November 2015

Abramov E, Cassiola F, Schwob O, Karsh-Bluman A, Shapero M, Ellis J, Luyindula D, Adini I, D'Amato RJ, Benny O. Cellular mechanism of oral absorption of solidified polymer micelles. Nanomedicine 2015;11(8):1993-2002.Abstract

UNLABELLED: Oral delivery of poorly soluble and permeable drugs represents a significant challenge in drug development. The oral delivery of drugs remains to be the ultimate route of any drugs. However, in many cases, drugs are not absorbed well in the gastrointestinal tract, or they lose their activity. Polymer micelles were recognized as an effective carrier system for drug encapsulation, and are now studied as a vehicle for oral delivery of insoluble compounds. We characterized the properties of monomethoxy polyethylene glycol-poly lactic acid (mPEG-PLA) micelles, and visualized their internalization in mouse small intestine. Using Caco-2 cells as a cellular model, we studied the kinetics of particle uptake, their transport, and the molecular mechanism of their intestinal absorption. Moreover, by inhibiting specific endocytosis pathways, pharmacologically and genetically, we found that mPEG-PLA nanoparticle endocytosis is mediated by clathrin in an energy-dependent manner, and that the low-density lipoprotein receptor is involved. FROM THE CLINICAL EDITOR: Many current drugs used are non-water soluble and indeed, the ability to deliver these drugs via the gastrointestinal tract remains the holy grail for many researchers. The authors in this paper developed monomethoxy polyethylene glycol-poly lactic acid (mPEG-PLA) micelles as a drug nanocarrier, and studied the mechanism of uptake across intestinal cells. The findings should improve our current understanding and point to the development of more nanocarriers.

Choi CJ, Bauza A, Yoon MK, Sobel RK, Freitag SK. Full-Thickness Skin Graft as an Independent or Adjunctive Technique for Repair of Cicatricial Lower Eyelid Ectropion Secondary to Actinic Skin Changes. Ophthal Plast Reconstr Surg 2015;31(6):474-7.Abstract

PURPOSE: To retrospectively review and describe full-thickness skin graft repair of lower eyelid cicatricial ectropion secondary to actinic skin. METHODS: A retrospective, noncomparative chart review of all patients who underwent lower eyelid ectropion repair with placement of a full-thickness skin graft between June 2004 and March 2014 was conducted with IRB approval. The etiology of lower eyelid ectropion, demographics including age, gender, ethnicity, laterality, graft donor site, additional surgical procedures, graft viability, surgical success rate, complications, and clinical exam findings were summarized. RESULTS: Twenty-nine eyelids in 24 patients underwent skin grafting for repair of cicatricial ectropion secondary to actinic skin changes. Ninety six percent of patients were male and 96% were Caucasian. Donor sites for skin grafts included upper eyelid (9, 31%), supraclavicular skin (9, 31%), postauricular skin (7, 24%), inner brachial skin (2, 7%), axilla (1, 3.5%), and preauricular skin (1, 3.5%). Twenty-four of 29 eyelids in the series underwent 1 or more additional procedures at the time of full-thickness skin grafting, including lateral tarsal strip (9 eyelids, 37.5%), punctoplasty (8, 33%), canthoplasty (7, 29%), excision of keratinized conjunctiva (2, 8%), transverse tarsotomy (1, 4%), ipsilateral external dacryocystorhinostomy (3, 12.5%), and lesion removal (1, 4%). There was 100% viability of the skin grafts. Overall surgical success rate was 76%, with asymptomatic recurrence rate of 17% and symptomatic recurrence rate of 7%. CONCLUSION: Repair of cicatricial lower eyelid ectropion secondary to actinic skin changes may be accomplished with full-thickness skin grafting, and is often performed in conjunction with additional procedures to fully address anatomic abnormalities.

