Inter-rater agreement for the annotation of neurologic signs and symptoms in electronic health records.

The extraction of patient signs and symptoms recorded as free text in electronic health records is critical for precision medicine. Once extracted, signs and symptoms can be made computable by mapping to signs and symptoms in an ontology. Extracting signs and symptoms from free text is tedious and time-consuming.

The visualization of Orphadata neurology phenotypes.

Disease phenotypes are characterized by signs (what a physician observes during the examination of a patient) and symptoms (the complaints of a patient to a physician). Large repositories of disease phenotypes are accessible through the Online Mendelian Inheritance of Man, Human Phenotype Ontology, and Orphadata initiatives. Many of the diseases in these datasets are neurologic.

Subtypes of relapsing-remitting multiple sclerosis identified by network analysis.

We used network analysis to identify subtypes of relapsing-remitting multiple sclerosis subjects based on their cumulative signs and symptoms. The electronic medical records of 113 subjects with relapsing-remitting multiple sclerosis were reviewed, signs and symptoms were mapped to classes in a neuro-ontology, and classes were collapsed into sixteen superclasses by subsumption. After normalization and vectorization of the data, bipartite (subject-feature) and unipartite (subject-subject) network graphs were created using NetworkX and visualized in Gephi.

Differential DNA methylation associated with multiple sclerosis and disease modifying treatments in an underrepresented minority population.

Black and Hispanic American patients frequently develop earlier onset of multiple sclerosis (MS) and a more severe disease course that can be resistant to disease modifying treatments. The objectives were to identify differential methylation of genomic DNA (gDNA) associated with disease susceptibility and treatment responses in a cohort of MS patients from underrepresented minority populations. Patients with MS and controls with non-inflammatory neurologic conditions were consented and enrolled under an IRB-approved protocol.

Regulation of expansion of CD11c B cells and anti-viral immunity by epithelial V-like antigen.

Prior work demonstrated that epithelial V-like antigen (EVA), a cell surface adhesion molecule, is expressed in B lymphocytes and is necessary for the efficacy of anti-alpha integrin treatment of experimental autoimmune encephalomyelitis (EAE), the mouse model of human multiple sclerosis. EVA deficiency is associated with a severe clinical phenotype of EAE in the presence or absence of treatment. Histological analysis revealed enhanced B cell-mediated autoimmunity and deposition of antibody and complement within the brain and spinal cord.

Activation of human macrophage sodium channels regulates RNA processing to increase expression of the DNA repair protein PPP1R10.

Prior work demonstrated that a splice variant of SCN5A, a voltage-gated sodium channel gene, acts as a cytoplasmic sensor for viral dsRNA in human macrophages. Expression of this channel also polarizes macrophages to an anti-inflammatory phenotype in vitro and in vivo. Here we utilized global expression analysis of splice variants to identify novel channel-dependent signaling mechanisms.

A sodium channel variant in Aedes aegypti as a candidate pathogen sensor for viral-associated molecular patterns.

Recent work demonstrated that a splice variant of a human macrophage voltage-gated sodium channel expressed on endosomes acts as an intracellular sensor for dsRNA, a viral-associated molecular pattern. Here our goal was to identify a candidate gene in a clinically relevant invertebrate model with related cellular and pattern recognition properties. The para gene in drosophila and other insects encodes voltage-gated sodium channels with similar electrophysiological properties to those found in vertebrate excitable membranes.

Human macrophage SCN5A activates an innate immune signaling pathway for antiviral host defense.

Pattern recognition receptors contain a binding domain for pathogen-associated molecular patterns coupled to a signaling domain that regulates transcription of host immune response genes. Here, a novel mechanism that links pathogen recognition to channel activation and downstream signaling is proposed. We demonstrate that an intracellular sodium channel variant, human macrophage SCN5A, initiates signaling and transcription through a calcium-dependent isoform of adenylate cyclase, ADCY8, and the transcription factor, ATF2.

Update on disease-modifying treatments for multiple sclerosis.

Purpose: The purpose of this review is to discuss the selection and use of disease- modifying treatments for patients with relapsing forms of multiple sclerosis (MS).

Methods: PubMed was searched (1966-2014) using the terms multiple sclerosis, treatment, interferon, glatiramer acetate, dimethyl fumarate, fingolimod, teriflunomide, natalizumab, rituximab, and alemtuzumab.

Findings: MS is a chronic neurological disorder that can cause a substantial degree of disability.

Innate immune viral recognition: relevance to CNS infections.

Innate immune responses mediated by mononuclear phagocytes represent the initial host response to acute viral infection. PRRs, including TLRs, retinoic RLRs,and NOD-like receptors, recognize viral nucleic acid and localized injury signals to initiate proinflammatory responses and activation of adaptive immunity. These responses are host- and viral-dependent.

Epithelial V-like antigen mediates efficacy of anti-alpha₄ integrin treatment in a mouse model of multiple sclerosis.

Natalizumab inhibits the transmigration of activated T lymphocytes into the brain and is highly efficacious in multiple sclerosis (MS). However, from a pharmacogenomic perspective, its efficacy and safety in specific patients remain unclear. Here our goal was to analyze the effects of epithelial V-like antigen (EVA) on anti-alpha₄ integrin (VLA4) efficacy in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE).

