Al-Moujahed A, Nicolaou F, Brodowska K, Papakostas TD, Marmalidou A, Ksander BR, Miller JW, Gragoudas E, Vavvas DG. Uveal melanoma cell growth is inhibited by aminoimidazole carboxamide ribonucleotide (AICAR) partially through activation of AMP-dependent kinase. Invest Ophthalmol Vis Sci 2014;55(7):4175-85.Abstract
PURPOSE: To evaluate the effects and mechanism of aminoimidazole carboxamide ribonucleotide (AICAR), an AMP-dependent kinase (AMPK) activator, on the growth of uveal melanoma cell lines. METHODS: Four different cell lines were treated with AICAR (1-4 mM). Cell growth was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay. Cell cycle analysis was conducted by flow cytometry; additionally, expression of cell-cycle control proteins, cell growth transcription factors, and downstream effectors of AMPK were determined by RT-PCR and Western blot. RESULTS: Aminoimidazole carboxamide ribonucleotide inhibited cell growth, induced S-phase arrest, and led to AMPK activation. Aminoimidazole carboxamide ribonucleotide treatment was associated with inhibition of eukaryotic translation initiation factor 4E-BP1 phosphorylation, a marker of mammalian target of rapamycin (mTOR) pathway activity. Aminoimidazole carboxamide ribonucleotide treatment was also associated with downregulation of cyclins A and D, but had minimal effects on the phosphorylation of ribosomal protein S6 or levels of the macroautophagy marker LC3B. The effects of AICAR were abolished by treatment with dipyridamole, an adenosine transporter inhibitor that blocks the entry of AICAR into cells. Treatment with adenosine kinase inhibitor 5-iodotubericidin, which inhibits the conversion of AICAR to its 5'-phosphorylated ribotide 5-aminoimidazole-4-carboxamide-1-D-ribofuranosyl-5'-monophosphate (ZMP; the direct activator of AMPK), reversed most of the growth-inhibitory effects, indicating that some of AICAR's antiproliferative effects are mediated at least partially through AMPK activation. CONCLUSIONS: Aminoimidazole carboxamide ribonucleotide inhibited uveal melanoma cell proliferation partially through activation of the AMPK pathway and downregulation of cyclins A1 and D1.
Damico FM, Takahashi BS, Acquesta FB. Transscleral delivery of Nd: YLF laser at 1,047 nm causes vascular occlusion in experimental pigmented choroidal melanoma. Retina 2014;34(4):792-800.Abstract
PURPOSE: The aims of this study were to determine the scleral attenuation of focused neodymium: yttrium-lanthanum-fluoride laser at 1,047 nm applied transsclerally and whether transscleral delivery can close the vascular supply at the base of experimental choroidal melanoma in rabbits. METHODS: Fifty-two New Zealand albino rabbits were included. Scleral laser attenuation was measured across fresh sclera. B16F10 melanomas were established in the subchoroidal space of 49 rabbits. Twenty-one animals were killed immediately after transscleral treatment, 14 were followed for 2 weeks to 4 weeks, and 14 were followed without treatment. Ophthalmoscopy, fundus photographs, and fluorescein angiography were performed before treatment, immediately after, and weekly during the follow-up. Eyes were examined by light microscopy. RESULTS: Sclera attenuated laser energy by 31% ± 7%. Immediately after treatment, angiography showed diffuse hypofluorescence in 71% (15 of 21 rabbits). Light microscopy showed vascular occlusion extending at least two thirds of the tumor thickness from the base. Seven of the 14 tumors followed for 15 days ± 8 days were eradicated. There was no correlation between tumor height and eradication. CONCLUSION: Rabbit sclera attenuated 31% ± 7% of laser energy. A single transscleral treatment causes tumor vascular closure at the base and may serve as an adjuvant therapy to ensure destruction of deep and intrascleral tumor cells.
Cohen LP, Pasquale LR. Clinical characteristics and current treatment of glaucoma. Cold Spring Harb Perspect Med 2014;4(6)Abstract
Glaucoma is a neurodegenerative disorder in which degenerating retinal ganglion cells (RGC) produce significant visual disability. Clinically, glaucoma refers to an array of conditions associated with variably elevated intraocular pressure (IOP) that contributes to RGC loss via mechanical stress, vascular abnormalities, and other mechanisms, such as immune phenomena. The clinical diagnosis of glaucoma requires assessment of the ocular anterior segment with slit lamp biomicroscopy, which allows the clinician to recognize signs of conditions that can produce elevated IOP. After measurement of IOP, a specialized prismatic lens called a gonioscope is used to determine whether the angle is physically open or closed. The structural manifestation of RGC loss is optic nerve head atrophy and excavation of the neuroretinal rim tissue. Treatment is guided by addressing secondary causes for elevated IOP (such as inflammation, infection, and ischemia) whenever possible. Subsequently, a variety of medical, laser, and surgical options are used to achieve a target IOP.
