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author:("Kim, woodin")
1.  High expression of long intervening non-coding RNA OLMALINC in the human cortical white matter is associated with regulation of oligodendrocyte maturation 
Molecular Brain  2015;8:2.
Background
Long intervening non-coding RNAs (lincRNAs) are a recently discovered subclass of non-coding RNAs. LincRNAs are expressed across the mammalian genome and contribute to the pervasive transcription phenomenon. They display a tissue-specific and species-specific mode of expression and are present abundantly in the brain.
Results
Here, we report the expression patterns of oligodendrocyte maturation-associated long intervening non-coding RNA (OLMALINC), which is highly expressed in the white matter (WM) of the human frontal cortex compared to the grey matter (GM) and peripheral tissues. Moreover, we identified a novel isoform of OLMALINC that was also up-regulated in the WM. RNA-interference (RNAi) knockdown of OLMALINC in oligodendrocytes, which are the major cell type in the WM, caused significant changes in the expression of genes regulating cytostructure, cell activation and membrane signaling. Gene ontology enrichment analysis revealed that over 10% of the top 25 up- and down-regulated genes were involved in oligodendrocyte maturation. RNAi experiments in neuronal cells resulted in the perturbation of genes controlling cell proliferation. Furthermore, we identified a novel cis-natural antisense non-coding RNA, which we named OLMALINC-AS, which maps to the first exon of the dominant isoform of OLMALINC.
Conclusions
Our study has demonstrated for the first time that a primate-specific lincRNA regulates the expression of genes critical to human oligodendrocyte maturation, which in turn might be regulated by an antisense counterpart.
Electronic supplementary material
The online version of this article (doi:10.1186/s13041-014-0091-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13041-014-0091-9
PMCID: PMC4302521  PMID: 25575711
Long intervening non-coding RNA; OLMALINC; Human brain; Frontal cortex; White and grey matter; Antisense RNA
2.  Exploring Myelin Dysfunction in Multiple System Atrophy 
Experimental Neurobiology  2014;23(4):337-344.
Multiple system atrophy (MSA) is a rare, yet fatal neurodegenerative disease that presents clinically with autonomic failure in combination with parkinsonism or cerebellar ataxia. MSA impacts on the autonomic nervous system affecting blood pressure, heart rate and bladder function, and the motor system affecting balance and muscle movement. The cause of MSA is unknown, no definitive risk factors have been identified, and there is no cure or effective treatment. The definitive pathology of MSA is the presence of α-synuclein aggregates in the brain and therefore MSA is classified as an α-synucleinopathy, together with Parkinson's disease and dementia with Lewy bodies. Although the molecular mechanisms of misfolding, fibrillation and aggregation of α-synuclein partly overlap with other α-synucleinopathies, the pathological pathway of MSA is unique in that the principal site for α-synuclein deposition is in the oligodendrocytes rather than the neurons. The sequence of pathological events of MSA is now recognized as abnormal protein redistributions in oligodendrocytes first, followed by myelin dysfunction and then neurodegeneration. Oligodendrocytes are responsible for the production and maintenance of myelin, the specialized lipid membrane that encases the axons of all neurons in the brain. Myelin is composed of lipids and two prominent proteins, myelin basic protein and proteolipid protein. In vitro studies suggest that aberration in protein distribution and lipid transport may lead to myelin dysfunction in MSA. The purpose of this perspective is to bring together available evidence to explore the potential role of α-synuclein, myelin protein dysfunction, lipid dyshomeostasis and ABCA8 in MSA pathogenesis.
doi:10.5607/en.2014.23.4.337
PMCID: PMC4276804  PMID: 25548533
Multiple system atrophy; oligodendrocyte; α-synuclein; myelin; lipid dyshomeostasis
3.  Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy 
Multiple system atrophy (MSA) is a rapidly-progressive neurodegenerative disease characterized by parkinsonism, cerebellar ataxia and autonomic failure. A pathological hallmark of MSA is the presence of α-synuclein deposits in oligodendrocytes, the myelin-producing support cells of the brain. Brain pathology and in vitro studies indicate that myelin instability may be an early event in the pathogenesis of MSA. Lipid is a major constituent (78% w/w) of myelin and has been implicated in myelin dysfunction in MSA. However, changes, if any, in lipid level/distribution in MSA brain are unknown. Here, we undertook a comprehensive analysis of MSA myelin. We quantitatively measured three groups of lipids, sphingomyelin, sulfatide and galactosylceramide, which are all important in myelin integrity and function, in affected (under the motor cortex) and unaffected (under the visual cortex) white matter regions. For all three groups of lipids, most of the species were severely decreased (40–69%) in affected but not unaffected MSA white matter. An analysis of the distribution of lipid species showed no significant shift in fatty acid chain length/content with MSA. The decrease in lipid levels was concomitant with increased α-synuclein expression. These data indicate that the absolute levels, and not distribution, of myelin lipids are altered in MSA, and provide evidence for myelin lipid dysfunction in MSA pathology. We propose that dysregulation of myelin lipids in the course of MSA pathogenesis may trigger myelin instability.
