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Li E, Greenberg PB, Voruganti I, Krzystolik MG. Cost and Selection of Ophthalmic Anti-Vascular Endothelial Growth Factor Agents. R I Med J (2013) 2016;99(5):15-7.Abstract

Anti-vascular endothelial growth factor (anti-VEGF) drugs - ranibizumab, aflibercept, and off-label bevacizumab - are vital to the treatment of common retinal diseases, including exudative age-related macular degeneration (AMD), diabetic macular edema (DME), and macular edema (ME) associated with retinal vein occlusion (RVO). Given the high prevalence of AMD and retinal vascular diseases, anti-VEGF agents represent a large cost burden to the United States (US) healthcare system. Although ranibizumab and aflibercept are 30-fold more expensive per injection than bevacizumab, the two more costly medications are commonly used in the US, even though all three have been shown to be effective and safe for treatment of these retinal diseases. We investigated the availability and content of professional ophthalmic guidelines on cost consideration in the selection of anti-VEGF agents. We found that current professional guidelines were limited in availability and lacked specific guidance on cost-based anti-VEGF drug selection. This represents a missed opportunity to encourage the practice of value-based medicine. [Full article available at http://rimed.org/rimedicaljournal-2016-05.asp, free with no login].

Cruzat A, Hamrah P, Cavalcanti BM, Zheng L, Colby K, Pavan-Langston D. Corneal Reinnervation and Sensation Recovery in Patients With Herpes Zoster Ophthalmicus: An In Vivo and Ex Vivo Study of Corneal Nerves. Cornea 2016;35(5):619-25.Abstract

PURPOSE: To study corneal reinnervation and sensation recovery in Herpes zoster ophthalmicus (HZO). METHODS: Two patients with HZO were studied over time with serial corneal esthesiometry and laser in vivo confocal microscopy (IVCM). A Boston keratoprosthesis type 1 was implanted, and the explanted corneal tissues were examined by immunofluorescence histochemistry for βIII-tubulin to stain for corneal nerves. RESULTS: The initial central corneal IVCM performed in each patient showed a complete lack of the subbasal nerve plexus, which was in accordance with severe loss of sensation (0 of 6 cm) measured by esthesiometry. When IVCM was repeated 2 years later before undergoing surgery, case 1 showed a persistent lack of central subbasal nerves and sensation (0 of 6). In contrast, case 2 showed regeneration of the central subbasal nerves (4786 μm/mm) with partial recovery of corneal sensation (2.5 of 6 cm). Immunostaining of the explanted corneal button in case 1 showed no corneal nerves, whereas case 2 showed central and peripheral corneal nerves. Eight months after surgery, IVCM was again repeated in the donor tissue around the Boston keratoprosthesis in both patients to study innervation of the corneal transplant. Case 1 showed no nerves, whereas case 2 showed new nerves growing from the periphery into the corneal graft. CONCLUSIONS: We demonstrate that regaining corneal innervation and corneal function are possible in patients with HZO as shown by corneal sensation, IVCM, and ex vivo immunostaining, indicating zoster neural damage is not always permanent and it may recover over an extended period of time.

Queisi MM, Zein M, Lamba N, Meese H, Foster CS. Update on ocular cicatricial pemphigoid and emerging treatments. Surv Ophthalmol 2016;61(3):314-7.Abstract

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.

Foxton R, Osborne A, Martin KR, Ng Y-S, Shima DT. Distal retinal ganglion cell axon transport loss and activation of p38 MAPK stress pathway following VEGF-A antagonism. Cell Death Dis 2016;7:e2212.Abstract

There is increasing evidence that VEGF-A antagonists may be detrimental to neuronal health following ocular administration. Here we investigated firstly the effects of VEGF-A neutralization on retinal neuronal survival in the Ins2(Akita) diabetic and JR5558 spontaneous choroidal neovascularization (CNV) mice, and then looked at potential mechanisms contributing to cell death. We detected elevated apoptosis in the ganglion cell layer in both these models following VEGF-A antagonism, indicating that even when vascular pathologies respond to treatment, neurons are still vulnerable to reduced VEGF-A levels. We observed that retinal ganglion cells (RGCs) seemed to be the cells most susceptible to VEGF-A antagonism, so we looked at anterograde transport in these cells, due to their long axons requiring optimal protein and organelle trafficking. Using cholera toxin B-subunit tracer studies, we found a distal reduction in transport in the superior colliculus following VEGF-A neutralization, which occurred prior to net RGC loss. This phenomenon of distal transport loss has been described as a feature of early pathological changes in glaucoma, Alzheimer's and Parkinson's disease models. Furthermore, we observed increased phosphorylation of p38 MAPK and downstream Hsp27 stress pathway signaling in the retinas from these experiments, potentially providing a mechanistic explanation for our findings. These experiments further highlight the possible risks of using VEGF-A antagonists to treat ocular neovascular disease, and suggest that VEGF-A may contribute to the maintenance and function of axonal transport in neurons of the retina.

