Science, Washington University at St. Louis, Rehabilitation Institute of St. Louis (TRISL), Parc Provence, 4488 Forest Park, St. Louis, MO, United States

c Yale University School of Medicine, VA Connecticut Healthcare System, PO Box 208025, New Haven, CT, United States

Abstract

The presence of dementia can have a profound effect on a person's capacity for driving, and will lead to eventual cessation of driving and reliance on alternative transportation options. This paper offers evidence and discussion that affirm eight consensus statements related to drivers with dementia and the impact of dementia on the driving task. These statements offer guidance for occupational therapy practitioners when addressing driving and community mobility, a valued instrumental task of daily living. © 2014 Informa Healthcare USA, Inc.

 

Author Keywords

Dementia;  Driving;  Instrumental activities of daily living

 

Document Type: Article

Source: Scopus

 

 

Tosoni, A.a b , Corbetta, M.c d e , Calluso, C.a b , Committeri, G.a b , Pezzulo, G.f , Romani, G.L.a b , Galati, G.g h

Decision and action planning signals in human posterior parietal cortex during delayed perceptual choices

(2014) European Journal of Neuroscience, 39 (8), pp. 1370-1383.

a Department of Neuroscience and Imaging, G. D'Annunzio University, Chieti, Italy

b Institute for Advanced Biomedical Technologies, G. D'Annunzio Foundation, Chieti, Italy

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

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

e Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO, United States

f Institute of Cognitive Sciences and Technologies, CNR, Roma, Italy

g Department of Psychology, Sapienza University of Rome, Roma, Italy

h Laboratory of Neuropsychology, Santa Lucia Foundation, Roma, Italy

 

Abstract

During simple perceptual decisions, sensorimotor neurons in monkey fronto-parietal cortex represent a decision variable that guides the transformation of sensory evidence into a motor response, supporting the view that mechanisms for decision-making are closely embedded within sensorimotor structures. Within these structures, however, decision signals can be dissociated from motor signals, thus indicating that sensorimotor neurons can play multiple and independent roles in decision-making and action selection/planning. Here we used functional magnetic resonance imaging to examine whether response-selective human brain areas encode signals for decision-making or action planning during a task requiring an arbitrary association between face pictures (male vs. female) and specific actions (saccadic eye vs. hand pointing movements). The stimuli were gradually unmasked to stretch the time necessary for decision, thus maximising the temporal separation between decision and action planning. Decision-related signals were measured in parietal and motor/premotor regions showing a preference for the planning/execution of saccadic or pointing movements. In a parietal reach region, decision-related signals were specific for the stimulus category associated with its preferred pointing response. By contrast, a saccade-selective posterior intraparietal sulcus region carried decision-related signals even when the task required a pointing response. Consistent signals were observed in the motor/premotor cortex. Whole-brain analyses indicated that, in our task, the most reliable decision signals were found in the same neural regions involved in response selection. However, decision- and action-related signals within these regions can be dissociated. Differences between the parietal reach region and posterior intraparietal sulcus plausibly depend on their functional specificity rather than on the task structure. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

 Author Keywords

Action planning;  Decision-making;  Delayed choice;  Evidence accumulation;  Stimulus unmasking

 

Document Type: Article

Source: Scopus

 

 

Greene, D.J.a b , Laumann, T.O.c , Dubis, J.W.c , Ihnen, S.K.c , Neta, M.c , Power, J.D.c , Pruett Jr., J.R.a , Black, K.J.a b c d , Schlaggar, B.L.b c d e

Developmental changes in the organization of functional connections between the basal ganglia and cerebral cortex

(2014) Journal of Neuroscience, 34 (17), pp. 5842-5854.

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States

b Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States

c Department of Neurology, 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

e Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract

The basal ganglia (BG) comprise a set of subcortical nuclei with sensorimotor, cognitive, and limbic subdivisions, indicative of functional organization. BG dysfunction in several developmental disorders suggests the importance of the healthy maturation of these structures. However, few studies have investigated the development of BG functional organization. Using resting-state functional connectivity MRI (rs-fcMRI), we compared human child and adult functional connectivity of the BG with rs-fcMRI-defined cortical systems. Because children move more than adults, customized preprocessing, including volume censoring, was used to minimize motion-induced rs-fcMRI artifact. Our results demonstrated functional organization in the adult BG consistent with subdivisions previously identified in anatomical tracing studies. Group comparisons revealed a developmental shift in bilateral posterior putamen/pallidum clusters from preferential connectivity with the somatomotor "face" system in childhood to preferential connectivity with control/attention systems (frontoparietal, ventral attention) in adulthood. This shift was due to a decline in the functional connectivity of these clusters with the somatomotor face system over development, and no change with control/attention systems. Applying multivariate pattern analysis, we were able to reliably classify individuals as children or adults based on BG-cortical system functional connectivity. Interrogation of the features driving this classification revealed, in addition to the somatomotor face system, contributions by the orbitofrontal, auditory, and somatomotor hand systems. These results demonstrate that BG-cortical functional connectivity evolves over development, and may lend insight into developmental disorders that involve BG dysfunction, particularly those involving motor systems (e.g., Tourette syndrome). © 2014 the authors.

 

Author Keywords

Basal ganglia;  Development;  Functional connectivity;  Resting state

Document Type: Article

Source: Scopus

 

 

Segal, M.M.a , Williams, M.S.b , Gropman, A.L.c , Torres, A.R.d , Forsyth, R.e , Connolly, A.M.f , El-Hattab, A.W.g , Perlman, S.J.f , Samanta, D.h , Parikh, S.i , Pavlakis, S.G.j , Feldman, L.K.a , Betensky, R.A.k , Gospe, S.M.l

Evidence-based decision support for neurological diagnosis reduces errors and unnecessary workup

(2014) Journal of Child Neurology, 29 (4), pp. 487-492.

a SimulConsult, 27 Crafts Road, Chestnut Hill, MA 02467, United States

b Genomic Medicine Institute, Geisinger Health System, Danville, PA, United States

c Neurogenetics Program, Children's National Medical Center, Washington, DC, United States

d Department of Neurology, Children's Hospital, Boston, MA, United States

e Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, United Kingdom

f Departments of Neurology and Pediatrics, Washington University, St Louis, MO, United States

g Department of Pediatrics, Children's Hospital, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia

h Department of Pediatrics, University of Virginia, Charlottesville, VA, United States

i Neurogenetics and Neurometabolism Program, Neurologic Institute, Cleveland Clinic, Cleveland, OH, United States

j Center for Brain and Behavior, Maimonides Medical Center, Brooklyn, NY, United States

k Department of Biostatistics, Harvard School of Public Health, Boston, MA, United States

l Departments of Neurology and Pediatrics, University of Washington, Seattle, WA, United States

Abstract

Using vignettes of real cases and the SimulConsult diagnostic decision support software, neurologists listed a differential diagnosis and workup before and after using the decision support. Using the software, there was a significant reduction in error, up to 75% for diagnosis and 56% for workup. This error reduction occurred despite the baseline being one in which testers were allowed to use narrative resources and Web searching. A key factor that improved performance was taking enough time (>2 minutes) to enter clinical findings into the software accurately. Under these conditions and for instances in which the diagnoses changed based on using the software, diagnostic accuracy improved in 96% of instances. There was a 6% decrease in the number of workup items accompanied by a 34% increase in relevance. The authors conclude that decision support for a neurological diagnosis can reduce errors and save on unnecessary testing. © The Author(s) 2013.

