September 2012

Intraoperative wavefront aberrometry is a relatively new technology that aims to improve refractive outcomes following cataract surgery by optimizing the spherical power of the intraocular lens implant or calculating the appropriate axis and power of toric lenses during cataract surgery in an aphakic state. This article reviews the literature on intraoperative wavefront aberrometry and provides a critical assessment of the benefits and shortcomings of that technology.

PURPOSE: Surgical treatment of myogenic ptosis usually requires a form of frontalis suspension. Complications can include entropion, headache, contour abnormalities, and poor eyelid excursion. The Levine palpebral spring has been used successfully to augment eyelid closure in more than 2,000 patients. The authors present a modified Levine spring to correct ptosis in a patient with poor levator function. METHODS: Interventional case report. A 55-year-old man with profound myogenic ptosis was treated with bilateral modified Levine palpebral springs. Eyelid position, contour and excursion, blink reflex, lagophthalmos, and ocular surface were evaluated. RESULTS: The Levine palpebral spring functioned well to open both eyelids. Margin reflex distance improved from -3 mm to 3 m postoperatively. Excellent contour and excursion were observed. Orbicularis action, including blink reflex, was preserved, and ocular surface was not compromised. CONCLUSION: The modified Levine palpebral spring is an alternative to frontalis suspension in treating select patients with eyelid ptosis with poor levator function.

PURPOSE: The purpose of this study is to report the use of intravitreal triamcinolone for treatment of cancer-associated retinopathy (CAR) refractory to systemic therapy. METHODS: This was a retrospective chart review study. RESULTS: A 67-year-old man presented with cancer-associated retinopathy with antibodies against a 46-kDa retinal protein, alpha enolase. There was disease progression despite therapy with mycophenolate and intravenous immunoglobulin. Serial intravitreal injections of triamcinolone resulted in restoration of photoreceptor anatomy on optical coherence tomography and visual improvement. The patient's vision was preserved at 20/40 OD and 20/32 OS until his death from lung cancer 31 months after CAR diagnosis. CONCLUSIONS: Intravitreal triamcinolone may be beneficial for maintenance of vision in patients with CAR.

PURPOSE: Thrombospondin-1 (TSP1) and TSP2 are matricellular proteins that have been shown to regulate cytoskeleton, cell adhesion, and extracellular matrix remodeling. Both TSP1 and TSP2 are found in the trabecular meshwork (TM). In cadaver eyes with primary open-angle glaucoma (POAG), TSP1 is increased in one third of patients. We hypothesized that TSP1 and TSP2 participate in the regulation of intraocular pressure (IOP). Methods. IOPs of TSP1-null, TSP2-null mice, and their corresponding wild-type (WT) mice were measured using a commercial rebound tonometer. Fluorophotometric measurements assessed aqueous turnover. Central corneal thickness (CCT) was measured by optical coherence tomography. Iridocorneal angles were examined using light microscopy (LM), immunofluorescence (IF), and transmission electron microscopy (TEM). RESULTS: Average IOPs of TSP1-null and TSP2-null mice were 10% and 7% less than that of the corresponding WT mice, respectively. CCTs were 6.5% less in TSP1-null mice (P < 0.05) and 1.1% less in TSP2-null mice (P > 0.05). Fluorophotometric measurements suggest that aqueous turnover rates in TSP1-null and TSP2-null mice are greater than those of WT mice. LM of the TSP1-null and TSP2-null iridocorneal angles reveals morphology, which is indistinguishable from that of their corresponding WTs. IF revealed possible concurrent underexpression of TSP2 in TSP1-null mice and of TSP1 in TSP2-null mice. TEM revealed larger collagen fibril diameters in TSP1-null and TSP2-null mice compared with WTs. CONCLUSIONS: TSP1-null and TSP2-null mice have lower IOPs than their WT counterparts. The rate of aqueous turnover suggests that the mechanism is enhanced outflow facility. An alteration in the extracellular matrix may contribute to this finding.

A new era of ocular imaging has recently begun with the advent of in vivo confocal microscopy (IVCM), shedding more light on the pathophysiology, diagnosis, and potential treatment strategies for dry eye disease. IVCM is a noninvasive and powerful tool that allows detection of changes in ocular surface epithelium, immune and inflammatory cells, corneal nerves, keratocytes, and meibomian gland structures on a cellular level. Ocular surface structures in dry eye-related conditions have been assessed and alterations have been quantified using IVCM. IVCM may aid in the assessment of dry eye disease prognosis and treatment, as well as lead to improved understanding of the pathophysiological mechanisms in this complex disease. Further, due to visualization of subclinical findings, IVCM may allow detection of disease at much earlier stages and allow stratification of patients for clinical trials. Finally, by providing an objective methodology to monitor treatment efficacy, image-guided therapy may allow the possibility of tailoring treatment based on cellular changes, rather than on clinical changes alone.