Chen Y, Liu F, Wang C, Zhao M, Deng L, Zhong J, Zhang Y, Ye J, Jing S, Cheng Z, Guan Y, Ma Y, Sun Y, Zhu B, Zhang Q. Molecular Identification and Epidemiological Features of Human Adenoviruses Associated with Acute Respiratory Infections in Hospitalized Children in Southern China, 2012-2013. PLoS One 2016;11(5):e0155412.Abstract

BACKGROUND: Acute respiratory infections (ARI) are the major worldwide health problem associated with high morbidity and mortality rates. Human adenovirus (HAdV) is one of the most common pathogens associated with viral ARI, and thus calls for specific diagnosis and better understanding of the epidemiology and clinical characteristics. METHODS: Total 4,130 children with ARI requiring hospitalization from 2012 to 2013 were retrospectively studied. Throat swab specimens were collected from each patient. Fluorescence Quantitative PCR was performed to detect adenovirus as well as other common ARI-related pathogens. The seven HAdV hypervariable regions (HVRs) of the hexon gene from fifty-seven HAdVs-positive samples collected in the seasonal peaks were sequenced. Phylogenetic analysis of HVRs was also conducted to confirm the molecular types and genetic variation. In addition, epidemiological features and co-infection with other human respiratory pathogens were investigated and analyzed. RESULTS: Of 4,130 hospitalized pediatric patients tested, the positive rates of respiratory syncytial virus (RSV), Mycoplasma pneumoniae (MP), and HAdV were 13.7%, 13.2%, and 12.0%, respectively. The HAdV positive patients accounted for 7.9%, 17.2%, 17.5% and 10.7% in age groups <1, 1-3, 3-6 and 6-14 years, respectively. Eighty-four HAdV positive children were co-infected with other respiratory pathogens (84/495, 17.0%). The most common co-infection pathogens with HAdV were MP (57.1%) and Human Bocavirus (HBoV) (16.7%). The majority of HAdV infected patients were totally recovered (96.9%, 480/495); However, four (0.8%) patients, who were previously healthy and at the age of 2 years or younger died of pneumonia. Seasonal peaks of HAdV infection occurred in the summer season of 2012 and 2013; the predominant HAdV type was HAdV-3 (70%), followed by HAdV-7 (28%). These epidemiological features were different from those in Northern China. The HAdV-55 was identified and reported for the first time in Guangzhou metropolitan area. Phylogenetic analysis indicated that all the HVR sequences of the hexon gene of HAdV-3 and -7 strains have high similarity within their individual types, and these strains were also similar to those circulating in China currently, indicating the conservation of hexon genes of both HAdV-3 and HAdV-7. CONCLUSIONS: Knowledge of the epidemiological features and molecular types of HAdV, a major pathogen of pediatric ARI, as well as other co-infected respiratory pathogens circulating in Guangzhou, southern China, is vital to predict and prevent future disease outbreaks in children. This study will certainly facilitate HAdV vaccine development and treatment of HAdV infections in children.

Suelves AM, Lamba N, Meese HK, Foster SC, González-Martín JM, Díaz-Llopis M, Christen WG. Nuclear cataract as an early predictive factor for recalcitrant juvenile idiopathic arthritis-associated uveitis. J AAPOS 2016;20(3):232-238.e1.Abstract

