Katherine M. Mullen

Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases.

Autoreactive memory T lymphocytes are implicated in the pathogenesis of autoimmune diseases. Here we demonstrate that disease-associated autoreactive T cells from patients with type-1 diabetes mellitus or rheumatoid arthritis (RA) are mainly CD4+CCR7−CD45RA− effector memory T cells (TEM cells) with elevated Kv1.3 potassium channel expression. In contrast, T cells with other antigen specificities from these patients, or autoreactive T cells from healthy individuals and disease controls, express low levels of Kv1.3 and are predominantly naïve or central-memory (TCM) cells. In TEM cells, Kv1.3 traffics to the immunological synapse during antigen presentation where it colocalizes with Kvβ2, SAP97, ZIP, p56lck, and CD4. Although Kv1.3 inhibitors [ShK(L5)-amide (SL5) and PAP1] do not prevent immunological synapse formation, they suppress Ca2+-signaling, cytokine production, and proliferation of autoantigen-specific TEM cells at pharmacologically relevant concentrations while sparing other classes of T cells. Kv1.3 inhibitors ameliorate pristane-induced arthritis in rats and reduce the incidence of experimental autoimmune diabetes in diabetes-prone (DP-BB/W) rats. Repeated dosing with Kv1.3 inhibitors in rats has not revealed systemic toxicity. Further development of Kv1.3 blockers for autoimmune disease therapy is warranted.

PRETERM BIRTH RESULTS IN ALTERATIONS IN NEURAL CONNECTIVITY AT AGE 16 YEARS

Very low birth weight preterm (PT) children are at high risk for brain injury. Employing diffusion tensor imaging (DTI), we tested the hypothesis that PT adolescents would demonstrate microstructural white matter disorganization relative to term controls at 16 years of age. Forty-four PT subjects (600-1250 g birth weight) without neonatal brain injury and 41 term controls were evaluated at age 16 years with DTI, the Wechsler Intelligence Scale for Children-III (WISC), the Peabody Picture Vocabulary Test-Revised (PPVT), and the Comprehensive Test of Phonological Processing (CTOPP). PT subjects scored lower than term subjects on WISC full scale (p=0.003), verbal (p=0.043), and performance IQ tests (p=0.001), as well as CTOPP phonological awareness (p=0.004), but scored comparably to term subjects on PPVT and CTOPP Rapid Naming tests. PT subjects had lower fractional anisotropy (FA) values in multiple regions including bilateral uncinate fasciculi (left: p=0.01; right: p=0.004), bilateral external capsules (left: p<0.001; right: p<0.001), the splenium of the corpus callosum (p=0.008), and white matter serving the inferior frontal gyrus bilaterally (left: p<0.001; right: p=0.011). FA values in both the left and right uncinate fasciculi correlated with PPVT scores (a semantic language task) in the PT subjects (left: r=0.314, p=0.038; right: r=0.336, p=0.026). FA values in the left and right arcuate fasciculi correlated with CTOPP Rapid Naming scores (a phonologic task) in the PT subjects (left: r=0.424, p=0.004; right: r=0.301, p=0.047). These data support for the first time that dual pathways underlying language function are present in PT adolescents. The striking bilateral dorsal correlations for the PT group suggest that prematurely born subjects rely more heavily on the right hemisphere than typically developing adults for performance of phonological language tasks. These findings may represent either a delay in maturation or the engagement of alternative neural pathways for language in the developing PT brain.

Interleukin-17 in transverse myelitis and multiple sclerosis

CSF IL-6 is elevated in transverse myelitis (TM) and predicts disability. Since IL-17 regulates cytokines (TNFalpha, IL-1beta and IL-6) known to stimulate IL-6 production by astrocytes, we sought to determine whether IL-17 was increased in TM and MS compared to healthy controls (HC) and other neurologic diseases (OND). IL-17 and IL-6 levels were measured in stimulated peripheral blood mononuclear cell (PBMC) supernatants from HC, MS, TM and OND. IL-17 was increased in TM compared to HC, MS, and OND (mean pg/ml+/-standard error; HC: 36.1+/-11.7, MS: 89.4+/-23.3, TM: 302.6+/-152.5, OND: 41.2+/-13.0, p=0.01). IL-6 was increased in TM relative to MS and HC (HC: 2624 pg/ml+/-641, MS: 6129+/-982, TM: 12,536+/-2657, OND: 6920+/-1801, p<0.002). MS patients with early disease (<2 years) also had increased levels of IL-17 (p<0.04) and IL-6 (p<0.05). Cytokine neutralization experiments demonstrated that IL-6 was the main inducer of astrocyte IL-6 production. We conclude that IL-17 and IL-6 production from PBMC in TM and early MS are increased and induce astrocyte IL-6 production through IL-6.

Potassium channels Kv1.3 and Kv1.5 are expressed on blood-derived dendritic cells in the central nervous system

Potassium (K+) channels on immune cells have gained attention recently as promising targets of therapy for immune‐mediated neurological diseases such as multiple sclerosis (MS). We examined K+ channels on dendritic cells (DCs), which infiltrate the brain in MS and may impact disease course.

Expression of CCR7 and CD45RA in CD4+ and CD8+ subsets in cerebrospinal fluid of 134 patients with inflammatory and non-inflammatory neurological diseases

We investigated CD45RA and CCR7 expression in CD4+ and CD8+ subsets of cerebrospinal fluid (CSF) lymphocytes, both immediately ex vivo and after stimulation, from 134 patients with a variety of inflammatory and non-inflammatory neurological diseases. Most inflammatory diseases had a higher CD4+:CD8+ ratio and higher percentage of effector memory T cells (T(EM)) than non-inflammatory controls, excluding active infection. Moreover, we found that patients with highly elevated cell counts in the CSF tended to have a lower percentage of central memory T cells (T(CM)) than patients with low or absent pleocytosis, with a concomitant increase in T(EM). We also found that samples with elevated IgG index or presence of oligoclonal bands had a significantly higher CD4+:CD8+ ratio than normal samples, consistent with increased CD4+ help for intrathecal IgG synthesis by B cells.