Cordero-Coma M, Sobrin L. Anti-tumor necrosis factor-α therapy in uveitis. Surv Ophthalmol 2015;60(6):575-89.Abstract

Since the first reported use in 2001 of an anti-tumor necrosis factor-alpha (TNF-α) agent, infliximab, for the treatment of uveitis, several new anti-TNF-α agents have emerged for the treatment of refractory noninfectious uveitides, although their use remains off-label in the US. These agents have demonstrated remarkable clinical antiinflammatory efficacy and a potential immunoregulatory role in selected uveitis patients, but it is currently unclear whether they can modify the natural history of disease. We review the rationale and clinical indications for this therapy, the differences between agents, how to manage dosing and intervals, and how to screen for and identify potential side effects. We also present a summary of the science behind the use of anti-TNF-α agents in ocular inflammation and the evidence for their efficacy.

Dib B, Lin H, Maidana DE, Tian B, Miller JB, Bouzika P, Miller JW, Vavvas DG. Mitochondrial DNA has a pro-inflammatory role in AMD. Biochim Biophys Acta 2015;1853(11 Pt A):2897-906.Abstract

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly of industrialized nations, and there is increasing evidence to support a role for chronic inflammation in its pathogenesis. Mitochondrial DNA (mtDNA) has been recently reported to be pro-inflammatory in various diseases such as Alzheimer's and heart failure. Here, we report that intracellular mtDNA induces ARPE-19 cells to secrete inflammatory cytokines IL-6 and IL-8, which have been consistently associated with AMD onset and progression. The induction was dependent on the size of mtDNA, but not on specific sequence. Oxidative stress plays a major role in the development of AMD, and our findings indicate that mtDNA induces IL-6 and IL-8 more potently when oxidized. Cytokine induction was mediated by STING (Stimulator of Interferon Genes) and NF-κB as evidenced by abrogation of the cytokine response with the use of specific inhibitors (siRNA and BAY 11-7082, respectively). Finally, mtDNA primed the NLRP3 inflammasome. This study contributes to our understanding of the potential pro-inflammatory role of mtDNA in the pathogenesis of AMD.

Drokhlyansky E, Soh TK, Cepko CL. Preferential Budding of Vesicular Stomatitis Virus from the Basolateral Surface of Polarized Epithelial Cells Is Not Solely Directed by Matrix Protein or Glycoprotein. J Virol 2015;89(22):11718-22.Abstract

Vesicular stomatitis virus has been shown to bud basolaterally, and the matrix protein, but not glycoprotein, was proposed to mediate this asymmetry. Using polarized T84 monolayers, we demonstrate that no single viral protein is sufficient for polarized budding. Particles are released from the apical and basolateral surfaces and are indistinguishable, indicating that there is no apical assembly defect. We propose that aspects of host cell polarity create a more efficient budding process at the basolateral surface.

Glass LDGR, Freitag SK. Management of orbital IgG4-related disease. Curr Opin Ophthalmol 2015;Abstract

PURPOSE OF REVIEW: IgG4-related disease (IgG4-RD) is a systemic process that can cause significant orbital disease. It can affect both sexes and all ages, with irreversible consequences if left untreated. Diagnosis is currently based upon a combination of clinical and imaging evidence of tissue swelling or mass, serum evidence of elevated IgG4 levels and histopathologic evidence of inappropriate IgG4 presence. The cause of IgG4-RD is as of yet unclear; this lack of understanding and the dearth of prospective studies have limited our ability to manage patients effectively. In this review, we discuss the most recent published evidence regarding best-practice management of IgG4-related orbital disease. RECENT FINDINGS: Recent literature remains retrospective, and has focused on the use of corticosteroid therapy as a first-line treatment. Rituximab infusions have also received significant attention, among other second-line agents. Radiation therapy has been reported to be effective. Long-term monitoring for relapse, involvement of other organ systems and potential neoplastic transformation is required. SUMMARY: The management of orbital IgG4-RD will gain from more targeted therapy in the future as the underlying cause is better understood. In the meantime, randomized, controlled trials of varying treatment regimens would be of benefit.