PURPOSE: To analyze factors predictive of having treatment-resistant uveitis in patients with juvenile idiopathic arthritis (JIA)-associated uveitis. METHODS: The medical records of patients diagnosed with JIA-associated uveitis treated at a single tertiary referral center from October 2005 to March 2013 were reviewed retrospectively. The main outcome measures were demographic characteristics, ocular comorbidity, clinical course, treatments, and baseline risk factors associated with poor response to first-line therapies. RESULTS: A total of 96 patients (175 eyes) were included. Of these, 58 patients (108 eyes) required biologic disease-modifying antirheumatic drugs or alkylating agents for their uveitis during follow-up (recalcitrant group), and 38 patients (67 eyes) did not (nonrecalcitrant group). Eyes of the recalcitrant group tended to have a higher incidence of cataract at baseline (49%; P < 0.0001). In the nonrecalcitrant group, the most frequent complications were cataract (20.9%) and secondary glaucoma (20.9%). The mean number of flares in the recalcitrant group was significantly reduced from 3.7/eye/year prior to cataract surgery to 1.6/eye/year after (P < 0.0001). Nuclear cataract was found to be an independent predictor for a severe course of JIA-associated uveitis. Any other type of cataract, posterior synechiae, male sex, or active uveitis at baseline were not found to be independently associated with recalcitrant uveitis. CONCLUSIONS: Nuclear cataract at baseline evaluation is a risk factor for poor response to first-line therapies in JIA-associated uveitis patients.

Paneghetti L, Ng Y-SE. A novel endothelial-derived anti-inflammatory activity significantly inhibits spontaneous choroidal neovascularisation in a mouse model. Vasc Cell 2016;8:2.Abstract

BACKGROUND: Endothelial cells (EC) grown on collagen particles inhibit intimal hyperplasia in animal models when applied perivascularly, and this effect appears to be, at least in part, the result of EC-derived soluble factors that suppress local vascular inflammation. To elucidate the molecular basis of the therapeutic effects of EC grown on collagen particles, the anti-inflammatory activity of conditioned medium from these cells was characterized. METHODS: Human aortic EC (HAEC) and, for chromatin immunoprecipitation assays, human umbilical vein EC (HUVEC) were treated with tumor necrosis factor alpha (TNFα) in the presence of conditioned medium generated by HAEC grown on collagen particles (ECPCM), and the anti-inflammatory effects were evaluated by analysing the expression of the inflammation-related adhesion molecules E-selectin and vascular cell adhesion molecule-1 (VCAM-1). The therapeutic activity of ECPCM was studied using the mouse strain JR5558, which develops spontaneous choroidal neovascularisation (CNV) lesions driven by local inflammation. RESULTS: ECPCM significantly suppressed TNFα-induced expression of E-selectin and VCAM-1. ECPCM did not affect the mRNA stability of the two genes, but suppressed TNFα-induced binding of the p65 subunit of NF-kB transcription factor to E-selectin and VCAM-1 promoters. In vivo, systemic ECPCM treatment significantly reduced the CNV area and the recruitment of activated macrophages to the lesions. Characterization of the molecule responsible for the anti-inflammatory activity in ECPCM indicates that it is unlikely to be a protein and that it is not any of the better characterized EC-derived anti-inflammatory molecules. CONCLUSIONS: Medium conditioned by HAEC grown on collagen particles exhibits significant anti-inflammatory activity via inhibition of genes that mediate inflammatory responses in EC.

Jakobiec FA, Thanos A, Stagner AM, Grossniklaus HE, Proia AD. So-called massive retinal gliosis: A critical review and reappraisal. Surv Ophthalmol 2016;61(3):339-56.Abstract

