Clinical Reasoning: A 51-Year-Old Woman With Diplopia and Headache.

A 51-year-old woman presented with a pressure-like headache behind her right eye and horizontal diplopia. On examination, she was unable to abduct or adduct the right eye but had intact vertical eye movements. Her deficits could not be overcome using the oculocephalic reflex. Imaging initially was interpreted as optic neuritis, but on careful review with radiology, a diffuse enhancing hyperintense signal within the orbital apex confirmed an orbital infiltrate. The focus of this case study is to review the localization approach for diplopia and build a differential diagnosis for orbital processes. Another key point is the importance of relying on the physical examination as the guide to a patient's management rather than imaging findings, which can often be misleading.

The CSF in neurosarcoidosis contains consistent clonal expansion of CD8 T cells, but not CD4 T cells.

The tissue-specific drivers of neurosarcoidosis remain poorly defined. To identify cerebrospinal fluid (CSF) specific, antigen-driven T and B cell responses, we performed single-cell RNA sequencing of CSF and blood cells from neurosarcoid participants coupled to T and B cell receptor sequencing. In contrast to pulmonary sarcoidosis, which is driven by CD4 T cells, we found CD8 T cell clonal expansion enriched in the neurosarcoid CSF. These CSF-enriched CD8 T cells were composed of two subsets with differential expression of EBI2, CXCR3, and CXCR4. Lastly, our data suggest that IFNγ signaling may distinguish neurosarcoidosis from other neurological disorders.

IgG4-Related Disease of the Skull and Skull Base-A Systematic Review and Report of Two Cases.

OBJECTIVE: IgG4-related disease (IgG4-RD) is an inflammatory process that uncommonly can present in the skull base and calvarium and mimic a tumor but the nature of this condition is not well summarized in the neurosurgical literature. METHODS: A review was performed of 2 cases of IgG4-RD in the skull base highlighting the diagnostic challenges with assessment of these skull base lesions, and a systematic review of relevant literature was carried out. RESULTS: A systematic review of the literature conducted in accordance with PRISMA guidelines identified 113 articles, with 184 cases of IgG4-RD in the skull base or calvarium. The most commonly affected locations include the meninges, cavernous sinus, base of the posterior fossa, clivus, and mastoid bone. Headache, visual and auditory disturbances, cranial nerve dysfunction, and seizures were the most common presenting symptoms. Medical treatment was highly successful and most commonly consisted of corticosteroids coadministered with immunosuppressive agents such as rituximab. Prevalence seemed to be equal between sexes, and serum IgG4 levels were increased in 61% of patients. Delayed diagnosis and a need for multiple biopsies were reported in numerous cases. Two cases of skull base IgG4-RD from the authors' institution show the variable presentations of this disease. More invasive surgical biopsies were required in both cases, and corticosteroid treatment led to significant clinical improvement. CONCLUSIONS: IgG4-RD is an uncommon condition with an increasing body of reported cases that can affect the skull base and calvarium and should be in the differential diagnosis, because delay in diagnosis and treatment may be common.

Responding to Racism in the Clinical Setting: A Novel Use of Forum Theatre in Social Medicine Education.

Issues of race have traditionally been addressed in medical school curricula in a didactic manner. However, medical school curricula often lack adequate opportunity for the application of learning material relating to race and culture. When confronted with acts of racism in clinical settings, students are left unprepared to respond appropriately and effectively. Forum Theatre offers a dynamic platform by which participants are empowered to actively engage with and become part of the performance. When used in an educational context, Forum Theatre can be a powerful tool for students to interact with a wide variety of social issues. This paper describes the process by which one medical school designed a workshop in the Forum Theatre style to equip students to respond to racism observed in clinical settings. Based on real student experiences, the Responding to Racism in the Clinical Setting workshop was designed to give students an opportunity to combine cultural humility, communication theory and conflict resolution skills in order to prepare for interactions in clinical stages of medical education. As a result of workshop evaluations, surveys, and written reflections, the authors propose that Forum Theatre is a novel teaching modality for incorporating issues of race and culture into medical curriculum.

Moving toward Narrative Competence and Inclusive Healthcare through the Open Book Project.

