Distinct Changes in Calpain and Calpastatin during PNS Myelination and Demyelination in Rodent Models.

Myelin forming around axons provides electrical insulation and ensures rapid and efficient transmission of electrical impulses. Disruptions to myelinated nerves often result in nerve conduction failure along with neurological symptoms and long-term disability. In the central nervous system, calpains, a family of calcium dependent cysteine proteases, have been shown to have a role in developmental myelination and in demyelinating diseases. The roles of calpains in myelination and demyelination in the peripheral nervous system remain unclear. Here, we show a transient increase of activated CAPN1, a major calpain isoform, in postnatal rat sciatic nerves when myelin is actively formed. Expression of the endogenous calpain inhibitor, calpastatin, showed a steady decrease throughout the period of peripheral nerve development. In the sciatic nerves of Trembler-J mice characterized by dysmyelination, expression levels of CAPN1 and calpastatin and calpain activity were significantly increased. In lysolecithin-induced acute demyelination in adult rat sciatic nerves, we show an increase of CAPN1 and decrease of calpastatin expression. These changes in the calpain-calpastatin system are distinct from those during central nervous system development or in acute axonal degeneration in peripheral nerves. Our results suggest that the calpain-calpastatin system has putative roles in myelination and demyelinating diseases of peripheral nerves.

Sensitization of depressive-like behavior is attenuated by disruption of prostaglandin synthesis days following brief early attachment-figure isolation.

Childhood psychological trauma appears to sensitize stress-related neuroinflammatory systems to increase later vulnerability for depression and other stress-related mental disorders. Isolation of guinea pig pups from the maternal attachment figure for 3 h in threatening surroundings leads to a sensitization of inflammatory-mediated, depressive-like behavior and fever during later isolations. A previous study found the non-selective COX inhibitor naproxen administered before the initial isolation moderated depressive-like behavior and its sensitization. Here, we examined effects of naproxen given following early isolation. Male and female guinea pig pups surgically implanted with telemetry devices to measure core temperature were isolated for 3 h on 2 consecutive days near weaning (first isolation Day 20-24). Several days later, they began 4 consecutive days of injection with either saline vehicle or 10 or 20 mg/kg naproxen prior to a third isolation in early adolescence, that is, 10 days after their first isolation. Across the first two isolations, depressive-like behavior and fever sensitized. Both doses of naproxen attenuated depressive-like behavior during the third isolation. Fever was unaffected. Results suggest prostaglandin mediation of sensitization of depressive-like behavioral, but not febrile, responses to subsequent isolation. Findings also support further study of anti-inflammatory treatments to mitigate lasting consequences of early-attachment disruption.

The Type 2 Diabetes Factor Methylglyoxal Mediates Axon Initial Segment Shortening and Alters Neuronal Function at the Cellular and Network Levels.

Recent evidence suggests that alteration of axon initial segment (AIS) geometry (i.e., length or location along the axon) contributes to CNS dysfunction in neurological diseases. For example, AIS length is shorter in the prefrontal cortex of type 2 diabetic mice with cognitive impairment. To determine the key type 2 diabetes-related factor that produces AIS shortening we modified levels of insulin, glucose, or the reactive glucose metabolite methylglyoxal in cultures of dissociated cortices from male and female mice and quantified AIS geometry using immunofluorescent imaging of the AIS proteins AnkyrinG and ßIV spectrin. Neither insulin nor glucose modification altered AIS length. Exposure to 100 but not 1 or 10 µm methylglyoxal for 24 h resulted in accumulation of the methylglyoxal-derived advanced glycation end-product hydroimidazolone and produced reversible AIS shortening without cell death. Methylglyoxal-evoked AIS shortening occurred in both excitatory and putative inhibitory neuron populations and in the presence of tetrodotoxin (TTX). In single-cell recordings resting membrane potential was depolarized at 0.5-3 h and returned to normal at 24 h. In multielectrode array (MEA) recordings methylglyoxal produced an immediate ∼300% increase in spiking and bursting rates that returned to normal within 2 min, followed by a ∼20% reduction of network activity at 0.5-3 h and restoration of activity to baseline levels at 24 h. AIS length was unchanged at 0.5-3 h despite the presence of depolarization and network activity reduction. Nevertheless, these results suggest that methylglyoxal could be a key mediator of AIS shortening and disruptor of neuronal function during type 2 diabetes.

