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Bai Q.,University of Pittsburgh | Parris R.S.,University of Pittsburgh | Burton E.A.,University of Pittsburgh | Burton E.A.,Geriatric Research Education and Clinical Center | Burton E.A.,Pittsburgh Veterans Affairs Healthcare System
Journal of Biological Chemistry | Year: 2014

Zebrafish CNS axons regenerate robustly following injury; it is thought that CNS oligodendrocytes contribute to this response by expressing growth-promoting molecules. We characterized the mpz gene, which encodes myelin protein zero and is up-regulated in oligodendroglia following axonal injury. The 2.5-kb mpz mRNA is expressed from a single TATA box promoter. Four independent Tg(mpz:egfp) transgenic zebrafish lines, in which GFP was expressed under the mpz promoter and 10 kb of genomic 5́-flanking sequence, showed transgene expression in CNS oligodendrocytes from larval development through adulthood. Following optic nerve crush injury, the mpz: egfp transgene was strongly up-regulated in oligodendrocytes along the regenerating retinotectal projection, mirroring up-regulation of endogenous mpz mRNA. GFP-expressing oligodendroglia were significantly more abundant in the regenerating optic pathway, resulting from both transgene induction in oligodendroglial precursors and the birth of new cells. Up-regulation of the mpz:egfp transgene was not dependent on axonal regeneration, suggesting that the primary signal may be axonal loss, debris, or microglial infiltration. Deletion experiments indicated that an oligodendroglial enhancer located in the region from -6 to -10 kb with respect to the mpz transcriptional start site is dissociable from the cis-regulatory element mediating the mpz transcriptional response to axonal injury, which is located between -1 and -4 kb. These data show that different mechanisms regulate expression of zebrafish mpz in myelinating oligodendrocytes and its induction following axonal injury. The underlying molecular events could potentially be exploited to enhance axonal repair following mammalian CNS injury. The transgenic lines and cis-regulatory constructs reported here will facilitate identification of the relevant signaling pathways.


Wendell J.,Oklahoma City Veterans Affairs Medical Center | Ratcliff C.G.,Michael bakey Veterans Affairs Medical Center | Ratcliff C.G.,Houston and D Center for Innovations in Quality | Ratcliff C.G.,Baylor College of Medicine | And 8 more authors.
Journal of Psychiatric Practice | Year: 2016

Suicide is a leading cause of death, and rates are especially high among medically ill, older individuals. Health-related psychosocial correlates of suicidal ideation (SI) may be particularly important for medically ill older adults as they may clarify who may benefit from interventions to reduce SI. This study examined whether demographic, physical health, and/or health-related psychosocial factors were associated with high frequency of SI in older, medically ill Veterans experiencing elevated anxiety or depression. This cross-sectional study included 302 Veterans with (1) a cardiopulmonary condition and functional impairment and (2) elevated symptoms of depression and/or anxiety. Participants were classified as having either no, low, or high SI, based on self-reported ideation, from the Patient Health Questionnaire-9. SI was reported in 26.8% of the full sample and high SI was reported by 12.6% of participants. Logistic regression analyses predicting high versus no SI found the odds of high SI increased 4.7 times (95% confidence interval, 2.6-8.3) for each 1-unit increase in maladaptive coping and 4.1 times (95% confidence interval, 1.2-14.3) for each 1-unit increase in physical health severity/functional limitations. Older, medically ill Veterans with comorbid depression and/or anxiety frequently reported SI and were at greater risk of experiencing a high frequency of SI if they engaged in maladaptive coping strategies and/or had high levels of functional impairment. Effective interventions to reduce SI for this population should focus on reducing maladaptive coping and minimizing negative behavioral, cognitive, and emotional reactions to functional limitations. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Zhou Y.,University of Pittsburgh | Cattley R.T.,University of Pittsburgh | Cario C.L.,Tsinghua University | Bai Q.,Geriatric Research | Burton E.A.,Pittsburgh Veterans Affairs Healthcare System
Nature Protocols | Year: 2014

This article describes a method to quantify the movements of larval zebrafish in multiwell plates, using the open-source MATLAB applications LSRtrack and LSRanalyze. The protocol comprises four stages: generation of high-quality, flatly illuminated video recordings with exposure settings that facilitate object recognition; analysis of the resulting recordings using tools provided in LSRtrack to optimize tracking accuracy and motion detection; analysis of tracking data using LSRanalyze or custom MATLAB scripts; and implementation of validation controls. The method is reliable, automated and flexible, requires <1 h of hands-on work for completion once optimized and shows excellent signal:noise characteristics. The resulting data can be analyzed to determine the following: positional preference; displacement, velocity and acceleration; and duration and frequency of movement events and rest periods. This approach is widely applicable to the analysis of spontaneous or stimulus-evoked zebrafish larval neurobehavioral phenotypes resulting from a broad array of genetic and environmental manipulations, in a multiwell plate format suitable for high-throughput applications. © 2014 Nature America, Inc. All rights reserved.


