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2014

2014 | 282 Publications
Jakobs T. Differential gene expression in glaucoma.. Cold Spring Harb Perspect Med. 2014;4(7):a020636.

In glaucoma, regardless of its etiology, retinal ganglion cells degenerate and eventually die. Although age and elevated intraocular pressure (IOP) are the main risk factors, there are still many mysteries in the pathogenesis of glaucoma. The advent of genome-wide microarray expression screening together with the availability of animal models of the disease has allowed analysis of differential gene expression in all parts of the eye in glaucoma. This review will outline the findings of recent genome-wide expression studies and discuss their commonalities and differences. A common finding was the differential regulation of genes involved in inflammation and immunity, including the complement system and the cytokines transforming growth factor β (TGFβ) and tumor necrosis factor α (TNFα). Other genes of interest have roles in the extracellular matrix, cell-matrix interactions and adhesion, the cell cycle, and the endothelin system.

Yanai R, Mulki L, Hasegawa E, Takeuchi K, Sweigard H, Suzuki J, Gaissert P, Vavvas D, Sonoda KH, Rothe M, Schunck WH, Miller J, Connor K. Cytochrome P450-generated metabolites derived from ω-3 fatty acids attenuate neovascularization. Proc Natl Acad Sci U S A. 2014;111(26):9603–8.
Ocular neovascularization, including age-related macular degeneration (AMD), is a primary cause of blindness in individuals of industrialized countries. With a projected increase in the prevalence of these blinding neovascular diseases, there is an urgent need for new pharmacological interventions for their treatment or prevention. Increasing evidence has implicated eicosanoid-like metabolites of long-chain polyunsaturated fatty acids (LCPUFAs) in the regulation of neovascular disease. In particular, metabolites generated by the cytochrome P450 (CYP)-epoxygenase pathway have been shown to be potent modulators of angiogenesis, making this pathway a reasonable previously unidentified target for intervention in neovascular ocular disease. Here we show that dietary supplementation with ω-3 LCPUFAs promotes regression of choroidal neovessels in a well-characterized mouse model of neovascular AMD. Leukocyte recruitment and adhesion molecule expression in choroidal neovascular lesions were down-regulated in mice fed ω-3 LCPUFAs. The serum of these mice showed increased levels of anti-inflammatory eicosanoids derived from eicosapentaenoic acid and docosahexaenoic acid. 17,18-epoxyeicosatetraenoic acid and 19,20-epoxydocosapentaenoic acid, the major CYP-generated metabolites of these primary ω-3 LCPUFAs, were identified as key lipid mediators of disease resolution. We conclude that CYP-derived bioactive lipid metabolites from ω-3 LCPUFAs are potent inhibitors of intraocular neovascular disease and show promising therapeutic potential for resolution of neovascular AMD.
Healy D, Lee G, Freitag S, Bleier B. Endoscopic bimanual approach to an intraconal cavernous hemangioma of the orbital apex with vascularized flap reconstruction.. Ophthal Plast Reconstr Surg. 2014;30(4):e104–6.

The aim of this study was to describe a transnasal endoscopic bimanual technique for the removal of an intraconal orbital apex cavernous hemangioma. Report of a surgical technique. A 39-year-old woman with unilateral visual loss and proptosis was found to have an intraconal orbital apex mass consistent radiographically with cavernous hemangioma. Because of its posteromedial location within the orbit, a transnasal 4-handed endoscopic technique was used with pedicled nasoseptal flap reconstruction. The tumor was excised, and the patient had no complications. The transnasal endoscopic approach to orbital apex cavernous hemangioma excision is a viable surgical approach for these difficult to access lesions. The medial orbital wall may be simultaneously reconstructed to prevent diplopia and enophthalmos.