More than 98% of a typical vertebrate genome does not code for proteins. Although non-coding regions are sprinkled with short (<200 bp) islands of evolutionarily conserved sequences, the function of most of these unannotated conserved islands remains unknown. One possibility is that unannotated conserved islands could encode non-coding RNAs (ncRNAs); alternatively, unannotated conserved islands could serve as promoter-distal regulatory factor binding sites (RFBSs) like enhancers. Here we assess these possibilities by comparing unannotated conserved islands in the human and mouse genomes to transcribed regions and to RFBSs, relying on a detailed case study of one human and one mouse cell type. We define transcribed regions by applying a novel transcript-calling algorithm to RNA-Seq data obtained from total cellular RNA, and we define RFBSs using ChIP-Seq and DNAse-hypersensitivity assays. We find that unannotated conserved islands are four times more likely to coincide with RFBSs than with unannotated ncRNAs. Thousands of conserved RFBSs can be categorized as insulators based on the presence of CTCF or as enhancers based on the presence of p300/CBP and H3K4me1. While many unannotated conserved RFBSs are transcriptionally active to some extent, the transcripts produced tend to be unspliced, non-polyadenylated and expressed at levels 10 to 100-fold lower than annotated coding or ncRNAs. Extending these findings across multiple cell types and tissues, we propose that most conserved non-coding genomic DNA in vertebrate genomes corresponds to promoter-distal regulatory elements.

Although the phenomenon of fundus autofluorescence has been known for decades, it has only recently been recognized as a measure of retinal pigment epithelial function and health. Characteristic fundus autofluorescence patterns have been described in eyes affected by inflammation of the posterior segment, and these patterns have provided insights into the pathogenesis of posterior uveitis entities. In addition, preliminary data indicate that fundus autofluorescence characteristics may serve as markers of disease activity, allow prediction of visual prognosis, and may help determine the adequacy of therapy. We provide an overview of the current state of fundus autofluorescence imaging technology and review our current knowledge of fundus autoflourescence findings and their clinical use in the posterior uveitis entities.

Uveitis is a potentially visually threatening disease accounting for 10% of vision loss in the developed world. The most common cause of vision loss in patients with uveitis has been shown to be macular edema (ME). The early detection and management of ME is critical to preserve vision in these patients. Optical coherence tomography (OCT) is a valuable tool in the management of many ocular diseases. The use of OCT has revolutionized the diagnosis and management of macular edema from a wide variety of ophthalmological diseases, including uveitis. In this review, we evaluate the role of OCT in the diagnosis and management of uveitic macular edema.

The global prevalence of diabetes is estimated to be 336 million people, with diabetic complications contributing to significant worldwide morbidity and mortality. Diabetic retinopathy results from cumulative microvascular damage to the retina and inflammation is recognized as a critical driver of this disease process. This paper outlines the pathophysiology leading to proliferative diabetic retinopathy and highlights many of the inflammatory, angiogenic, and cytokine mediators implicated in the development and progression of this disease. We focus a detailed discussion on the current targeted therapeutic interventions used to treat diabetic retinopathy.

PURPOSE: To analyze the morphologic features of corneal epithelial cells and keratocytes by in vivo confocal microscopy in patients with herpes simplex keratitis (HSK) as associated with corneal innervation. DESIGN: Prospective, cross-sectional, controlled, single-center study. PARTICIPANTS: Thirty-one eyes with the diagnosis HSK and their contralateral clinically unaffected eyes were studied and compared with normal controls (n = 15). METHODS: In vivo confocal microscopy (Confoscan 4; Nidek Technologies, Gamagori, Japan) and corneal esthesiometry (Cochet-Bonnet; Luneau Ophthalmologie, Chartres, France) of the central cornea were performed bilaterally in all patients and controls. Patients were grouped into normal (>5.5 cm), mild (>2.5-5.5 cm), and severe (<2.5 cm) loss of sensation. MAIN OUTCOME MEASURES: Changes in morphologic features and density of the superficial and basal epithelial cells, as well as stromal keratocytes, were assessed by 2 masked observers. Changes were correlated to corneal sensation, number of nerves, and total length of nerves. RESULTS: There was a significant and gradual decrease in the density of superficial epithelial cells in HSK eyes, with 852.50 ± 24.4 cells/mm(2) in eyes with severe sensation loss and 2435.23 ± 224.3 cells/mm(2) in control eyes (P = 0.008). Superficial epithelial cell size was 2.5-fold larger in HSK eyes (835.3 μm(2)) compared with contralateral or normal eyes (407.4 μm(2); P = 0.003). A significant number of hyperreflective desquamating superficial epithelial cells were present in HSK eyes with normal (6.4%), mild (29.1%), and severe (52.2%) loss of sensation, but were absent in controls. The density of basal epithelial cells, anterior keratocytes, and posterior keratocytes did not show statistical significance between patients and controls. Changes in superficial epithelial cell density and morphologic features correlated strongly with total nerve length, number, and corneal sensation. Scans of contralateral eyes did not show any significant epithelial or stromal changes compared with controls. CONCLUSIONS: In vivo confocal microscopy reveals profound HSK-induced changes in the superficial epithelium, as demonstrated by increase in cell size, decrease in cell density, and squamous metaplasia. This study demonstrated that these changes correlate strongly with changes in corneal innervation.