 Author Keywords

decision support;  diagnosis;  errors;  genetics;  medical informatics;  neurogenetics

 Document Type: Article

Source: Scopus

 

Stein, L.R.a , Wozniak, D.F.b c , Dearborn, J.T.b , Kubota, S.d , Apte, R.S.a d , Izumi, Y.b c , Zorumski, C.F.b e , Imai, S.-I.a

Expression of nampt in hippocampal and cortical excitatory neurons is critical for cognitive function

(2014) Journal of Neuroscience, 34 (17), pp. 5800-5815.

a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States

b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States

c The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO 63110, United States

d Department of Ophthalmology, Washington University School of Medicine, St. Louis, MO 63110, United States

e Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract

Nicotinamide adenine dinucleotide (NAD+) is an enzyme cofactor or cosubstrate in many essential biological pathways. To date, the primary source of neuronal NAD+ has been unclear. NAD+ can be synthesized from several different precursors, among which nicotinamide is the substrate predominantly used in mammals. The rate-limiting step in the NAD+ biosynthetic pathway from nicotinamide is performed by nicotinamide phosphoribosyltransferase (Nampt). Here, we tested the hypothesis that neurons use intracellular Namptmediated NAD+ biosynthesis by generating and evaluating mice lacking Nampt in forebrain excitatory neurons (CaMKIIαNampt-/- mice). CaMKIIαNampt-/- mice showed hippocampal and cortical atrophy, astrogliosis, microgliosis, and abnormal CA1 dendritic morphology by 2-3 months of age. Importantly, these histological changes occurred with altered intrahippocampal connectivity and abnormal behavior; including hyperactivity, some defects in motor skills, memory impairment, and reduced anxiety, but in the absence of impaired sensory processes or long-term potentiation of the Schaffer collateral pathway. These results clearly demonstrate that forebrain excitatory neurons mainly use intracellular Nampt-mediated NAD+ biosynthesis to mediate their survival and function. Studying this particular NAD+ biosynthetic pathway in these neurons provides critical insight into their vulnerability to pathophysiological stimuli and the development of therapeutic and preventive interventions for their preservation. © 2014 the authors.

Author Keywords

CA1;  Cognition;  Hippocampus;  Nampt

 Document Type: Article

Source: Scopus

 

Loukola, A.a , Wedenoja, J.a , Keskitalo-Vuokko, K.a , Broms, U.a b , Korhonen, T.a b , Ripatti, S.b c d , Sarin, A.-P.b c , Pitkäniemi, J.a , He, L.a , Häppölä, A.a , Heikkilä, K.a , Chou, Y.-L.e , Pergadia, M.L.e , Heath, A.C.e , Montgomery, G.W.f , Martin, N.G.f , Madden, P.A.F.e , Kaprio, J.a b c

Genome-wide association study on detailed profiles of smoking behavior and nicotine dependence in a twin sample

(2014) Molecular Psychiatry, 19 (5), pp. 615-624. Cited 1 time.

a Department of Public Health, Hjelt Institute, University of Helsinki, PO Box 41, Helsinki FI-00014, Finland

b National Institute for Health and Welfare, Helsinki, Finland

c Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland

d Wellcome Trust Sanger Institute, Cambridge, United Kingdom

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

f Queensland Institute of Medical Research, Brisbane, QLD, Australia

Abstract

Smoking is a major risk factor for several somatic diseases and is also emerging as a causal factor for neuropsychiatric disorders. Genome-wide association (GWA) and candidate gene studies for smoking behavior and nicotine dependence (ND) have disclosed too few predisposing variants to account for the high estimated heritability. Previous large-scale GWA studies have had very limited phenotypic definitions of relevance to smoking-related behavior, which has likely impeded the discovery of genetic effects. We performed GWA analyses on 1114 adult twins ascertained for ever smoking from the population-based Finnish Twin Cohort study. The availability of 17 smoking-related phenotypes allowed us to comprehensively portray the dimensions of smoking behavior, clustered into the domains of smoking initiation, amount smoked and ND. Our results highlight a locus on 16p12.3, with several single-nucleotide polymorphisms (SNPs) in the vicinity of CLEC19A showing association (P<1 × 10-6) with smoking quantity. Interestingly, CLEC19A is located close to a previously reported attention-deficit hyperactivity disorder (ADHD) linkage locus and an evident link between ADHD and smoking has been established. Intriguing preliminary association (P<1 × 10-5) was detected between DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) ND diagnosis and several SNPs in ERBB4, coding for a Neuregulin receptor, on 2q33. The association between ERBB4 and DSM-IV ND diagnosis was replicated in an independent Australian sample. Recently, a significant increase in ErbB4 and Neuregulin 3 (Nrg3) expression was revealed following chronic nicotine exposure and withdrawal in mice and an association between NRG3 SNPs and smoking cessation success was detected in a clinical trial. ERBB4 has previously been associated with schizophrenia; further, it is located within an established schizophrenia linkage locus and within a linkage locus for a smoker phenotype identified in this sample. In conclusion, we disclose novel tentative evidence for the involvement of ERBB4 in ND, suggesting the involvement of the Neuregulin/ErbB signalling pathway in addictions and providing a plausible link between the high co-morbidity of schizophrenia and ND.

 

Author Keywords

ADHD;  genome-wide association analysis;  nicotine dependence;  schizophrenia;  smoking behavior;  smoking quantity

Document Type: Article

Source: Scopus

 

Dowling, M.M.a , Noetzel, M.J.b , Rodeghier, M.J.c , Quinn, C.T.d , Hirtz, D.G.e , Ichord, R.N.f , Kwiatkowski, J.L.f , Roach, E.S.g , Kirkham, F.J.h , Casella, J.F.i , Debaun, M.R.j

Headache and migraine in children with sickle cell disease are associated with lower hemoglobin and higher pain event rates but not silent cerebral infarction

(2014) Journal of Pediatrics, 164 (5), pp. 1175-1180.e4.

a Department of Pediatrics and Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, United States

b Department of Neurology, St Louis Children's Hospital, Washington University School of Medicine, St Louis, MO, United States

c Rodeghier Consultants, Chicago, IL, United States

d Division of Hematology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States

e National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States

f Department of Neurology and Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, United States

g Division of Child Neurology, Ohio State College of Medicine, Columbus, OH, United States

h Neurosciences Unit, Institute of Child Health, University College London, London, United Kingdom

i Division of Pediatric Hematology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States

j Department of Pediatrics Vanderbilt-Meharry-Matthew, Walker Center of Excellence in Sickle Cell Disease, Vanderbilt University School of Medicine, Nashville, TN, United States

 

Abstract

Objective To identify risk factors for headache and migraine in children with sickle cell disease and test the hypothesis that either or both are independently associated with silent cerebral infarcts. Study design In this cross-sectional study, we evaluated the health history, laboratory values, and brain magnetic resonance imaging findings of participants with sickle cell disease (hemoglobinSS or hemoglobinSβ°-thalassemia) with no history of overt stroke or seizures. Participants characterized headache severity and quality. Migraine was defined by International Headache Society criteria modified for increased sensitivity in children. Neuroradiology and neurology committees adjudicated the presence of silent cerebral infarction by review of magnetic resonance imaging and standardized examination by pediatric neurologists. Results The cohort included 872 children (51.1% males), ranging in age from 5 to 15 years (mean age, 9.1 years). Of these children, 317 (36.4%) reported recurrent headaches, and 132 (15.1%) reported migraines. In multivariable logistic regression analyses, both were associated with lower steady-state hemoglobin (P =.01 for headaches; P <.01 for migraines) and higher pain rate (P <.01 for headaches; P <.01 for migraines), defined as the number of admissions requiring opioids in the previous 3 years. The presence of silent cerebral infarction was not associated with recurrent headaches or migraines. Only 1.9% (6 of 317) of children with recurrent headaches received medication for headache prophylaxis. Conclusion Recurrent headaches and migraines are common and undertreated in children with sickle cell disease. Low hemoglobin levels and high pain rates are associated with recurrent headaches and migraines; whereas, silent cerebral infarction is not. © 2014 The Authors.