Lin Y, Gardiner M. Fingernail-induced corneal abrasions: case series from an ophthalmology emergency department. Cornea. 2014;33(7):691–5.
PURPOSE: Fingernail-induced corneal abrasions are one of the most common eye injuries that present to the emergency department, and yet there is little literature available to offer guidelines for management. We analyzed the treatment used in cases of fingernail-induced corneal abrasions that presented to the Massachusetts Eye and Ear Infirmary Emergency Department and studied its relationship to the development of complications such as recurrent erosion syndrome and infection. METHODS: We performed a retrospective review of 99 patients who presented to the Massachusetts Eye and Ear Infirmary Emergency Department with fingernail-induced corneal abrasions between January 1, 2009 and December 31, 2009. We followed the patients for 12 months and documented demographics, nature of the injury, treatment, and complications. RESULTS: The average age was 29.4 (range, 2-89) years. Forty-four percent (n = 44) were female and 56% (n = 55) were male. Of the 99 subjects, 39 had a full 12 month follow-up, and 7 developed a complication from the injury. Compared with the 32 subjects without complications, there was no difference in age or gender. However, there was a significant difference in that adults scratched by another adult were more highly represented in the group with complications (43%, n = 3/7 vs. 3%, n = 1/32; P = 0.0017). There was no significant difference in outcome by treatment used. CONCLUSIONS: This is the largest fingernail-induced corneal abrasion study completed to date. Patients are at risk of developing complications, but there is scant evidenced-based literature available for treating this common injury. Prospective trials should be performed to better optimize and standardize treatments.
Mauris J, Woodward A, Cao Z, Panjwani N, Argüeso P. Molecular basis for MMP9 induction and disruption of epithelial cell-cell contacts by galectin-3. J Cell Sci. 2014;127(Pt 14):3141–8.
Dynamic modulation of the physical contacts between neighboring cells is integral to epithelial processes such as tissue repair and cancer dissemination. Induction of matrix metalloproteinase (MMP) activity contributes to the disassembly of intercellular junctions and the degradation of the extracellular matrix, thus mitigating the physical constraint to cell movement. Using the cornea as a model, we show here that a carbohydrate-binding protein, galectin-3, promotes cell-cell detachment and redistribution of the tight junction protein occludin through its N-terminal polymerizing domain. Notably, we demonstrate that galectin-3 initiates cell-cell disassembly by inducing matrix metalloproteinase expression in a manner that is dependent on the interaction with and clustering of the matrix metalloproteinase inducer CD147 (also known as EMMPRIN and basigin) on the cell surface. Using galectin-3-knockout mice in an in vivo model of wound healing, we further show that increased synthesis of MMP9 at the leading edge of migrating epithelium is regulated by galectin-3. These findings establish a new galectin-3-mediated regulatory mechanism for induction of metalloproteinase expression and disruption of cell-cell contacts required for cell motility in migrating epithelia.
Karamichos, Hutcheon, Zieske. Reversal of fibrosis by TGF-β3 in a 3D in vitro model. Exp Eye Res. 2014;124:31–6.
Corneal scarring following moderate to severe injury is inevitable. Despite significant advancements in the field, current treatments following these types of injuries are limited, and often, the visual recovery is poor. One of the problems and limitations is that corneal wound healing is a complex process, involving corneal cells, extracellular matrix components and growth factors. Therefore, further understanding is required, along with new treatments and techniques to reduce or prevent corneal scarring following injury. Two isoforms of transforming growth factor-beta (TGF-β), TGF-β1 and -β3 (T1 and T3, respectively), are associated with corneal wound healing. T1 has been shown to drive the corneal keratocytes to differentiate into myofibroblasts; whereas, T3 has been found to inhibit fibrotic markers. In the current study, we examined whether the fibrotic characteristics expressed by human corneal fibroblasts (HCF) in our 3-dimensional (3D) construct following T1 stimulation could be reversed by introducing T3 to the in vitro system. To do this, HCF were isolated and cultured in 10% serum, and when they reached confluence, the cells were stimulated with a stable Vitamin C (VitC) derivative for 4 weeks, which allowed them to secrete a self-assembled matrix. Three conditions were tested: (1) CONTROL: 10% serum (S) only, (2) T1: 10%S + T1, or (3) Rescue: 10%S + T1 for two weeks and then switched to 10%S + T3 for another two weeks. At the end of 4 weeks, the constructs were processed for analysis by indirect-immunofluorescence (IF) and transmission electron microscopy (TEM). Different collagens that are normally present in healthy corneas in vivo, such as Type I and V, as well as Type III, which is a fibrotic indicator, were examined. In addition, we examined smooth muscle actin (SMA), a marker of myofibroblasts, and thrombospondin-1 (TSP-1), a multifunctional matrix protein known to activate the latent complex of TGF-β and appear upon wounding in vivo. Our data showed high expression of collagens type I and V under all conditions throughout the 3D constructs; however, type III and SMA expression were higher in the constructs that were stimulated with T1 and reduced to almost nothing in the Rescue samples. A similar pattern was seen with TSP-1, where TSP-1 expression following "rescue" was decreased considerably. Overall, this data is in agreement with our previous observations that T3 has a significant non-fibrotic effect on HCFs, and presents a novel model for the "rescue" of both cellular and matrix fibrotic components with a single growth factor.
Luo G, Garaas T, Pomplun M. Salient stimulus attracts focus of peri-saccadic mislocalization. Vision Res. 2014;100:93–8.
Visual localization during saccadic eye movements is prone to error. Flashes shortly before and after the onset of saccades are usually perceived to shift towards the saccade target, creating a "compression" pattern. Typically, the saccade landing point coincides with a salient saccade target. We investigated whether the mislocalization focus follows the actual saccade landing point or a salient stimulus. Subjects made saccades to either a target or a memorized location without target. In some conditions, another salient marker was presented between the initial fixation and the saccade landing point. The experiments were conducted on both black and picture backgrounds. The results show that: (a) when a saccade target or a marker (spatially separated from the saccade landing point) was present, the compression pattern of mislocalization was significantly stronger than in conditions without them, for both black and picture background conditions, and (b) the mislocalization focus tended towards the salient stimulus regardless of whether it was the saccade target or the marker. Our results suggest that a salient stimulus presented in the scene may have an attracting effect and therefore contribute to the non-uniformity of saccadic mislocalization of a probing flash.
Feke G, Bex P, Taylor C, Rhee D, Turalba A, Chen T, Wand M, Pasquale L. Effect of brimonidine on retinal vascular autoregulation and short-term visual function in normal tension glaucoma.. Am J Ophthalmol. 2014;158(1):105–112.e1.

PURPOSE: To assess whether brimonidine 0.15% alters retinal vascular autoregulation and short-term visual function in normal tension glaucoma patients who demonstrate retinal vascular dysregulation. DESIGN: Nonrandomized clinical trial. METHODS: In this prospective study, 46 normal tension glaucoma patients not previously treated with brimonidine underwent retinal vascular autoregulation testing and visual function assessment using frequency doubling technology perimetry and equivalent noise motion sensitivity testing. We measured blood flow in a major temporal retinal artery with subjects seated and then while reclined for 30 minutes. Patients having a change in retinal blood flow with posture change outside the range previously found in healthy subjects were classified as having retinal vascular dysregulation. They were treated with brimonidine 0.15% for 8 weeks and designated for retesting. RESULTS: Twenty-three patients demonstrated retinal vascular dysregulation at the initial visit. Younger age (P = .050) and diabetes (P = .055) were marginally significant risk factors for retinal vascular dysregulation. After the 8-week course with brimonidine, 14 of the 17 patients who completed the study showed a return of posture-induced retinal blood flow changes to levels consistent with normal retinal vascular autoregulation (P < .0001). We found no significant changes in frequency doubling technology perimetry or in motion detection parameters following treatment with brimondine (P > .09 for all tests performed). CONCLUSIONS: Brimonidine significantly improved impaired retinal vascular autoregulation in normal tension glaucoma patients, but short-term alteration in visual function could not be demonstrated.

Bleier B, Healy D, Chhabra N, Freitag S. Compartmental endoscopic surgical anatomy of the medial intraconal orbital space.. Int Forum Allergy Rhinol. 2014;4(7):587–91.

BACKGROUND: Surgical management of intraconal pathology represents the next frontier in endoscopic endonasal surgery. Despite this, the medial intraconal space remains a relatively unexplored region, secondary to its variable and technically demanding anatomy. The purpose of this study is to define the neurovascular structures in this region and introduce a compartmentalized approach to enhance surgical planning. METHODS: This study was an institutional review board (IRB)-exempt endoscopic anatomic study in 10 cadaveric orbits. After dissection of the medial intraconal space, the pattern and trajectory of the oculomotor nerve and ophthalmic arterial arborizations were analyzed. The position of all vessels as well as the length of the oculomotor trunk and branches relative to the sphenoid face were calculated. RESULTS: A mean of 1.5 arterial branches were identified (n = 15; range, 1-4) at a mean of 8.8 mm from the sphenoid face (range, 4-15 mm). The majority of the arteries (n = 7) inserted adjacent to the midline of medial rectus. The oculomotor nerve inserted at the level of the sphenoid face and arborized with a large proximal trunk 5.5 ± 1.1 mm in length and multiple branches extending 13.2 ± 2.7 mm from the sphenoid face. The most anterior nerve and vascular pedicle were identified at 17.0 and 15.0 mm from the sphenoid face, respectively. CONCLUSION: The neurovascular supply to the medial rectus muscle describes a varied but predictable pattern. This data allows the compartmentalization of the medial intraconal space into 3 zones relative to the neurovascular supply. These zones inform the complexity of the dissection and provide a guideline for safe medial rectus retraction relative to the fixed landmark of the sphenoid face.