Mechanical Low Back Pain.

Low back pain is usually nonspecific or mechanical. Mechanical low back pain arises intrinsically from the spine, intervertebral disks, or surrounding soft tissues. Clinical clues, or red flags, may help identify cases of nonmechanical low back pain and prompt further evaluation or imaging. Red flags include progressive motor or sensory loss, new urinary retention or overflow incontinence, history of cancer, recent invasive spinal procedure, and significant trauma relative to age. Imaging on initial presentation should be reserved for when there is suspicion for cauda equina syndrome, malignancy, fracture, or infection. Plain radiography of the lumbar spine is appropriate to assess for fracture and bony abnormality, whereas magnetic resonance imaging is better for identifying the source of neurologic or soft tissue abnormalities. There are multiple treatment modalities for mechanical low back pain, but strong evidence of benefit is often lacking. Moderate evidence supports the use of nonsteroidal anti-inflammatory drugs, opioids, and topiramate in the short-term treatment of mechanical low back pain. There is little or no evidence of benefit for acetaminophen, antidepressants (except duloxetine), skeletal muscle relaxants, lidocaine patches, and transcutaneous electrical nerve stimulation in the treatment of chronic low back pain. There is strong evidence for short-term effectiveness and moderate-quality evidence for long-term effectiveness of yoga in the treatment of chronic low back pain. Various spinal manipulative techniques (osteopathic manipulative treatment, spinal manipulative therapy) have shown mixed benefits in the acute and chronic setting. Physical therapy modalities such as the McKenzie method may decrease the recurrence of low back pain and health care expenditures. Physical therapy modalities such as the McKenzie method may decrease the recurrence of low back pain and use of health care. Educating patients on prognosis and incorporating psychosocial components of care such as identifying comorbid psychological problems and barriers to treatment are essential components of long-term management.

GLYDE-II: The GLYcan data exchange format.

The GLYcan Data Exchange (GLYDE) standard has been developed for the representation of the chemical structures of monosaccharides, glycans and glycoconjugates using a connection table formalism formatted in XML. This format allows structures, including those that do not exist in any database, to be unambiguously represented and shared by diverse computational tools. GLYDE implements a partonomy model based on human language along with rules that provide consistent structural representations, including a robust namespace for specifying monosaccharides. This approach facilitates the reuse of data processing software at the level of granularity that is most appropriate for extraction of the desired information. GLYDE-II has already been used as a key element of several glycoinformatics tools. The philosophical and technical underpinnings of GLYDE-II and recent implementation of its enhanced features are described.

Automated Predictive Big Data Analytics Using Ontology Based Semantics.

Predictive analytics in the big data era is taking on an ever increasingly important role. Issues related to choice on modeling technique, estimation procedure (or algorithm) and efficient execution can present significant challenges. For example, selection of appropriate and optimal models for big data analytics often requires careful investigation and considerable expertise which might not always be readily available. In this paper, we propose to use semantic technology to assist data analysts and data scientists in selecting appropriate modeling techniques and building specific models as well as the rationale for the techniques and models selected. To formally describe the modeling techniques, models and results, we developed the Analytics Ontology that supports inferencing for semi-automated model selection. The SCALATION framework, which currently supports over thirty modeling techniques for predictive big data analytics is used as a testbed for evaluating the use of semantic technology.

Qrator: a web-based curation tool for glycan structures.