Graeber CP, Hunter DG. Changes in Lateral Comitance After Asymmetric Horizontal Strabismus Surgery. JAMA Ophthalmol 2015;133(11):1241-6.Abstract

IMPORTANCE: Asymmetric horizontal strabismus surgery is often performed to correct primary gaze alignment without considering the symptoms that may result from misalignment in the patient's side gaze. Surgical choices influence alignment in side gaze and may contribute to functional and social deficits. OBJECTIVE: To identify the surgical procedures associated with changes of alignment in side gaze to help inform surgical planning for patients with horizontal strabismus. DESIGN, SETTING, AND PARTICIPANTS: The medical records of 1081 horizontal strabismus surgical procedures that were performed at Boston Children's Hospital during a 2-year period were retrospectively reviewed. Only records with strabismus measurements recorded in the right and left gaze before and after surgery were included. Data analysis was conducted from September 1, 2012, through June 7, 2015. MAIN OUTCOMES AND MEASURES: Change in comitance (CIC), determined by measuring the horizontal comitance (the difference between right- and left-gaze strabismus measurements) before and after surgery. RESULTS: The review identified 569 patients who met the inclusion criteria. Of the 491 patients with comitant preoperative alignment, 59 developed postoperative incomitance, of whom 53 (89.9%) had asymmetric surgery. Of the 78 patients with incomitant preoperative alignment, 36 patients' (46.2%) deviation had improved to comitance after surgery; 32 (88.9%) of these patients had asymmetric surgery. Asymmetric 2-muscle surgery had a median CIC of 4.0 while symmetric 2-muscle surgery had a median CIC of 1.5 (difference in CIC, 2.5; 95% CI, 2.0-3.0; P < .001). A CIC of 25 prism diopters or more was observed in 6 patients who underwent asymmetric surgery (0 with symmetric surgery). New postoperative incomitance was symptomatic in at least 17 patients (28.8%). CONCLUSIONS AND RELEVANCE: Asymmetric strabismus surgery can treat incomitant deviations, but it can also create symptomatic incomitant deviations in patients who were previously comitant. Surgical planning should include consideration of the potential for CIC, including the potential for unsatisfactory appearance in side gaze. Patients with binocular vision will be sensitive to diplopia in any gaze direction; in such cases, the consequences of asymmetric surgery should be considered with particular care.

Grassi CM, Cruzat A, Taniguchi EV, Crnej A, Colby KA, Dohlman CH, Chodosh J. Periprosthetic Tissue Loss in Patients With Idiopathic Vitreous Inflammation After the Boston Keratoprosthesis. Cornea 2015;34(11):1378-82.Abstract

PURPOSE: Idiopathic vitritis is a poorly understood complication after Boston keratoprosthesis surgery with unclear etiology. We sought to determine whether an association exists between periprosthetic corneal tissue loss and the development of idiopathic vitritis in keratoprosthesis recipients. METHODS: Thirteen Boston type I keratoprosthesis recipient eyes with a history of idiopathic vitritis and 34 type I keratoprosthesis recipient eyes with no history of idiopathic vitritis underwent anterior segment optical coherence tomography (AS-OCT) at a median time postoperatively of 2.4 years versus 1.9 years (range, 0.5-14.2 vs. 0.1-13.6 years), respectively. Areas of corneal graft tissue loss ("gaps") around the keratoprosthesis stem were identified and analyzed by 2 masked observers. The difference in the presence, number, and size of gaps was compared between cases and controls. RESULTS: A periprosthetic gap was identified more commonly in idiopathic vitritis cases than in controls on AS-OCT (11/13, 86% vs. 11/34, 33.3%, P < 0.001). The number of gaps between cases and controls was also significantly different (2.6 ± 1.6 vs. 0.5 ± 0.8, P < 0.001), but not the estimated gap area (0.056 ± 0.049 mm vs. 0.039 ± 0.025 mm, P = 0.22). CONCLUSIONS: A significantly higher proportion of keratoprosthesis recipient eyes with idiopathic vitritis had corneal tissue loss around the keratoprosthesis stem than did controls. Tissue loss could serve as an entry point for debris or bacterial components, triggering idiopathic vitritis. Our study underscores the utility of AS-OCT imaging in the postoperative management of keratoprosthesis patients.