Chen L, Kim IK, Lane AM, Gauthier D, Munzenrider JE, Gragoudas ES, Miller JW. Proton beam irradiation for non-AMD CNV: 2-year results of a randomised clinical trial. Br J Ophthalmol 2014;98(9):1212-7.Abstract
AIMS: To evaluate safety and visual outcomes after proton beam irradiation (PBI) therapy for subfoveal choroidal neovascularisation (CNV) secondary to causes other than age-related macular degeneration (AMD). METHODS: This study is a prospective, unmasked and randomised clinical trial using two dosage regimens, conducted in the Massachusetts Eye and Ear Infirmary. The study included 46 patients with CNV secondary to non-AMD and best-corrected visual acuity of 20/320 or better. Patients were randomly assigned to receive 16 or 24 cobalt gray equivalents (CGE) of PBI in two equal fractions. Complete ophthalmological examinations, fundus photography and fluorescein angiography were performed at baseline and 6, 12, 18 and 24 months after treatment. RESULTS: At 1 year after treatment, 82% and 72% lost fewer than 1.5 lines of vision in the 16 CGE and in 24 CGE groups, respectively. At 2 years after therapy, 77% in the lower dose group and 64% in the higher dose group lost fewer than 1.5 lines of vision. Mild radiation complications such as radiation vasculopathy developed in 17.6% of patients. CONCLUSIONS: PBI is a safe and efficacious treatment for subfoveal CNV not due to AMD. The data with respect to visual outcomes and radiation complications trend in favour of the 16 CGE group, although differences do not reach statistical significance. PBI may be considered as an alternative to current therapies.
Buys ES, Potter LR, Pasquale LR, Ksander BR. Regulation of intraocular pressure by soluble and membrane guanylate cyclases and their role in glaucoma. Front Mol Neurosci 2014;7:38.Abstract
Glaucoma is a progressive optic neuropathy characterized by visual field defects that ultimately lead to irreversible blindness (Alward, 2000; Anderson et al., 2006). By the year 2020, an estimated 80 million people will have glaucoma, 11 million of which will be bilaterally blind. Primary open-angle glaucoma (POAG) is the most common type of glaucoma. Elevated intraocular pressure (IOP) is currently the only risk factor amenable to treatment. How IOP is regulated and can be modulated remains a topic of active investigation. Available therapies, mostly geared toward lowering IOP, offer incomplete protection, and POAG often goes undetected until irreparable damage has been done, highlighting the need for novel therapeutic approaches, drug targets, and biomarkers (Heijl et al., 2002; Quigley, 2011). In this review, the role of soluble (nitric oxide (NO)-activated) and membrane-bound, natriuretic peptide (NP)-activated guanylate cyclases that generate the secondary signaling molecule cyclic guanosine monophosphate (cGMP) in the regulation of IOP and in the pathophysiology of POAG will be discussed.
