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FAS-dependent cell death in a-synuclein transgenic oligodendrocyte models of multiple system atrophy

Fri, 25 Jan 2013 00:00:00 GMT

Title: FAS-dependent cell death in a-synuclein transgenic oligodendrocyte models of multiple system atrophy Authors: Kragh, Christine L; Fillon, Gwenaelle; Gysbers, Amanda; Hansen, Hanne D; Neumann, Manuela; Richter-Landsberg, Christiane; Haass, Christian; Zalc, Bernard; Lubetzki, Catherine; Gai, Wei Ping; Halliday, Glenda M; Kahle, Philipp J; Jensen, Poul H Abstract: Multiple system atrophy is a parkinsonian neurodegenerative disorder. It is cytopathologically characterized by accumulation of the protein p25α in cell bodies of oligodendrocytes followed by accumulation of aggregated α-synuclein in so-called glial cytoplasmic inclusions. p25α is a stimulator of α-synuclein aggregation, and coexpression of α-synuclein and p25α in the oligodendroglial OLN-t40-AS cell line causes α-synuclein aggregate-dependent toxicity. In this study, we investigated whether the FAS system is involved in α-synuclein aggregate dependent degeneration in oligodendrocytes and may play a role in multiple system atrophy. Using rat oligodendroglial OLN-t40-AS cells we demonstrate that the cytotoxicity caused by coexpressing α-synuclein and p25α relies on stimulation of the death domain receptor FAS and caspase-8 activation. Using primary oligodendrocytes derived from PLP-α-synuclein transgenic mice we demonstrate that they exist in a sensitized state expressing pro-apoptotic FAS receptor, which makes them sensitive to FAS ligand-mediated apoptosis. Immunoblot analysis shows an increase in FAS in brain extracts from multiple system atrophy cases. Immunohistochemical analysis demonstrated enhanced FAS expression in multiple system atrophy brains notably in oligodendrocytes harboring the earliest stages of glial cytoplasmic inclusion formation. Oligodendroglial FAS expression is an early hallmark of oligodendroglial pathology in multiple system atrophy that mechanistically may be coupled to α-synuclein dependent degeneration and thus represent a potential target for protective intervention.

The reliability of single-field fundus photography in screening for diabetic retinopathy: the Central Australian Ocular Health Study

Fri, 26 Oct 2012 00:00:00 GMT

Title: The reliability of single-field fundus photography in screening for diabetic retinopathy: the Central Australian Ocular Health Study Authors: Ku, Janice J-Y; Landers, John; Henderson, T R; Craig, Jamie E Abstract: Objective: To assess the accuracy of grading diabetic retinopathy (DR) using single-field digital fundus photography compared with clinical grading from a dilated slit-lamp fundus examination in Indigenous Australians living in Central Australia. Design, setting and participants: Cross-sectional study comparing DR grades in participants with diabetes mellitus presenting for examination at remote community clinics from 1 July 2005 to 30 June 2008. Main outcome measures: Sensitivity and specificity of grading using digital photography compared with the clinical gold standard of slit-lamp fundus examination. Results: Of the 1884 participants recruited for the study, 1040 had self-reported diabetes mellitus and, of those, 360 had fundus photographs available (706 eyes) that were able to be graded. On clinical grading, 163 eyes had any DR and 51 eyes had vision-threatening DR (VTDR). The sensitivity and specificity for detecting any DR were 74% (95% CI, 67%–80%) and 92% (95% CI, 90%–94%), respectively. The sensitivity and specificity for detecting VTDR were 86% (95% CI, 77%–96%) and 95% (95% CI, 93%–97%), respectively. Conclusion: Single-field digital fundus photography is a valid screening tool for DR in remote communities of central Australia and may be used to provide eye care services to this region with acceptable accuracy.