 

Author Keywords

ACS;  Acute chest syndrome;  CBF;  Cerebral blood flow;  Hemoglobin;  Hgb;  Magnetic resonance imaging;  MRI;  SCD;  Sickle cell disease;  Silent Cerebral Infarct Transfusion;  SIT;  TCD;  Transcranial Doppler ultrasound;  Variance inflation factor;  VIF

 

Document Type: Article

Source: Scopus

 

He, Y.a , Brunstrom-Hernandez, J.E.b , Thio, L.L.b , Lackey, S.c , Gaebler-Spira, D.d e , Kuroda, M.M.e , Stashinko, E.f , Hoon Jr., A.H.f , Vargus-Adams, J.g , Stevenson, R.D.h , Lowenhaupt, S.i , McLaughlin, J.F.j , Christensen, A.j , Dosa, N.P.k , Butler, M.l , Schwabe, A.m , Lopez, C.n , Roge, D.o , Kennedy, D.o , Tilton, A.p , Krach, L.E.q , Lewandowski, A.r , Dai, H.s , Gaedigk, A.t , Leeder, J.S.t , Jusko, W.J.a

Population pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy

 (2014) Journal of Pediatrics, 164 (5), pp. 1181-1188.e8.

a Department of Pharmaceutical Sciences, University at Buffalo SUNY, 404 Kapoor Hall, Buffalo, NY 14214, United States

b Departments of Neurology and Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO, United States

c Department of Urology, St. Louis Children's Hospital, St. Louis, MO, United States

d Rehabilitation Institute of Chicago, Feinberg School of Medicine at Northwestern University, Chicago, IL, United States

e Department of Physical Medicine and Rehabilitation, Feinberg School of Medicine at Northwestern University, Chicago, IL, United States

f Department of Neurology and Developmental Medicine, Kennedy Krieger Institute and Johns Hopkins University, Baltimore, MD, United States

g Division of Pediatric Rehabilitation, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, United States

h Department of Pediatrics-Developmental Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, United States

i Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, United States

j Department of Pediatrics Developmental Medicine, Seattle Children's Hospital, Seattle, WA, United States

k Center for Development, Behavior and Genetics, SUNY Upstate Medical University, Syracuse, NY, United States

l Department of Pediatrics, SUNY Upstate Medical University, Syracuse, NY, United States

m Department of Physical Medicine and Rehabilitation, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, United States

n Department of Pediatric Neurology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, United States

o Department of Rehabilitation Medicine, Children's Mercy Hospital, Kansas City, MO, United States

p Department of Neurology and Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA, United States

q Department of Physical Medicine and Rehabilitation, University of Minnesota, Minneapolis, MN, United States

r EMMES Corporation, Rockville, MD, United States

s Department of Medical Research, Children's Mercy Hospitals and Clinics, Kansas City, MO, United States

t Division of Clinical Pharmacology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, MO, United States

Abstract

Objective To characterize the population pharmacokinetics (PK) of oral baclofen and assess impact of patient-specific covariates in children with cerebral palsy (CP) in order to support its clinical use. Subjects design Children (2-17 years of age) with CP received a dose of titrated oral baclofen from 2.5 mg 3 times a day to a maximum tolerated dose of up to 20 mg 4 times a day. PK sampling followed titration of 10-12 weeks. Serial R- and S-baclofen plasma concentrations were measured for up to 16 hours in 49 subjects. Population PK modeling was performed using NONMEM 7.1 (ICON PLC; Ellicott City, Maryland). Results R- and S-baclofen showed identical concentration-time profiles. Both baclofen enantiomers exhibited linear and dose/kg-proportional PK, and no sex differences were observed. Average baclofen terminal half-life was 4.5 hours. A 2-compartment PK model with linear elimination and transit absorption steps adequately described concentration-time profiles of both baclofen enantiomers. The mean population estimate of apparent clearance/F was 0.273 L/h/kg with 33.4% inter-individual variability (IIV), and the apparent volume of distribution (Vss/F) was 1.16 L/kg with 43.9% IIV. Delayed absorption was expressed by a mean transit time of 0.389 hours with 83.7% IIV. Body weight, a possible genetic factor, and age were determinants of apparent clearance in these children. Conclusion The PK of oral baclofen exhibited dose-proportionality and were adequately described by a 2-compartment model. Our population PK findings suggest that baclofen dosage can be based on body weight (2 mg/kg per day) and the current baclofen dose escalation strategy is appropriate in the treatment of children with CP older than 2 years of age. © 2014 The Authors.

 

Author Keywords

3 times a day;  4 times a day;  Area under the curve within the dosing interval;  AUCτ;  Body weight in kg;  Bootstrap;  BS;  Cerebral palsy;  CL;  Clearance;  CP;  Creatinine clearance;  GAGE;  Gastroesophageal reflux disease;  GERD;  Gestational age;  IIV;  Inter-individual variability;  Mean transit time;  MTT;  NCA;  Noncompartmental analysis;  PG;  Pharmacogenomics;  Pharmacokinetics;  PK;  PopPK;  Population pharmacokinetics;  QID;  Single-nucleotide polymorphism;  SNP;  Standardized visual predictive check;  SVPC;  TDOS;  TID;  Total daily dose;  WTKG

 

Document Type: Article

Source: Scopus

 

Leuthardt, E.C., Hawasli, A.H.

Response to journal club: Magnetic resonance imaging-guided focused laser interstitial thermal therapy for intracranial lesions: Single-institution series

(2014) Neurosurgery, 74 (5), p. 565.

 Department of Neurosurgery, Washington University School of Medicine, Campus Box 8057, 660 South Euclid, St. Louis, MO 63130., United States

 

Document Type: Note

Source: Scopus

 

 

Lai, H.H.a b , Gardner, V.a , Ness, T.J.c , Gereau IV, R.W.b

Segmental hyperalgesia to mechanical stimulus in interstitial cystitis/bladder pain syndrome: Evidence of central sensitization

(2014) Journal of Urology, 191 (5), pp. 1294-1299.

a Division of Urologic Surgery, Department of Surgery, Washington University School of Medicine, 4960 Children's Place, St. Louis, MO 63110, United States

b Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, United States

c Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL, United States

Abstract

Purpose We investigate if subjects with interstitial cystitis/bladder pain syndrome demonstrate mechanical or thermal hyperalgesia, and whether the hyperalgesia is segmental or generalized (global). Materials and Methods Ten female subjects with interstitial cystitis/bladder pain syndrome and 10 age matched female controls without comorbid fibromyalgia or narcotic use were recruited for quantitative sensory testing. Using the method of limits, pressure pain and heat pain thresholds were measured. Using the method of fixed stimulus, the visual analog scale pain experienced was recorded when a fixed pressure/temperature was applied. Results The visual analog scale pain rated by female subjects with interstitial cystitis/bladder pain syndrome was significantly higher than that rated by female control subjects when a fixed mechanical pressure (2 or 4 kg) was applied to the suprapubic (T11) area (p = 0.028). There was an up shift of the stimulus-response curve, which corresponded to the presence of mechanical hyperalgesia in the suprapubic area in interstitial cystitis/bladder pain syndrome. However, the visual analog scale pain rated by subjects with interstitial cystitis/bladder pain syndrome was not different from that rated by controls when a fixed pressure was applied at the other body sites (T1 arm, L4 leg, S2-3 sacral). No difference in visual analog scale pain rating was noted when a fixed heat stimulus (35C or 37C) was applied to any of the body sites tested (T1, T11, L4, S2). There was no difference in pressure pain thresholds or thermal pain thresholds between subjects with interstitial cystitis/bladder pain syndrome and controls. Conclusions Female subjects with interstitial cystitis/bladder pain syndrome showed segmental hyperalgesia to mechanical pressure stimulation in the suprapubic area (T10-T12). This segmental hyperalgesia may be explained in part by spinal central sensitization. © 2014 by American Urological Association Education and Research, Inc.

 

Author Keywords

central nervous system sensitization;  cystitis;  hyperalgesia;  interstitial;  pain measurement

Document Type: Article

Source: Scopus

 

 

Marrus, N.a , Veenstra-Vanderweele, J.b , Hellings, J.A.c , Stigler, K.A.d , Szymanski, L.e , King, B.H.f , Carlisle, L.L.f , Cook Jr., E.H.g , Pruett, J.R.a , Azeem, M.W.h , Barnhill Jr., L.J.h , Friedman, N.h , Grelotti, D.h , Gurumurthy, S.h , Handler, R.h , Joshi, G.h , Kim, S.-J.h , Kornhaber, A.h , Liu, S.h , Mao, A.h , Siegel, M.h , Sikich, L.h , Tsappis, M.W.h

Training of child and adolescent psychiatry fellows in autism and intellectual disability

(2014) Autism, 18 (4), pp. 471-475.

a Department of Psychiatry, School of Medicine, Washington University, 660 South Euclid Avenue, Box 8134, St. Louis, MO 63110, United States

b Vanderbilt University, United States

c Ohio State University, Nisonger Center, United States

d Indiana University, School of Medicine, United States

e Boston Children's Hospital, United States

f University of Washington, School of Medicine, Seattle Children's Hospital, United States

g University of Illinois at Chicago, United States

Abstract

Patients with autism spectrum disorders and intellectual disability can be clinically complex and often have limited access to psychiatric care. Because little is known about post-graduate clinical education in autism spectrum disorder and intellectual disability, we surveyed training directors of child and adolescent psychiatry fellowship programs. On average, child and adolescent psychiatry directors reported lectures of 3 and 4 h per year in autism spectrum disorder and intellectual disability, respectively. Training directors commonly reported that trainees see 1-5 patients with autism spectrum disorder or intellectual disability per year for outpatient pharmacological management and inpatient treatment. Overall, 43% of directors endorsed the need for additional resources for training in autism spectrum disorder and intellectual disability, which, coupled with low didactic and clinical exposure, suggests that current training is inadequate. © 2013 The Author(s).