Massive retinal gliosis, a nonneoplastic retinal glial proliferation, was first described in detail over 25 years ago, before the era of immunohistochemistry, in a series of 38 cases-to which can be added 30 case reports or small series (no more than 3 cases) subsequently. We analyze a new series of 3 nontumoral intraretinal glioses and 15 cases of tumoral retinal gliosis, not all of which, strictly speaking, were massive. The data from this series are compared with the findings in previously published cases. Included are 2 cases of massive retinal gliosis diagnosed from evisceration specimens. In reviewing all published and current cases, we were able to establish 3 subgroups of retinal tumoral glioses rather than a single "massive" category: focal nodular gliosis, submassive gliosis, and massive gliosis. Among 43 reported cases, including the present series, but excluding the previous large series of 38 cases in which substantial clinical data were omitted, there were 19 men and 24 women. Their mean and median ages were 36.2 years and 36 years, respectively, with a range of 2 to 79 years. All lesions were composed of mitotically quiet, compact spindled fibrous astrocytes devoid of an Alcian blue-positive myxoid matrix. The most common associated ocular conditions were phthisis bulbi and congenital diseases or malformations. Histopathologically, all 3 tumoral categories were accompanied by progressively more extensive fibrous and osseous metaplasia of the pigment epithelium, the latter forming a clinically and diagnostically useful, almost continuous, outer rim of eggshell calcification in the submassive and massive categories that should be detectable with appropriate imaging studies. In decreasing order of frequency, microcysts and macrocysts, vascular sclerosis, exudates, calcospherites, and Rosenthal fibers were observed among the proliferating fibrous astrocytes. Immunohistochemistry was positive for glial fibrillary acidic protein in all cases and nestin in most (an intermediate cytoplasmic filament typically restricted to embryonic and reparative neural tissue). The nonneoplastic nature of all categories of gliosis was confirmed by absent TP53 (tumor suppressor gene) dysregulation, Ki-67 negativity, and intact p16 expression (the protein product of the p16 tumor suppressor gene) in the overwhelming majority of cases. These findings indicate an intrinsic attempt to regulate and maintain a low level of glial cell proliferation that becomes unsuccessful as the disease evolves. The categories of tumoral proliferation appeared to constitute a spectrum. We conclude that focal nodular tumors encompass lesions previously called retinal vasoproliferative lesions, which display the same histopathologic and immunohistochemical findings as 3 major categories of retinal gliosis characterized herein.

Dordea AC, Bray M-A, Allen K, Logan DJ, Fei F, Malhotra R, Gregory MS, Carpenter AE, Buys ES. An open-source computational tool to automatically quantify immunolabeled retinal ganglion cells. Exp Eye Res 2016;147:50-6.Abstract

A fully automated and robust method was developed to quantify β-III-tubulin-stained retinal ganglion cells, combining computational recognition of individual cells by CellProfiler and a machine-learning tool to teach phenotypic classification of the retinal ganglion cells by CellProfiler Analyst. In animal models of glaucoma, quantification of immunolabeled retinal ganglion cells is currently performed manually and remains time-consuming. Using this automated method, quantifications of retinal ganglion cell images were accelerated tenfold: 1800 images were counted in 3 h using our automated method, while manual counting of the same images took 72 h. This new method was validated in an established murine model of microbead-induced optic neuropathy. The use of the publicly available software and the method's user-friendly design allows this technique to be easily implemented in any laboratory.

Rapoport Y, Singer JM, Ling JD, Gregory A, Kohanim S. A Comprehensive Review of Sex Disparities in Symptoms, Pathophysiology, and Epidemiology of Dry Eye Syndrome. Semin Ophthalmol 2016;Abstract

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.

Silpa-Archa S, Lee JJ, Boonsopon S, Lizárraga MT, Preble JM, Sujirarat D, Patel P, Foster SC. POOR PROGNOSTIC FACTORS IN PATIENTS WITH BIRDSHOT RETINOCHOROIDOPATHY. Retina 2016;36(11):2220-2226.Abstract

PURPOSE: To identify prognostic factors for poor visual outcome in patients with birdshot retinochoroidopathy. METHODS: A case-control study of 98 patients with birdshot retinochoroidopathy (196 eyes) was evaluated with a follow-up period of at least 12 months. After exclusion of glaucoma, optic atrophy, and macular scar, the remaining eligible patients were categorized into two groups: poor visual outcomes and good visual outcomes. Poor visual outcome was defined as less than -6 mean deviation score on Swedish interactive threshold algorithm (SITA) short-wavelength automated perimetry (SWAP) test and abnormality (amplitude or implicit time) of 30 Hz flicker electroretinogram at 4-year follow-up and at the most recent visit for separate analysis. Potential factors between both groups were statistically analyzed by Chi-square test and logistic regression model. RESULTS: After the aforementioned exclusion, the remaining 77 patients with an average follow-up period of 52 ± 29 months (335 person-years, 36% with follow-up of more than 5 years) were divided into two groups. Sixteen patients were categorized as having poor visual outcome. Univariate analysis identified significant association of abnormal 30 Hz flicker electroretinogram amplitude (P = 0.004), implicit time (P = 0.002), and SITA SWAP mean deviation at the initial visit (P < 0.001) in the poor visual outcome group. Multivariate logistic regression analysis identified only SITA SWAP mean deviation to be associated with poor visual outcome (adjusted odds ratio, 32.50; 95% confidence interval [3.84-275.32]; P = 0.001) at the initial visit. To verify the model validity, an analysis of 42 patients at 4-year follow-up was performed and the outcome was confirmed (adjusted odds ratio, 8.80; 95% confidence interval [1.58-49.16]; P = 0.013). CONCLUSION: Worse SITA SWAP mean deviation at the initial visit is a predictor of poor visual outcome in patients with birdshot retinochoroidopathy, and may serve as a proxy marker for delayed effective steroid sparing therapy in patients with birdshot retinochoroidopathy.