This essay offers a layered account of the origins and enactment of a narrative medicine program at the Ohio University Heritage College of Osteopathic Medicine titled the Open Book Project (OBP). Narrative medicine positions clinical judgment as involving both scientific and narrative reasoning, a set of practices particularly well-suited to fostering inclusive health care and social justice. The OBP involved first-year medical students who met bi-monthly to witness, reflect on, and write about literary passages, visual images, music and lyrics, and other works of art. Sessions also provided opportunities for participants to attentively listen and respond to others, opening themselves to diverse ways of knowing and being. The authors move between academic literature, participants' compositions developed during the project, and students' testimonies to illustrate the dividends and difficulties of narrative medicine.

Inhibition of System Xc(-) Transporter Attenuates Autoimmune Inflammatory Demyelination.

T cell infiltration into the CNS is a significant underlying pathogenesis in autoimmune inflammatory demyelinating diseases. Several lines of evidence suggest that glutamate dysregulation in the CNS is an important consequence of immune cell infiltration in neuroinflammatory demyelinating diseases; yet, the causal link between inflammation and glutamate dysregulation is not well understood. A major source of glutamate release during oxidative stress is the system Xc(-) transporter; however, this mechanism has not been tested in animal models of autoimmune inflammatory demyelination. We find that pharmacological and genetic inhibition of system Xc(-) attenuates chronic and relapsing-remitting experimental autoimmune encephalomyelitis (EAE). Remarkably, pharmacological blockade of system Xc(-) 7 d after induction of EAE attenuated T cell infiltration into the CNS, but not T cell activation in the periphery. Mice harboring a Slc7a11 (xCT) mutation that inactivated system Xc(-) were resistant to EAE, corroborating a central role for system Xc(-) in mediating immune cell infiltration. We next examined the role of the system Xc(-) transporter in the CNS after immune cell infiltration. Pharmacological inhibitors of the system Xc(-) transporter administered during the first relapse in a SJL animal model of relapsing-remitting EAE abrogated clinical disease, inflammation, and myelin loss. Primary coculture studies demonstrate that myelin-specific CD4(+) Th1 cells provoke microglia to release glutamate via the system Xc(-) transporter, causing excitotoxic death to mature myelin-producing oligodendrocytes. Taken together, these studies support a novel role for the system Xc(-) transporter in mediating T cell infiltration into the CNS as well as promoting myelin destruction after immune cell infiltration in EAE.

Expression of Interferon-γ Receptor Genes in Peripheral Blood Mononuclear Cells Is Associated With Rheumatoid Arthritis and Its Radiographic Severity in African Americans.

OBJECTIVE: The factors responsible for radiographic severity in African American patients with rheumatoid arthritis (RA) are poorly understood. We sought to identify genes whose expression in peripheral blood mononuclear cells is associated with radiographic severity in RA. METHODS: In the first phase of the study, we performed real-time quantitative polymerase chain reaction to analyze the expression of 182 candidate genes in 40 African American RA patients with extremes of radiographic damage (low versus high radiographic scores) and disease duration (≤2 years versus >2 years) and 20 healthy African American control subjects; the genes were selected based on plausible immune pathways. In the second phase, we analyzed the expression of the genes that were shown to be significantly associated with radiographic scores in 576 African American patients with RA and 51 African American control subjects who had not been studied previously, accounting for autoantibody status and disease duration. RESULTS: We observed significant differences in IFNGR1 expression between patients with RA and control subjects (adjusted P [P(adj)] = 6 × 10(-14)) and in IFNGR2 expression between RA patients with erosions and those with no erosions (P(adj) = 0.01 by Wilcoxon's rank sum test). We also observed significant correlations between IFNGR2 expression and radiographic scores (P(adj) = 0.03 for erosions, P(adj) = 0.04 for joint space narrowing, and P(adj) = 0.03 for total radiographic score [zero-inflated negative binomial regression model]) and annualized progression rate (P(adj) = 0.0024 by Spearman's correlation analysis). CONCLUSION: These findings have important implications with respect to the role of interferon-γ (IFNγ) in the pathogenesis of RA and may lead to identification of a biomarker for radiographic damage. Additional studies are needed to define the cell subsets responsible for the association of IFNγ receptor gene expression with radiographic findings, which downstream mechanisms are involved, and generalizability to other RA populations.

IL-27 inhibits OSM-mediated TNF-alpha and iNOS gene expression in microglia.