for the Group WTDCCT/EDICR, Gubitosi-Klug RA, Sun W, Cleary PA, Braffett BH, Aiello LP, Das A, Tamborlane W, Klein R. Effects of Prior Intensive Insulin Therapy and Risk Factors on Patient-Reported Visual Function Outcomes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Cohort. JAMA Ophthalmol 2015;:1-10.Abstract

Importance: Preservation of vision in patients with diabetes mellitus is critical. Interventions to improve glycemic control through early intensive treatment of diabetes reduce rates of severe retinopathy and preserve visual acuity. Objective: To assess the effects of prior intensive insulin treatment and risk factors on patient-reported visual function in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. Design, Setting, and Participants: Cohort study of 1184 participants with type 1 diabetes from the DCCT/EDIC study (randomized clinical trial followed by an observational follow-up study) who completed the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) during EDIC years 17 through 20 (September 1, 2009, through April 30, 2014) in 28 institutions across the United States and Canada. Main Outcomes and Measures: The primary outcome was the composite NEI-VFQ-25 score. Secondary outcomes were visual acuity (measured by the Early Treatment Diabetic Retinopathy Study protocol), retinopathy level (determined by masked grading of stereoscopic color fundus photographs), and NEI-VFQ-25 subscale scores. The composite NEI-VFQ-25 scale and its subscales were scored 0 to 100, corresponding to poor to excellent function, respectively. Results: The overall average NEI-VFQ-25 score for 1184 DCCT/EDIC participants (mean [SD] age, 52.3 [6.9] years; 48% female) with a 30-year duration of diabetes was high (all participants: median, 91.7; interquartile range [IQR], 89.7-96.9; intensive treatment [n = 605]: median, 94.7; IQR, 91.0-97.2; conventional treatment [n = 579]: median, 94.0; IQR, 88.4-96.1; P = .006 for intensive vs conventional). After adjustment for sex, age, hemoglobin A1c level, and retinopathy level at DCCT baseline, the former intensive treatment group had a significant, albeit modest, improvement in overall NEI-VFQ-25 score compared with the former conventional diabetes treatment group (median difference, -1.0; 95% CI, -1.7 to -0.3; P = .006). This beneficial treatment effect was fully attributed to the prior glycemic control in DCCT (explained treatment effect: 100%). Those with visual acuity worse than 20/100 reported the largest decline in visual function (median difference, -21.0; 95% CI, -40.5 to -1.6; P = .03). Conclusions and Relevance: In the DCCT/EDIC cohort, patient-reported visual function remains high in both treatment groups, comparable to previous reports of overall health-related quality of life. Intensive diabetes therapy modestly improved NEI-VFQ-25 score 30 years after the start of the DCCT, the benefit underestimated owing to more nonparticipants from the conventional treatment group. Visual acuity had the greatest effect on patient-reported visual function from among all risk factors. Trial Registration: Identifiers: NCT00360815 and NCT00360893.

Jakobiec FA, Stagner AM, Lefebvre DR. Uniformly Sclerotic Diffuse Large B-Cell Lymphoma of the Orbit. Ophthal Plast Reconstr Surg 2015;Abstract

Over a year, a 51-year-old man developed a mass in the anteromedial orbit in the region of the lacrimal sac that caused epiphora. Imaging studies disclosed no bone destruction. On biopsy, a sclerotic lesion was discovered populated by hyperchromatic cells that had been apparently distorted by crush artifact, indicative of fragile cells. The lesion simulated a sclerosing inflammatory process or a desmoplastic metastatic carcinoma. CD20 revealed that the background cells were large neoplastic B-lymphocytes. A systemic workup uncovered widespread skeletal disease. The patient is undergoing R-CHOP chemotherapy with a relatively favorable prognosis due to negative testing for MYC.