Contreras-Ruiz L, Ryan D, Sia R, Bower K, Dartt DA, Masli S. Polymorphism in THBS1 gene is associated with post-refractive surgery chronic ocular surface inflammation. Ophthalmology. 2014;121(7):1389–97.
PURPOSE: To determine the association of single nucleotide polymorphisms (SNPs) of the thrombospondin 1 (THBS1) gene with development of chronic ocular surface inflammation (keratoconjunctivitis) after refractive surgery. DESIGN: Retrospective cohort study. PARTICIPANTS: Active duty U.S. Army soldiers (n = 143) who opted for refractive surgery. METHODS: Conjunctival impression cytology samples collected from participants before the surgery were used to harvest DNA for genotyping 5 THBS1 SNPs (rs1478604, rs2228262, rs2292305, rs2228262, and rs3743125) using the Sequenom iPLEX Gold platform (Sequenom, San Diego, CA). Samples collected after surgery were used to harvest RNA for gene expression analysis by real-time polymerase chain reaction (PCR). Participants were followed for 1 year after surgery to monitor the status of keratoconjunctivitis. MAIN OUTCOME MEASURES: Genetic basis of the development of chronic keratoconjunctivitis after refractive surgery. RESULTS: Carriers of minor alleles of 3 SNPs each were found to be more susceptible to developing chronic keratoconjunctivitis (rs1478604: odds ratio [OR], 2.5; 95% confidence interval [CI], 1.41-4.47; P = 2.5 × 10(-3); rs2228262 and rs2292305: OR, 1.9; 95% CI, 1.05-3.51; P = 4.8 × 10(-2)). Carriers of the rs1478604 minor allele expressed significantly reduced levels of thrombospondin 1 (TSP1) (P = 0.042) and increased levels of an inflammatory cytokine associated with keratoconjunctivitis, interleukin-1β (P = 0.025), in their ocular surface epithelial cells compared with homozygous major allele controls. CONCLUSIONS: Genetic variation in the THBS1 gene that results in decreased expression of the encoded glycoprotein TSP1 in ocular surface epithelial cells significantly increases the susceptibility to develop chronic ocular surface inflammation after refractive surgery. Further investigation of THBS1 SNPs in a larger sample size is warranted.
Sweigard H, Yanai R, Gaissert P, Saint-Geniez M, Kataoka K, Thanos A, Stahl G, Lambris J, Connor K. The alternative complement pathway regulates pathological angiogenesis in the retina. FASEB J. 2014;28(7):3171–82.
A defining feature in proliferative retinopathies is the formation of pathological neovessels. In these diseases, the balance between neovessel formation and regression determines blindness, making the modulation of neovessel growth highly desirable. The role of the immune system in these retinopathies is of increasing interest, but it is not completely understood. We investigated the role of the alternative complement pathway during the formation and resolution of aberrant neovascularization. We used alternative complement pathway-deficient (Fb(-/-)) mice and age- and strain-matched control mice to assess neovessel development and regression in an oxygen-induced retinopathy (OIR) mouse model. In the control mice, we found increased transcription of Fb after OIR treatment. In the Fb(-/-) mice, we prepared retinal flatmounts and identified an increased number of neovessels, peaking at postnatal day 17 (P17; P=0.001). Subjecting human umbilical vein endothelial cells (HUVECs) to low oxygen, mimicking a characteristic of neovessels, decreased the expression of the complement inhibitor Cd55. Finally, using laser capture microdissection (LCM) to isolate the neovessels after OIR, we found decreased expression of Cd55 (P=0.005). Together, our data implicate the alternative complement pathway in facilitating neovessel clearance by down-regulating the complement inhibitor Cd55 specifically on neovessels, allowing for their targeted removal while leaving the established vasculature intact.-Sweigard, J. H., Yanai, R., Gaissert, P., Saint-Geniez, M., Kataoka, K., Thanos, A., Stahl, G. L., Lambris, J. D., Connor, K. M. The alternative complement pathway regulates pathological angiogenesis in the retina.
MacKinnon S, Oystreck D, Andrews C, Chan WM, Hunter D, Engle E. Diagnostic distinctions and genetic analysis of patients diagnosed with moebius syndrome. Ophthalmology. 2014;121(7):1461–8.
OBJECTIVE: To improve diagnostic assessment in Moebius syndrome by (1) creating more selective diagnostic subgroups and (2) conducting genetic evaluation in a large patient cohort. DESIGN: Prospective, observational study. PARTICIPANTS: Attendees of 3 consecutive Moebius syndrome conferences held in the United States, with a prior diagnosis of Moebius syndrome, were invited to participate. METHODS: Participants underwent standardized ophthalmologic examination for Moebius syndrome minimum diagnostic criteria (MDC) (congenital, nonprogressive facial palsy, and abduction deficit) and genetic testing for HOXA1, HOXB1, and TUBB3 mutations. MAIN OUTCOME MEASURES: The number of patients meeting MDC and the number of patients with confirmed genetic mutation. RESULTS: A total of 112 participants from 107 families enrolled. Nineteen percent of participants (21/112) did not meet accepted MDC for Moebius syndrome because they had abduction deficits without facial palsy or facial palsy with full ocular motility. All 5 families with 2 affected individuals had at least 1 family member in this category, including 2 siblings with comitant strabismus who harbored a HOXB1 mutation. Four unrelated participants, also not meeting MDC, had large-angle exotropia, vertical gaze deficiency, and ptosis consistent with congenital fibrosis of the extraocular muscles type 3 (CFEOM3); 1 patient harbored a novel TUBB3 mutation, and 3 patients harbored previously reported de novo TUBB3 mutations. Three percent of participants (3/112) met MDC but also had restricted vertical gaze. The remaining 88 participants (79%) met MDC and had full vertical gaze. This group had relatively homogeneous findings, and none had a family history of Moebius syndrome. Two previously undescribed phenomena were observed in this category: (1) volitional Bell's phenomenon and (2) intorsion with fixation. CONCLUSIONS: Although the genetic contributors to classic Moebius syndrome remain elusive, accuracy in clinical evaluation will properly subdivide patients to facilitate genetic testing as new candidate genes are identified. Failure to test ocular motility may lead to misdiagnosis of Moebius syndrome, especially in patients who have facial palsy with full ductions. Patients with exotropia, vertical gaze limitation, and ptosis do not have classic Moebius syndrome and may have TUBB3 mutations associated with CFEOM3. To optimize genetic analysis, we propose adding "full vertical motility" to the MDC for Moebius syndrome.
Sahin O, Ziaei A. The role of methotrexate in resolving ocular inflammation after specific therapy for presumed latent syphilitic uveitis and presumed tuberculosis-related uveitis. Retina. 2014;34(7):1451–9.
PURPOSE: This study was designed to investigate whether the antiinflammatory and antiproliferative activity of oral and intravitreal methotrexate (MTX) suppresses intraocular inflammation in patients with presumed latent syphilitic uveitis and presumed tuberculosis-related uveitis. METHODS: Interventional prospective study including three cases with presumed latent syphilitic uveitis treated with intravenous penicillin and oral MTX, and two cases with presumed tuberculosis-related uveitis treated with standard antituberculosis therapy and intravitreal MTX injections. Treatment efficacy of all cases was assessed by best-corrected visual acuity, fundus fluorescein angiography, and optical coherence tomography. RESULTS: Four eyes of 3 patients with presumed latent syphilitic uveitis had improved best-corrected visual acuity, suppression of intraocular inflammation, and resolution of cystoid macular edema in 6 months with oral MTX therapy. No recurrence of intraocular inflammation was observed in 6 months to 18 months of follow-up period after cessation of MTX. Two eyes of two patients with presumed tuberculosis-related uveitis showed improved best-corrected visual acuity, suppression of intraocular inflammation, and resolution of cystoid macular edema after intravitreal injections of MTX. No recurrence of intraocular inflammation was observed in 6 months to 8 months of follow-up period after cessation of antituberculous therapy. CONCLUSION: For the first time in the treatment of presumed latent syphilitic uveitis and presumed tuberculosis-related uveitis, we believe that MTX might have an adjunctive role to suppress intraocular inflammation, reduce uveitic macular edema, and prevent the recurrences of the diseases.
Isayama T, Chen Y, Kono M, Fabre E, Slavsky M, DeGrip W, Ma JX, Crouch R, Makino C. Coexpression of three opsins in cone photoreceptors of the salamander Ambystoma tigrinum. J Comp Neurol. 2014;522(10):2249–65.
Although more than one type of visual opsin is present in the retina of most vertebrates, it was thought that each type of photoreceptor expresses only one opsin. However, evidence has accumulated that some photoreceptors contain more than one opsin, in many cases as a result of a developmental transition from the expression of one opsin to another. The salamander UV-sensitive (UV) cone is particularly notable because it contains three opsins (Makino and Dodd [1996] J Gen Physiol 108:27-34). Two opsin types are expressed at levels more than 100 times lower than the level of the primary opsin. Here, immunohistochemical experiments identified the primary component as a UV cone opsin and the two minor components as the short wavelength-sensitive (S) and long wavelength-sensitive (L) cone opsins. Based on single-cell recordings of 156 photoreceptors, the presence of three components in UV cones of hatchlings and terrestrial adults ruled out a developmental transition. There was no evidence for multiple opsin types within rods or S cones, but immunohistochemistry and partial bleaching in conjunction with single-cell recording revealed that both single and double L cones contained low levels of short wavelength-sensitive pigments in addition to the main L visual pigment. These results raise the possibility that coexpression of multiple opsins in other vertebrates was overlooked because a minor component absorbing at short wavelengths was masked by the main visual pigment or because the expression level of a component absorbing at long wavelengths was exceedingly low.
Lefebvre D, Robinson-Bostom L, Migliori M. Cellular neurothekeoma of the eyelid: a unique internal palpebral presentation. Ophthalmic Plast Reconstr Surg. 2014;30(4):e91–2.
A 50-year-old woman presented with a mass lesion of the inferolateral palpebral conjunctiva similar in appearance to a chalazion, but unusual enough in presentation that excisional biopsy was initially performed. Histopathologic analysis revealed a dermal fibrohistiocytic neoplasm consistent with cellular neurothekeoma. Neurothekeoma is a benign tumor; the cellular variant is rare and of unclear histogenesis. Completely internal eyelid location is particularly rare, with other identifiable case reports of cellular neurothekeoma palpebrae referring to external or unspecified eyelid location. This case provides an example of the chalazion as masquerader and re-emphasizes the importance of maintaining a broad differential diagnosis and high index of suspicion regarding atypically appearing chalazia.
Yadav P, Jakobiec F, De Castro D, Mendoza P, Fay A. Extruded, partially disintegrated, poly-HEMA orbital implant (AlphaSphere). Ophthalmic Plast Reconstr Surg. 2014;30(4):e86–91.
A 54-year-old diabetic man underwent enucleation for endophthalmitis. Secondary implantation of a 2-hydroxyethyl methacrylate (HEMA) sphere (AlphaSphere, Addition Technology) was performed 2 weeks later. Six weeks after insertion, noninfectious disintegration of sutured tissue planes represented by Tenon's capsule, rectus muscle, and conjunctiva occurred, requiring removal of the fragmenting implant before uncontrolled extrusion occurred. Histopathologic analysis revealed an absence of infectious pathogens and no tissue necrosis, but rather breakup of the implant material that elicited a granulomatous response with sparse T-lymphocytes and almost no polymorphonuclear leukocytes. This distinctively designed poly-HEMA orbital implant incited a dramatic and irreversible host tissue response. Investigation of other cases will be necessary to determine the frequency of such a complication and should include rigorous histopathologic techniques.
Villarreal G, Chatterjee A, Oh S, Oh DJ, Kang MH, Rhee D. Canonical Wnt signaling regulates extracellular matrix expression in the trabecular meshwork.. Invest Ophthalmol Vis Sci. 2014;