 

Author Keywords

autism;  education;  fellowship training;  intellectual disability

 

Document Type: Article

 

Source: Scopus

 

May 5, 2014

Harari, O.a , Cruchaga, C.a g , Kauwe, J.S.K.i , Ainscough, B.J.h , Bales, K.j , Pickering, E.H.j , Bertelsen, S.a , Fagan, A.M.b f g , Holtzman, D.M.b e f g , Morris, J.C.b c f g , Goate, A.M.a b d f g Phosphorylated tau-Aβ42 ratio as a continuous trait for biomarker discovery for early-stage Alzheimer's disease in multiplex immunoassay panels of cerebrospinal fluid  (2014) Biological Psychiatry, 75 (9), pp. 723-731.

 

a Department of Psychiatry, Washington University School of Medicine, 425 S. Euclid Avenue, St. Louis, MO 63110, 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 Genetics, Washington University School of Medicine, St. Louis, MO, United States

e Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States

f Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States

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

h Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, United States

i Department of Biology, Brigham Young University, Provo, UT, United States

j Neuroscience Research Unit, Worldwide Research and Development, Pfizer, Inc., Groton, CT, United States

 

 

Abstract

Background Identification of the physiologic changes that occur during the early stages of Alzheimer's disease (AD) may provide critical insights for the diagnosis, prognosis, and treatment of disease. Cerebrospinal fluid (CSF) biomarkers are a rich source of information that reflect the brain proteome. Methods A novel approach was applied to screen a panel of ~190 CSF analytes quantified by multiplex immunoassay, and common associations were detected in the Knight Alzheimer's Disease Research Center (N = 311) and the Alzheimer's Disease Neuroimaging Initiative (N = 293) cohorts. Rather than case-control status, the ratio of CSF levels of tau phosphorylated at threonine 181 (ptau181) and Aβ42 was used as a continuous trait in these analyses. Results The ptau181-Aβ42 ratio has more statistical power than traditional modeling approaches, and the levels of CSF heart-type fatty acid binding protein (FABP) and 12 other correlated analytes increase as AD progresses. These results were validated using the traditional case-control status model. Stratification of the dataset demonstrated that increases in these analytes occur very early in the disease course and were apparent even in nondemented individuals with AD pathology (low ptau181, low Aβ42) compared with elderly control subjects with no pathology (low ptau181, high Aβ42). The FABP-Aβ42 ratio demonstrates a similar hazard ratio for disease conversion to ptau181-Aβ42 even though the overlap in classification is incomplete suggesting that FABP contributes independent information as a predictor of AD. Conclusions Our results indicate that the approach presented here can be used to identify novel biomarkers for AD correctly and that CSF heart FABP levels start to increase at very early stages of AD. © 2014 Society of Biological Psychiatry.

 

 

Author Keywords

Alzheimer's disease;  biomarkers;  brain proteome - Rules Based Medicine Discovery Multi-Analyte Profile 1.0;  cerebrospinal fluid (CSF);  heart-type fatty acid binding protein

 

Document Type: Article

Source: Scopus

 

 

Shin, S.a , Walz, K.A.a , Archambault, A.S.a , Sim, J.b , Bollman, B.P.a , Koenigsknecht-Talboo, J.a , Cross, A.H.a c , Holtzman, D.M.a b c , Wu, G.F.a c d

Apolipoprotein E mediation of neuro-inflammation in a murine model of multiple sclerosis

(2014) Journal of Neuroimmunology, . Article in Press.

 

a Department of Neurology, Washington University in St. Louis School of Medicine, Box 8111, 660 S. Euclid Avenue, St. Louis, MO 63110, United States

b Department of Developmental Biology, Washington University in St. Louis School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States

c Hope Center for Neurological Disorders, Washington University in St. Louis School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States

d Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States

 

 

Abstract

Apolipoprotein E (ApoE) functions as a ligand in receptor-mediated endocytosis of lipoprotein particles and has been demonstrated to play a role in antigen presentation. To explore the contribution of ApoE during autoimmune central nervous system (CNS) demyelination, we examined the clinical, cellular immune function, and pathologic consequences of experimental autoimmune encephalomyelitis (EAE) induction in ApoE knockout (ApoE-/-) mice. We observed reduced clinical severity of EAE in ApoE-/- mice in comparison to WT mice that was concomitant with an early reduction of dendritic cells (DCs) followed by a reduction of additional innate cells in the spinal cord at the peak of disease without any differences in axonal damage. While T cell priming was enhanced in ApoE-/- mice, reduced severity of EAE was also observed in ApoE-/- recipients of encephalitogenic wild type T cells. Expression of ApoE during EAE was elevated within the CNS of wild type mice, particularly by innate cells such as DCs. Overall, ApoE promotes clinical EAE, likely by mediation of inflammation localized within the CNS. © 2014 Elsevier B.V. All rights reserved.

 

 

Author Keywords

Antigen presentation;  Apolipoprotein E;  Dendritic cells;  EAE

 

Document Type: Article in Press

Source: Scopus

 

Imai, S.-i.a , Guarente, L.b c d

NAD+ and sirtuins in aging and disease

(2014) Trends in Cell Biology, . Article in Press.

 

a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA

b Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

c Glenn Laboratory for the Science of Aging, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

d Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

 

 

Abstract

Nicotinamide adenine dinucleotide (NAD+) is a classical coenzyme mediating many redox reactions. NAD+ also plays an important role in the regulation of NAD+-consuming enzymes, including sirtuins, poly-ADP-ribose polymerases (PARPs), and CD38/157 ectoenzymes. NAD+ biosynthesis, particularly mediated by nicotinamide phosphoribosyltransferase (NAMPT), and SIRT1 function together to regulate metabolism and circadian rhythm. NAD+ levels decline during the aging process and may be an Achilles' heel, causing defects in nuclear and mitochondrial functions and resulting in many age-associated pathologies. Restoring NAD+ by supplementing NAD+ intermediates can dramatically ameliorate these age-associated functional defects, counteracting many diseases of aging, including neurodegenerative diseases. Thus, the combination of sirtuin activation and NAD+ intermediate supplementation may be an effective antiaging intervention, providing hope to aging societies worldwide. © 2014 Elsevier Ltd. All rights reserved.

 

 

Author Keywords

NAD+;  nicotinamide mononucleotide;  nicotinamide phosphoribosyltransferase;  nicotinamide riboside;  poly-ADP-ribose polymerases;  sirtuins

 

Document Type: Article in Press

Source: Scopus

 

Bedont, JosephL.a , LeGates, TaraA.h , Slat, EmilyA.i , Byerly, MardiS.c , Wang, H.a , Hu, J.b , Rupp, AlanC.h , Qian, J.b , Wong, G. .c f , Herzog, ErikD.i , Hattar, S.a h , Blackshaw, S.a b c d e g

Lhx1 Controls Terminal Differentiation and Circadian Function of the Suprachiasmatic Nucleus

(2014) Cell Reports, . Article in Press.

 

 

a Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

b Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

c Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

d Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

e Center for High-Throughput Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

f Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

g Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

h Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA

i Department of Biology, Washington University, St. Louis, MO 63130, USA

 

 

Abstract

Vertebrate circadian rhythms are organized by the hypothalamic suprachiasmatic nucleus (SCN). Despite its physiological importance, SCN development is poorly understood. Here, we show that Lim homeodomain transcription factor 1 (Lhx1) is essential for terminal differentiation and function of the SCN. Deletion of Lhx1 in the developing SCN results in loss of SCN-enriched neuropeptides involved in synchronization and coupling to downstream oscillators, among other aspects of circadian function. Intact, albeit damped, clock gene expression rhythms persist in Lhx1-deficient SCN; however, circadian activity rhythms are highly disorganized and susceptible to surprising changes in period, phase, and consolidation following neuropeptide infusion. Our results identify a factor required for SCN terminal differentiation. In addition, our in vivo study of combinatorial SCN neuropeptide disruption uncovered synergies among SCN-enriched neuropeptides in regulating normal circadian function. These animals provide a platform for studying the central oscillator's role in physiology and cognition. © 2014 The Authors.