doi:10.1186/s40478-014-0150-6
PMCID: PMC4228091  PMID: 25358962
Multiple system atrophy; Myelin; Lipid; α-synuclein; Sphingomyelin; Sulfatide; Galactosylceramide; MSA white matter
4.  Alpha-synuclein biology in Lewy body diseases 
α-Synuclein is an abundantly expressed neuronal protein that is at the center of focus in understanding a group of neurodegenerative disorders called α-synucleinopathies, which are characterized by the presence of aggregated α-synuclein intracellularly. Primary α-synucleinopathies include Parkinson’s disease (PD), dementia with Lewy bodies and multiple system atrophy, with α-synuclein also found secondarily in a number of other diseases, including Alzheimer’s disease. Understanding how α-synuclein aggregates form in these different disorders is important for the understanding of its pathogenesis in Lewy body diseases. PD is the most prevalent of the α-synucleinopathies and much of the initial research on α-synuclein Lewy body pathology was based on PD but is also relevant to Lewy bodies in other diseases (dementia with Lewy bodies and Alzheimer’s disease). Polymorphism and mutation studies of SNCA, the gene that encodes α-synuclein, provide much evidence for a causal link between α-synuclein and PD. Among the primary α-synucleinopathies, multiple system atrophy is unique in that α-synuclein deposition occurs in oligodendrocytes rather than neurons. It is unclear whether α-synuclein originates from oligodendrocytes or whether it is transmitted somehow from neurons. α-Synuclein exists as a natively unfolded monomer in the cytosol, but in the presence of lipid membranes it is thought to undergo a conformational change to a folded α-helical secondary structure that is prone to forming dimers and oligomers. Posttranslational modification of α-synuclein, such as phosphorylation, ubiquitination and nitration, has been widely implicated in α-synuclein aggregation process and neurotoxicity. Recent studies using animal and cell models, as well as autopsy studies of patients with neuron transplants, provided compelling evidence for prion-like propagation of α-synuclein. This observation has implications for therapeutic strategies, and much recent effort is focused on developing antibodies that target extracellular α-synuclein.
doi:10.1186/s13195-014-0073-2
PMCID: PMC4288216  PMID: 25580161
5.  An Interactive RADIANCE Toolkit for Customizable CT Dose Monitoring and Reporting 
Journal of Digital Imaging  2013;26(4):663-667.
The need for tools to monitor imaging-related radiation has grown dramatically in recent years. RADIANCE, a freely available open-source dose-monitoring tool, was developed in response to the need for an informatics solution in this realm. A number of open-source as well as commercial solutions have since been developed to enable radiology practices to monitor radiation dose parameters for modalities ranging from computed tomography to radiography to fluoroscopy. However, it is not sufficient to simply collect this data; it is equally important to be able to review it in the appropriate context. Most of the currently available dose-monitoring solutions have some type of reporting capability, such as a real-time dashboard or a static report. Previous versions of RADIANCE have included a real-time dashboard with pre-set screens that plot effective dose estimates according to different criteria, as well as monthly scorecards to summarize dose estimates for individuals within a radiology practice. In this work, we present the RADIANCE toolkit, a customizable reporting solution that allows users to generate reports of interest to them, summarizing a variety of metrics that can be grouped according to useful parameters. The output of the toolkit can be used for real-time dose monitoring or scheduled reporting, such as to a quality assurance committee. Making dose parameter data more accessible and more meaningful to the user promotes dose reduction efforts such as regular protocol review and optimization, and ultimately improves patient care by decreasing unnecessary radiation exposure.
doi:10.1007/s10278-013-9570-2
PMCID: PMC3705013  PMID: 23359090
Radiation dose monitoring; Dose reduction; RADIANCE
6.  Using the Microsoft Kinect for Patient Size Estimation and Radiation Dose Normalization: Proof of Concept and Initial Validation 
Journal of Digital Imaging  2013;26(4):657-662.
Monitoring patients' imaging-related radiation is currently a hot topic, but there are many obstacles to accurate, patient-specific dose estimation. While some, such as easier access to dose data and parameters, have been overcome, the challenge remains as to how accurately these dose estimates reflect the actual dose received by the patient. The main parameter that is often not considered is patient size. There are many surrogates—weight, body mass index, effective diameter—but none of these truly reflect the three-dimensional “size” of an individual. In this work, we present and evaluate a novel approach to estimating patient volume using the Microsoft Kinect™, a combination RGB camera-infrared depth sensor device. The goal of using this device is to generate a three-dimensional estimate of patient size, in order to more effectively model the dimensions of the anatomy of interest and not only enable better normalization of dose estimates but also promote more patient-specific protocoling of future CT examinations. Preliminary testing and validation of this system reveals good correlation when individuals are standing upright with their arms by their sides, but demonstrates some variation with arm position. Further evaluation and testing is necessary with multiple patient positions and in both adult and pediatric patients. Correlation with other patient size metrics will also be helpful, as the ideal measure of patient “size” may in fact be a combination of existing metrics and newly developed techniques.
doi:10.1007/s10278-012-9567-2
PMCID: PMC3705007  PMID: 23344260
Radiation dose monitoring; Patient size estimation
7.  Mapping cellular hierarchy by single cell analysis of the cell surface repertoire 
Cell stem cell  2013;13(4):10.1016/j.stem.2013.07.017.