Most currently available glycan structure databases use their own proprietary structure representation schema and contain numerous annotation errors. These cause problems when glycan databases are used for the annotation or mining of data generated in the laboratory. Due to the complexity of glycan structures, curating these databases is often a tedious and labor-intensive process. However, rigorously validating glycan structures can be made easier with a curation workflow that incorporates a structure-matching algorithm that compares candidate glycans to a canonical tree that embodies structural features consistent with established mechanisms for the biosynthesis of a particular class of glycans. To this end, we have implemented Qrator, a web-based application that uses a combination of external literature and database references, user annotations and canonical trees to assist and guide researchers in making informed decisions while curating glycans. Using this application, we have started the curation of large numbers of N-glycans, O-glycans and glycosphingolipids. Our curation workflow allows creating and extending canonical trees for these classes of glycans, which have subsequently been used to improve the curation workflow.

EUROCarbDB(CCRC): a EUROCarbDB node for storing glycomics standard data.

MOTIVATION: In the field of glycomics research, several different techniques are used for structure elucidation. Although multiple techniques are often used to increase confidence in structure assignments, most glycomics databases allow storing of only a single type of experimental data. In addition, the methods used to prepare a sample for analysis is seldom recorded making it harder to reproduce the analytical data and results. RESULTS: We have extended the freely available EUROCarbDB framework to allow the submission of experimental data and the reporting of several orthogonal experimental datasets. The features aim to increase the understandability and reproducibility of the reported data. AVAILABILITY AND IMPLEMENTATION: The installation with the glycan standards is available at http://glycomics.ccrc.uga.edu/eurocarb/. The source code of the project is available at https://code.google.com/p/ucdb/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Computed tomographic angiography identification of intramural segments in anomalous coronary arteries with interarterial course.

Certain coronary anomalies are associated with high risk features. We sought to determine the diagnostic accuracy of coronary computed tomographic angiography (CTA) in determining high-risk features, particularly intramural segments. Anomalous coronary arteries can be associated with adverse clinical events. Anomalous coronaries that course between the great vessels (interarterial) have been associated with sudden death. High-risk features of interarterial vessels described in the literature include; a slit-like orifice, acute angle of origin, and intramural segments (within the wall of the aorta). Although computed tomography (CT) findings of acute angle and slit like orifice have been described previously no prior evaluations regarding CT identification of an intramural segment have been reported. An intramural segment has distinct surgical management implications. All interarterial anomalous coronary arteries do not have an intramural segment. Since October 2004, 15 patients were diagnosed by CTA as having an anomalous coronary artery with an interarterial course, which were then confirmed by intraoperative examination of their coronary origins and course during aortic root/coronary artery surgery. The CTA images were retrospectively analyzed for the presence of high-risk features by a radiologist blinded to the surgical findings. Comparison of these findings was made to the findings at surgery. The anomalous coronary was the right coronary artery in 10 patients and the left coronary artery in 5. Eleven patients had an intramural segment identified at surgery. Pre-operative coronary CTA showed that all patients with an intramural course of the anomalous artery, had slit-like orifice, an acute angle of origin (mean 18.4 ± 3.4°), and an elliptical shaped cross-section throughout the intramural segment of the anomalous vessel. The average vessel height/width ratio for anomalous coronary vessels without an intramural segment was 1.03; compared to a ratio of 2.19 for anomalous vessels with an intramural segment (P = 0.003). Coronary CTA can identify an intramural segment of an anomalous interarterial coronary artery by its elliptical shape. Identifying an intramural segment has important clinical and surgical implications.

Recurrent pulmonary intimal sarcoma involving the right ventricular outflow tract.

Intimal sarcoma of the pulmonary artery is commonly misdiagnosed as chronic pulmonary embolism. Rarely, it can involve the right ventricular outflow tract and the pulmonary valve. We report a patient who was treated surgically for an intimal sarcoma of the pulmonary artery involving the right ventricular outflow tract and the pulmonary valve. The sarcoma recurred in about 8 weeks. It responded favorably to chemoradiation therapy and shows some signs of regression.

Paradoxical embolus caught in transit through a patent foramen ovale.