Characterization of serous retinal detachments in uveitis patients with optical coherence tomography

Sat, 02 Jun 2012 00:00:00 GMT

Title: Characterization of serous retinal detachments in uveitis patients with optical coherence tomography Authors: Simmons-Rear, Annamieka; Yeh, Steven; Chan-Kai, Brian T; Lauer, Andreas K; Flaxel, Christina J; Smith, Justine R; Rosenbaum, James T; Suhler, Eric B Abstract: To determine the prevalence of serous retinal detachments (SRD) using optical coherence tomography (OCT) in a large database of patients with uveitis from a tertiary referral setting, to describe clinical features of patients with SRD, and to ascertain retinal architectural features found in association with SRD. Main outcome measures Prevalence of SRD in uveitis patients imaged with OCT, correlation of visual acuity with SRD, anatomic subtypes of uveitis identified, and association of SRD with various subtypes of macular edema (focal and diffuse) and retinal architectural abnormalities. Design Retrospective, single-setting cross-sectional study of all OCTs in a digital imaging base ordered on patients from a tertiary referral uveitis clinic between July 2006 and March 2008. Results SRD were identified in 17 of 111 uveitis patients (15 %) reviewed; bilateral SRD were found in 5 of 17 patients (29 %). Intermediate uveitis was the most common disease association (47 %), but other conditions identified included Vogt-Koyanagi-Harada syndrome, multifocal choroiditis/panuveitis, and sarcoidosis. Retinal architectural features identified in association with SRD included focal macular edema (59 %), diffuse macular edema (50 %), any intraretinal edema (77 %), both diffuse and focal macular edema (32 %), and retinal pigment epithelial alteration (27 %). Moderate or severe visual impairment, defined as visual acuity 20/50 or poorer was seen in 71 % of patients with SRD. Poorer visual acuity was correlated with increased central subfield thickness in patients with SRD (r2=0.41, p<0.001). Conclusion SRD were present in 15 % of the uveitis patients reviewed. Moderate to severe vision impairment was present in the majority of eyes (71 %) with SRD. Diffuse macular edema and focal cystoid macular edema were the OCT features most commonly associated with SRD. Intermediate and panuveitis were the most common anatomic sites of inflammation. A variety of pathogenic mechanisms, both inflammatory and non-inflammatory, may be involved in SRD in uveitis patients; identification of the precise mechanism is important for appropriate therapy.

Clinical spectum of tuberculous optic neuropathy

Tue, 22 May 2012 00:00:00 GMT

Title: Clinical spectum of tuberculous optic neuropathy Authors: Davis, Ellen J; Rathinam, Sivakumar R; Okada, Annabelle A; Tow, Sharon L; Petrushkin, Harry; Graham, Elizabeth M; Smith, Justine R Abstract: Purpose Tuberculous optic neuropathy may follow infection with Mycobacterium tuberculosis or administration of the bacille Calmette–Guerin. However, this condition is not well described in the ophthalmic literature. Methods Ophthalmologists, identified through professional electronic networks or previous publications, collected standardized clinical data relating to 62 eyes of 49 patients who they had managed with tuberculous optic neuropathy. Results Tuberculous optic neuropathy was most commonly manifested as papillitis (51.6 %), neuroretinitis (14.5 %), and optic nerve tubercle (11.3 %). Uveitis was an additional ocular morbidity in 88.7 % of eyes. In 36.7 % of patients, extraocular tuberculosis was present. The majority of patients (69.4 %) had resided in and/or traveled to an endemic area. Although initial visual acuity was 20/50 or worse in 62.9 % of 62 eyes, 76.7 % of 60 eyes followed for a median of 12 months achieved visual acuities of 20/40 or better. Visual field defects were reported for 46.8 % of eyes, but these defects recovered in 63.2 % of 19 eyes with follow-up. Conclusion Visual recovery from tuberculous optic neuropathy is common, if the diagnosis is recognized and appropriate treatment is instituted. A tuberculous etiology should be considered when evaluating optic neuropathy in persons from endemic areas.