PURPOSE: Eyelid dysmotility may result from trauma, tumors, inflammation, infection, and a variety of other conditions. In these cases, a mechanical effect is disrupting a normal neuromuscular apparatus. Dysmotility can also be caused by paralytic eyelid disorders; included in this broad category are neurologic and myogenic disorders of eyelid opening and/or closure. Secondary effects include spastic eyelid closure and synkinesis syndromes. These conditions, by definition, are disorders of movement, and can only be studied adequately using dynamic imaging techniques. METHODS: A comprehensive literature search was performed on PubMed. Ninety abstracts were reviewed. RESULTS: Dynamic eyelid imaging has evolved dramatically over the past two decades, at least partially due to the rise of inexpensive digital technology. Magnetic search coil imaging, high- and low-speed videography, electromyography, and high-resolution microscopy coil magnetic resonance imaging each has its advantages and disadvantages, an understanding of which will guide appropriate selection of technology in any given clinical situation. CONCLUSIONS: Dynamic eyelid imaging is useful to study dysmotility. The optimal technique depends upon the clinical setting and the physiologic or pathologic topic of interest. To our knowledge, a report of this type has not been previously summarized.

OBJECTIVES: Polyanionic polymers, including lipoteichoic acid and wall teichoic acid, are important determinants of the charged character of the staphylococcal cell wall. This study was designed to investigate the extent to which teichoic acid contributes to protection from anionic azo dyes and to identify barriers to drug penetration for development of new antibiotics for multidrug-resistant Staphylococcus aureus infection. METHODS: We studied antimicrobial activity of azo dyes against S. aureus strains with or without inhibition of teichoic acid in vitro and in vivo. RESULTS: We observed that inhibition of wall teichoic acid expression resulted in an ∼1000-fold increase in susceptibility to azo dyes such as Congo red, reducing its MIC from >1024 to <4 mg/L. Sensitization occurred when the first step in the wall teichoic acid pathway, catalysed by TarO, was inhibited either by mutation or by chemical inhibition. In contrast, genetic blockade of lipoteichoic acid biosynthesis did not confer Congo red susceptibility. Based on this finding, combination therapy was tested using the highly synergistic combination of Congo red plus tunicamycin at sub-MIC concentrations (to inhibit wall teichoic acid biosynthesis). The combination rescued Caenorhabditis elegans from a lethal challenge of S. aureus. CONCLUSIONS: Our studies show that wall teichoic acid confers protection to S. aureus from anionic azo dyes and related compounds, and its inhibition raises the prospect of development of new combination therapies based on this inhibition.

BACKGROUND: Loss of vision in glaucoma is due to apoptotic retinal ganglion cell loss. While p53 modulates apoptosis, gene association studies between p53 variants and glaucoma have been inconsistent. In this study we evaluate the association between a p53 variant functionally known to influence apoptosis (codon 72 Pro/Arg) and the subset of primary open angle glaucoma (POAG) patients with early loss of central visual field. METHODS: Genotypes for the p53 codon 72 polymorphism (Pro/Arg) were obtained for 264 POAG patients and 400 controls from the U.S. and in replication studies for 308 POAG patients and 178 controls from Australia (GIST). The glaucoma patients were divided into two groups according to location of initial visual field defect (either paracentral or peripheral). All cases and controls were Caucasian with European ancestry. RESULTS: The p53-PRO/PRO genotype was more frequent in the U.S. POAG patients with early visual field defects in the paracentral regions compared with those in the peripheral regions or control group (p=2.7 × 10(-5)). We replicated this finding in the GIST cohort (p  =7.3 × 10(-3), and in the pooled sample (p=6.6 × 10(-7)) and in a meta-analysis of both the US and GIST datasets (1.3 × 10(-6), OR 2.17 (1.58-2.98 for the PRO allele). CONCLUSIONS: These results suggest that the p53 codon 72 PRO/PRO genotype is potentially associated with early paracentral visual field defects in primary open-angle glaucoma patients.

In vivo confocal microscopy (IVCM) of the cornea is becoming an indispensable tool in the cellular study of corneal physiology and disease. This technique offers non-invasive imaging of the living cornea with images comparable to that of ex vivo histology. The ability to provide high-resolution images of all layers in the living cornea has resulted in new discoveries of corneal pathology at the cellular level. The IVCM analysis of corneal dystrophies is of importance to clinicians, as current methods of diagnosis involve slit-lamp characteristics, genetic analysis, and invasive biopsy. IVCM is helpful in evaluating the morphological characteristics of corneal dystrophies at the histological level and may be helpful in diagnosis, determination of progression, and understanding the pathophysiology of disease. The purpose of this review is to describe the principles, applications, and clinical correlation of IVCM in the study of corneal dystrophies.

PURPOSE: To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes. DESIGN: Sibling correlation study and genome-wide association study (GWAS). PARTICIPANTS: For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls. METHODS: Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts. MAIN OUTCOME MEASURES: Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes. RESULTS: The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2 × 10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3 × 10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4 × 10(-14) for combined discovery and replication analysis). CONCLUSIONS: Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies.