April 2012

PURPOSE: To evaluate the effect of a single treatment with the LipiFlow(®) Thermal Pulsation System on signs of meibomian gland dysfunction (MGD) and dry eye symptoms over a 9-month period. METHODS: Patients (n = 42 eyes, 21 subjects) diagnosed with MGD and dry eye symptoms were recruited for a non-significant risk, prospective, open-label, 1-month clinical trial. Patients received a single 12-minute treatment using the LipiFlow(®) Thermal Pulsation System on each eye. The LipiFlow(®) device applies heat to the conjunctival surfaces of the upper and lower inner eyelids while simultaneously applying pulsatile pressure to the outer eyelid surfaces to express the meibomian glands. Patient symptoms were evaluated using the Ocular Surface Disease Index (OSDI) and Standard Patient Evaluation for Eye Dryness (SPEED) dry eye questionnaires; tear break-up time was measured with the dry eye test (DET™); and meibomian gland function was evaluated using a standardized diagnostic expression technique. Data are presented for patient's pre-treatment (baseline) and at 1-month and 9-month post-treatment. RESULTS: Meibomian gland secretion scores improved significantly from baseline (4.4 ± 4.0) to 1-month post-treatment (11.3 ± 6.2; p < 0.0001) and this improvement was maintained with no significant regression at 9 months (11.7 ± 5.9). Similarly, baseline tear break-up time (4.8 ± 3.2) was significantly increased at 1 month (9.6 ± 7.6; p < 0.001) and this increase was maintained with no significant regression at 9 months (7.1 ± 5.6). Symptom scores on both OSDI and SPEED questionnaires improved significantly at 1 month (p < 0.0001) and this improvement was maintained at 9 months. CONCLUSION: With such prolonged improvement in signs and symptoms of dry eye disease, the LipiFlow(®) Thermal Pulsation System offers a technological advancement for the treatment of dry eye disease secondary to meibomian gland dysfunction. A single 12-minute LipiFlow(®) treatment results in up to 9 months of sustained improvement of meibomian gland function, tear break-up time and dry eye symptoms that are unparalleled with current dry eye treatments.

PURPOSE: Androgens exert a significant influence on the structure, function and/or pathophysiology of the meibomian gland and conjunctiva. We sought to determine whether this hormone action involves the regulation of epithelial cell gene expression in these tissues. METHODS: Immortalized human meibomian gland and conjunctival epithelial cells were treated with placebo or dihydrotestosterone (DHT) and processed for molecular biologic procedures. Gene expression was evaluated with BeadChips and data were analyzed with bioinformatic and statistical software. RESULTS: Androgen treatment significantly influenced the expression of approximately 3,000 genes in immortalized human meibomian gland and conjunctival epithelial cells. The nature of DHT action on gene activity was predominantly cell-specific. Similarly, DHT exerted a significant, but primarily cell-specific, influence on many gene ontologies and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. These included groups of genes related, for example, to lipid dynamics, innate immunity, cell cycle, Janus kinase (JAK)-signal transducer and activator of transcription (stat) cascades, oxidative phosphorylation, the proteasome, and mammalian target of rapamycin (mTOR), Wnt, and peroxisome proliferator-activated receptor (PPAR) signaling. CONCLUSIONS: Our findings support our hypothesis that androgens regulate gene expression in human meibomian gland and conjunctival epithelial cells. Our ongoing studies are designed to determine whether many of these genes are translated and play a role in the health and well being of the eye.

The genome of human adenovirus (HAdV) D30 was sequenced in depth. Sequence assembly and analysis revealed two distinct viral sequences with identical hexon genes, which were the same as the one previously reported for HAdV-D30. However, one of the two viruses was found to be a recombinant of HAdV-D29. Exclusive reliance on serum neutralization can lead to mischaracterization of adenoviruses and miss coinfections. Whole-genome sequencing remains the gold standard for proper classification of HAdVs.

Rod outer segment membrane guanylate cyclase (ROS-GC1) is a bimodal Ca(2+) signal transduction switch. Lowering [Ca(2+)](i) from 200 to 20 nM progressively turns it "ON" as does raising [Ca(2+)](i) from 500 to 5000 nM. The mode operating at lower [Ca(2+)](i) plays a vital role in phototransduction in both rods and cones. The physiological function of the mode operating at elevated [Ca(2+)](i) is not known. Through comprehensive studies on mice involving gene deletions, biochemistry, immunohistochemistry, electroretinograms and single cell recordings, the present study demonstrates that the Ca(2+)-sensor S100B coexists with and is physiologically linked to ROS-GC1 in cones but not in rods. It up-regulates ROS-GC1 activity with a K(1/2) for Ca(2+) greater than 500 nM and modulates the transmission of neural signals to cone ON-bipolar cells. Furthermore, a possibility is raised that under pathological conditions where [Ca(2+)](i) levels rise to and perhaps even enter the micromolar range, the S100B signaling switch will be turned "ON" causing an explosive production of CNG channel opening and further rise in [Ca(2+)](i) in cone outer segments. The findings define a new cone-specific Ca(2+)-dependent feature of photoreceptors and expand our understanding of the operational principles of phototransduction machinery.