PURPOSE. Canonical Wnt signaling has emerged as a critical regulator of aqueous outflow facility and intraocular pressure (IOP). In this study, we examine the role of canonical Wnt signaling on extracellular matrix (ECM) expression in the trabecular meshwork (TM) and explore the molecular mechanisms involved. METHODS. β-catenin localization in human TM tissue was examined using immunofluorescent staining. Primary human TM cells were incubated with lithium chloride (LiCl) and the effect on active β-catenin expression was assessed by immunoblot. Adenovirus expressing a dominant-negative TCF4 mutant that lacks a β-catenin binding domain was used. Changes in the levels of the microRNA-29 (miR-29) family and ECM proteins were determined by real-time quantitative PCR and immunoblot analysis, respectively. RESULTS. β-catenin was expressed throughout the TM, with localization primarily to the plasma membrane. Incubation of TM cells with lithium chloride increased the expression of active β-catenin. Lithium chloride treatment upregulated miR-29b expression, and suppressed the levels of various ECM proteins under both basal and TGF-β2 stimulatory conditions. Infection of TM cells with a dominant-negative TCF4 mutant induced ECM levels without a significant change in the expression of the miR-29 family. CONCLUSIONS. Collectively, our data identify the canonical Wnt signaling pathway as an important modulator of ECM expression in the TM and provide a mechanistic framework for its regulation of outflow facility and IOP.