SUMMARY
Stem cell differentiation pathways are most often studied at the population level, whereas critical decisions are executed at the level of single cells. We have established a highly multiplexed, quantitative PCR assay to profile in an unbiased manner a panel of all commonly used cell surface markers (280 genes) from individual cells. With this method we analyzed over 1500 single cells throughout the mouse hematopoietic system, and illustrate its utility for revealing important biological insights. The comprehensive single cell dataset permits mapping of the mouse hematopoietic stem cell (HSC) differentiation hierarchy by computational lineage progression analysis. Further profiling of 180 intracellular regulators enabled construction of a genetic network to assign the earliest differentiation event during hematopoietic lineage specification. Analysis of acute myeloid leukemia elicited by MLL-AF9 uncovered a distinct cellular hierarchy containing two independent self-renewing lineages with different clonal activities. The strategy has broad applicability in other cellular systems.
doi:10.1016/j.stem.2013.07.017
PMCID: PMC3845089  PMID: 24035353
8.  Targeted Disruption of the EZH2/EED Complex Inhibits EZH2-dependent Cancer 
Nature chemical biology  2013;9(10):643-650.
Enhancer of zeste homolog2 (EZH2) is the histone lysine N-methyltransferase component of the Polycomb repressive complex 2 (PRC2), which in conjunction with embryonic ectoderm development (EED) and suppressor of zeste 12 homolog (SUZ12), regulates cell lineage determination and homeostasis. Enzymatic hyperactivity has been linked to aberrant repression of tumor suppressor genes in diverse cancers. Here, we report the development of stabilized alpha-helix of EZH2 (SAH-EZH2) peptides that selectively inhibit H3 Lys27 trimethylation by dose-responsively disrupting the EZH2/EED complex and reducing EZH2 protein levels, a mechanism distinct from that reported for small molecule EZH2 inhibitors targeting the enzyme catalytic domain. MLL-AF9 leukemia cells, which are dependent on PRC2, undergo growth arrest and monocyte/macrophage differentiation upon treatment with SAH-EZH2, consistent with observed changes in expression of PRC2-regulated, lineage-specific marker genes. Thus, by dissociating the EZH2/EED complex, we pharmacologically modulate an epigenetic “writer” and suppress PRC2-dependent cancer cell growth.
doi:10.1038/nchembio.1331
PMCID: PMC3778130  PMID: 23974116
9.  Lipid dysfunction and pathogenesis of multiple system atrophy 
Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by the accumulation of α-synuclein protein in the cytoplasm of oligodendrocytes, the myelin-producing support cells of the central nervous system (CNS). The brain is the most lipid-rich organ in the body and disordered metabolism of various lipid constituents is increasingly recognized as an important factor in the pathogenesis of several neurodegenerative diseases. α-Synuclein is a 17 kDa protein with a close association to lipid membranes and biosynthetic processes in the CNS, yet its precise function is a matter of speculation, particularly in oligodendrocytes. α-Synuclein aggregation in neurons is a well-characterized feature of Parkinson’s disease and dementia with Lewy bodies. Epidemiological evidence and in vitro studies of α-synuclein molecular dynamics suggest that disordered lipid homeostasis may play a role in the pathogenesis of α-synuclein aggregation. However, MSA is distinct from other α-synucleinopathies in a number of respects, not least the disparate cellular focus of α-synuclein pathology. The recent identification of causal mutations and polymorphisms in COQ2, a gene encoding a biosynthetic enzyme for the production of the lipid-soluble electron carrier coenzyme Q10 (ubiquinone), puts membrane transporters as central to MSA pathogenesis, although how such transporters are involved in the early myelin degeneration observed in MSA remains unclear. The purpose of this review is to bring together available evidence to explore the potential role of membrane transporters and lipid dyshomeostasis in the pathogenesis of α-synuclein aggregation in MSA. We hypothesize that dysregulation of the specialized lipid metabolism involved in myelin synthesis and maintenance by oligodendrocytes underlies the unique neuropathology of MSA.
doi:10.1186/2051-5960-2-15
PMCID: PMC3922275  PMID: 24502382
Multiple system atrophy; Lipid; α-synuclein; Oligodendrocyte; COQ2; ABCA8
10.  Unique Transcriptome Patterns of the White and Grey Matter Corroborate Structural and Functional Heterogeneity in the Human Frontal Lobe 
PLoS ONE  2013;8(10):e78480.
