2016

PURPOSE: Horizontal peripheral prisms for hemianopia provide field expansion above and below the horizontal meridian; however, there is a vertical gap leaving the central area (important for driving) without expansion. In the oblique design, tilting the bases of both prism segments toward the horizontal meridian moves the field expansion area vertically and centrally (closing the central gap) while the prisms remain in the peripheral location. However, tilting the prisms results also in a reduction of the lateral field expansion. Higher prism powers are needed to counter this effect. METHODS: We developed, implemented, and tested a series of designs aimed at increasing the prism power to reduce the central gap while maintaining wide lateral expansion. The designs included inserting the peripheral prisms into carrier lenses that included yoked prism in the opposite direction, combination of two Fresnel segments attached at the base and angled to each other (bi-part prisms), and creating Fresnel prism-like segments from nonparallel periscopic mirror pairs (reflective prisms). RESULTS: A modest increase in lateral power was achieved with yoked-prism carriers. Bi-part combination of 36Δ Fresnel segments provided high power with some reduction in image quality. Fresnel reflective prism segments have potential for high power with superior optical quality but may be limited in field extent or by interruptions of the expanded field. Extended apical scotomas, even with unilateral fitting, may limit the utility of very high power prisms. The high-power bi-part and reflective prisms enable a wider effective eye scanning range (more than 15 degrees) into the blind hemifield. CONCLUSIONS: Conventional prisms of powers higher than the available 57Δ are limited by the binocular impact of a wider apical scotoma and a reduced effective eye scanning range to the blind side. The various designs that we developed may overcome these limitations and find use in various other field expansion applications.

PURPOSE: To assess personal and demographic risk factors for proliferative diabetic retinopathy in African Americans with type 2 diabetes. METHODS: In this prospective, non-interventional, cross-sectional case-control study, 380 African Americans with type 2 diabetes were enrolled. Participants were recruited prospectively and had to have either: (1) absence of diabetic retinopathy after ≥10 years of type 2 diabetes, or (2) presence of proliferative diabetic retinopathy when enrolled. Dilated, 7-field fundus photographs were graded using the Early Treatment Diabetic Retinopathy Study scale. Covariates including hemoglobin A1C (HbA1C), blood pressure, height, weight and waist circumference were collected prospectively. Multivariate regression models adjusted for age, sex and site were constructed to assess associations between risk factors and proliferative diabetic retinopathy. RESULTS: Proliferative diabetic retinopathy was associated with longer duration of diabetes (odds ratio, OR, 1.62, p < 0.001), higher systolic blood pressure (OR 1.65, p < 0.001) and insulin use (OR 6.65, p < 0.001) in the multivariate regression analysis. HbA1C was associated with proliferative diabetic retinopathy in the univariate analysis (OR 1.31, p = 0.002) but was no longer significant in the multivariate analysis. CONCLUSIONS: In this case-control study of African Americans with type 2 diabetes, duration of diabetes, systolic hypertension and insulin use were strong risk factors for the development of proliferative diabetic retinopathy. Interestingly, HbA1C did not confer additional risk in this cohort.

Vascular endothelial cell growth factor A (VEGF) is a biologically and therapeutically important growth factor because it promotes angiogenesis in response to hypoxia, which underlies a wide variety of both physiological and pathological settings. We report here that both VEGF receptor 2 (VEGFR2)-positive and -negative cells depended on VEGF to endure hypoxia. VEGF enhanced the viability of platelet-derived growth factor receptor α (PDGFRα)-positive and VEGFR2-negative cells by enabling indirect activation of PDGFRα, thereby reducing the level of p53. We conclude that the breadth of VEGF's influence extends beyond VEGFR-positive cells and propose a plausible mechanistic explanation of this phenomenon.

Mutations in NOTCH 3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a neurological disorder characterized by stroke, and vascular cognitive impairment and dementia. Loss of vascular smooth muscle cells (VSMC) and accumulation of granular osmiophilic material (GOM) deposits are hallmarks of CADASIL. There are no therapies for CADASIL and experimental endpoints to examine the preclinical efficacy of potential drugs are lacking. This study aims to use a mouse carrying the C455R mutation in Notch 3 to identify biomarkers associated with CADASIL. Mass spectrometry and antibody arrays were used to explore the aorta and blood proteomes of CADASIL mice, ELISA assays were utilized for biomarker validation, a ligand-dependent assay was applied to examine the relationship between Notch signaling and biomarker expression, and retinal histology was performed for quantification of VSMC loss in arteries. Two-hundred day-old mice with the C455R CADASIL mutation in Notch 3 mice display robust VSMC loss in retinal arteries and had increased plasma levels of collagen18α1/endostatin (col18α1) and high-temperature requirement A serine peptidase 1 (HTRA1) and reduced levels of Notch 3 extracellular domain (N3ECD), compared to control wild type mice. Measurements of plasma endostatin, HTRA1 and N3ECD, along with VSMC quantification in retinal arteries, may serve as surrogate endpoints for assessing efficacy in preclinical therapeutic studies of CADASIL using mice.