Garanto A, Chung DC, Duijkers L, Corral-Serrano JC, Messchaert M, Xiao R, Bennett J, Vandenberghe LH, Collin RWJ. In vitro and in vivo rescue of aberrant splicing in CEP290-associated LCA by antisense oligonucleotide delivery. Hum Mol Genet 2016;Abstract

Leber congenital amaurosis (LCA) is a severe disorder resulting in visual impairment usually starting in the first year of life. The most frequent genetic cause of LCA is an intronic mutation in CEP290 (c.2991+1655A>G) that creates a cryptic splice donor site resulting in the insertion of a pseudoexon (exon X) into CEP290 mRNA. Previously, we showed that naked antisense oligonucleotides (AONs) effectively restored normal CEP290 splicing in patient-derived lymphoblastoid cells. We here explore the therapeutic potential treatment of naked and AAV-packaged AONs in vitro and in vivo In both cases, AON delivery fully restored CEP290 pre-mRNA splicing, significantly increased CEP290 protein levels and rescued a ciliary phenotype present in patient-derived fibroblast cells. Moreover, administration of naked and AAV-packaged AONs to the retina of a humanized mutant Cep290 mouse model, carrying the intronic mutation, showed a statistically significant reduction of exon X-containing Cep290 transcripts, without compromising the retinal structure. Together, our data highlight the tremendous therapeutic prospective of AONs for the treatment of not only CEP290-associated LCA but potentially many other subtypes of retinal dystrophy caused by splicing mutations.

Gaca AO, Gilmore MS. A lysin to kill. Elife 2016;5Abstract

An enzyme produced by a bacteriophage can enter human cells and kill intracellular Streptococcus pyogenes.

Crnej A, Omoto M, Dohlman TH, Gonzalez-Andrades M, Paschalis EI, Cruzat A, Vu KTH, Doorenbos M, Chen DF, Dohlman CH, Dana R. Effect of Penetrating Keratoplasty and Keratoprosthesis Implantation on the Posterior Segment of the Eye. Invest Ophthalmol Vis Sci 2016;57(4):1643-8.Abstract

PURPOSE: To compare the effects of post-penetrating keratoplasty (PK) and post-keratoprosthesis (KPro) surgery-related inflammation on the posterior segment of the eye and to assess inhibition of tumor necrosis factor alpha (TNFα) and interleukin-1 beta (IL-1β) on these effects. METHODS: BALB/C (syngeneic) or C57BL/6 (allogeneic) corneas were transplanted onto BALB/C host beds as part of PK or miniature KPro (m-KPro) implantation. Intraocular pressure (IOP) was measured via an intracameral pressure sensor; tissues were harvested and analyzed 8 weeks after surgery. Expression of TNFα and IL-1β in the retina was analyzed using real-time quantitative (q)PCR. Optic nerve degeneration (axon count, circularity, and area) was assessed quantitatively using ImageJ software. After m-KPro implantation, mice were treated with saline, anti-TNFα, or anti-IL-1β antibody, and axonal loss was assessed after 10 weeks. RESULTS: Mean IOP was within normal limits in the operated and fellow eyes in all groups. The mRNA expression of TNFα and IL-1β was highest in m-KPro groups with either syngeneic or an allogeneic carrier. We observed optic nerve degeneration in both allogeneic PK and m-KPro implanted eyes with an allogeneic carrier. However, TNFα blockade significantly reduced axonal loss by 35%. CONCLUSIONS: Allogeneic PK and m-KPro implants with an allogeneic carrier lead to chronic inflammation in the posterior segment of the eye, resulting in optic nerve degeneration. In addition, blockade of TNFα prevents axonal degeneration in this preclinical model of allogeneic m-KPro (alloKPro) implantation.

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