Murine models of spinocerebellar ataxia type 5

University of Minnesota Ph.D. dissertation. June 2009. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisor:Laura P. W. Ranum, Ph.D. 1 computer file (PDF); x, 127 pages.Spinocerebellar ataxia type 5 (SCA5) is a slowly progressive neurodegenerative disease of the cerebellum caused by mutations in the SPTBN2 gene, which encodes the protein β-III spectrin. To characterize how β-III spectrin with the American SCA5 mutation causes Purkinje cell degeneration and cerebellar dysfunction, I developed the first transgenic murine models of SCA5 and identified brain proteins that potentially interact with the region of β-III spectrin where the American SCA5 mutation occurs. Behavioral studies with a conditional model that drives expression of untagged β-III spectrin and a second 3xFLAG-tagged SCA5 model show that overexpressing mutant β- III spectrin in murine cerebellar Purkinje cells causes cerebellar dysfunction. Further studies with the conditional tet-regulated mice show that untagged mutant β-III spectrin alters the localization of the glutamate transporter EAAT4 and the metabotropic glutamate receptor mGluR1α and produces a concomitant deficit in mGluR1 function. Histologic analysis of the 3xFLAG-tagged SCA5 murine model shows that the American SCA5 mutation also alters the Purkinje cell distribution of the mutant β-III spectrin protein itself. Additionally, I identified a number of brain proteins that are novel β-III spectrin interaction candidates, including the dynactin subunit p150Glued. I show that the American and French SCA5 mutations alter the interaction strength of β-III spectrin with p150Glued and α-II spectrin respectively

Corticosteroid-Resistant Sarcoid Choroidal Granuloma Presenting With Optic Disc Edema

A54-year-old man with untreated psoriatic arthritis was referred for evaluation of optic disc edema in his right eye. He was found to have an associated peripapillary choroidal granuloma, verified by enhanced depth imaging optical coherence tomography (EDI-OCT)

Incident Ocular Inflammation After COVID-19 Infection in a US Veteran Population

To investigate whether COVID-19 infection is a risk factor for incident ocular inflammatory disease. Retrospective case-crossover study. The US Veterans Health Administration Corporate Data Warehouse was used to identify patients with positive COVID-19 testing and incident ocular inflammatory disease between March 2020 and May 2022. The timing of incident ocular inflammation and COVID-19 testing was assessed for each participant to determine whether positive COVID-19 testing occurred 0–60 days prior to incident ocular inflammation diagnosis (risk period) or 15–75 days after incident ocular inflammation diagnosis (control period). The main outcome measure was the odds of positive COVID-19 testing in the risk period versus control period. Of the 1006 patients with incident ocular inflammation and a positive COVID-19 test in the study period, the age mean ± standard deviation was 62.6 ± 9.8 years and 840 (83%) were male. The odds of COVID-19 exposure was higher in the risk than control period (odds ratio [OR], 1.56; 95% confidence interval [CI], 1.04–2.36; P = 0.03). Ocular inflammation was more likely to be bilateral in the risk period (OR, 3.97; 95% CI, 1.01–23.01; P = 0.03). Other ocular features and demographic characteristics were similar in the risk and control periods. Most cases of ocular inflammation were quiescent at the most recent eye examination. Incident ocular inflammation is associated with COVID-19 infection, but the increased risk is small, and the ocular inflammation is typically acute.</p

Uveitis reactivation following recombinant zoster vaccination

Purpose: Describe three cases of uveitis reactivation following immunization with recombinant zoster vaccine (RZV). Observations: One patient developed reactivation of previously controlled multifocal choroiditis within one week of receiving RZV, requiring treatment with systemic corticosteroids. Two patients with previously controlled anterior uveitis developed new anterior segment inflammation after RZV; both were treated with topical corticosteroids and systemic antiviral therapy. Conclusion and importance: Uveitis recurrence is an infrequent but serious potential ocular side effect of recombinant zoster vaccination

Silicic acid supplied to coastal diatom communities influences cellular silicification and the potential export of carbon