PURPOSE: To validate the Ocular Pain Assessment Survey (OPAS), specifically designed to measure ocular pain and quality of life for use by eye care practitioners and researchers. DESIGN: A single-center cohort study was conducted among patients with and without corneal and ocular surface pain at initial and follow-up visits over a 6-month period. The content of the OPAS was guided by literature review, a body of experts, and incorporating conceptual frameworks from existing pain questionnaires. The Wong-Baker FACES Pain Rating Scale served as the gold standard for measuring the intensity of ocular pain. PARTICIPANTS: A total of 102 patients aged 18 to 80 years completed the OPAS at the initial visit. A total of 21 patients were followed up after treatment. METHODS: Indices of validity and internal consistency (Spearman's rank-order, rs, or Pearson's correlation coefficients, rp), and coefficient of reliability (Cronbach's α) were determined in addition to equivalence testing, exploratory factor analysis (EFA), and diagnostic analysis. MAIN OUTCOME MEASURES: Eye pain intensity was the primary outcome measure, and interference with quality of life (QoL), aggravating factors, associated factors, associated non-eye pain intensity, and self-reported symptomatic relief were the secondary outcome measures. RESULTS: The OPAS had criterion validity at both initial (rs = 0.71; n = 102; P < 0.01) and follow-up visits (rs = 0.97; n = 21; P < 0.01). Equivalence tests yielded OPAS and gold standard equivalence for both the initial and follow-up visits. The EFA supported 6 subscales (eye pain intensity at 24 hours and 2 weeks, non-eye pain intensity, QoL, aggravating factors, and associated factors) confirming multidimensionality. Cronbach's α >0.83 for all subscales established strong internal consistency, which correlated with the gold standard, including 24-hour eye pain intensity and QoL interference scores (rp = 0.81, 0.64, respectively P < 0.001). At follow-up, reduction in pain scores was accompanied by improvement in all dimensions of the OPAS. Percentage change in QoL correlated to percentage change in the gold standard (rp = 0.53; P < 0.05). The OPAS was sensitive (94%), specific (81%), and accurate (91%), with a diagnostic odds ratio >50. CONCLUSIONS: The OPAS is a valid, reliable, and responsive tool with strong psychometric and diagnostic properties in the multidimensional quantification of corneal and ocular surface pain intensity, and QoL.

Mucous membrane pemphigoid is a systemic disorder that primarily affects mucous membranes. When localized to the conjunctiva, it is known as ocular cicatricial pemphigoid, a potentially blinding disease. Ocular cicatricial pemphigoid is an indication for systemic immunosuppressive treatment to achieve adequate remission. Immunosuppressive agents are selected with a "stepladder" approach, commencing with medications having the fewest side effects. We provide an update of the literature on immunomodulatory agents since 2011 as additional treatment modalities have been explored in the last 4 years.

Ocular tick infestation is a rare occurrence. The authors report a case that is unique for being the first published example from New England, for its chronic presentation, and for the inclusion of histopathologic analysis in its diagnostic workup. A 75-year-old man was evaluated for a persistent eyelid growth secondary to an incompletely removed tick that had attached 6 months earlier. The lesion was completely excised, and a partially destroyed arthropod was observed embedded within the tissue. Light microscopy demonstrated a mixed granulomatous reaction. Given the disruption of the tick's anatomy, speciation could not be performed. The patient had an uneventful recovery. A corresponding review of tick bites to the eye is provided.