Kheirkhah A, Rahimi Darabad R, Cruzat A, Hajrasouliha AR, Witkin D, Wong N, Dana R, Hamrah P. Corneal Epithelial Immune Dendritic Cell Alterations in Subtypes of Dry Eye Disease: A Pilot In Vivo Confocal Microscopic Study. Invest Ophthalmol Vis Sci 2015;56(12):7179-85.Abstract

PURPOSE: To evaluate density and morphology of corneal epithelial immune dendritic cells (DCs) in different subtypes of dry eye disease (DED) using in vivo confocal microscopy (IVCM). METHODS: This retrospective study included 59 eyes of 37 patients with DED and 40 eyes of 20 age-matched healthy controls. Based on clinical tests, eyes with DED were categorized into two subtypes: aqueous-deficient (n = 35) and evaporative (n = 24). For all subjects, images of laser scanning in vivo confocal microscopy (IVCM) of the central cornea were analyzed for DC density and DC morphology (DC size, number of dendrites, and DC field). These DC parameters were compared among all dry eye and control groups. RESULTS: Compared with the controls, patients with DED had significantly higher DC density, larger DC size, higher number of dendrites, and larger DC field (all P < 0.001). Comparison between aqueous-deficient and evaporative subtypes demonstrated that DC density was significantly higher in aqueous-deficient subtype (189.8 ± 36.9 vs. 58.9 ± 9.4 cells/mm2, P = 0.001). However, there were no significant differences in morphologic parameters between DED subtypes. When aqueous-deficient DED with underlying systemic immune disease (Sjögren's syndrome and graft versus host disease) were compared with nonimmune conditions, the immunologic subgroup showed significantly higher DC density, DC size, and number of dendrites (all P < 0.05). CONCLUSIONS: Corneal IVCM demonstrated differential changes in DC density and morphologic DC parameters between subtypes of DED. These changes, which reflect the degree of immune activation and inflammation in DED, can be used for clinical practice and endpoints in clinical trials.

Matsumoto H, Murakami Y, Kataoka K, Notomi S, Mantopoulos D, Trichonas G, Miller JW, Gregory MS, Ksander BR, Marshak-Rothstein A, Vavvas DG. Membrane-bound and soluble Fas ligands have opposite functions in photoreceptor cell death following separation from the retinal pigment epithelium. Cell Death Dis 2015;6:e1986.Abstract

Fas ligand (FasL) triggers apoptosis of Fas-positive cells, and previous reports described FasL-induced cell death of Fas-positive photoreceptors following a retinal detachment. However, as FasL exists in membrane-bound (mFasL) and soluble (sFasL) forms, and is expressed on resident microglia and infiltrating monocyte/macrophages, the current study examined the relative contribution of mFasL and sFasL to photoreceptor cell death after induction of experimental retinal detachment in wild-type, knockout (FasL-/-), and mFasL-only knock-in (ΔCS) mice. Retinal detachment in FasL-/- mice resulted in a significant reduction of photoreceptor cell death. In contrast, ΔCS mice displayed significantly more apoptotic photoreceptor cell death. Photoreceptor loss in ΔCS mice was inhibited by a subretinal injection of recombinant sFasL. Thus, Fas/FasL-triggered cell death accounts for a significant amount of photoreceptor cell loss following the retinal detachment. The function of FasL was dependent upon the form of FasL expressed: mFasL triggered photoreceptor cell death, whereas sFasL protected the retina, indicating that enzyme-mediated cleavage of FasL determines, in part, the extent of vision loss following the retinal detachment. Moreover, it also indicates that treatment with sFasL could significantly reduce photoreceptor cell loss in patients with retinal detachment.