 

 

Document Type: Article in Press

Source: Scopus

 

Wagner, J.M.a , Kremer, T.R.b , Van Dillen, L.R.c , Naismith, R.T.d

Plantarflexor Weakness Negatively Impacts Walking in Persons With Multiple Sclerosis More Than Plantarflexor Spasticity

(2014) Archives of Physical Medicine and Rehabilitation, . Article in Press.

 

a Program in Physical Therapy, Department of Physical Therapy and Athletic Training, Doisy College of Health Sciences, Saint Louis University, St Louis, MO

b School of Medicine, Saint Louis University, St Louis, MO

c Program in Physical Therapy, Washington University School of Medicine, St Louis, MO

d Department of Neurology, Washington University School of Medicine, St Louis, MO

 

 

Abstract

Objectives: To determine whether plantarflexor (PF) spasticity or ankle strength best predicts variance in walking capacity or self-perceived limitations in walking in persons with multiple sclerosis (MS) and whether persons with MS with PF spasticity are weaker and have greater walking dysfunction than do persons with MS without PF spasticity. Design: Cross-sectional study. Setting: University research laboratory. Participants: Forty-two adults with MS (mean age, 42.9±10.1y; Expanded Disability Status Scale score, median=3.0, range=0-6) and 14 adults without disability (mean age, 41.9±10.1y). Intervention: Not applicable. Main Outcome Measures: PF spasticity and dorsiflexion and PF maximum voluntary isometric torque were assessed using the modified Ashworth Scale and a computerized dynamometer, respectively. The Timed 25-Foot Walk Test was the primary outcome measure of walking capacity. Secondary measures included the 6-Minute Walk Test and the 12-item Multiple Sclerosis Walking Scale. Results: PF strength was the most consistent predictor of variance in walking capacity (Timed 25-Foot Walk Test: R2 change=.23-.29, P≤.001; 6-Minute Walk Test: R2 change=.12-.29, P≤.012), and self-perceived limitations of walking (12-item Multiple Sclerosis Walking Scale: R2 change=.04-.14, P&lt;.18). There were no significant differences (P&gt;.05) between persons with MS with PF spasticity and persons with MS without PF spasticity for any of the outcome measures. Conclusions: Our study suggests a unique contribution of PF weakness to walking dysfunction in persons with MS, and highlights the importance of evaluating PF strength in this clinical population. © 2014 American Congress of Rehabilitation Medicine.

 

Author Keywords

Ankle;  Multiple sclerosis;  Muscle spasticity;  Muscle strength dynamometer;  Rehabilitation;  Walking

 

Document Type: Article in Press

Source: Scopus

 

 

Black, K.J.a , Jankovic, J.b , Hershey, T.c , McNaught, K.St.P.d , Mink, J.W.e , Walkup, J.f

Progress in research on Tourette syndrome

(2014) Journal of Obsessive-Compulsive and Related Disorders, . Article in Press.

 

 

a Departments of Psychiatry, Neurology, Radiology, and Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States

b Department of Neurology, Baylor College of Medicine, Houston, TX, United States

c Departments of Psychiatry, Neurology, and Radiology, Washington University School of Medicine, and Department of Psychology, Washington University, St. Louis, MO, United States

d Tourette Syndrome Association, Bayside, New York, NY, United States

e Departments of Neurology, Neurobiology and Anatomy, Brain and Cognitive Sciences, and Pediatrics, University of Rochester, Rochester, NY, United States

f Division of Child and Adolescent Psychiatry, Department of Psychiatry, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, NY, United States

 

 

Abstract

Tourette syndrome (TS) is a heritable neuropsychiatric disorder commonly complicated by obsessions and compulsions, but defined by frequent unwanted movements (motor tics) and vocalizations (phonic tics) that develop in childhood or adolescence. In recent years, research on TS has progressed rapidly on several fronts. Inspired by the Fifth International Scientific Symposium on Tourette Syndrome, the articles in this special issue review advances in the phenomenology, epidemiology, genetics, pathophysiology, and treatment of TS. © 2014 Elsevier Ltd. All rights reserved.

 

 

Author Keywords

Epidemiology;  Genetics;  Nosology;  Pathophysiology;  Phenomenology;  Research;  Review;  Tourette syndrome;  Treatment

 

Document Type: Article in Press

Source: Scopus

 

Weeke, P.a b , Mosley, J.D.a , Hanna, D.c , Delaney, J.T.a , Shaffer, C.a , Wells, Q.S.a , Van Driest, S.d , Karnes, J.H.a , Ingram, C.a , Guo, Y.e , Shyr, Y.e , Norris, K.a , Kannankeril, P.J.d , Ramirez, A.H.a , Smith, J.D.c , Mardis, E.R.f , Nickerson, D.c , George Jr., A.L.g , Roden, D.M.g

Exome sequencing implicates an increased burden of rare potassium channel variants in the risk of drug-induced long QT interval syndrome

(2014) Journal of the American College of Cardiology, 63 (14), pp. 1430-1437. Cited 1 time.

 

 

a Department of Medicine, Vanderbilt University, Nashville, TN, United States

b Department of Cardiology, Copenhagen University Hospital, Gentofte, Denmark

c Department of Genome Sciences, University of Washington, Seattle, WA, United States

d Department of Pediatrics, Vanderbilt University, School of Medicine, Nashville, TN, United States

e Vanderbilt Technologies for Advanced Genomics Analysis and Research Design, Nashville, TN, United States

f Genome Institute, Washington University, St. Louis, MO, United States

g Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, TN, United States

 

 

Abstract

Objectives The aim of this study was to test the hypothesis that rare variants are associated with drug-induced long QT interval syndrome (diLQTS) and torsades de pointes. Background diLQTS is associated with the potentially fatal arrhythmia torsades de pointes. The contribution of rare genetic variants to the underlying genetic framework predisposing to diLQTS has not been systematically examined. Methods We performed whole-exome sequencing on 65 diLQTS patients and 148 drug-exposed control subjects of European descent. We used rare variant analyses (variable threshold and sequence kernel association test) and gene-set analyses to identify genes enriched with rare amino acid coding (AAC) variants associated with diLQTS. Significant associations were reanalyzed by comparing diLQTS patients with 515 ethnically matched control subjects from the National Heart, Lung, and Blood Grand Opportunity Exome Sequencing Project. Results Rare variants in 7 genes were enriched in the diLQTS patients according to the sequence kernel association test or variable threshold compared with drug-exposed controls (p < 0.001). Of these, we replicated the diLQTS associations for KCNE1 and ACN9 using 515 Exome Sequencing Project control subjects (p < 0.05). A total of 37% of the diLQTS patients also had 1 or more rare AAC variants compared with 21% of control subjects (p = 0.009), in a pre-defined set of 7 congenital long QT interval syndrome (cLQTS) genes encoding potassium channels or channel modulators (KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1, AKAP9). Conclusions By combining whole-exome sequencing with aggregated rare variant analyses, we implicate rare variants in KCNE1 and ACN9 as risk factors for diLQTS. Moreover, diLQTS patients were more burdened by rare AAC variants in cLQTS genes encoding potassium channel modulators, supporting the idea that multiple rare variants, notably across cLQTS genes, predispose to diLQTS.

 

Author Keywords

adverse drug event;  exome;  genetics;  long QT interval syndrome;  torsade des pointes

 

Document Type: Article

Source: Scopus

 

 

Carlsson, A.E.a , Bayly, P.V.b

Force generation by endocytic actin patches in budding yeast

(2014) Biophysical Journal, 106 (8), pp. 1596-1606.