Diagnosing a paradoxical embolism is challenging, and it can be proven only if the thrombus is identified across the intracardiac defect. Very few cases have been diagnosed as an impending paradoxical embolism. Recently, the diagnosis and management of these entities have greatly improved with the advent of transesophageal echocardiography (compared with transthoracic echocardiography). Pulmonary hypertension may cause right-to-left shunting across a patent foramen ovale and predispose development of a paradoxical embolism. We report a patient with an impending paradoxical embolism that was caught in transit across the patent foramen ovale. The patient was treated successfully with emergent surgery.

DeMO: An Ontology for Discrete-event Modeling and Simulation.

Several fields have created ontologies for their subdomains. For example, the biological sciences have developed extensive ontologies such as the Gene Ontology, which is considered a great success. Ontologies could provide similar advantages to the Modeling and Simulation community. They provide a way to establish common vocabularies and capture knowledge about a particular domain with community-wide agreement. Ontologies can support significantly improved (semantic) search and browsing, integration of heterogeneous information sources, and improved knowledge discovery capabilities. This paper discusses the design and development of an ontology for Modeling and Simulation called the Discrete-event Modeling Ontology (DeMO), and it presents prototype applications that demonstrate various uses and benefits that such an ontology may provide to the Modeling and Simulation community.

Evaluation of coronary CTA Appropriateness Criteria in an academic medical center.

BACKGROUND: The aim of this study was to evaluate published appropriateness criteria for CT angiography (CTA) at the authors' academic medical center. METHODS: Two observers independently reviewed the medical records of 251 patients who had undergone dual-source coronary CTA from June 1 to December 31, 2007. Patients were assigned to indications from 1 of 7 tables from the American College of Cardiology Foundation and ACR Appropriateness Criteria. Agreement between the two observers was assessed using kappa statistics. Disagreements were resolved by consensus panel. The final numbers of appropriate, uncertain, inappropriate, and not classifiable indications were recorded. RESULTS: Indications for testing were classified as appropriate in 69 patients (27%), inappropriate in 42 patients (17%), and uncertain in 25 patients (10%). One hundred fifteen indications for coronary CTA (46%) were not classifiable. Analysis of interobserver variability for overall appropriateness yielded a kappa value of 0.31, which was considered to indicate fair agreement. CONCLUSION: The results of this study suggest that a significant proportion (46%) of the coronary CTA studies performed at the authors' institution are for indications that are not covered by the published appropriateness criteria. Modifications to these criteria could help decrease the number of studies that are not classifiable. Physician education could decrease the number of inappropriate studies.

EuPathDB: a portal to eukaryotic pathogen databases.

EuPathDB (http://EuPathDB.org; formerly ApiDB) is an integrated database covering the eukaryotic pathogens of the genera Cryptosporidium, Giardia, Leishmania, Neospora, Plasmodium, Toxoplasma, Trichomonas and Trypanosoma. While each of these groups is supported by a taxon-specific database built upon the same infrastructure, the EuPathDB portal offers an entry point to all these resources, and the opportunity to leverage orthology for searches across genera. The most recent release of EuPathDB includes updates and changes affecting data content, infrastructure and the user interface, improving data access and enhancing the user experience. EuPathDB currently supports more than 80 searches and the recently-implemented 'search strategy' system enables users to construct complex multi-step searches via a graphical interface. Search results are dynamically displayed as the strategy is constructed or modified, and can be downloaded, saved, revised, or shared with other database users.

TriTrypDB: a functional genomic resource for the Trypanosomatidae.