In September 2010, a Symposium in Florence, Italy, was held to address the unmet need for global treatments for dry eye disease (DED). It was sponsored by The Tear Film & Ocular Surface Society (TFOS; www.TearFilm.org) and co-sponsored by the Association for Research in Vision & Ophthalmology (www.arvo.org). The Symposium objectives were two-fold: first, to discuss accepted and emerging clinical endpoints of DED with regulatory experts from around the world; and second, to consider how to improve clinical trials of treatments for DED. The Symposium focused on the personal and collective burden of DED, as well as the developmental and regulatory challenges associated with generating new DED therapeutics. This article provides a synopsis of many of the presentations, discussions and recommendations of this Symposium.

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86×10⁻¹⁸), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87×10⁻¹¹). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17×10⁻¹²) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88×10⁻¹⁰). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54-1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

Conjunctival cysts unrelated to surgery or trauma are uncommon adnexal lesions in children and may be difficult to recognize. We report the clinical and pathological findings of an apparently spontaneous conjunctival cyst in the upper eyelid of a child whose first ophthalmological examination was at 7 months of age. The cyst was surgically excised at 5 years of age.

Herpes simplex keratitis (HSK) is a major cause of corneal blindness in the world. Following the primary infection, the virus enters into a latent phase. Recurrent infectious or immune keratitis cause structural damage to the cornea, scarring, and may lead to blindness. Several commercially available topical and oral antiviral drugs for HSK are currently available. However, toxicity and low patient compliance hamper their use in HSK. Further, oral antiviral drugs alone are not always effective in HSK. Thus, there had been a need for safe and effective topical antiviral agents against HSK. Systemic ganciclovir has been in use for the treatment of cytomegalovirus infections. Recently, topical ganciclovir has become available for use in patients with HSK. Ganciclovir 0.15% ophthalmic gel has been shown to be both safe and effective against viruses of the herpes family. Topical ganciclovir ophthalmic gel is well tolerated and does not cause significant toxic effects on the ocular surface. Several multicenter studies have revealed the potential role of ganciclovir ophthalmic gel in the treatment and prophylaxis of epithelial HSK. In this paper, we have reviewed the pharmacology, efficacy, side effects, and the role of ganciclovir ophthalmic gel 0.15% in the treatment of acute herpetic keratitis.

BACKGROUND: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a rare but severe and sometimes fatal condition associated with exposure to medications; sulfamethoxazole is among the most common causes. We sought to address the safety of acetazolamide, a chemically related compound, in patients with prior SJS/TEN and glaucoma. A retrospective case series is described of patients at the Massachusetts Eye and Ear Infirmary who underwent keratoprosthesis surgery for corneal blindness from SJS/TEN, and later required oral acetazolamide for elevated intraocular pressure. FINDINGS: Over the last 10 years, 17 patients with SJS/TEN received a Boston keratoprosthesis. Of these, 11 developed elevated intraocular pressure that required administration of oral acetazolamide. One of 11 developed a mild allergic reaction, but no patient experienced a recurrence of SJS/TEN or any severe adverse reaction. CONCLUSION: Although an increase in the rate of recurrent SJS/TEN due to oral acetazolamide would not necessarily be apparent after treating only 11 patients, in our series, acetazolamide administration was well tolerated without serious sequela.

Herein, we report that vascular endothelial growth factor A (VEGF-A) engages the PI3K/Akt pathway by a previously unknown mechanism that involves three tyrosine kinases. Upon VEGF-A-dependent activation of VEGF receptor-2 (VEGFR-2), and subsequent TSAd-mediated activation of Src family kinases (SFKs), SFKs engage the receptor tyrosine kinase Axl via its juxtamembrane domain to trigger ligand-independent autophosphorylation at a pair of YXXM motifs that promotes association with PI3K and activation of Akt. Other VEGF-A-mediated signalling pathways are independent of Axl. Interfering with Axl expression or function impairs VEGF-A- but not bFGF-dependent migration of endothelial cells. Similarly, Axl null mice respond poorly to VEGF-A-induced vascular permeability or angiogenesis, whereas other agonists induce a normal response. These results elucidate the mechanism by which VEGF-A activates PI3K/Akt, and identify previously unappreciated potential therapeutic targets of VEGF-A-driven processes.