 

 

a Department of Physics, Washington University, St. Louis, MI, United States

b Department of Mechanical Engineering, Washington University, St. Louis, MI, United States

 

 

Abstract

Membrane deformation during endocytosis in yeast is driven by local, templated assembly of a sequence of proteins including polymerized actin and curvature-generating coat proteins such as clathrin. Actin polymerization is required for successful endocytosis, but it is not known by what mechanisms actin polymerization generates the required pulling forces. To address this issue, we develop a simulation method in which the actin network at the protein patch is modeled as an active gel. The deformation of the gel is treated using a finite-element approach. We explore the effects and interplay of three different types of force driving invagination: 1), forces perpendicular to the membrane, generated by differences between actin polymerization rates at the edge of the patch and those at the center; 2), the inherent curvature of the coat-protein layer; and 3), forces parallel to the membrane that buckle the coat protein layer, generated by an actomyosin contractile ring. We find that with optimistic estimates for the stall stress of actin gel growth and the shear modulus of the actin gel, actin polymerization can generate almost enough force to overcome the turgor pressure. In combination with the other mechanisms, actin polymerization can the force over the critical value. © 2014 Biophysical Society.

 

Document Type: Article

Source: Scopus

 

Genin, G.M.

Nanoscopic injury with macroscopic consequences: Tau proteins as mediators of diffuse axonal injury

 (2014) Biophysical Journal, 106 (8), pp. 1551-1552.

 

Department of Mechanical Engineering and Materials Science, Washington University School of Medicine, St. Louis, MO, United States

 

Document Type: Note

Source: Scopus

 

 

Jallouk, A.P.a , Cummings, P.T.b c

Audibilization: Data analysis by ear

(2014) Journal of Chemical Theory and Computation, 10 (4), pp. 1387-1394.

 

 

a Medical Scientist Training Program, Washington University in St. Louis, St. Louis, MO 63110-1093, United States

b Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235-1604, United States

c Center for Nanophase Materials Sciences, Oak Ridge National Laboratory, Oak Ridge, TN 37831-6494, United States

 

 

Abstract

As molecular dynamics simulations continue to grow in size and complexity, new techniques are needed to rapidly identify regions of data likely to benefit from further analysis. Audibilization, the conversion of data to sound, facilitates this task by taking advantage of the user's innate ability to identify anomalies in patterns of sound. Audibilization also complements visualization of a molecular simulation by allowing the user to easily correlate changes in numerical quantities with changes in the overall structure of the molecular system. Here we present three examples highlighting the utility of audibilization in the analysis of three different molecular simulations. First, we present a simulation of liquid water in which the lengths of the O-H bonds are calculated at each time step and audibilized. Interestingly, we find that anomalies in the pattern of bond vibration are due to intermolecular interactions but do not correlate with the formation of hydrogen bonds. Next, we present a simulation of the rupture of a gold nanowire. Here we audibilize the nanowire potential energy and illustrate that sharp changes in this value coincide with important structural events such as the formation of monatomic chains and dislocations. Finally, we present a simulation of single-stranded DNA passing through a nanogap. Here the bond angle is audibilized and used to illustrate the conformational changes of each base as it passes through the nanogap. This simulation also illustrates the use of more advanced audibilization techniques such as the multiplexing of audibilized signals and the weighting of certain segments of data relative to others. © 2014 American Chemical Society.

 

Document Type: Article

Source: Scopus

 

 

Burton, H.a b , Snyder, A.Z.b , Raichle, M.E.b

Resting state functional connectivity in early blind humans

(2014) Frontiers in Systems Neuroscience, 8 (1 APR), art. no. 51, .

 

 

a Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States

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

 

 

Abstract

Task-based neuroimaging studies in early blind humans (EB) have demonstrated heightened visual cortex responses to non-visual paradigms. Several prior functional connectivity studies in EB have shown altered connections consistent with these task-based results. But these studies generally did not consider behavioral adaptations to lifelong blindness typically observed in EB. Enhanced cognitive abilities shown in EB include greater serial recall and attention to memory. Here, we address the question of the extent to which brain intrinsic activity in EB reflects such adaptations. We performed a resting-state functional magnetic resonance imaging study contrasting 14 EB with 14 age/gender matched normally sighted controls (NS). A principal finding was markedly greater functional connectivity in EB between visual cortex and regions typically associated with memory and cognitive control of attention. In contrast, correlations between visual cortex and non-deprived sensory cortices were significantly lower in EB. Thus, the available data, including that obtained in prior task-based and resting state fMRI studies, as well as the present results, indicate that visual cortex in EB becomes more heavily incorporated into functional systems instantiating episodic recall and attention to non-visual events. Moreover, EB appear to show a reduction in interactions between visual and non-deprived sensory cortices, possibly reflecting suppression of inter-sensory distracting activity. © 2014 Burton, Snyder and Raichle.

 

 

Author Keywords

Blindness;  FMRI;  Functional connectivity;  Human;  Visual cortex

Document Type: Article

Source: Scopus

 

 

Lorca, R.A.a b , Stamnes, S.J.b , Pillai, M.K.a , Hsiao, J.J.b , Wright, M.E.b , England, S.K.a b b

N-terminal isoforms of the large-conductance Ca2+-activated K+ channel are differentially modulated by the auxiliary β1-subunit

(2014) Journal of Biological Chemistry, 289 (14), pp. 10095-10103.

 

 

a Department of Obstetrics and Gynecology, Washington University in St. Louis School of Medicine, 425 South Euclid Ave., Campus Bx. 8064, St., St. Louis, MO 63110, United States

b Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, United States

 

 

Abstract

The large-conductance Ca2+-activated K+ (BK Ca) channel is essential for maintaining the membrane in a hyperpolarized state, thereby regulating neuronal excitability, smooth muscle contraction, and secretion. The BKCa α-subunit has three predicted initiation codons that generate proteins with N-terminal ends starting with the amino acid sequences MANG, MSSN, or MDAL.Because the N-terminal region and first transmembrane domain of the α-subunit are required for modulation by auxiliary β1-subunits, we examined whether β1 differentially modulates the N-terminal BKCa α-subunit isoforms. In the absence of β1, all isoforms had similar single-channel conductances and voltage-dependent activation. However, whereas β1 did not modulate the voltage-activation curve of MSSN, β1 induced a significant leftward shift of the voltage activation curves of both the MDAL and MANG isoforms. These shifts, of which the MDALwas larger, occurred at both 10 μMand 100μMCa2+. The β1-subunit increased the open dwell times of all three isoforms and decreased the closed dwell times of MANG and MDAL but increased the closed dwell times of MSSN. The distinct modulation of voltage activation by the β1-subunit may be due to the differential effect of β1 on burst duration and interburst intervals observed among these isoforms. Additionally, we observed that the related β2-subunit induced comparable leftward shifts in the voltage-activation curves of all three isoforms, indicating that the differential modulation of these isoforms was specific to β1. These findings suggest that the relative expression of the N-terminal isoforms can fine-tune BKCa channel activity in cells, highlighting a novel mechanism of BKCa channel regulation. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

 

Document Type: Article

Source: Scopus

 

Lin, C.-C.a , Bradstreet, T.R.a , Schwarzkopf, E.A.a , Sim, J.b , Carrero, J.A.a , Chou, C.a , Cook, L.E.a , Egawa, T.a , Taneja, R.c , Murphy, T.L.a , Russell, J.H.b , Edelson, B.T.a

Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation

(2014) Nature Communications, 5, art. no. 3551, .

 

a Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, United States

b Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore

c Department of Developmental Biology, Washington University School of Medicine, St Louis, MO 63110, United States

 

 

Abstract

T H 1 and T H 17 cells mediate neuroinflammation in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Pathogenic T H cells in EAE must produce the pro-inflammatory cytokine granulocyte-macrophage colony stimulating factor (GM-CSF). T H cell pathogenicity in EAE is also regulated by cell-intrinsic production of the immunosuppressive cytokine interleukin 10 (IL-10). Here we demonstrate that mice deficient for the basic helix-loop-helix (bHLH) transcription factor Bhlhe40 (Bhlhe40 -/-) are resistant to the induction of EAE. Bhlhe40 is required in vivo in a T cell-intrinsic manner, where it positively regulates the production of GM-CSF and negatively regulates the production of IL-10. In vitro, GM-CSF secretion is selectively abrogated in polarized Bhlhe40 -/- T H 1 and T H 17 cells, and these cells show increased production of IL-10. Blockade of IL-10 receptor in Bhlhe40 -/- mice renders them susceptible to EAE. These findings identify Bhlhe40 as a critical regulator of autoreactive T-cell pathogenicity. © 2014 Macmillan Publishers Limited.