UNLABELLED: Staphylococcus aureus is a leading cause of life-threatening infections worldwide. The MIC of an antibiotic against S. aureus, as well as other microbes, is determined by the affinity of the antibiotic for its target in addition to a complex interplay of many other cellular factors. Identifying nontarget factors impacting resistance to multiple antibiotics could inform the design of new compounds and lead to more-effective antimicrobial strategies. We examined large collections of transposon insertion mutants in S. aureus using transposon sequencing (Tn-Seq) to detect transposon mutants with reduced fitness in the presence of six clinically important antibiotics-ciprofloxacin, daptomycin, gentamicin, linezolid, oxacillin, and vancomycin. This approach allowed us to assess the relative fitness of many mutants simultaneously within these libraries. We identified pathways/genes previously known to be involved in resistance to individual antibiotics, including graRS and vraFG (graRS/vraFG), mprF, and fmtA, validating the approach, and found several to be important across multiple classes of antibiotics. We also identified two new, previously uncharacterized genes, SAOUHSC_01025 and SAOUHSC_01050, encoding polytopic membrane proteins, as important in limiting the effectiveness of multiple antibiotics. Machine learning identified similarities in the fitness profiles of graXRS/vraFG, SAOUHSC_01025, and SAOUHSC_01050 mutants upon antibiotic treatment, connecting these genes of unknown function to modulation of crucial cell envelope properties. Therapeutic strategies that combine a known antibiotic with a compound that targets these or other intrinsic resistance factors may be of value for enhancing the activity of existing antibiotics for treating otherwise-resistant S. aureus strains. IMPORTANCE: Bacterial resistance to every major class of antibiotics has emerged, and we are entering a "post-antibiotic era" where relatively minor infections can lead to serious complications or even death. The utility of an antibiotic for a specific pathogen is limited by both intrinsic and acquired factors. Identifying the repertoire of intrinsic resistance factors of an antibiotic for Staphylococcus aureus, a leading cause of community- and hospital-acquired infections, would inform the design of new drugs as well as the identification of compounds that enhance the activity of existing drugs. To identify factors that limit the activity of antibiotics against S. aureus, we used Tn-Seq to simultaneously assess fitness of transposon mutants in every nonessential gene in the presence of six clinically important antibiotics. This work provides an efficient approach for identifying promising targets for drugs that can enhance susceptibility or restore sensitivity to existing antibiotics.

Within the next decade, we will see many gene therapy clinical trials for eye diseases progress, which may lead to treatments for thousands of visually impaired people around the world. To target retinal diseases that affect specific cell types, several recombinant adeno-associated virus (AAV) serotypes have been generated and used successfully in pre-clinical mouse studies. Because there are numerous anatomic, and physiologic differences between the eyes of mice and 'men' and because surgical delivery approaches and immunologic responses also differ between these species, we evaluated the transduction characteristics of two promising new serotypes AAV7m8 and AAV8BP2, in retinas of animals that are most similar to those of humans: non-human primates (NHPs). We report that while AAV7m8 efficiently targets a variety of cell types by subretinal injection in NHPs, transduction after intravitreal delivery was mostly restricted to the inner retina at lower doses that did not induce an immune response. AAV8BP2 targets the cone photoreceptors efficiently but bipolar cells inefficiently by subretinal injection. Additionally, we observed transduction of both serotypes in the anterior chamber of the eye and the optic pathway of the brain post intravitreal delivery. Finally, we assessed immunogenicity, keeping in mind that these AAV capsids may be used in future clinical trials. We found that AAV8BP2 had a better safety profile compared to AAV7m8 even at the highest doses administered. Our studies underscore the differences in AAV transduction between mice and primates highlighting the importance of careful evaluation of therapeutic vectors in NHPs prior to moving into clinical trials.

Despite being one of the most studied signalling pathways, precisely how phospholipid synthesis is regulated in the phosphoinositide signalling cascade remains unclear. The scaffold protein IQGAP1 is now shown to orchestrate the assembly of a multi-enzyme complex that streamlines PtdIns(3,4,5)P3 synthesis to facilitate Akt activation in response to extracellular stimuli.

The cornea contains a heterogeneous population of antigen-presenting cells with the capacity to contribute to immune responses. Adenovirus keratitis is a severe corneal infection with acute and chronic phases. The role of resident corneal antigen-presenting cells in adenovirus keratitis has not been studied. We utilized transgenic MaFIA mice in which c-fms expressing macrophages and dendritic cells can be induced to undergo apoptosis, in a mouse model of adenovirus keratitis. Clinical keratitis and recruitment of myeloperoxidase and CD45(+) cells were diminished in c-fms depleted, adenovirus infected mice, as compared to controls, consistent with a role for myeloid-lineage cells in adenovirus keratitis.

