2012

Multivalent galactose ligands have been proposed for selective targeting of carbohydrate-binding proteins on epithelial cell surfaces, both in normal and pathological conditions. One cellular partner is galectin-3, a β-galactoside-binding protein present on many epithelial linings, such as those of the ocular surface. In this study, we investigated the ability of hydroxypropyl guar galactomannan (HPGG) to bind recombinant galectin-3 and to target the apical surface of differentiated human corneal keratinocytes. Pull-down and slot-blot assays demonstrated that fluorescence-labeled HPGG bound recombinant galectin-3 through a galactose-dependent mechanism. In contrast, no binding of HPGG could be detected towards recombinant galectin-8 or -9. In a cell culture system, HPGG bound weakly to biotinylated cell surface corneal isolates containing endogenous galectin-3, and incubation of HPGG with corneal keratinocytes in culture resulted in discrete, galactose-independent, binding to the cell surface. Moreover, HPGG failed to elute the biological counter-receptor MUC16 from galectin-3 affinity columns. We conclude that HPGG binds galectin-3 through the conventional carbohydrate-recognition domain in vitro, but not in a biological system, suggesting that endogenous carbohydrate ligands on epithelial cell surface glycocalyces impair HPGG biorecognition.

OBJECTIVE: To assess WINROP (https://winrop.com), an algorithm using postnatal weight measurements, as a tool for the prediction of retinopathy of prematurity (ROP) in a large geographically and racially diverse study population. METHODS: WINROP analysis was performed retrospectively on conventionally at-risk infants from 10 neonatal intensive careunits.Weight measurements were entered into WINROP, which signals an alarm for an abnormal weight gain rate. Infants were classified into categories of no alarm (unlikely to develop type 1ROP)and alarm (at risk for developing type 1ROP).Use of WINROP requires that an infant has (1) gestational age less than 32 weeks at birth, (2) weekly weight measurements,(3) physiologic weight gain,and(4)absence of other pathologic retinal vascular disease. RESULTS: A total of 1706 infants with a median gestational age of 28 weeks (range, 22-31 weeks) and median birth weight of 1016 g (range, 378-2240 g) were included in the study analysis. An alarm occurred in 1101 infants (64.5%), with a median time from birth to alarm of 3 weeks (range, 0-12 weeks) and from alarm to treatment of 8 weeks (range, 1 day to 22 weeks). The sensitivity of WINROP was 98.6% and the negative predictive value was 99.7%. Two infants with type 1 ROP requiring treatment after 40 weeks' postmenstrual age did not receive an alarm. CONCLUSION: The WINROP system is a useful adjunct for ROP screening that identifies high-risk infants early to optimize care and potentially reduce the overall number of diagnostic ROP examinations.

PURPOSE: To determine the diagnostic capability of spectral-domain optical coherence tomography in glaucoma patients with visual field defects. DESIGN: Prospective, cross-sectional study. METHODS: SETTINGS: Participants were recruited from a university hospital clinic. STUDY POPULATION: One eye of 85 normal subjects and 61 glaucoma patients with average visual field mean deviation of -9.61 ± 8.76 dB was selected randomly for the study. A subgroup of the glaucoma patients with early visual field defects was calculated separately. OBSERVATION PROCEDURES: Spectralis optical coherence tomography (Heidelberg Engineering, Inc) circular scans were performed to obtain peripapillary retinal nerve fiber layer (RNFL) thicknesses. The RNFL diagnostic parameters based on the normative database were used alone or in combination for identifying glaucomatous RNFL thinning. MAIN OUTCOME MEASURES: To evaluate diagnostic performance, calculations included areas under the receiver operating characteristic curve, sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio. RESULTS: Overall RNFL thickness had the highest area under the receiver operating characteristic curve values: 0.952 for all patients and 0.895 for the early glaucoma subgroup. For all patients, the highest sensitivity (98.4%; 95% confidence interval, 96.3% to 100%) was achieved by using 2 criteria: ≥ 1 RNFL sectors being abnormal at the < 5% level and overall classification of borderline or outside normal limits, with specificities of 88.9% (95% confidence interval, 84.0% to 94.0%) and 87.1% (95% confidence interval, 81.6% to 92.5%), respectively, for these 2 criteria. CONCLUSIONS: Statistical parameters for evaluating the diagnostic performance of the Spectralis spectral-domain optical coherence tomography were good for early perimetric glaucoma and were excellent for moderately advanced perimetric glaucoma.

Pathological neovascularization (NV) is a hallmark of late stage neovascular age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinopathy of prematurity (ROP). There is accumulating evidence that alterations in inflammatory and immune system pathways that arise from genetic differences, injury, and disease can predispose individuals to retinal neovascular eye diseases. Yet the mechanism of disease progression with respect to the complement system in these maladies is not fully understood. Recent studies have implicated the complement system as an emerging player in the etiology of several retinal diseases. We will summarize herein several of the complement system pathways known to be involved in ocular neovascular pathologies. Current treatment for many neovascular eye diseases focuses on suppression of NV with laser ablation, photodynamic therapy, or anti-VEGF angiogenic inhibitors. However, these treatments do not address the underlying cause of many of these diseases. A clear understanding of the cellular and molecular mechanisms could bring a major shift in our approach to disease treatment and prevention.

