Survey of ocular abnormalities in draft horses.

OBJECTIVE: To determine the prevalence of ocular disease in draft horses in the United States. ANIMALS: Draft horses of various breeds and ages. PROCEDURE: Nondilated ophthalmic examination was performed using slit lamp biomicroscopy and indirect ophthalmoscopy. Intraocular pressures were measured when possible. RESULTS: One hundred sixty-five draft horses were examined. Age range: 10 days to 33 years (mean 10.8 years, median 10 years); 87 geldings (52.7%), 71 mares (43.0%), 7 stallions (4.2%); 64 Percherons (38.8%), 51 Belgians (30.9%), 29 Clydesdales (17.6%), 15 Shires (9%), and 6 other draft breed (3.6%). Intraocular pressure: mean 24.7 mmHg OD, range 13-37 mmHg; mean 25.0 mmHg OS, range 11-37 mmHg. Vision-threatening disease was present in 9 horses (5.5%): complete cataracts 1, post-traumatic optic nerve atrophy 1, uveitis and secondary glaucoma 1, retinal detachment 1, large chorioretinal scar 3, phthisis bulbi 2. Non-vision-threatening ocular disease was present in 56 horses (33.9%) involving one or more ocular structures: eyelid trauma/notch defect 14 (8.5%), SCC-type adnexal lesions 12 (7.3%), corneal scars 16 (9.7%), keratitis 6 (3.6%), corpora nigra cyst 15 (9.1%), incipient/punctate cataract 50 (30.3%), vitreous degeneration 10 (6.1%), asteroid hyalosis 1, "bullethole" chorioretinal scars 3, RPE coloboma 1. Linear keratopathy was present in 28 horses (17%) with 2/28 having concurrent vision threatening ocular disease. CONCLUSIONS: Ocular abnormalities, in particular minor cataracts, were relatively common in this population, but not typically vision-threatening. Additionally, this survey demonstrated a greater prevalence of linear keratopathy in draft horses compared with reports in other breeds; however, it does not appear to be associated with concurrent ocular disease.

Hyphema and secondary glaucoma as a presenting complaint in a dog with chronic lymphocytic leukemia.

A 5-year-old Pomeranian was diagnosed with anterior uveitis, hyphema, and secondary glaucoma OD. Concurrent retinal hemorrhage, perivascular sheathing, and papilledema were identified OS. Work-up identified small cell lymphocytosis (>900 × 109/L), anemia, and thrombocytopenia. The patient was diagnosed with B-cell chronic lymphocytic leukemia as a cause of the ocular findings.

RPE65 and the Accumulation of Retinyl Esters in Mouse Retinal Pigment Epithelium.

The RPE65 protein of the retinal pigment epithelium (RPE) enables the conversion of retinyl esters to the visual pigment chromophore 11-cis retinal. Fresh 11-cis retinal is generated from retinyl esters following photoisomerization of the visual pigment chromophore to all-trans during light detection. Large amounts of esters accumulate in Rpe65-/- mice, indicating their continuous formation when 11-cis retinal generation is blocked. We hypothesized that absence of light, by limiting the conversion of esters to 11-cis retinal, would also result in the build-up of retinyl esters in the RPE of wild-type mice. We used HPLC to quantify ester levels in organic extracts of the RPE from wild-type and Rpe65-/- mice. Retinyl ester levels in Sv/129 wild-type mice that were dark adapted for various intervals over a 4-week period were similar to those in mice raised in cyclic light. In C57BL/6 mice however, which contain less Rpe65 protein, dark adaptation was accompanied by an increase in ester levels compared to cyclic light controls. Retinyl ester levels were much higher in Rpe65-/- mice compared to wild type and kept increasing with age. The results suggest that the RPE65 role in retinyl ester homeostasis extends beyond enabling the formation of 11-cis retinal.

Genetic mapping at 3-kilobase resolution reveals inositol 1,4,5-triphosphate receptor 3 as a risk factor for type 1 diabetes in Sweden.

We mapped the genetic influences for type 1 diabetes (T1D), using 2,360 single-nucleotide polymorphism (SNP) markers in the 4.4-Mb human major histocompatibility complex (MHC) locus and the adjacent 493 kb centromeric to the MHC, initially in a survey of 363 Swedish T1D cases and controls. We confirmed prior studies showing association with T1D in the MHC, most significantly near HLA-DR/DQ. In the region centromeric to the MHC, we identified a peak of association within the inositol 1,4,5-triphosphate receptor 3 gene (ITPR3; formerly IP3R3). The most significant single SNP in this region was at the center of the ITPR3 peak of association (P=1.7 x 10(-4) for the survey study). For validation, we typed an additional 761 Swedish individuals. The P value for association computed from all 1,124 individuals was 1.30 x 10(-6) (recessive odds ratio 2.5; 95% confidence interval [CI] 1.7-3.9). The estimated population-attributable risk of 21.6% (95% CI 10.0%-31.0%) suggests that variation within ITPR3 reflects an important contribution to T1D in Sweden. Two-locus regression analysis supports an influence of ITPR3 variation on T1D that is distinct from that of any MHC class II gene.

Protein kinase A negatively modulates the nuclear accumulation of NF-ATc1 by priming for subsequent phosphorylation by glycogen synthase kinase-3.

The nuclear localization and transcriptional activity of the NF-ATc family of transcription factors, essential to many developmental, differentiation, and adaptation processes, are determined by the opposing activities of the phosphatase calcineurin, which promotes nuclear accumulation of NF-ATc, and several kinases, which promote cytoplasmic accumulation. Many reports suggest that protein kinase A (PKA) negatively modulates calcineurin-mediated NF-ATc activation. Here we show that overexpression of PKA causes phosphorylation and cytoplasmic accumulation of NF-ATc1 in direct opposition to calcineurin by phosphorylating Ser-245, Ser-269, and Ser-294 in the conserved serine-proline repeat domain, and that mutation of these serines blocks the effect of PKA. Activation of endogenous PKA is similarly able to promote phosphorylation of these sites on NF-ATc1 in two lymphoid cell lines. We further show that a complete block of NF-ATc1 nuclear localization by PKA requires a second kinase activity that can be supplied by glycogen synthase kinase-3 (GSK-3), and that mutation of either the PKA phosphorylation sites or the upstream GSK-3 sites prevents the effect of PKA. Thus, we propose that PKA functions cooperatively as a priming kinase for further phosphorylation by GSK-3 to oppose calcineurin-mediated nuclear accumulation and transcriptional activity of NF-ATc1 and that, through this mechanism, PKA may be an important modulator of many NF-ATc-dependent processes.