Artornsombudh P, Pistilli M, Foster SC, Pujari SS, Gangaputra SS, Jabs DA, Levy-Clarke GA, Nussenblatt RB, Rosenbaum JT, Suhler EB, Thorne JE, Kempen JH. Factors predictive of remission of new-onset anterior uveitis. Ophthalmology 2014;121(3):778-84.Abstract
PURPOSE: To identify factors predictive of remission of inflammation in new-onset anterior uveitis cases treated at tertiary uveitis care facilities. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients seeking treatment at participating academic uveitis clinics within 90 days of initial diagnosis of anterior uveitis. METHODS: Retrospective cohort study based on standardized chart review. MAIN OUTCOME MEASURES: Factors predictive of remission (no disease activity without corticosteroid or immunosuppressive treatments at all visits during a 90-day period). RESULTS: Nine hundred ninety eyes (687 patients) had a first-ever diagnosis of anterior uveitis within 90 days before initial presentation and had follow-up visits thereafter. The median follow-up time was 160 days. Systemic diagnoses with juvenile idiopathic arthritis (JIA; adjusted hazard ratio [aHR], 0.38; 95% confidence interval [CI], 0.19-0.74) and Behçet's disease (aHR, 0.10; 95% CI, 0.01-0.85) were associated with a lower incidence of uveitis remission. Cases of bilateral uveitis (aHR, 0.68; 95% CI, 0.54-0.87) and those with a history of cataract surgery before presentation (aHR, 0.51; 95% CI, 0.29-0.87) also had a lower incidence of remission. Regarding clinical findings at the initial visit, a high degree of vitreous cells at initial presentation was associated with a lower incidence of remission (for 1+ or more vs. none: aHR, 0.72; 95% CI, 0.55-0.95). An initial visual acuity of 20/200 or worse, with respect to 20/40 or better, also was predictive of a lower incidence of remission (aHR, 0.52; 95% CI, 0.32-0.86). CONCLUSIONS: Factors associated with a lower incidence of remission among new-onset anterior uveitis cases included diagnosis with JIA, Behçet's disease, bilateral uveitis, history of cataract surgery, findings of 1+ or more vitreous cells at presentation, and an initial visual acuity of 20/200 or worse. Patients with these risk factors seem to be at higher risk of persistent inflammation; reciprocally, patients lacking these factors would be more likely to experience remission. Patients with risk factors for nonremission of uveitis should be managed taking into account the higher probability of a chronic inflammatory course.
Alberti CF, Peli E, Bowers AR. Driving with hemianopia: III. Detection of stationary and approaching pedestrians in a simulator. Invest Ophthalmol Vis Sci 2014;55(1):368-74.Abstract
PURPOSE: To compare blind-side detection performance of drivers with homonymous hemianopia (HH) for stationary and approaching pedestrians, initially appearing at small (4°) or large (14°) eccentricities in a driving simulator. While the stationary pedestrians did not represent an imminent threat, as their eccentricity increased rapidly as the vehicle advanced, the approaching pedestrians maintained a collision course with approximately constant eccentricity, walking or running, toward the travel lane as if to cross. METHODS: Twelve participants with complete HH and without spatial neglect pressed the horn whenever they detected a pedestrian while driving along predetermined routes in two driving simulator sessions. Miss rates and reaction times were analyzed for 52 stationary and 52 approaching pedestrians. RESULTS: Miss rates were higher and reaction times longer on the blind than the seeing side (P < 0.01). On the blind side, miss rates were lower for approaching than stationary pedestrians (16% vs. 29%, P = 0.01), especially at larger eccentricities (20% vs. 54%, P = 0.005), but reaction times for approaching pedestrians were longer (1.72 vs. 1.41 seconds; P = 0.03). Overall, the proportion of potential blind-side collisions (missed and late responses) was not different for the two paradigms (41% vs. 35%, P = 0.48), and significantly higher than for the seeing side (3%, P = 0.002). CONCLUSIONS: In a realistic pedestrian detection task, drivers with HH exhibited significant blind-side detection deficits. Even when approaching pedestrians were detected, responses were often too late to avoid a potential collision.
Connors EC, Chrastil ER, Sánchez J, Merabet LB. Virtual environments for the transfer of navigation skills in the blind: a comparison of directed instruction vs. video game based learning approaches. Front Hum Neurosci 2014;8:223.Abstract
For profoundly blind individuals, navigating in an unfamiliar building can represent a significant challenge. We investigated the use of an audio-based, virtual environment called Audio-based Environment Simulator (AbES) that can be explored for the purposes of learning the layout of an unfamiliar, complex indoor environment. Furthermore, we compared two modes of interaction with AbES. In one group, blind participants implicitly learned the layout of a target environment while playing an exploratory, goal-directed video game. By comparison, a second group was explicitly taught the same layout following a standard route and instructions provided by a sighted facilitator. As a control, a third group interacted with AbES while playing an exploratory, goal-directed video game however, the explored environment did not correspond to the target layout. Following interaction with AbES, a series of route navigation tasks were carried out in the virtual and physical building represented in the training environment to assess the transfer of acquired spatial information. We found that participants from both modes of interaction were able to transfer the spatial knowledge gained as indexed by their successful route navigation performance. This transfer was not apparent in the control participants. Most notably, the game-based learning strategy was also associated with enhanced performance when participants were required to find alternate routes and short cuts within the target building suggesting that a ludic-based training approach may provide for a more flexible mental representation of the environment. Furthermore, outcome comparisons between early and late blind individuals suggested that greater prior visual experience did not have a significant effect on overall navigation performance following training. Finally, performance did not appear to be associated with other factors of interest such as age, gender, and verbal memory recall. We conclude that the highly interactive and immersive exploration of the virtual environment greatly engages a blind user to develop skills akin to positive near transfer of learning. Learning through a game play strategy appears to confer certain behavioral advantages with respect to how spatial information is acquired and ultimately manipulated for navigation.