Meyer Zu Horste G, Derksen A, Stassart R, Szepanowski F, Thanos M, Stettner M, Boettcher C, Lehmann HC, Hartung H-P, Kieseier BC. Neuronal ADAM10 Promotes Outgrowth of Small-Caliber Myelinated Axons in the Peripheral Nervous System. J Neuropathol Exp Neurol 2015;74(11):1077-85.Abstract

The regulation of myelination and axonal outgrowth in the peripheral nervous system is controlled by a complex signaling network involving various signaling pathways. Members of the A Disintegrin And Metalloproteinase (ADAM) family are membrane-anchored proteinases with both proteolytic and disintegrin characteristics that modulate the function of signaling molecules. One family member, ADAM17, is known to influence myelination by cleaving and thus regulating one of the key signals, neuregulin-1, which controls peripheral nervous system myelination. A similar function for ADAM10 had been suggested by previous in vitro studies. Here, we assessed whether ADAM10 exerts a similar function in vivo and deleted ADAM10 in a cell type-specific manner in either neurons or Schwann cells. We found that ADAM10 is not required in either Schwann cells or neurons for normal myelination during development or for remyelination after injury. Instead, ADAM10 is required specifically in neurons for the outgrowth of myelinated small-fiber axons in vitro and after injury in vivo. Thus, we report for the first time a neuron-intrinsic function of ADAM10 in axonal regeneration that is distinct from that of the related protein family member ADAM17 and that may have implications for targeting ADAM function in nervous system diseases.

Müller RT, Abedi F, Cruzat A, Witkin D, Baniasadi N, Cavalcanti BM, Jamali A, Chodosh J, Dana R, Pavan-Langston D, Hamrah P. Degeneration and Regeneration of Subbasal Corneal Nerves after Infectious Keratitis: A Longitudinal InVivo Confocal Microscopy Study. Ophthalmology 2015;122(11):2200-9.Abstract

PURPOSE: To investigate the longitudinal alterations of subbasal corneal nerves in patients with infectious keratitis (IK) during the acute phase, cessation of treatment, and the recovery phase by in vivo confocal microscopy (IVCM). DESIGN: Prospective, longitudinal, case-control, single-center study. PARTICIPANTS: Fifty-six eyes of 56 patients with the diagnosis of bacterial (n = 28), fungal (n = 15), or Acanthamoeba (n = 13) keratitis were included in the study. Thirty eyes of 30 normal volunteers constituted the control group. METHODS: Corneal sensation and serial IVCM of the central cornea were performed prospectively using the Heidelberg Retina Tomograph 3/Rostock Cornea Module (Heidelberg Engineering, Heidelberg, Germany). The IVCM images were assessed at 3 time points: at the acute phase (first visit to the cornea service), at cessation of antimicrobial treatment, and up to 6 months after the resolution of infection. MAIN OUTCOME MEASURES: Total nerve number and length, main nerve trunks, branching, and corneal sensation were assessed during the follow-up period. RESULTS: Corneal nerves were reduced significantly during the acute phase in eyes with IK compared with controls across all subgroups, with total nerve length of 5.47±0.69 mm/mm(2) versus 20.59±1.06 mm/mm(2) (P <0.0001). At the cessation of treatment, corneal nerves in patients with IK had regenerated, including total nerve length (8.49±0.94 mm/mm(2); P = 0.02) and nerve branch length (4.80±0.37 mm/mm(2); P = 0.005). During the recovery phase, after resolution of infection, corneal nerves regenerated further, including total nerve length (12.13±1.97 mm/mm(2); P = 0.005), main nerve trunk length (5.80±1.00 mm/mm(2); P = 0.01), and nerve branch length (6.33±0.76 mm/mm(2); P = 0.003) as compared with the acute phase, but were still significantly lower when compared with controls (P < 0.05 for all parameters). Corneal degeneration and regeneration correlated with corneal sensation (r = 0.47; P = 0.0009). CONCLUSIONS: Patients with IK who sustain profound loss of corneal nerves during the acute phase of infection demonstrate increased corneal nerve density during the first 6 months after the resolution of infection. However, despite significant nerve regeneration, corneal nerve density does not recover fully and remains low compared to controls. By providing an objective methodology to monitor corneal re-innervation, IVCM adds potentially important findings that may have implications for clinical management and surgical planning.