INTRODUCTION: The etiology, frequency, manifestation, and treatment of dry eye syndrome are commonly influenced by sex and gender. MATERIALS AND METHODS: This study aims to review the differences in epidemiology, pathophysiology, and associated diseases between the sexes. The terms men and male and women and female are used interchangeably throughout the review to refer to biological sex. RESULTS: There are numerous objective and subjective markers of dry eye syndrome but not one diagnostic criterion. There are numerous associated conditions with dry eye syndrome varying from autoimmune to allergic. Large epidemiologic studies reviewed suggest that there does indeed exist a difference between dry eye symptoms between men and women, with women having dry eye signs and reporting dry eye symptoms more often than men. The increased prevalence in women could be correlated to an increased association with certain systemic diseases, specifically autoimmune diseases, and to hormonal variations. Several studies found equivocal data about prevalence of dry eye symptoms between men and women. DISCUSSION: Interpreting studies that investigate epidemiology, pathogenesis, and treatment of dry-eye conditions is complicated by the lack of universally adapted diagnostic criteria and standardized, specific diagnostic tests, and inter-study variability in the definition of dry eye syndrome.

PURPOSE: The aim of the study was to present the long-term anatomical and visual outcomes of retinal detachment repair in patients with Stickler syndrome. PATIENTS AND METHODS: This study is a retrospective, interventional, consecutive case series of patients with Stickler syndrome undergoing retinal reattachment surgery from 2009 to 2014 at the Associated Retinal Consultants, William Beaumont Hospital. RESULTS: Sixteen eyes from 13 patients were identified. Patients underwent a mean of 3.1 surgical interventions (range: 1-13) with a mean postoperative follow-up of 94 months (range: 5-313 months). Twelve eyes (75%) developed proliferative vitreoretinopathy. Retinal reattachment was achieved in 100% of eyes, with ten eyes (63%) requiring silicone oil tamponade at final follow-up. Mean preoperative visual acuity (VA) was 20/914, which improved to 20/796 at final follow-up (P=0.81). There was a significant correlation between presenting and final VA (P<0.001), and patients with poorer presenting VA were more likely to require silicone oil tamponade at final follow-up (P=0.04). CONCLUSION: Repair of retinal detachment in patients with Stickler syndrome often requires multiple surgeries, and visual outcomes are variable. Presenting VA is significantly predictive of long-term VA outcomes.

PURPOSE: To investigate the tear levels of matrix metalloproteinases (MMPs), myeloperoxidase (MPO), and tissue inhibitor of metalloproteinase-1 in eyes after Boston keratoprosthesis type I (B-KPro) implantation and to correlate these markers with the established B-KPro prognostic categories. METHODS: Tear washes were collected from 40 patients (7 with autoimmune disease, 2 with chemical burn, and 31 with other noncicatrizing diagnoses). Tear levels of MMPs, MPO, and tissue inhibitor of metalloproteinase-1 were quantified using multianalyte bead-based enzyme-linked immunosorbent assays. The total MMP activity was determined using a fluorimetric assay. The analytes were compared to the underlying diagnosis and other clinical factors. RESULTS: The MMP-8, MMP-9, and MPO levels were markedly elevated in the eyes with B-KPro (80 ± 31, 291 ± 77, and 244 ± 33 pg/μg, respectively). Chemical burn was associated with significantly higher tear MMP-8 (474 ± 376 pg/μg) and MMP-9 levels (1300 ± 635 pg/μg) compared with noncicatrizing diseases (MMP-8: 41 ± 15 pg/μg, P = 0.02 and MMP-9: 196 ± 57 pg/μg, P = 0.02) and higher MMP-9 levels compared with autoimmune diseases (MMP-8: 96 ± 65 pg/μg, P = 0.21 and MMP-9: 306 ± 196 pg/μg, P = 0.04). Similar analyte levels were observed in the B-KPro eye and the contralateral non-B-KPro eye of patients with bilateral diseases. MMP-8, MMP-9, and total MMP activities correlated strongly with each other. CONCLUSIONS: In the eyes with B-KPro, tear MMP-8 and MMP-9 levels seem to be related to the underlying ocular surface pathology and not significantly influenced by the presence of the prosthesis.

PURPOSE: To describe the fabrication, evaluation, and preliminary in vivo safety of a new drug delivery system (DDS) for topical anti-TNF-α antibody administration. METHODS: A DDS was fabricated using inverse template fabrication of a hydrophobic three-dimensional porous scaffold (100-300 μm in diameter porosity) loaded with 10% polyvinyl alcohol hydrogel carrying 5 mg/ml (weight/volume) of anti-TNF-α antibody. Drug-loaded DDS was sterilized with 25 kGy of gamma irradiation. Long-term in vitro antibody affinity and release was evaluated at room temperature or 37°C using enzyme-linked immunosorbent assay (ELISA) and protein fluorescence. In vivo clinical and histolopathological assessment was performed by subcutaneous implantation in BALB/c mice for 3 months. RESULTS: Gamma irradiation, repeated dry/wet cycles, and storage at room temperature for 1 year or 37°C for 1 month had no deleterious effects on antibody affinity. Anti-TNF-α release was high during the first minutes of aqueous exposure, followed by stabilization and gradual, low-dose, antibody release over the next 30 days. Histopathologic evaluation of explanted DDS showed a fibrous pseudocapsule and a myxoid acute/chronic inflammation without granuloma formation surrounding the implants. CONCLUSIONS: Sustained local delivery of anti-TNF-α antibody is feasible using the described DDS, which provides stability of the enclosed antibody for up to 1 year of storage. Preliminary results show good in vivo tolerance following subcutaneous placement for 3 months. The proposed fabrication and sterilization process opens new possibilities for the delivery of biologic agents to the anterior surface of the eye. TRANSLATIONAL RELEVANCE: The described DDS will facilitate the treatment of ocular surface diseases amenable to biologic therapy.