Cheng L, Desai J, Miranda CJ, Duncan JS, Qiu W, Nugent AA, Kolpak AL, Wu CC, Drokhlyansky E, DeLisle MM, Chan W-M, Wei Y, Propst F, Reck-Peterson SL, Fritzsch B, Engle EC. Human CFEOM1 mutations attenuate KIF21A autoinhibition and cause oculomotor axon stalling. Neuron 2014;82(2):334-49.Abstract
The ocular motility disorder "Congenital fibrosis of the extraocular muscles type 1" (CFEOM1) results from heterozygous mutations altering the motor and third coiled-coil stalk of the anterograde kinesin, KIF21A. We demonstrate that Kif21a knockin mice harboring the most common human mutation develop CFEOM. The developing axons of the oculomotor nerve's superior division stall in the proximal nerve; the growth cones enlarge, extend excessive filopodia, and assume random trajectories. Inferior division axons reach the orbit but branch ectopically. We establish a gain-of-function mechanism and find that human motor or stalk mutations attenuate Kif21a autoinhibition, providing in vivo evidence for mammalian kinesin autoregulation. We identify Map1b as a Kif21a-interacting protein and report that Map1b⁻/⁻ mice develop CFEOM. The interaction between Kif21a and Map1b is likely to play a critical role in the pathogenesis of CFEOM1 and highlights a selective vulnerability of the developing oculomotor nerve to perturbations of the axon cytoskeleton.
Carnes MU, Liu YP, Allingham RR, Whigham BT, Havens S, Garrett ME, Qiao C, Qiao C, Katsanis N, Wiggs JL, Pasquale LR, Ashley-Koch A, Oh EC, Hauser MA. Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma. PLoS Genet 2014;10(5):e1004372.Abstract
Glaucoma is a leading cause of blindness worldwide. Primary open-angle glaucoma (POAG) is the most common subtype and is a complex trait with multigenic inheritance. Genome-wide association studies have previously identified a significant association between POAG and the SIX6 locus (rs10483727, odds ratio (OR) = 1.32, p = 3.87×10(-11)). SIX6 plays a role in ocular development and has been associated with the morphology of the optic nerve. We sequenced the SIX6 coding and regulatory regions in 262 POAG cases and 256 controls and identified six nonsynonymous coding variants, including five rare and one common variant, Asn141His (rs33912345), which was associated significantly with POAG (OR = 1.27, p = 4.2×10(-10)) in the NEIGHBOR/GLAUGEN datasets. These variants were tested in an in vivo Danio rerio (zebrafish) complementation assay to evaluate ocular metrics such as eye size and optic nerve structure. Five variants, found primarily in POAG cases, were hypomorphic or null, while the sixth variant, found only in controls, was benign. One variant in the SIX6 enhancer increased expression of SIX6 and disrupted its regulation. Finally, to our knowledge for the first time, we have identified a clinical feature in POAG patients that appears to be dependent upon SIX6 genotype: patients who are homozygous for the SIX6 risk allele (His141) have a statistically thinner retinal nerve fiber layer than patients homozygous for the SIX6 non-risk allele (Asn141). Our results, in combination with previous SIX6 work, lead us to hypothesize that SIX6 risk variants disrupt the development of the neural retina, leading to a reduced number of retinal ganglion cells, thereby increasing the risk of glaucoma-associated vision loss.
Borodic GE, Caruso P, Acquadro M, Chick S. Parry-Romberg syndrome vasculopathy and its treatment with botulinum toxin. Ophthalmic Plast Reconstr Surg 2014;30(1):e22-5.Abstract
Parry-Romberg syndrome is a rare condition characterized by progressive, hemifacial atrophy, hair loss, enophthalmos, retinal vasculopathy occasionally associated with hemicranial pain syndrome (secondary trigeminal neuralgia). The cause of the condition is unknown; however, substantial evidence suggests that vasculopathy plays a significant role in the genesis of the neurologic damage and facial lipodystrophy. Herein describes a case of Parry-Romberg syndrome treated with repetitive botulinum type A toxin injections, with almost complete resolution of severe chronic pain.