for the Network WCDRCR, Gross JG, Glassman AR, Jampol LM, Inusah S, Aiello LP, Antoszyk AN, Baker CW, Berger BB, Bressler NM, Browning D, Elman MJ, Ferris FL, Friedman SM, Marcus DM, Melia M, Stockdale CR, Sun JK, Beck RW. Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial. JAMA 2015;314(20):2137-46.Abstract

IMPORTANCE: Panretinal photocoagulation (PRP) is the standard treatment for reducing severe visual loss from proliferative diabetic retinopathy. However, PRP can damage the retina, resulting in peripheral vision loss or worsening diabetic macular edema (DME). OBJECTIVE: To evaluate the noninferiority of intravitreous ranibizumab compared with PRP for visual acuity outcomes in patients with proliferative diabetic retinopathy. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial conducted at 55 US sites among 305 adults with proliferative diabetic retinopathy enrolled between February and December 2012 (mean age, 52 years; 44% female; 52% white). Both eyes were enrolled for 89 participants (1 eye to each study group), with a total of 394 study eyes. The final 2-year visit was completed in January 2015. INTERVENTIONS: Individual eyes were randomly assigned to receive PRP treatment, completed in 1 to 3 visits (n = 203 eyes), or ranibizumab, 0.5 mg, by intravitreous injection at baseline and as frequently as every 4 weeks based on a structured re-treatment protocol (n = 191 eyes). Eyes in both treatment groups could receive ranibizumab for DME. MAIN OUTCOMES AND MEASURES: The primary outcome was mean visual acuity change at 2 years (5-letter noninferiority margin; intention-to-treat analysis). Secondary outcomes included visual acuity area under the curve, peripheral visual field loss, vitrectomy, DME development, and retinal neovascularization. RESULTS: Mean visual acuity letter improvement at 2 years was +2.8 in the ranibizumab group vs +0.2 in the PRP group (difference, +2.2; 95% CI, -0.5 to +5.0; P < .001 for noninferiority). The mean treatment group difference in visual acuity area under the curve over 2 years was +4.2 (95% CI, +3.0 to +5.4; P < .001). Mean peripheral visual field sensitivity loss was worse (-23 dB vs -422 dB; difference, 372 dB; 95% CI, 213-531 dB; P < .001), vitrectomy was more frequent (15% vs 4%; difference, 9%; 95% CI, 4%-15%; P < .001), and DME development was more frequent (28% vs 9%; difference, 19%; 95% CI, 10%-28%; P < .001) in the PRP group vs the ranibizumab group, respectively. Eyes without active or regressed neovascularization at 2 years were not significantly different (35% in the ranibizumab group vs 30% in the PRP group; difference, 3%; 95% CI, -7% to 12%; P = .58). One eye in the ranibizumab group developed endophthalmitis. No significant differences between groups in rates of major cardiovascular events were identified. CONCLUSIONS AND RELEVANCE: Among eyes with proliferative diabetic retinopathy, treatment with ranibizumab resulted in visual acuity that was noninferior to (not worse than) PRP treatment at 2 years. Although longer-term follow-up is needed, ranibizumab may be a reasonable treatment alternative, at least through 2 years, for patients with proliferative diabetic retinopathy. TRIAL REGISTRATION: Identifier: NCT01489189.

Pasquale LR, Hanyuda A, Ren A, Giovingo M, Greenstein SH, Cousins C, Patrianakos T, Tanna AP, Wanderling C, Norkett W, Wiggs JL, Green K, Kang JH, Knepper PA. Nailfold Capillary Abnormalities in Primary Open-Angle Glaucoma: A Multisite Study. Invest Ophthalmol Vis Sci 2015;56(12):7021-8.Abstract