Mediation of protection and recovery from experimental autoimmune encephalomyelitis by macrophages expressing the human voltage-gated sodium channel NaV1.5.

Multiple sclerosis (MS) is the most common nontraumatic cause of neurologic disability in young adults. Despite treatment, progressive tissue injury leads to accumulation of disability in many patients. Here, our goal was to develop an immune-mediated strategy to promote tissue repair and clinical recovery in an MS animal model.

Current Immunotherapy of Multiple Sclerosis and Future Challenges: Relevance of Immune-mediated Repair.

Multiple sclerosis is the most common chronic inflammatory disease of the central nervous system and can cause severe neurological disability. Current immune therapy with beta-interferons, glatiramer acetate, immune suppressives, or selective adhesion molecule inhibitors can reduce the frequency and severity of acute attacks in a majority of patients but have little effect on the progressive phase of the disease. Patients who require aggressive immune therapy are also at risk for the development of potentially fatal opportunistic infections.

Current immunotherapy of multiple sclerosis and future challenges: relevance of immune-mediated repair.

Multiple sclerosis is the most common chronic inflammatory disease of the central nervous system and can cause severe neurological disability. Current immune therapy with beta-interferons, glatiramer acetate, immune suppressives, or selective adhesion molecule inhibitors can reduce the frequency and severity of acute attacks in a majority of patients but have little effect on the progressive phase of the disease. Patients who require aggressive immune therapy are also at risk for the development of potentially fatal opportunistic infections.

The human macrophage sodium channel NaV1.5 regulates mycobacteria processing through organelle polarization and localized calcium oscillations.

Phagocytosis and intracellular processing of mycobacteria by macrophages are complex cellular processes that require spatial and temporal coordination of particle uptake, organelle movement, activation of signaling pathways, and channel-mediated ionic flux. Recent work demonstrated that human macrophage NaV1.5, an intracellular voltage-gated sodium channel expressed on late endosomes, enhances endosomal acidification and phagocytosis.

Characterization of epithelial V-like antigen in human choroid plexus epithelial cells: potential role in CNS immune surveillance.

Prior work demonstrated that immune surveillance of the brain occurs primarily through the blood-cerebrospinal (CSF) fluid barrier rather than the blood-brain barrier endothelium. Recently, we identified epithelial V-like antigen (EVA), an immunoglobulin-like adhesion molecule, as a regulator of blood-CSF barrier integrity in a mouse model. Here we characterized EVA expression and function in human choroid plexus epithelial cells and analyzed its role in CD4 T lymphocyte adhesion.

Regulation of podosome formation in macrophages by a splice variant of the sodium channel SCN8A.

Voltage-gated sodium channels initiate electrical signaling in excitable cells such as muscle and neurons. They also are expressed in non-excitable cells such as macrophages and neoplastic cells. Previously, in macrophages, we demonstrated expression of SCN8A, the gene that encodes the channel NaV1.

Epithelial V-like antigen regulates permeability of the blood-CSF barrier.

Epithelial V-like antigen (EVA), a CD3-binding immunoglobulin-like protein, regulates embryonic thymic development. Here we demonstrate that EVA is expressed in choroid plexus from mature immune competent and lymphocyte-deficient (RAG-/-) mice. Choroid plexus epithelial cells from RAG-/- mice demonstrated reduced junctional integrity and enhanced permeability that was associated with decreased expression of E-cadherin and EVA mRNA as compared to wild-type mice.

Expression of the voltage-gated sodium channel NaV1.5 in the macrophage late endosome regulates endosomal acidification.

Voltage-gated sodium channels expressed on the plasma membrane activate rapidly in response to changes in membrane potential in cells with excitable membranes such as muscle and neurons. Macrophages also require rapid signaling mechanisms as the first line of defense against invasion by microorganisms. In this study, our goal was to examine the role of intracellular voltage-gated sodium channels in macrophage function.

Characterization of a severe parenchymal phenotype of experimental autoimmune encephalomyelitis in (C57BL6xB10.PL)F1 mice.

We here describe a novel CD4 T cell adoptive transfer model of severe experimental autoimmune encephalomyelitis in (C57BL6xB10.PL)F1 mice. This FI cross developed severe disease characterized by extensive parenchymal spinal cord and brain periventricular white matter infiltrates.

Role of genetic background in P selectin-dependent immune surveillance of the central nervous system.

Although the blood-brain barrier and blood cerebrospinal fluid barrier maintain the central nervous system (CNS) as an immunologically privileged site, T lymphocytes can migrate through unstimulated brain endothelium and epithelium to perform immune surveillance or initiate inflammation. Our prior results suggested that early CNS migration of a CD4 Th1 cell line was facilitated by P selectin (CD62P) in (PL/JxSJL/J)F1 mice. Here, quantitative analysis of migration 2 h following adoptive transfer of fluorescently labeled cells revealed a 53-72% decrease in activated splenocyte, CD4 Th1 and CD8 migration, but not CD4 Th2, in CD62P-deficient C57BL6/J mice.