PURPOSE: To report our experience using intravenous infliximab for the treatment of tissue melt after Boston keratoprosthesis (B-KPro) types I and II in patients with autoimmune disease. METHODS: Case series. RESULTS: We identified four patients who were treated with intravenous infliximab in the context of tissue melt after B-KPro. Stevens-Johnson syndrome-associated corneal blindness was the primary surgical indication for B-KPro implantation in all patients. Two patients received a B-KPro type I and two patients received a B-KPro type II. The patients received intravenous infliximab for skin retraction around B-KPro type II, melting of the carrier graft or leak. Treatment resulted in a dramatic decrease in inflammation and, in some cases, arrest of the melting process. Cost and patient adherence were limiting factors to pursuing infliximab therapy. In addition, one patient developed infusion reactions. CONCLUSIONS: Intravenous infliximab may be considered as globe- and sight-saving therapy for tissue melt after B-KPro.

PURPOSE: To assess diurnal changes in the signs and symptoms of dry eyes and their relationship to diurnal interblink interval (IBI) in normal subjects and in subjects with dry eye. METHODS: Blink data were collected from 9:00 AM to 8:00 PM during 2 days of normal activity using an electrocardiogram monitoring device. All subjects recorded ocular discomfort (0-5 scale) and primary activity hourly each day in a diary. Inferior and central fluorescein staining was graded by slit lamp (0-4) at the start and end of each day. Blink activity was detected using an algorithm based on recognition of the waveform corresponding to the kinematic properties of the blink signal. RESULTS: Normal subjects (N = 12) reported negligible symptoms, and results did not show a diurnal change in group hourly IBI. Mean daily IBI for the group with dry eye (N = 15) (4.63 ± 1.63 s) was shorter than that for the normal group (5.28 ± 1.48 s) (P = 0.0483). Correlation of diurnal symptoms and mean hourly IBI was relatively weak (r = -0.248). A repeated-measures model found IBI to be significantly associated with the time of day (P = 0.0028). Inferior corneal staining showed a small but significant diurnal increase for both normal group and group with dry eyes. CONCLUSIONS: Diurnal blink tracking reveals significant trending with symptoms. Diurnal change in IBI may be an appropriate surrogate for symptoms in the study of dry eye.

OBJECTIVE: To test the applicability of existing retinopathy of prematurity (ROP) guidelines on Iranian patients and to develop novel ROP screening criteria in Iran. METHODS: Both eyes of 1932 infants born ≤37 weeks of gestation and/or weighting ≤3000 g were included in this prospective cohort study that was conducted across nine neonatal intensive care units and a tertiary eye hospital ROP clinic. The patients were examined for ROP and the need for treatment (type 1 ROP or worse). All the patients were screened 4 weeks after birth or at 31 weeks of postmenstrual age, whichever was later. The patients were followed until retinal vascularisation was completed or the patients reached 50 weeks of gestational age (GA) without prethreshold ROP. A receiver operating characteristic curve was used to determine the best screening criteria for ROP. Screening criteria from other countries were applied to our patient data to determine their ability to appropriately detect ROP. MAIN OUTCOME MEASURE: Patients with ROP requiring treatment. RESULTS: The mean GA±SD and birth weight (BW)±SD of the screened patients were 32±2.7 weeks and 1713±516 g, respectively. Using criteria of GA≤32 weeks or BW ≤2000 yielded sensitivity and specificity of 100% and 26.7%, respectively, for treatment requiring ROP regardless of clinical comorbidities. Using screening recommendations of American Academy of Pediatrics would miss 25.4% of ROP and 8.4%ROP requiring treatment in our cohort. CONCLUSIONS: Other countries screening recommendations would result in a significant amount of missed cases of treatment requiring ROP when applied to Iran. As a result, we have proposed new guidelines for premature babies in Iran.