The human frontal lobe has undergone accelerated evolution, leading to the development of unique human features such as language and self-reflection. Cortical grey matter and underlying white matter reflect distinct cellular compositions in the frontal lobe. Surprisingly little is known about the transcriptomal landscape of these distinct regions. Here, for the first time, we report a detailed transcriptomal profile of the frontal grey (GM) and white matter (WM) with resolution to alternatively spliced isoforms obtained using the RNA-Seq approach. We observed more vigorous transcriptome activity in GM compared to WM, presumably because of the presence of cellular bodies of neurons in the GM and RNA associated with the nucleus and perinuclear space. Among the top differentially expressed genes, we also identified a number of long intergenic non-coding RNAs (lincRNAs), specifically expressed in white matter, such as LINC00162. Furthermore, along with confirmation of expression of known markers for neurons and oligodendrocytes, we identified a number of genes and splicing isoforms that are exclusively expressed in GM or WM with examples of GABRB2 and PAK2 transcripts, respectively. Pathway analysis identified distinct physiological and biochemical processes specific to grey and white matter samples with a prevalence of synaptic processes in GM and myelination regulation and axonogenesis in the WM. Our study also revealed that expression of many genes, for example, the GPR123, is characterized by isoform switching, depending in which structure the gene is expressed. Our report clearly shows that GM and WM have perhaps surprisingly divergent transcriptome profiles, reflecting distinct roles in brain physiology. Further, this study provides the first reference data set for a normal human frontal lobe, which will be useful in comparative transcriptome studies of cerebral disorders, in particular, neurodegenerative diseases.
doi:10.1371/journal.pone.0078480
PMCID: PMC3808538  PMID: 24194939
11.  Endogenous progesterone levels and frontotemporal dementia: modulation of TDP-43 and Tau levels in vitro and treatment of the A315T TARDBP mouse model 
Disease Models & Mechanisms  2013;6(5):1198-1204.
SUMMARY
Frontotemporal dementia (FTD) is associated with motor neurone disease (FTD-MND), corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome (PSPS). Together, this group of disorders constitutes a major cause of young-onset dementia. One of the three clinical variants of FTD is progressive nonfluent aphasia (PNFA), which is focused on in this study. The steroid hormone progesterone (PROG) is known to have an important role as a neurosteroid with potent neuroprotective and promyelination properties. In a case-control study of serum samples (39 FTD, 91 controls), low serum PROG was associated with FTD overall. In subgroup analysis, low PROG levels were significantly associated with FTD-MND and CBS, but not with PSPS or PNFA. PROG levels of >195 pg/ml were significantly correlated with lower disease severity (frontotemporal dementia rating scale) for individuals with CBS. In the human neuroblastoma SK-N-MC cell line, exogenous PROG (9300–93,000 pg/ml) had a significant effect on overall Tau and nuclear TDP-43 levels, reducing total Tau levels by ∼1.5-fold and increasing nuclear TDP-43 by 1.7- to 2.0-fold. Finally, elevation of plasma PROG to a mean concentration of 5870 pg/ml in an Ala315Thr (A315T) TARDBP transgenic mouse model significantly reduced the rate of loss of locomotor control in PROG-treated, compared with placebo, mice. The PROG treatment did not significantly increase survival of the mice, which might be due to the limitation of the transgenic mouse to accurately model TDP-43-mediated neurodegeneration. Together, our clinical, cellular and animal data provide strong evidence that PROG could be a valid therapy for specific related disorders of FTD.
doi:10.1242/dmm.011460
PMCID: PMC3759339  PMID: 23798570
12.  Transcriptome Analysis of the Small Brown Planthopper, Laodelphax striatellus Carrying Rice stripe virus 
The Plant Pathology Journal  2013;29(3):330-337.
Rice stripe virus (RSV), the type member of the genus Tenuivirus, transmits by the feeding behavior of small brown planthopper (SBPH), Laodelphax striatellus. To investigate the interactions between the virus and vector insect, total RNA was extracted from RSV-viruliferous SBPH (RVLS) and non-viruliferous SBPH (NVLS) adults to construct expressed sequence tag databases for comparative transcriptome analysis. Over 30 million bases were sequenced by 454 pyrosequencing to construct 1,538 and 953 of isotigs from the mRNA of RVLS and NVLS, respectively. The gene ontology (GO) analysis demonstrated that both libraries have similar GO structures, however, the gene expression pattern analysis revealed that 17.8% and 16.8% of isotigs were up- and down-regulated significantly in the RVLS, respectively. These RSV-dependently regulated genes possibly have important roles in the physiology of SBPH, transmission of RSV, and RSV and SBPH interaction.
doi:10.5423/PPJ.NT.01.2013.0001
PMCID: PMC4174806  PMID: 25288960
Laodelphax striatellus; Rice stripe virus; small brown planthopper; tenuivirus; transcriptome
13.  Modulation of Protease Activated Receptor 1 Influences Human Metapneumovirus Disease Severity in a Mouse Model 
PLoS ONE  2013;8(8):e72529.