 

Document Type: Article

Source: Scopus

 

 

Scratch, S.E.a b , Hunt, R.W.a b , Thompson, D.K.a b , Ahmadzai, Z.M.a , Doyle, L.W.a b d , Inder, T.E.a c , Anderson, P.J.b c

Free thyroxine levels after very preterm birth and neurodevelopmental outcomes at a?e 7 years

(2014) Pediatrics, 133 (4), pp. e955-e963.

 

 

a Clinical Sciences, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC, Australia

b Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia

c School of Medicine, Washington University of St. Louis, St. Louis, MI, United States

d Royal Women's Hospital, Melbourne, VIC, Australia

 

 

Abstract

BACKGROUND AND OBJECTIVES: Preterm infants commonly have transient hypothyroxinemia of prematurity after birth, which has been associated with deficits in general intellectual functioning, memory, attention, and academic achievement. However, research has predominantly focused on thyroxine levels in the first 2 weeks of life and outcomes are limited to the preschool period. Our objective was to evaluate the relationships between free thyroxine (fT 4) levels over the first 6 weeks after very preterm (VPT) birth with cognitive functioning and brain development at age 7 years. METHODS: A total of 83 infants born VPT (&lt;30 weeks' gestation) had fT4 concentrations measured postnatally and 2- and 6-week area under the curve (AUC) summary measures were calculated. Follow-up at age 7 years included a neuropsychological assessment and brain MRI. Univariable and multivariable regression modeling was used where AUC for fT4 was the main predictor of neurodevelopmental outcome at age 7 years. RESULTS: Multivariable modeling revealed that higher, not lower, postnatal fT4 levels (2-week AUC) were associated with poorer cognitive performances at age 7 years on tasks of verbal learning (P = .02), verbal memory (P = .03), and simple reaction time (P &lt; .001). A similar pattern of results was found when the 6-week AUC was examined. No significant associations between postnatal fT4 levels and brain volumes at age 7 years were identified. CONCLUSIONS: Results are contradictory to previous observations and suggest that after adjustment for confounders, higher postnatal fT4 levels in VPT infants, rather than lower levels, may be a marker of adverse neuropsychological development in childhood. © 2014 by the American Academy of Pediatrics.

 

 

Author Keywords

Brain volumes;  Cognitive outcome;  Hormones;  Preterm infants;  Thyroxine

 

Document Type: Article

Source: Scopus

 

 

Li, L.a b , Yeh, C.a b , Hu, S.b c , Wang, L.b , Soetikno, B.T.b , Chen, R.d , Zhou, Q.d , Shung, K.K.d , Maslov, K.I.b , Wang, L.V.a b

Fully motorized optical-resolution photoacoustic microscopy

(2014) Optics Letters, 39 (7), pp. 2117-2120.

 

 

a Department of Electrical and System Engineering, Washington University in St. Louis One Brookings, St. Louis, MO 63130, United States

b Optical Imaging Laboratory, Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States

c Department of Biomedical Engineering, University of Virginia, P.O. Box 800759, Charlottesville, VA 22908, United States

d Resource Center for Medical Ultrasonic Transducer Technology, Department of Biomedical Engineering, University of Southern California, 1042 Downey Way, Los Angeles, CA 90089-1111, United States

 

 

Abstract

We have developed fully motorized optical-resolution photoacoustic microscopy (OR-PAM), which integrates five complementary scanning modes and simultaneously provides a high imaging speed and a wide field of view (FOV) with 2.6 μm lateral resolution. With one-dimensional (1D) motion-mode mechanical scanning, we measured the blood flow through a cross section of a blood vessel in vivo. With two-dimensional (2D) optical scanning at a laser repetition rate of 40 kHz, we achieved a 2 kHz B-scan rate over a range of 50 μm with 20 A-lines and 50 Hz volumetric-scan rate over a FOV of 50 μm × 50 μm with 400 A-lines, which enabled real-time tracking of cellular dynamics in vivo. With synchronized 1D optical and 2D mechanical hybrid scanning, we imaged a 10 mm × 8 mm FOV within three minutes, which is 20 times faster than the conventional mechanical scan in our second-generation OR-PAM. With three-dimensional mechanical contour scanning, we maintained the optimal signal-to-noise ratio and spatial resolution of OR-PAM while imaging objects with uneven surfaces, which is essential for quantitative studies. © 2014 Optical Society of America.

 

 

Document Type: Article

Source: Scopus

 

Saez, P.A.a b e , Bender, H.A.c , Barr, W.B.a , Mindt, M.R.b c , Morrison, C.E.a , Hassenstab, J.d , Rodriguez, M.a , Vazquez, B.a

The impact of education and acculturation on nonverbal neuropsychological test performance among latino/a patients with epilepsy

(2014) Applied Neuropsychology:Adult, 21 (2), pp. 108-119.

 

 

a NYU Langone Medical Center, School of Medicine, New York University, New York, NY, United States

b Psy., Fordham University, Bronx, NY, United States

c Neurology and Psychiatry, Mount Sinai School of Medicine, New York, NY, United States

d Neurology and Psychology, Washington University, School of Medicine, St. Louis, Missouri, United States

e NYU Langone Medical Center, Comprehensive Epilepsy Center, Department of Neurology, 223 East 34th Street, New York, NY 10016, United States

 

 

Abstract

The present study examined the relationship between various sociocultural factors (e.g., acculturation, education), neurological variables (e.g., epilepsy duration and seizure frequency) and nonverbal neuropsychological (NP) test performance in a sample of 305 Latino/a and Non-Latino/a White adults with and without epilepsy. All participants completed nonverbal NP measures of visuospatial skills, memory, executive functioning, and psychomotor speed. An acculturation scale was administered to Spanish-speaking epilepsy patients and controls. Education was strongly correlated with performance on all but one of the nonverbal measures across the entire sample. Among Spanish-speaking Latino/a patients with epilepsy, level of acculturation to U.S. culture was associated with a measure of behavioral inflexibility (p <.05) and with a composite measure of nonverbal NP test performance (p <.05). Finally, the results of hierarchical regression models showed that sociocultural factors accounted for a greater proportion of variance in nonverbal NP test performance than did neurological factors. These results provide further evidence that sociocultural factors are strong predictors of NP test performance in clinical populations, even on nonverbal tests. Assessment of acculturation may be as critical as assessment of disease factors in interpreting cognitive performance in Latino/a individuals. © 2014 Copyright Taylor & Francis Group, LLC.

 

 

Author Keywords

cross-cultural;  Hispanic Americans;  tests

Document Type: Article

Source: Scopus

 

 

Frauscher, B.a , Jennum, P.b , Ju, Y.-E.S.c , Postuma, R.B.d , Arnulf, I.e , De Cock, V.C.f , Dauvilliers, Y.f , Fantini, M.L.g h , Ferini-Strambi, L.i , Gabelia, D.a , Iranzo, A.j , Leu-Semenescu, S.e , Mitterling, T.a , Miyamoto, M.k , Miyamoto, T.l , Montplaisir, J.Y.m , Oertel, W.n , Pelletier, A.o , Prunetti, P.p , Puligheddu, M.q , Santamaria, J.j , Sonka, K.r , Unger, M.n s , Wolfson, C.o , Zucconi, M.i , Terzaghi, M.i p , Högl, B.a , Mayer, G.t , Manni, R.p

Comorbidity and medication in REM sleep behavior disorder: A multicenter case-control study

 (2014) Neurology, 82 (12), pp. 1076-1079.