Liu J.,University of Pittsburgh | Rattan R.,University of Pittsburgh | Adelstein E.,University of Pittsburgh | Barrington W.,University of Pittsburgh | And 11 more authors.
Circulation: Arrhythmia and Electrophysiology | Year: 2012

Background-The Food and Drug Administration recently issued a class I recall of the St. Jude Medical Riata implantable cardioverter-defibrillator lead presumably because of increased risk of electric failure and mechanical separation via inside-out abrasion. We sought to examine the incidence and time dependence of inside-out abrasion in asymptomatic patients implanted with the Riata lead. Methods and Results-Asymptomatic patients implanted with the Riata lead at our institution were offered voluntary fluoroscopic screening in 3 views. Electric testing of the Riata lead with provocative isometric muscle contraction was performed at the time of fluoroscopic screening. Of the 245 patients undergoing fluoroscopic screening, 53 (21.6%) patients showed clear evidence of lead separation. Of these externalized leads, 0%, 13%, and 26% had a dwell time of <3 years, 3 to 5 years, and >5 years, respectively (P=0.037). Externalized leads had a significantly pronounced decrease in R-wave amplitude (?1.7±2.9 mV versus +0.35±2.5 mV; P<0.001), and more patients with externalized leads had ?25% decrease in R-wave amplitude from baseline (28.0% versus 8.1%; P=0.018). One patient with externalization exhibited new noise on near-field electrogram. Conclusions-The Riata lead exhibits time-dependent high rates of cable externalization exceeding 20% at >5 years of dwell time. Externalized leads are associated with a more pronounced decrease in R-wave amplitude, which may be an early marker of future electric failure. The use of fluoroscopic and electric screening of asymptomatic patients with the Riata lead remains controversial in the management of patients affected by the recent Food and Drug Administration recall. © 2012 American Heart Association, Inc.


Sager J.J.,University of Pittsburgh | Torres G.E.,University of Pittsburgh | Burton E.A.,University of Pittsburgh | Burton E.A.,Geriatric Research | Burton E.A.,Pittsburgh Veterans Affairs Healthcare System
PLoS ONE | Year: 2012

DYT1 dystonia is caused by mutation of the TOR1A gene, resulting in the loss of a single glutamic acid residue near the carboxyl terminal of TorsinA. The neuronal functions perturbed by TorsinA[ΔE] are a major unresolved issue in understanding the pathophysiology of dystonia, presenting a critical roadblock to developing effective treatments. We identified and characterized the zebrafish homologue of TOR1A, as a first step towards elucidating the functions of TorsinA in neurons, in vivo, using the genetically-manipulable zebrafish model. The zebrafish genome was found to contain a single alternatively-spliced tor1 gene, derived from a common ancestral locus shared with the dual TOR1A and TOR1B paralogues found in tertrapods. tor1 was expressed ubiquitously during early embryonic development and in multiple adult tissues, including the CNS. The 2.1 kb tor1 mRNA encodes Torsin1, which is 59% identical and 78% homologous to human TorsinA. Torsin1 was expressed as major 45 kDa and minor 47 kDa glycoproteins, within the cytoplasm of neurons and neuropil throughout the CNS. Similar to previous findings relating to human TorsinA, mutations of the ATP hydrolysis domain of Torsin1 resulted in relocalization of the protein in cultured cells from the endoplasmic reticulum to the nuclear envelope. Zebrafish embryos lacking tor1 during early development did not show impaired viability, overt morphological abnormalities, alterations in motor behavior, or developmental defects in the dopaminergic system. Torsin1 is thus non-essential for early development of the motor system, suggesting that important CNS functions may occur later in development, consistent with the critical time window in late childhood when dystonia symptoms usually emerge in DYT1 patients. The similarities between Torsin1 and human TorsinA in domain organization, expression pattern, and cellular localization suggest that the zebrafish will provide a useful model to understand the neuronal functions of Torsins in vivo.

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