Human metapneumovirus (hMPV) infection causes acute respiratory tract infections (RTI) which can result in hospitalization of both children and adults. To date, no antiviral or vaccine is available for this common viral infection. Immunomodulators could represent an interesting strategy for the treatment of severe viral infection. Recently, the role of protease-activated receptors (PAR) in inflammation, coagulation and infection processes has been of growing interest. Herein, the effects of a PAR1 agonist and a PAR1 antagonist on hMPV infection were investigated in BALB/c mice. Intranasal administration of the PAR1 agonist resulted in increased weight loss and mortality of infected mice. Conversely, the PAR1 antagonist was beneficial to hMPV infection by decreasing weight loss and clinical signs and by significantly reducing pulmonary inflammation, pro-inflammatory cytokine levels (including IL-6, KC and MCP-1) and recruitment of immune cells to the lungs. In addition, a significant reduction in pulmonary viral titers was also observed in the lungs of PAR1 antagonist-treated mice. Despite no apparent direct effect on virus replication during in vitro experiments, an important role for PAR1 in the regulation of furin expression in the lungs was shown for the first time. Further experiments indicated that the hMPV fusion protein can be cleaved by furin thus suggesting that PAR1 could have an effect on viral infectivity in addition to its immunomodulatory properties. Thus, inhibition of PAR1 by selected antagonists could represent an interesting strategy for decreasing the severity of paramyxovirus infections.
doi:10.1371/journal.pone.0072529
PMCID: PMC3755973  PMID: 24015257
14.  Elevation in Sphingomyelin Synthase Activity Is Associated with Increases in Amyloid-Beta Peptide Generation 
PLoS ONE  2013;8(8):e74016.
A pathological hallmark of Alzheimer’s disease (AD) is the presence of amyloid-beta peptide (Aβ) plaques in the brain. Aβ is derived from a sequential proteolysis of the transmenbrane amyloid precursor protein (APP), a process which is dependent on the distribution of lipids present in the plasma membrane. Sphingomyelin is a major membrane lipid, however its role in APP processing is unclear. Here, we assessed the expression of sphingomyelin synthase (SGMS1; the gene responsible for sphingomyelin synthesis) in human brain and found that it was significantly elevated in the hippocampus of AD brains, but not in the cerebellum. Secondly, we assessed the impact of altering SGMS activity on Aβ generation. Inhibition of SGMS activity significantly reduced the level of Aβ in a dose- and time dependent manner. The decrease in Aβ level occurred without changes in APP expression or cell viability. These results when put together indicate that SGMS activity impacts on APP processing to produce Aβ and it could be a contributing factor in Aβ pathology associated with AD.
doi:10.1371/journal.pone.0074016
PMCID: PMC3748018  PMID: 23977395
15.  Mechanisms of Electroacupuncture-Induced Analgesia on Neuropathic Pain in Animal Model 
Neuropathic pain remains as one of the most difficult clinical pain syndromes to treat. Electroacupuncture (EA), involving endogenous opioids and neurotransmitters in the central nervous system (CNS), is reported to be clinically efficacious in various fields of pain. Although multiple experimental articles were conducted to assess the effect of EA-induced analgesia, no review has been published to assess the efficacy and clarify the mechanism of EA on neuropathic pain. To this aim, this study was firstly designed to evaluate the EA-induced analgesic effect on neuropathic pain and secondly to guide and help future efforts to advance the neuropathic pain treatment. For this purpose, articles referring to the analgesic effect of acupuncture on neuropathic pain and particularly the work performed in our own laboratory were analyzed. Based on the articles reviewed, the role of spinal opioidergic, adrenergic, serotonergic, cholinergic, and GABAergic receptors in the mechanism of EA-induced analgesia was studied. The results of this research demonstrate that μ and δ opioid receptors, α2-adrenoreceptors, 5-HT1A and 5-HT3 serotonergic receptors, M1 muscarinic receptors, and GABAA and GABAB GABAergic receptors are involved in the mechanisms of EA-induced analgesia on neuropathic pain.
doi:10.1155/2013/436913
PMCID: PMC3747484  PMID: 23983779
16.  Loss of Endothelial Furin Leads to Cardiac Malformation and Early Postnatal Death 
Molecular and Cellular Biology  2012;32(17):3382-3391.
In mammals, seven proprotein convertases (PCs) cleave secretory proteins after basic residues, and four of them are called furin-like PCs: furin, PC5, PACE4, and PC7. In vitro, they share many substrates. However, furin is essential during development since deficient embryos die at embryonic day 11 and exhibit multiple developmental defects, particularly defects related to the function of endothelial cells. To define the role of furin in endothelial cells, an endothelial cell-specific knockout (ecKO) of the Furin gene was generated. Newborns die shortly after birth, indicating that furin is essential in these cells. Magnetic resonance imaging revealed that ecKO embryos exhibit ventricular septal defects (VSD) and/or valve malformations. In addition, primary cultures of wild-type and ecKO lung endothelial cells revealed that ecKO cells are unable to grow. Growth was efficiently rescued by extracellular soluble furin. Analysis of the processing of precursors of endothelin-1 (ET-1), adrenomedullin (Adm), transforming growth factor β1 (TGF-β1), and bone morphogenetic protein 4 (BMP4) confirmed that ET-1, Adm, and TGF-β1 are in vivo substrates of endothelial furin. Mature ET-1 and BMP4 forms were reduced by ∼90% in ecKO purified endothelial cells from lungs.
doi:10.1128/MCB.06331-11
PMCID: PMC3422005  PMID: 22733989
17.  An Algorithm for Intelligent Sorting of CT-Related Dose Parameters 
Journal of Digital Imaging  2011;25(1):179-188.