Allmendinger AM, M Mallery R, Magro CM, Wang N, Egan RA, Samuels MA, Callahan A, Viswanadhan N, Klufas RA, Hsu L, Prasad S. Cauda equina involvement in Susac's syndrome. J Neurol Sci 2014;337(1-2):91-6.Abstract
Susac's syndrome is a rare autoimmune microangiopathy characterized by the clinical triad of encephalopathy, branch retinal artery occlusions, and sensorineural hearing loss. In many cases, the clinical triad is not fully present at the onset of symptoms. MRI studies often show characteristic punched out lesions of the central fibers of the corpus callosum, and leptomeningeal enhancement and deep gray matter lesions may also be seen. Here we present a case of Susac's syndrome in a middle aged man with the unique clinical finding of cauda equina syndrome and spinal MRI showing diffuse lumbosacral nerve root enhancement. Biopsy specimens of the brain, leptomeninges, and skin showed evidence of a pauci-immune endotheliopathy, consistent with pathology described in previous cases of Susac's syndrome. This case is important not only because it expands the clinical features of Susac's syndrome but also because it clarifies the mechanism of a disorder of the endothelium, an important target for many disorders of the nervous system.
Aggarwal S, Cavalcanti BM, Pavan-Langston D. Treatment of pseudodendrites in herpes zoster ophthalmicus with topical ganciclovir 0.15% gel. Cornea 2014;33(2):109-13.Abstract
PURPOSE: There is no standard of treatment for epithelial pseudodendrites in herpes zoster ophthalmicus (HZO). The purpose of this study is to report the topical antiviral drug, 0.15% ganciclovir for treatment of these lesions. METHODS: This is a retrospective, interventional case series of 4 patients who were diagnosed with HZO epithelial pseudodendrites despite being given oral antiviral treatment and who underwent 0.15% ganciclovir gel topical treatment. Main outcome measures included epithelial healing time, visual acuity, and corneal sensation. RESULTS: All 4 patients were immunocompetent and had epithelial lesions unresponsive to antiviral treatment with oral valacyclovir. Treatment with topical 0.15% ganciclovir gel 5 times a day resulted in the lesions healing successfully within 7 days with improved visual acuity in 3 patients and an increase in corneal sensation in 2 of the 4 patients. CONCLUSIONS: Topical 0.15% ganciclovir gel, 5 times a day until pseudodendritic lesion healing and tapering to bid for 2 to 4 weeks thereafter, is an effective treatment for pseudodendrites in HZO-affected cases that are often a challenge to manage with other oral or topical antivirals.
Cruz NM, Yuan Y, Leehy BD, Baid R, Kompella U, Deangelis MM, Escher P, Haider NB. Modifier genes as therapeutics: the nuclear hormone receptor Rev Erb alpha (Nr1d1) rescues Nr2e3 associated retinal disease. PLoS One 2014;9(1):e87942.Abstract
Nuclear hormone receptors play a major role in many important biological processes. Most nuclear hormone receptors are ubiquitously expressed and regulate processes such as metabolism, circadian function, and development. They function in these processes to maintain homeostasis through modulation of transcriptional gene networks. In this study we evaluate the effectiveness of a nuclear hormone receptor gene to modulate retinal degeneration and restore the integrity of the retina. Currently, there are no effective treatment options for retinal degenerative diseases leading to progressive and irreversible blindness. In this study we demonstrate that the nuclear hormone receptor gene Nr1d1 (Rev-Erbα) rescues Nr2e3-associated retinal degeneration in the rd7 mouse, which lacks a functional Nr2e3 gene. Mutations in human NR2E3 are associated with several retinal degenerations including enhanced S cone syndrome and retinitis pigmentosa. The rd7 mouse, lacking Nr2e3, exhibits an increase in S cones and slow, progressive retinal degeneration. A traditional genetic mapping approach previously identified candidate modifier loci. Here, we demonstrate that in vivo delivery of the candidate modifier gene, Nr1d1 rescues Nr2e3 associated retinal degeneration. We observed clinical, histological, functional, and molecular restoration of the rd7 retina. Furthermore, we demonstrate that the mechanism of rescue at the molecular and functional level is through the re-regulation of key genes within the Nr2e3-directed transcriptional network. Together, these findings reveal the potency of nuclear receptors as modulators of disease and specifically of NR1D1 as a novel therapeutic for retinal degenerations.