Sadaka A, Palmer K, Suzuki T, Gilmore M. In vitro and in vivo models of Staphylococcus aureus endophthalmitis implicate specific nutrients in ocular infection. PLoS One. 2014;9(10):e110872.
PURPOSE: To define global transcriptional responses of Staphylococcus aureus and its codY mutant (CodY is a transcription regulator of virulence and metabolic genes in response to branched-chain amino acids) when growing in bovine aqueous (AH) and vitreous humor (VH) in vitro, and to investigate the impact of codY deletion on S. aureus virulence in a novel murine anterior chamber (AC) infection model. METHODS: For the in vitro model, differential transcriptomic gene expression of S. aureus and its codY mutant grown in chemically defined medium (CDM), AH, and VH was analyzed. Furthermore, the strains were inoculated into the AC of mice. Changes in bacterial growth, electroretinography and inflammation scores were monitored. RESULTS: Bovine AH and VH provide sufficient nutrition for S. aureus growth in vitro. Transcriptome analysis identified 72 unique open reading frames differentially regulated ≥10-fold between CDM, AH, and VH. In the AC model, we found comparable growth of the codY mutant and wild type strains in vivo. Average inflammation scores and retinal function were significantly worse for codY mutant-infected eyes at 24 h post-infection. CONCLUSION: Our in vitro bovine AH and VH models identified likely nutrient sources for S. aureus in the ocular milieu. The in vivo model suggests that control of branched-chain amino acid availability has therapeutic potential in limiting S. aureus endophthalmitis severity.
Yamaguchi T, Calvacanti B, Cruzat A, Qazi Y, Ishikawa S, Osuka A, Lederer JA, Hamrah P. Correlation between Human Tear Cytokine Levels and Cellular Corneal Changes in Patients with Bacterial Keratitis by In Vivo Confocal Microscopy.. Invest Ophthalmol Vis Sci. 2014;