Imaging centers nationwide are seeking innovative means to record and monitor computed tomography (CT)-related radiation dose in light of multiple instances of patient overexposure to medical radiation. As a solution, we have developed RADIANCE, an automated pipeline for extraction, archival, and reporting of CT-related dose parameters. Estimation of whole-body effective dose from CT dose length product (DLP)—an indirect estimate of radiation dose—requires anatomy-specific conversion factors that cannot be applied to total DLP, but instead necessitate individual anatomy-based DLPs. A challenge exists because the total DLP reported on a dose sheet often includes multiple separate examinations (e.g., chest CT followed by abdominopelvic CT). Furthermore, the individual reported series DLPs may not be clearly or consistently labeled. For example, “arterial” could refer to the arterial phase of the triple liver CT or the arterial phase of a CT angiogram. To address this problem, we have designed an intelligent algorithm to parse dose sheets for multi-series CT examinations and correctly separate the total DLP into its anatomic components. The algorithm uses information from the departmental PACS to determine how many distinct CT examinations were concurrently performed. Then, it matches the number of distinct accession numbers to the series that were acquired and anatomically matches individual series DLPs to their appropriate CT examinations. This algorithm allows for more accurate dose analytics, but there remain instances where automatic sorting is not feasible. To ultimately improve radiology patient care, we must standardize series names and exam names to unequivocally sort exams by anatomy and correctly estimate whole-body effective dose.
doi:10.1007/s10278-011-9410-1
PMCID: PMC3264706  PMID: 21796491
RADIANCE; Computed tomography; Dose monitoring; CT series separation; Radiation dose; Data extraction; Databases
18.  Automated Detection of Critical Results in Radiology Reports 
Journal of Digital Imaging  2011;25(1):30-36.
The goal of this study was to develop and validate text-mining algorithms to automatically identify radiology reports containing critical results including tension or increasing/new large pneumothorax, acute pulmonary embolism, acute cholecystitis, acute appendicitis, ectopic pregnancy, scrotal torsion, unexplained free intraperitoneal air, new or increasing intracranial hemorrhage, and malpositioned tubes and lines. The algorithms were developed using rule-based approaches and designed to search for common words and phrases in radiology reports that indicate critical results. Certain text-mining features were utilized such as wildcards, stemming, negation detection, proximity matching, and expanded searches with applicable synonyms. To further improve accuracy, the algorithms utilized modality and exam-specific queries, searched under the “Impression” field of the radiology report, and excluded reports with a low level of diagnostic certainty. Algorithm accuracy was determined using precision, recall, and F-measure using human review as the reference standard. The overall accuracy (F-measure) of the algorithms ranged from 81% to 100%, with a mean precision and recall of 96% and 91%, respectively. These algorithms can be applied to radiology report databases for quality assurance and accreditation, integrated with existing dashboards for display and monitoring, and ported to other institutions for their own use.
doi:10.1007/s10278-011-9426-6
PMCID: PMC3264731  PMID: 22038514
Algorithms; Communication; Critical Results Reporting; Data Mining; Natural Language Processing; Quality Assurance; Quality Control
19.  Development of Automated Detection of Radiology Reports Citing Adrenal Findings 
Journal of Digital Imaging  2011;25(1):43-49.
The aim of this study was to determine the feasibility of automated detection of adrenal nodules, a common finding on CT, using a newly developed search engine that mines dictated radiology reports. To ensure Health Insurance Portability and Accountability Act compliance, we utilized a preexisting de-identified database of 32,974 CT reports from February 1, 2009 to February 28, 2010. Common adrenal descriptors from 29 staff radiologists were used to develop an automated rule-based algorithm targeting adrenal findings. Each sentence within the free text of reports was searched with an adapted NegEx negation algorithm. The algorithm was refined using a 2-week test period of reports and subsequently validated using a 6-week period. Manual review of the 3,693 CT reports in the validation period identified 222 positive reports while the algorithm detected 238 positive reports. The algorithm identified one true positive report missed on manual review for a total of 223 true positive reports. This resulted in a precision of 91% (217 of 238) and a recall of 97% (217 of 223). The sensitivity of the query was 97.3% (95% confidence interval (CI), 93.9–98.9%), and the specificity was 99.3% (95% CI, 99.1–99.6%). The positive predictive value of the algorithm was 91.0% (95% CI, 86.6–94.3%), and the negative predictive value was 99.8% (95% CI, 99.6–99.9%). The prevalence of true positive adrenal findings identified by the query (7.1%) was nearly identical to the true prevalence (7.2%). Automated detection of language describing common findings in imaging reports, such as adrenal nodules on CT, is feasible.
doi:10.1007/s10278-011-9425-7
PMCID: PMC3264732  PMID: 22042494
Data mining; Radiology information systems (RIS); Natural language; Processing; Computed tomography; Radiology reporting; Adrenal nodules; Negation algorithm; Unstructured radiology reports
20.  Orion: A Web-Based Application Designed to Monitor Resident and Fellow Performance On-Call 
Journal of Digital Imaging  2011;24(5):897-907.