Microcosm experiments were conducted along the Washington and Oregon coasts in May 2009, May 2010, and July 2010 to determine whether variation in the supply of silicic acid from the Columbia River could influence the silicification and sinking potential of coastal diatom blooms. The chlorophyll a concentration increased similarly in communities incubated with added nitrate or both nitrate and silicic acid, indicating that growth was limited by nitrate availability. Communities that grew in the treatment with added silicic acid and nitrate were more silicified than communities in the treatment with only nitrate added. No difference in community composition was detected between these treatments in three out of four experiments. Isolates of Minutocellus, Cylindrotheca, Thalassiosira, and Odontella were obtained from the microcosm experiment conducted in May 2010 and were maintained in the laboratory in 20 μmol L-1 silicic acid. All four diatom isolates contained ~ 2.5 times more silica per cell when silicic acid concentration in the media was increased to 80 μmol L-1. The intensity of a fluorescent cellular stain of newly precipitated silica (2-(4-pyridyl)-5{[4-dimethylaminoethyl-aminocarbamoyl)-methoxy]phenyl}oxazole) strongly correlated with silica content among species, but was a less sensitive indicator of changing silicification within a single species. Changes in silicification were not correlated with changes in the transcript abundance of silicic acid transporters. Sinking rates increased roughly 2-fold for cells that contained ~ 2.5 times more silica. Variation in silicic acid supply alters the silicification of nitrate-fueled coastal diatom blooms and the potential sink of carbon from coastal zones. © 2013, by the Association for the Sciences of Limnology and Oceanography, Inc

Therapeutic Outcomes of Non-Infectious Scleritis Treated with Tumor Necrosis Factor-Alpha Inhibitors

We determine the efficacy of tumor necrosis factor-α (TNF) inhibitors in establishing scleritis quiescence. We conducted a multicenter retrospective chart review of patients with non-infectious scleritis treated with a TNF inhibitor for at least 6 months. The primary endpoint was scleritis quiescence at 6 months. Secondary endpoints included scleritis quiescence at 12 months, TNF inhibitor effects on concurrent doses of systemic corticosteroids and visual acuity outcomes at 6 and 12 months. At 6 months, 82.2% (37/45) of subjects obtained scleritis quiescence with TNF inhibition. At 12 months, 76.2% (32/42) of subjects remained quiescent. Baseline daily corticosteroid use (21.5 ± 21.6 mg) decreased to 5.4 ± 8.3 mg by 6 months (p p p = 0.52). TNF inhibitors are an effective scleritis therapy with significant systemic corticosteroid sparing effect.</p

Elevated CD1c(+) Myeloid Dendritic Cell Proportions Associate With Clinical Activity and Predict Disease Reactivation in Noninfectious Uveitis

PURPOSE. To test the association between elevated proportions of CD1c(+) myeloid dendritic cells (mDCs) and disease activation/reactivation in noninfectious uveitis. METHODS. Noninfectious uveitis patients (n = 89) and healthy controls (n = 111) were recruited. The proportion of CD1c(+) mDCs in the total dendritic cell (DC) population of peripheral blood was measured by flow cytometry (CD1c(+) mDCs gated on Lineage 1(+)HLADR(+) DCs). Disease activity was assessed per Standardization of Uveitis Nomenclature criteria. Uveitis reactivation was ascribed to clinically quiescent patients who developed reactivation of intraocular inflammation within 6 months. RESULTS. The proportions of CD1c(+) mDCs were increased in noninfectious uveitis patients, especially in active disease, compared to healthy controls. This CD1c(+) mDC elevation was not associated with underlying systemic diseases, anatomic locations of uveitis, medications, or demographic factors. Longitudinal data showed that the dynamics of CD1c(+) mDC levels were correlated with disease activity. The average proportion of CD1c(+) mDCs in active uveitis patients was 60% so we set this as the cutoff between high and low CD1c(+) mDC levels. Although 74% of quiescent patients had low proportions of CD1c(+) mDCs, 26% still had high proportions. Quiescent patients with high CD1c(+) mDC proportions showed increased risk of disease reactivation, compared to quiescent patients with low CD1c(+) mDC proportions. CONCLUSIONS. Increased proportions of CD1c(+) mDCs were associated with clinical activity, and quiescent patients with elevated CD1c(+) mDCs were more likely to undergo reactivation. This suggests that CD1c(+) mDC proportion may be a potential biomarker for assessing clinical activation and reactivation in noninfectious uveitis.National Institutes of Health (NIH)/National Eye Institute (NEI) NIH Medical Research Scholars Program Pan-American Ophthalmological Foundation/Retina Research Foundation CONICY

Immunology and Microbiology Elevated CD1c þ Myeloid Dendritic Cell Proportions Associate With Clinical Activity and Predict Disease Reactivation in Noninfectious Uveitis

Citation: Chen P, Urzua CA, Knickelbein JE, et al. Elevated CD1c þ myeloid dendritic cell proportions associate with clinical activity and predict disease reactivation in noninfectious uveitis