Elevated levels of Oncostatin M (OSM), an interleukin-6 family cytokine, have been observed in multiple sclerosis (MS), HIV-associated neurocognitive disorder (HAND), and glioblastoma (GBM); however, its effects within the CNS are not well understood. OSM regulates gene expression primarily by activating the JAK/STAT, NF-kappaB, and/or MAPK pathways, in a cell-type specific manner. In our studies, OSM induces the production of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) from microglia in an NF-kappaB-dependent manner. This expression also partially requires the intermediate production of TNF-alpha and subsequent NF-kappaB activation via TNF-R1. We also demonstrate that OSM-induced TNF-alpha production from microglia is neurotoxic. The IL-12 family member, IL-27, suppresses OSM-mediated TNF-alpha and iNOS expression at the transcriptional level by inhibiting activation of the NF-kappaB pathway, and rescues the neurotoxicity induced by OSM-stimulated microglia. These studies are the first to demonstrate the proinflammatory effects of OSM in microglia, and also identify IL-27 as a novel inhibitor of inflammatory processes in these cells.

IL-17 enhancement of the IL-6 signaling cascade in astrocytes.

Astrocytes have important physiological roles in CNS homeostasis and serve as a bridge between the CNS and immune system. IL-17 and IL-6 are important in many CNS disorders characterized by neuroinflammation. We examined the role of IL-17 on the IL-6 signaling cascade in primary astrocytes. IL-17 functioned in a synergistic manner with IL-6 to induce IL-6 expression in astrocytes. The synergistic effect involved numerous signaling pathways including NF-kappaB, JNK MAPK, and p38 MAPK. The NF-kappaB pathway inhibitor BAY-11, JNK inhibitor JNKi II, and p38 inhibitor SB203580 suppressed the synergistic effect of IL-6 and IL-17 on IL-6 expression. IL-17 synergized with IL-6 to enhance the recruitment of activated NF-kappaB p65, c-Fos, c-Jun, and the histone acetyltransferases CREB-binding protein and p300 to the IL-6 promoter in vivo to induce IL-6 transcription. This was accompanied by enhanced acetylation of histones H3 and H4 on the IL-6 promoter. Moreover, we elucidated an important role for suppressor of cytokine signaling (SOCS) 3 in IL-17 enhancement of IL-6 signaling in astrocytes. SOCS3 small interfering RNA knockdown and SOCS3 deletion in astrocytes augmented the synergistic effect of IL-6 and IL-17 due to an enhancement of activation of the NF-kappaB and MAPK pathways. These results indicate that astrocytes can serve as a target of Th17 cells and IL-17 in the CNS, and SOCS3 participates in IL-17 functions in the CNS as a negative feedback regulator.

Regulated exocytosis in astrocytic signal integration.

Astrocytes can be considered as signal integrators in central nervous system activity. These glial cells can respond to signals from the heterocellular milieu of the brain and subsequently release various molecules to signal to themselves and/or other neighboring neural cells. An important functional module that enables signal integration in astrocytes is exocytosis, a Ca(2+)-dependent process consisting of vesicular fusion to the plasma membrane. Astrocytes utilize regulated exocytosis to release various signaling molecules stored in the vesicular lumen. Here we review the properties of exocytotic release of three classes of gliotransmitters: (i) amino acids, (ii) nucleotides and (iii) peptides. Vesicles may carry not only lumenal cargo, but also membrane-associated molecules. Therefore, we also discuss exocytosis as a delivery mechanism for transporters and receptors to the plasma membrane, where these proteins are involved in astrocytic intercellular signaling.

SOCS1 and SOCS3 in the control of CNS immunity.

In the decade following their initial discovery, the suppressor of cytokine signaling (SOCS) proteins have been studied for their potential use as immunomodulators in disease. SOCS proteins, especially SOCS1 and SOCS3, are expressed by immune cells and cells of the central nervous system (CNS) and have the potential to impact immune processes within the CNS, including inflammatory cytokine and chemokine production, activation of microglia, macrophages and astrocytes, immune cell infiltration and autoimmunity. We describe CNS-relevant in vitro and in vivo studies that have examined the function of SOCS1 or SOCS3 under various neuroinflammatory or neuropathological conditions, including exposure of CNS cells to inflammatory cytokines or bacterial infection, demyelinating insults, stroke, spinal cord injury, multiple sclerosis and glioblastoma multiforme.

Expression and functional significance of SOCS-1 and SOCS-3 in astrocytes.