Purpose: To investigate bilateral tear cytokine levels in patients with unilateral bacterial keratitis (BK) as associated with in vivo confocal microscopic (IVCM) alterations in corneal nerves and dendritiform immune cells (DCs). Methods: Fifty-four (13 BK, 13 contralateral, 28 healthy controls) tear samples were collected prospectively and analyzed by multiplex microbeads assay. IVCM of the central cornea was performed on the same day and assessed for corneal nerve and DC alterations Results: Interleukin (IL)-1β, IL-6, and IL-8 were significantly elevated only in affected eyes (66.6±26.8 ρg/ml, 7,174±2,430, 810±315, P=0.04, P<0.001 and P<0.001), compared to healthy controls (13.0±4.0 ρg/ml, 171.8±32.1, 56.5±33.8). CCL-2, IL-10 and IL-17a were elevated only in contralateral eyes (813±478 ρg/ml, 86.7±38.3, 3,350±881, P=0.02, P=0.01, P=0.04), compared to controls (73.7±25.3 ρg/ml, 17.5 ±4.9, 1,350±337). Triggering receptor expressed on myeloid cells (TREM)-1 was significantly elevated in both affected (551±231 ρg/ml, P=0.02) and contralateral unaffected eyes (545±298 ρg/ml, P=0.03), compared to controls (31.3±12.4 ρg/ml). The density of DCs was significantly increased in both affected (226.9±37.3 cells/mm2, P<0.001) and unaffected eyes (122.3±23.7 cells/mm2, P<0.001) compared to controls (22.7±5.9 cells/mm2). Subbasal nerve density significantly decreased in affected eyes (3,337±1,615 μm/mm2, P<0.001) and contralateral eyes (13,230±1,635 μm/mm2, P<0.001) compared to controls (21,200±545 μm/mm2). IL-1β, IL-6 and IL-8 were significantly correlated with DC density (R=0.40, R=0.55 and R=0.31, all P<0.02) and nerve density (R=-0.30, R=-0.53 and R=-0.39, all P<0.01). Conclusions: Pro-inflammatory tear cytokines are elevated bilaterally in patients with unilateral BK, and are correlated strongly with alterations in DCs and nerve density as detected by IVCM.

Schroedl F, Kaser-Eichberger A, Schlereth S, Bock F, Regenfuss B, Reitsamer H, Lutty G, Maruyama K, Chen L, Lütjen-Drecoll E, Dana R, Kerjaschki D, Alitalo K, De Stefano ME, Junghans B, Heindl L, Cursiefen C. Consensus statement on the immunohistochemical detection of ocular lymphatic vessels.. Invest Ophthalmol Vis Sci. 2014;55(10):6440–2.

There is currently considerable controversy about existence and classification of "lymphatic vessels" in the eye. Some of the confusion is certainly caused by inappropriate use (or nonuse) of the correct immunohistochemical markers. Many experts in the field expressed the need for a consensus statement, and, in this perspective, authors offer arguments and solutions to reliably continue with immunohistochemical ocular lymphatic research.

Van Tyne D, Gilmore M. A delicate balance: maintaining mutualism to prevent disease.. Cell Host Microbe. 2014;16(4):425–7.

The intestinal microbial ecosystem is complex, and few of the principles that contribute to homeostasis in health are well understood. Pham et al. (2014) show that a network including the epithelial interleukin-22 receptor protects against infection with the opportunistic pathogen Enterococcus faecalis through promotion of host-microbiota mutualism.

Yonekawa Y, Kim I. Clinical Characteristics and Current Treatment of Age-Related Macular Degeneration.. Cold Spring Harb Perspect Med. 2014;

Age-related macular degeneration (AMD) is a multifactorial degeneration of photoreceptors and retinal pigment epithelium. The societal impact is significant, with more than 2 million individuals in the United States alone affected by advanced stages of AMD. Recent progress in our understanding of this complex disease and parallel developments in therapeutics and imaging have translated into new management paradigms in recent years. However, there are many unanswered questions, and diagnostic and prognostic precision and treatment outcomes can still be improved. In this article, we discuss the clinical features of AMD, provide correlations with modern imaging and histopathology, and present an overview of treatment strategies.