A ring-enhancing lesion is an uncommon cause of a dorsal midbrain syndrome. Here, we describe the case of a 60-year-old man with eye movement and pupillary findings consistent with dorsal midbrain syndrome, and in whom neuroimaging showed a single ring-enhancing lesion in the right midbrain and thalamus. Further investigation revealed a longstanding right groin mass which proved to be a malignant melanoma. His intracranial lesion was presumed to be a metastatic lesion, and treated with stereotactic radiosurgery. We report the patient's clinical course, and discuss the diagnosis and management of the solitary midbrain lesion.

Uveal melanoma is the most common primary intraocular malignancy in adults. The disease overwhelmingly affects white populations. Other risk factors include fair skin, light iris color, ancestry from northern latitudes, and ocular/oculodermal melanocytosis. Historically, enucleation was the definitive treatment of uveal melanoma, but brachytherapy and proton beam irradiation are now the most commonly used treatment methods. However, there are still no effective therapies against metastatic uveal melanoma, which is almost always fatal. Continued advances in understanding of the molecular mechanisms of uveal melanoma will facilitate the identification of prognostic markers and therapeutic targets.

PURPOSE OF REVIEW: Pseudophakic cystoid macular edema (PCME) is a common cause of visual impairment after cataract surgery. This article systematically reviews and discusses the epidemiology, risk factors, diagnosis, and treatment of PCME, with a focus on advances in the past 1-2 years. RECENT FINDINGS: The incidence of PCME has declined with the advent of modern surgical techniques. Optical coherence tomography (OCT) has become an important adjunct to biomicroscopy and fluorescein angiography. PCME prophylaxis with topical nonsteroidal anti-inflammatory drugs remains unproven because long-term visual outcomes and comparative effectiveness studies are lacking. Chronic, refractory CME remains a therapeutic challenge, but investigational therapies with potential include corticosteroid intravitreal injections and implants, and intravitreal anti-vascular endothelial growth factor treatments. Few studies have assessed surgical options. SUMMARY: There is currently a lack of well designed randomized clinical trials to guide the treatment of PCME.

In our effort to understand genetic disorders of the photoreceptor cells of the retina, we have focused on intraflagellar transport in photoreceptor sensory cilia. From previous mouse proteomic data we identified a cilia protein Ttc26, orthologue of dyf-13 in Caenorhabditis elegans, as a target. We localized Ttc26 to the transition zone of photoreceptor and to the transition zone of cilia in cultured murine inner medullary collecting duct 3 (mIMCD3) renal cells. Knockdown of Ttc26 in mIMCD3 cells produced shortened and defective primary cilia, as revealed by immunofluorescence and scanning electron microscopy. To study Ttc26 function in sensory cilia in vivo, we utilized a zebrafish vertebrate model system. Morpholino knockdown of ttc26 in zebrafish embryos caused ciliary defects in the pronephric kidney at 27 h postfertilization and distension/dilation of pronephros at 5 d postfertilization (dpf). In the eyes, the outer segments of photoreceptor cells appeared shortened or absent, whereas cellular lamination appeared normal in retinas at 5 dpf. This suggests that loss of ttc26 function prevents normal ciliogenesis and differentiation in the photoreceptor cells, and that ttc26 is required for normal development and differentiation in retina and pronephros. Our studies support the importance of Ttc26 function in ciliogenesis and suggest that screening for TTC26 mutations in human ciliopathies is justified.

PURPOSE: Human adenovirus species D type 19 (HAdV-D19) has been associated with epidemic keratoconjunctivitis (EKC), a highly inflammatory infection of the ocular surface. Confusion exists regarding the origins of HAdV-D19. The prototype virus (HAdV-D19p) does not cause EKC, while a virus identified later with the identical serologic determinant is a significant ocular pathogen. METHODS: High throughput genome sequencing and bioinformatics analysis were performed on HAdV-D19p and three HAdV-D19 EKC strains, and compared to the previously sequenced clinical isolate, HAdV-D19 (C) and HAdV-D37. Corneas of C57BL/6J mice were injected with HAdV-D19p, HAdV-D19 (C), or virus-free buffer, and inflammation assessed by clinical examination, flow cytometry, and cytokine ELISA. Confocal microscopy and real-time PCR of infected corneal cell cultures were used to test viral entry. RESULTS: HAdV-D19 (C) and the other clinical EKC isolates showed nearly 100% sequence identity. EKC strains diverged from HAdV-D19p in the penton base, E3, and fiber transcription units. Simplot analysis showed recombination between EKC-associated HAdV-D19 with HAdV-D37, HAdV-D22, and HAdV-D19p, the latter contributing only the hexon gene, the principal serum neutralization determinant. HAdV-D19p induced stromal keratitis in the C57BL/6J mouse, but failed to infect productively human corneal epithelial cells. These data led to retyping of the clinical EKC isolates with a HAdV-D19 hexon gene as HAdV-D64. CONCLUSIONS: HAdV-D19 associated with EKC (HAdV-D64) originated from a recombination between HAdV-D19p, HAdV-D37, and HAdV-D22, and was mischaracterized because of a shared hexon gene. HAdV-D19p is not infectious for corneal epithelial cells, thus explaining the lack of any association with keratitis.