Outcomes of Pregnancies With a Low-Lying Placenta Diagnosed on Second-Trimester Sonography

The purpose of this study was to determine how often a low‐lying placenta, defined as a placenta ending within 2 cm of the internal cervical os but not covering it, diagnosed sonographically in the second trimester resolves before delivery.

Reduced Radiation Exposure for Face Transplant Surgical Planning Computed Tomography Angiography

Objective To test the hypothesis that wide area detector face transplant surgical planning CT angiograms with simulated lower radiation dose and iterative reconstruction (AIDR3D) are comparable in image quality to those with standard tube current and filtered back projection (FBP) reconstruction. Materials and Methods The sinograms from 320-detector row CT angiography of four clinical candidates for face transplantation were processed utilizing standard FBP, FBP with simulated 75, 62, and 50% tube current, and AIDR3D with corresponding dose reduction. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were measured at muscle, fat, artery, and vein. Image quality for each reconstruction strategy was assessed by two independent readers using a 4-point scale. Results Compared to FBP, the median SNR and CNR for AIDR3D images were higher at all sites for all 4 different tube currents. The AIDR3D with simulated 50% tube current achieved comparable SNR and CNR to FBP with standard dose (median muscle SNR: 5.77 vs. 6.23; fat SNR: 6.40 vs. 5.75; artery SNR: 43.8 vs. 45.0; vein SNR: 54.9 vs. 55.7; artery CNR: 38.1 vs. 38.6; vein CNR: 49.0 vs. 48.7; all p-values >0.19). The interobserver agreement in the image quality score was good (weighted κ = 0.7). The overall score and the scores for smaller arteries were significantly lower when FBP with 50% dose reduction was used. The AIDR3D reconstruction images with 4 different simulated doses achieved a mean score ranging from 3.68 to 3.82 that were comparable to the scores from images reconstructed using FBP with original dose (3.68–3.77). Conclusions Simulated radiation dose reduction applied to clinical CT angiography for face transplant planning suggests that AIDR3D allows for a 50% reduction in radiation dose, as compared to FBP, while preserving image quality.

Teaching NeuroImages: massive abdominal CSFoma.

A 31-year-old woman with congenital hydrocephalus status post ventriculoperitoneal shunt placement 23 years earlier presented with abdominal distention. The patient denied fever, headache, or sensory or motor abnormalities. Examination was notable for a tense abdomen. CT of the abdomen and pelvis demonstrated a massive, loculated, CSFoma, or CSF pseudocyst (figure). Ventriculoperitoneal shunts are associated with a variety of complications including disruption of the tube, obstruction of the tip, infection, intestinal perforation, tip migration, and CSFoma development.1 CSFoma is a rare complication, thought to be caused by low-grade shunt infection, chronic inflammation, increased CSF protein, or peritoneal adhesions, and is estimated to occur in 1.0% to 4.5% of cases, with a typical occurrence within 3 weeks to 5 years of shunt placement.2,3 Treatment consists of external drainage or surgical excision followed by reconstruction of the shunt system.4

An Update on the Approach to the Imaging of Brain Tumors

Purpose of ReviewNeuroimaging plays a critical role in diagnosis of brain tumors and in assessment of response to therapy. However, challenges remain, including accurately and reproducibly assessing response to therapy, defining endpoints for neuro-oncology trials, providing prognostic information, and differentiating progressive disease from post-therapeutic changes particularly in the setting of antiangiogenic and other novel therapies.Recent FindingsRecent advances in the imaging of brain tumors include application of advanced MRI imaging techniques to assess tumor response to therapy and analysis of imaging features correlating to molecular markers, grade, and prognosis.SummaryThis review aims to summarize recent advances in imaging as applied to current diagnostic and therapeutic neuro-oncologic challenges.

Yield of urinary tract cancer diagnosis with repeat CT urography in patients with hematuria.

OBJECTIVE. The purpose of this study was to evaluate the yield of repeat CT urography (CTU) in detecting urinary tract malignancies in patients with hematuria. MATERIALS AND METHODS. A review of 5525 patients who underwent CTU between 2000 and 2011 revealed 751 (13.6%) patients who underwent repeat CTU. We excluded 127 patients with more than 3 years between examinations, 409 with nonhematuria indications, and 13 with less than 1 year of follow-up from a negative repeat examination. An additional 54 patients with malignancy diagnosed on the initial evaluation were excluded, leaving 148 patients in the study cohort (77 men and 71 women; mean age, 57 years). Patients were categorized on the basis of the presence or absence of findings suspicious for malignancy on initial CTU reports. Repeat CTU reports were correlated with cystoscopy, pathology, and clinical follow-up to determine the incidence of malignancy. Examinations negative for malignancy were confirmed with at least 1 year of clinical follow-up. CTU examinations of patients diagnosed with malignancy on repeat examination were reviewed by two radiologists in consensus. RESULTS. Initial CTU showed no findings suspicious for malignancy in 103 (70%) of 148 patients; of these, none had malignancy identified on repeat CTU. Among 45 (30%) patients with suspicious initial CTU findings, four malignancies were identified on repeat CTU (8.9%). Three were incidental to the initial suspicious finding; in retrospect, two were present on the initial CTU examination. CONCLUSION. In patients with hematuria, repeat CTU within 3 years is unlikely to show a urinary tract malignancy. These results support currently published guidelines.