Astrocytes play a number of important physiological roles in CNS homeostasis. Inflammation stimulates astrocytes to secrete cytokines and chemokines that guide macrophages/microglia and T cells to sites of injury/inflammation. Herein, we describe how these processes are controlled by the suppressor of cytokine signaling (SOCS) proteins, a family of proteins that negatively regulate adaptive and innate immune responses. In this study, we describe that the immunomodulatory cytokine IFN-beta induces SOCS-1 and SOCS-3 expression in primary astrocytes at the transcriptional level. SOCS-1 and SOCS-3 transcriptional activity is induced by IFN-beta through IFN-gamma activation site (GAS) elements within their promoters. Studies in STAT-1alpha-deficient astrocytes indicate that STAT-1alpha is required for IFN-beta-induced SOCS-1 expression, while STAT-3 small interfering RNA studies demonstrate that IFN-beta-induced SOCS-3 expression relies on STAT-3 activation. Specific small interfering RNA inhibition of IFN-beta-inducible SOCS-1 and SOCS-3 in astrocytes enhances their proinflammatory responses to IFN-beta stimulation, such as heightened expression of the chemokines CCL2 (MCP-1), CCL3 (MIP-1alpha), CCL4 (MIP-1beta), CCL5 (RANTES), and CXCL10 (IP-10), and promoting chemotaxis of macrophages and CD4(+) T cells. These results indicate that IFN-beta induces SOCS-1 and SOCS-3 in primary astrocytes to attenuate its own chemokine-related inflammation in the CNS.

Molecular basis of oncostatin M-induced SOCS-3 expression in astrocytes.

Under neuropathological conditions, reactive astrocytes release cytokines and chemokines, which act in an autocrine and/or paracrine fashion to modulate production of immunoregulatory factors from cells including microglia, astrocytes, and neurons. In this way, astrocytes play an important role in orchestrating immune responses within the central nervous system (CNS). Suppressor of cytokine signaling (SOCS) proteins are endogenous, negative regulators of the JAK/STAT signaling pathway and function as attenuators of the immune and inflammatory responses. As such, SOCS proteins may have critical roles in the CNS under neuroinflammatory conditions. In the inflamed CNS, expression of IL-6 cytokine family member oncostatin M (OSM) is elevated; however, its functional effects are not well understood. We demonstrate that OSM is a potent inducer of SOCS-3 in astrocytes. Analysis of the SOCS-3 promoter revealed that an AP-1 element, two IFN-gamma activation sequence (GAS) elements, and a GC-rich region are crucial for SOCS-3 gene expression. Using small interfering RNA against STAT-3, as well as a STAT-3 dominant-negative construct, we demonstrate that STAT-3 activation is critical for OSM induction of SOCS-3 expression. The ERK1/2 and JNK pathways also contribute to OSM-induced SOCS-3 gene expression. OSM stimulation led to a time-dependent recruitment of the transcription factors STAT-3, c-Fos, c-Jun, and Sp1 and the coactivators CREB-binding protein (CBP) and p300 to the endogenous SOCS-3 promoter. These data indicate that OSM-induced activation of STAT-3 and the ERK1/2 and JNK pathways are critical for astrocytic expression of SOCS-3, which provides for feedback inhibition of cytokine-induced inflammatory responses in the CNS.

IL-10 inhibits lipopolysaccharide-induced CD40 gene expression through induction of suppressor of cytokine signaling-3.

Costimulation between T cells and APCs is required for adaptive immune responses. CD40, an important costimulatory molecule, is expressed on a variety of cell types, including macrophages and microglia. The aberrant expression of CD40 is implicated in diseases including multiple sclerosis, rheumatoid arthritis, and Alzheimer's disease, and inhibition of CD40 signaling has beneficial effects in a number of animal models of autoimmune diseases. In this study, we discovered that IL-10, a cytokine with anti-inflammatory properties, inhibits LPS-induced CD40 gene expression. We previously demonstrated that LPS induction of CD40 in macrophages/microglia involves both NF-kappaB activation and LPS-induced production of IFN-beta, which subsequently activates STAT-1alpha. IL-10 inhibits LPS-induced IFN-beta gene expression and subsequent STAT-1alpha activation, but does not affect NF-kappaB activation. Our results also demonstrate that IL-10 inhibits LPS-induced recruitment of STAT-1alpha, RNA polymerase II, and the coactivators CREB binding protein and p300 to the CD40 promoter, as well as inhibiting permissive histone H3 acetylation (AcH3). IL-10 and LPS synergize to induce suppressor of cytokine signaling (SOCS)-3 gene expression in macrophages and microglia. Ectopic expression of SOCS-3 attenuates LPS-induced STAT activation, and inhibits LPS-induced CD40 gene expression, comparable to that seen by IL-10. These results indicate that SOCS-3 plays an important role in the negative regulation of LPS-induced CD40 gene expression by IL-10.