TriTrypDB (http://tritrypdb.org) is an integrated database providing access to genome-scale datasets for kinetoplastid parasites, and supporting a variety of complex queries driven by research and development needs. TriTrypDB is a collaborative project, utilizing the GUS/WDK computational infrastructure developed by the Eukaryotic Pathogen Bioinformatics Resource Center (EuPathDB.org) to integrate genome annotation and analyses from GeneDB and elsewhere with a wide variety of functional genomics datasets made available by members of the global research community, often pre-publication. Currently, TriTrypDB integrates datasets from Leishmania braziliensis, L. infantum, L. major, L. tarentolae, Trypanosoma brucei and T. cruzi. Users may examine individual genes or chromosomal spans in their genomic context, including syntenic alignments with other kinetoplastid organisms. Data within TriTrypDB can be interrogated utilizing a sophisticated search strategy system that enables a user to construct complex queries combining multiple data types. All search strategies are stored, allowing future access and integrated searches. 'User Comments' may be added to any gene page, enhancing available annotation; such comments become immediately searchable via the text search, and are forwarded to curators for incorporation into the reference annotation when appropriate.

GiardiaDB and TrichDB: integrated genomic resources for the eukaryotic protist pathogens Giardia lamblia and Trichomonas vaginalis.

GiardiaDB (http://GiardiaDB.org) and TrichDB (http://TrichDB.org) house the genome databases for Giardia lamblia and Trichomonas vaginalis, respectively, and represent the latest additions to the EuPathDB (http://EuPathDB.org) family of functional genomic databases. GiardiaDB and TrichDB employ the same framework as other EuPathDB sites (CryptoDB, PlasmoDB and ToxoDB), supporting fully integrated and searchable databases. Genomic-scale data available via these resources may be queried based on BLAST searches, annotation keywords and gene ID searches, GO terms, sequence motifs and other protein characteristics. Functional queries may also be formulated, based on transcript and protein expression data from a variety of platforms. Phylogenetic relationships may also be interrogated. The ability to combine the results from independent queries, and to store queries and query results for future use facilitates complex, genome-wide mining of functional genomic data.

PlasmoDB: a functional genomic database for malaria parasites.

PlasmoDB (http://PlasmoDB.org) is a functional genomic database for Plasmodium spp. that provides a resource for data analysis and visualization in a gene-by-gene or genome-wide scale. PlasmoDB belongs to a family of genomic resources that are housed under the EuPathDB (http://EuPathDB.org) Bioinformatics Resource Center (BRC) umbrella. The latest release, PlasmoDB 5.5, contains numerous new data types from several broad categories--annotated genomes, evidence of transcription, proteomics evidence, protein function evidence, population biology and evolution. Data in PlasmoDB can be queried by selecting the data of interest from a query grid or drop down menus. Various results can then be combined with each other on the query history page. Search results can be downloaded with associated functional data and registered users can store their query history for future retrieval or analysis.

Mapping by sequencing the Pneumocystis genome using the ordering DNA sequences V3 tool.

A bioinformatics tool called ODS3 has been created for mapping by sequencing. The tool allows the creation of integrated genomic maps from genetic, physical mapping, and sequencing data and permits an integrated genome map to be stored, retrieved, viewed, and queried in a stand-alone capacity, in a client/server relationship with the Fungal Genome Database (FGDB), and as a web-browsing tool for the FGDB. In that ODS3 is programmed in Java, the tool promotes platform independence and supports export of integrated genome-mapping data in the extensible markup language (XML) for data interchange with other genome information systems. The tool ODS3 is used to create an initial integrated genome map of the AIDS-related fungal pathogen, Pneumocystis carinii. Contig dynamics would indicate that this physical map is approximately 50% complete with approximately 200 contigs. A total of 10 putative multigene families were found. Two of these putative families were previously characterized in P. carinii, namely the major surface glycoproteins (MSGs) and HSP70 proteins; three of these putative families (not previously characterized in P. carinii) were found to be similar to families encoding the HSP60 in Schizosaccharomyces pombe, the heat-shock psi protein in S. pombe, and the RNA synthetase family (i.e., MES1) in Saccharomyces cerevisiae. Physical mapping data are consistent with the 16S, 5.8S, and 26S rDNA genes being single copy in P. carinii. No other fungus outside this genus is known to have the rDNA genes in single copy.