 

 

a Department of Neurology, Innsbruck Medical University, Austria

b Danish Center for Sleep Medicine, University of Copenhagen, Denmark

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

d Department of Neurology, McGill University, Montreal General Hospital, Canada

e Unité des Pathologies du Sommeil, Hôpital Pitié-Salpêtrière, Marie Curie University, Paris, France

f Sleep Unit, Department of Neurology, Hôpital Gui de Chauliac, Montpellier, Montpellier, France

g Sleep Disorders Center, Department of Neurosciences, University of Turin, Italy

h UFR Medecine, EA 7280, University Clermont 1, France

i Sleep Disorders Center, Università Vita-Salute San Raffaele, Milan, Italy

j Neurology Service, Hospital Clinic de Barcelona, IDIBAPS, Spain

k Department of Neurology, Dokkyo Medical University, School of Medicine, Tochigi, Japan

l Department of Neurology, Dokkyo Medical University Koshigaya Hospital, Saitama, Japan

m Centre D'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Coeur de Montréal, Canada

n Philipps-Universität, Marburg, Germany

o Neuroepidemiology Research Unit, Research Institute of the McGill University Health Centre, Montreal, Canada

p Unit of Sleep Medicine, National Institute of Neurology IRCCS, C. Mondino Foundation, Pavia, Italy

q Sleep Center, Department of Cardiovascular and Neurological Sciences, University of Cagliari, Italy

r Department of Neurology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic

s Department of Neurology, Saarland University, Homburg/Saar, Germany

t Hephata Klinik, Schwalmstadt-Treysa, Germany

 

 

Abstract

Objective: This controlled study investigated associations between comorbidity and medication in patients with polysomnographically confirmed idiopathic REM sleep behavior disorder (iRBD), using a large multicenter clinic-based cohort. Methods: Data of a self-administered questionnaire on comorbidity and medication use of 318 patients with iRBD and 318 matched controls were analyzed. Comparisons between cases and controls were made using logistic regression analysis. Results: Patients with iRBD were more likely to report depression (odds ratio [OR] 2.0, 95% confidence interval [CI] 1.3-2.9) and concomitant antidepressant use (OR 2.2, 95% CI 1.4-3.6). Subanalysis of antidepressant agents revealed that the increased use of antidepressants in iRBD was due to selective serotoninergic reuptake inhibitors (OR 3.6, 95% CI 1.8-7.0) and not due to other antidepressant classes. Patients with iRBD reported more lifetime antidepressant use than comorbid depression (antidepressant use: OR 1.9, 95%CI 1.1-3.3; depression: OR 1.6, 95%CI 1.0-2.5). Patients with iRBD reported more ischemic heart disease (OR 1.9, 95% CI 1.1-3.1). This association did not change substantially when adjusting for cardiovascular risk factors (OR 2.3, 95% CI 1.3-3.9). The use of inhaled glucocorticoids was higher in patients with iRBD compared to controls (OR 5.3, 95% CI 1.8-15.8), likely reflecting the higher smoking rate in iRBD (smoking: OR 15.3, 95%CI 2.0-118.8; nonsmoking: OR 2.4, 95%CI 0.4-13.2) and consequent pulmonary disease. Conclusions: This large study confirms the association between comorbid depression and antidepressant use in iRBD. In addition, there was an unexpected association of iRBD with ischemic heart disease that was not explained by cardiovascular risk factors. © 2014 American Academy of Neurology.

 

 

Document Type: Article

Source: Scopus

 

 

Powers, W.J.a , Clarke, W.R.b , Grubb Jr., R.L.c d , Videen, T.O.d e , Adams Jr., H.P.f , Derdeyn, C.P.c d e

Lower stroke risk with lower blood pressure in hemodynamic cerebral ischemia

(2014) Neurology, 82 (12), pp. 1027-1032. Cited 1 time.

 

 

a Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, United States

b Clinical Trials Statistics and Data Management Center, University of Iowa College of Public Health, Iowa City, United States

c Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States

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

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

f Department of Neurology, University of Iowa Carver School of Medicine, Iowa City, United States

 

 

Abstract

Objective: To determine whether strict blood pressure (BP) control is the best medical management for patients with symptomatic carotid artery occlusion and hemodynamic cerebral ischemia. Methods: In this prospective observational cohort study, we analyzed data from91 participants in the nonsurgical group of the Carotid Occlusion Surgery Study (COSS) who had recent symptomatic internal carotid artery occlusion and hemodynamic cerebral ischemia manifested by ipsilateral increased oxygen extraction fraction. The target BP goal in COSS was ≤130/85 mm Hg. We compared the occurrence of ipsilateral ischemic stroke during follow-up in the 41 participants with mean BP ≤130/85 mm Hg to the remaining 50 with higher BP. Results: Of 16 total ipsilateral ischemic strokes that occurred during follow-up, 3 occurred in the 41 participants with mean follow-up BP of >130/85 mm Hg, compared to 13 in the remaining 50 participants with mean follow-up BP .130/85 mm Hg (hazard ratio 3.742, 95% confidence interval 1.065-13.152, log-rank p 5 0.027). Conclusion: BPs ≤130/85 mm Hg were associated with lower subsequent stroke risk in these patients. Classification of evidence: This study provides Class III evidence that control of hypertension ≤130/85 mm Hg is associated with a reduced risk of subsequent ipsilateral ischemic stroke in patients with recently symptomatic carotid occlusion and hemodynamic cerebral ischemia (increased oxygen extraction fraction). © 2014 American Academy of Neurology. 

Document Type: Article

Source: Scopus

 

 

Dobrowolska, J.A.a , Kasten, T.a , Huang, Y.a , Benzinger, T.L.S.c , Sigurdson, W.a d , Ovod, V.a , Morris, J.C.a b d , Bateman, R.J.a d e
Diurnal patterns of soluble amyloid precursor protein metabolites in the human central nervous system

(2014) PLoS ONE, 9 (3), art. no. e89998, .

 

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

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

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

d Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States

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

 

 

Abstract

The amyloid-β (Aβ) protein is diurnally regulated in both the cerebrospinal fluid and blood in healthy adults; circadian amplitudes decrease with aging and the presence of cerebral Aβ deposits. The cause of the Aβ diurnal pattern is poorly understood. One hypothesis is that the Amyloid Precursor Protein (APP) is diurnally regulated, leading to APP product diurnal patterns. APP in the central nervous system is processed either via the β-pathway (amyloidogenic), generating soluble APP-β (sAPPβ) and Aβ, or the α-pathway (non-amyloidogenic), releasing soluble APP-α (sAPPα). To elucidate the potential contributions of APP to the Aβ diurnal pattern and the balance of the α- and β- pathways in APP processing, we measured APP proteolytic products over 36 hours in human cerebrospinal fluid from cognitively normal and Alzheimer's disease participants. We found diurnal patterns in sAPPα, sAPPβ, Aβ40&lt;1inf&gt;, and Aβ42, which diminish with increased age, that support the hypothesis that APP is diurnally regulated in the human central nervous system and thus results in Aβ diurnal patterns. We also found that the four APP metabolites were positively correlated in all participants without cerebral Aβ deposits. This positive correlation suggests that the α- and β- APP pathways are non-competitive under normal physiologic conditions where APP availability may be the limiting factor that determines sAPPα and sAPPβ production. However, in participants with cerebral Aβ deposits, there was no correlation of Aβ to sAPP metabolites, suggesting that normal physiologic regulation of cerebrospinal fluid Aβ is impaired in the presence of amyloidosis. Lastly, we found that the ratio of sAPPβ to sAPPα was significantly higher in participants with cerebral Aβ deposits versus those without deposits. Therefore, the sAPPβ to sAPPα ratio may be a useful biomarker for cerebral amyloidosis. © 2014 Dobrowolska et al.

 

Document Type: Article

Source: Scopus

 

 

Zheng, X.a , Valakh, V.b , DiAntonio, A.b c , Ben-Shahar, Y.a
Natural antisense transcripts regulate the neuronal stress response and excitability

(2014) eLife, 2014 (3), art. no. e01849, .

a Department of Biology, Washington University in St. Louis, St. Louis, United States

b Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States

c Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, United States

 

Abstract

Neurons regulate ionic fluxes across their plasma membrane to maintain their excitable properties under varying environmental conditions. However, the mechanisms that regulate ion channels abundance remain poorly understood. Here we show that pickpocket 29 (ppk29), a gene that encodes a Drosophila degenerin/epithelial sodium channel (DEG/ENaC), regulates neuronal excitability via a protein-independent mechanism. We demonstrate that the mRNA 3′UTR of ppk29 affects neuronal firing rates and associated heat-induced seizures by acting as a natural antisense transcript (NAT) that regulates the neuronal mRNA levels of seizure (sei), the Drosophila homolog of the human Ether-à-go-go Related Gene (hERG) potassium channel. We find that the regulatory impact of ppk29 mRNA on sei is independent of the sodium channel it encodes. Thus, our studies reveal a novel mRNA dependent mechanism for the regulation of neuronal excitability that is independent of protein-coding capacity. © Zheng et al.

 

Document Type: Article

 

Source: Scopus