Radiology residency and fellowship training provides a unique opportunity to evaluate trainee performance and determine the impact of various educational interventions. We have developed a simple software application (Orion) using open-source tools to facilitate the identification and monitoring of resident and fellow discrepancies in on-call preliminary reports. Over a 6-month period, 19,200 on-call studies were interpreted by 20 radiology residents, and 13,953 on-call studies were interpreted by 25 board-certified radiology fellows representing eight subspecialties. Using standard review macros during faculty interpretation, each of these reports was classified as “agreement”, “minor discrepancy”, and “major discrepancy” based on the potential to impact patient management or outcome. Major discrepancy rates were used to establish benchmarks for resident and fellow performance by year of training, modality, and subspecialty, and to identify residents and fellows demonstrating a significantly higher major discrepancy rate compared with their classmates. Trends in discrepancies were used to identify subspecialty-specific areas of increased major discrepancy rates in an effort to tailor the didactic and case-based curriculum. A series of missed-case conferences were developed based on trends in discrepancies, and the impact of these conferences is currently being evaluated. Orion is a powerful information technology tool that can be used by residency program directors, fellowship programs directors, residents, and fellows to improve radiology education and training.
doi:10.1007/s10278-011-9360-7
PMCID: PMC3180545  PMID: 21249419
Software design; Quality improvement; Residency; Medical informatics applications; Natural language processing; Performance measurement; Discrepancies; Performance; Web-based; Residents
21.  Role of Abca7 in Mouse Behaviours Relevant to Neurodegenerative Diseases 
PLoS ONE  2012;7(9):e45959.
ATP-binding cassette transporters of the subfamily A (ABCA) are responsible for the translocation of lipids including cholesterol, which is crucial for neurological function. Recent studies suggest that the ABC transporter ABCA7 may play a role in the development of brain disorders such as schizophrenia and Alzheimer’s disease. However, Abca7’s role in cognition and other behaviours has not been investigated. Therefore, we characterised homozygous Abca7 knockout mice in a battery of tests for baseline behaviours (i.e. physical exam, baseline locomotion and anxiety) and behaviours relevant to schizophrenia (i.e. prepulse inhibition and locomotor response to psychotropic drugs) and Alzheimer’s disease (i.e. cognitive domains). Knockout mice had normal motor functions and sensory abilities and performed the same as wild type-like animals in anxiety tasks. Short-term spatial memory and fear-associated learning was also intact in Abca7 knockout mice. However, male knockout mice exhibited significantly impaired novel object recognition memory. Task acquisition was unaffected in the cheeseboard task. Female mice exhibited impaired spatial reference memory. This phenomenon was more pronounced in female Abca7 null mice. Acoustic startle response, sensorimotor gating and baseline locomotion was unaltered in Abca7 knockout mice. Female knockouts showed a moderately increased motor response to MK-801 than control mice. In conclusion, Abca7 appears to play only a minor role in behavioural domains with a subtle sex-specific impact on particular cognitive domains.
doi:10.1371/journal.pone.0045959
PMCID: PMC3454356  PMID: 23029339
22.  HelicoVax: Epitope-based therapeutic H. pylori vaccination in a mouse model 
Vaccine  2011;29(11):2085-2091.
Helicobacter pylori is the leading cause of gastritis, peptic ulcer disease and gastric adenocarcinoma and lymphoma in humans. Due to the decreasing efficacy of anti-H. pylori antibiotic therapy in clinical practice, there is renewed interest in the development of anti-H. pylori vaccines. In this study an in silico-based approach was utilized to develop a multi-epitope DNA-prime/peptide-boost immunization strategy using informatics tools. The efficacy of this construct was then assessed as a therapeutic vaccine in a mouse model of gastric cancer induced by chronic H. pylori infection. The multi-epitope vaccine administered intranasally induced a broad immune response as determined by interferon-gamma production in ELISpot assays. This was associated with a significant reduction in H. pylori colonization compared with mice immunized with the same vaccine intramuscularly, given an empty plasmid, or given a whole H. pylori lysate intranasally as the immunogen. Total scores of gastric histological changes were not significantly different among the 4 experimental groups. These results suggest that further development of an epitope-based mucosal vaccine may be beneficial in eradicating H. pylori and reducing the burden of the associated gastric diseases in humans.
doi:10.1016/j.vaccine.2010.12.130
PMCID: PMC3046230  PMID: 21236233
23.  Ontology-Assisted Analysis of Web Queries to Determine the Knowledge Radiologists Seek 
Journal of Digital Imaging  2010;24(1):160-164.