PURPOSE: There is considerable evidence for systemic vascular dysfunction in primary open-angle glaucoma (POAG). We performed nailfold capillary video microscopy to observe directly the nature of nonocular microvasculature abnormalities in POAG. METHODS: We enrolled 199 POAG patients and 124 control subjects from four sites. We used JH-1004 capillaroscopes to perform nailfold capillary video microscopy on the fourth and fifth digits of each subject's nondominant hand. Videos were evaluated for hemorrhages, dilated capillary loops > 50 μm, and avascular zones > 100 μm by graders masked to case status. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) for POAG were obtained by means of logistic regression analyses that were applied to data from all cases and controls. Corresponding estimates of moderate or severe POAG versus mild POAG (based on the Hodapp-Anderson-Parrish scale) were obtained among cases only. RESULTS: After controlling for demographic factors, family history of glaucoma, systemic diseases, and use of anticoagulation and antiplatelet therapy, for each 100 nailfold capillaries assessed, all types of microvascular abnormalities were significantly associated with POAG. Specifically, the presence of any dilated capillaries (OR = 2.9; 95% CI, 1.6-5.6), avascular zones (OR = 4.4; 95% CI, 1.7-11.3) and hemorrhages (OR = 12.2; 95% CI, 5.9-25.1) were associated with POAG. Among cases, the frequency of microvascular abnormalities was not associated with glaucoma severity (P ≥ 0.43). CONCLUSIONS: These data provided support for nonocular capillary bed abnormalities in POAG. Comparable vascular abnormalities in the optic nerve may render it susceptible to glaucomatous damage.

Rao R, MacIntosh PW, Yoon MK, Lefebvre DR. Current trends in the management of thyroid eye disease. Curr Opin Ophthalmol 2015;26(6):484-90.Abstract

PURPOSE OF REVIEW: The present review summarizes the body of literature concerning the medical and surgical treatment of thyroid eye disease (TED) from 1 January 2014 through 30 March 2015. RECENT FINDINGS: Corticosteroids continue to be the primary medical therapy for TED. Recent research has offered insight into potential differences between oral corticosteroid and intravenous corticosteroid treatment regimens in terms of efficacy and side-effect profiles. Steroid-sparing medications, for example, rituximab and others, are an area of active study. There has been renewed interest in the role of radiation therapy as a nonmedical treatment for TED with some promising data. The use of balanced orbital decompression techniques have become popular, although the data regarding postoperative diplopia are mixed, and 'fat decompression' offers an alternative or an augmentation to bony decompression. Stereotactic image guidance is a useful adjunct to orbital decompression surgery. SUMMARY: TED continues to be a difficult condition for the patient to cope with and for the clinician to treat, and recent research builds on the present foundation of knowledge and treatments, but unfortunately does not offer paradigm-shifting information at the present time.

Singh G, Zhou X, Lee JY, Yousuf MA, Ramke M, Ismail AM, Lee JS, Robinson CM, Seto D, Dyer DW, Jones MS, Rajaiya J, Chodosh J. Recombination of the epsilon determinant and corneal tropism: Human adenovirus species D types 15, 29, 56, and 69. Virology 2015;485:452-9.Abstract

Viruses within human adenovirus species D (HAdV-D) infect epithelia at essentially every mucosal site. Hypervariable loops 1 and 2 of the hexon capsid protein contain epitopes that together form the epsilon determinant for serum neutralization. We report our analyses comparing HAdV-D15, 29, 56, and the recently identified type 69, each with highly similar hexons and the same serum neutralization profile, but otherwise disparate genomes. Of these, only HAdV-D type 56 is associated with epidemic keratoconjunctivitis (EKC), a severe infection of ocular surface epithelium and underlying corneal stroma. In the mouse adenovirus keratitis model, all four viruses induced inflammation. However, HAdV-D56 entry into human corneal epithelial cells and fibroblasts in vitro dramatically exceeded that of the other three viruses. We conclude that the hexon epsilon determinant is not a prime contributor to corneal tropism.

Tsilimbaris MK, Vavvas DG, Bechrakis NE. Myopic foveoschisis: an ectatic retinopathy, not a schisis. Eye (Lond) 2015;