Radiologists frequently search the Web to find information they need to improve their practice, and knowing the types of information they seek could be useful for evaluating Web resources. Our goal was to develop an automated method to categorize unstructured user queries using a controlled terminology and to infer the type of information users seek. We obtained the query logs from two commonly used Web resources for radiology. We created a computer algorithm to associate RadLex-controlled vocabulary terms with the user queries. Using the RadLex hierarchy, we determined the high-level category associated with each RadLex term to infer the type of information users were seeking. To test the hypothesis that the term category assignments to user queries are non-random, we compared the distributions of the term categories in RadLex with those in user queries using the chi square test. Of the 29,669 unique search terms found in user queries, 15,445 (52%) could be mapped to one or more RadLex terms by our algorithm. Each query contained an average of one to two RadLex terms, and the dominant categories of RadLex terms in user queries were diseases and anatomy. While the same types of RadLex terms were predominant in both RadLex itself and user queries, the distribution of types of terms in user queries and RadLex were significantly different (p < 0.0001). We conclude that RadLex can enable processing and categorization of user queries of Web resources and enable understanding the types of information users seek from radiology knowledge resources on the Web.
doi:10.1007/s10278-010-9289-2
PMCID: PMC3046796  PMID: 20354755
Ontologies; terminologies; vocabularies; RadLex; software tools; controlled vocabulary; natural language processing; web technology
24.  Analysis of the Genome of the Sexually Transmitted Insect Virus Helicoverpa zea Nudivirus 2 
Viruses  2012;4(1):28-61.
The sexually transmitted insect virus Helicoverpa zea nudivirus 2 (HzNV-2) was determined to have a circular double-stranded DNA genome of 231,621 bp coding for an estimated 113 open reading frames (ORFs). HzNV-2 is most closely related to the nudiviruses, a sister group of the insect baculoviruses. Several putative ORFs that share homology with the baculovirus core genes were identified in the viral genome. However, HzNV-2 lacks several key genetic features of baculoviruses including the late transcriptional regulation factor, LEF-1 and the palindromic hrs, which serve as origins of replication. The HzNV-2 genome was found to code for three ORFs that had significant sequence homology to cellular genes which are not generally found in viral genomes. These included a presumed juvenile hormone esterase gene, a gene coding for a putative zinc-dependent matrix metalloprotease, and a major facilitator superfamily protein gene; all of which are believed to play a role in the cellular proliferation and the tissue hypertrophy observed in the malformation of reproductive organs observed in HzNV-2 infected corn earworm moths, Helicoverpa zea.
doi:10.3390/v4010028
PMCID: PMC3280521  PMID: 22355451
nudivirus; sterile insects; baculovirus; sexually transmitted virus; virus genome; juvenile hormone esterase; HzNV-2; HzNV-1; corn earworm; Helicoverpa zea
25.  Lipid Pathway Alterations in Parkinson's Disease Primary Visual Cortex 
PLoS ONE  2011;6(2):e17299.
Background
We present a lipidomics analysis of human Parkinson's disease tissues. We have focused on the primary visual cortex, a region that is devoid of pathological changes and Lewy bodies; and two additional regions, the amygdala and anterior cingulate cortex which contain Lewy bodies at different disease stages but do not have as severe degeneration as the substantia nigra.
Methodology/Principal Findings
Using liquid chromatography mass spectrometry lipidomics techniques for an initial screen of 200 lipid species, significant changes in 79 sphingolipid, glycerophospholipid and cholesterol species were detected in the visual cortex of Parkinson's disease patients (n = 10) compared to controls (n = 10) as assessed by two-sided unpaired t-test (p-value <0.05). False discovery rate analysis confirmed that 73 of these 79 lipid species were significantly changed in the visual cortex (q-value <0.05). By contrast, changes in 17 and 12 lipid species were identified in the Parkinson's disease amygdala and anterior cingulate cortex, respectively, compared to controls; none of which remained significant after false discovery rate analysis. Using gas chromatography mass spectrometry techniques, 6 out of 7 oxysterols analysed from both non-enzymatic and enzymatic pathways were also selectively increased in the Parkinson's disease visual cortex. Many of these changes in visual cortex lipids were correlated with relevant changes in the expression of genes involved in lipid metabolism and an oxidative stress response as determined by quantitative polymerase chain reaction techniques.
Conclusions/Significance
The data indicate that changes in lipid metabolism occur in the Parkinson's disease visual cortex in the absence of obvious pathology. This suggests that normalization of lipid metabolism and/or oxidative stress status in the visual cortex may represent a novel route for treatment of non-motor symptoms, such as visual hallucinations, that are experienced by a majority of Parkinson's disease patients.
doi:10.1371/journal.pone.0017299
PMCID: PMC3046155  PMID: 21387008

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