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2018

Peiris T, Indaram M, Koo E, Soul J, Hunter D. Congenital muscular dystrophy-dystroglycanopathy, type A, featuring bilateral retinal dysplasia and vertical angle kappa. J AAPOS. 2018;22(3):242–244.e1.
Muscular dystrophy-dystroglycanopathy type A (MDDGA3), one of a group of diseases collectively known as congenital muscular dystrophies, is an alpha-dystroglycanopathy with characteristic brain and ocular abnormalities. We report the case of a 9-month-old boy with developmental delay whose family sought evaluation for esotropia. Subsequent examination, imaging, and testing revealed significant motor and cognitive delay, marked weakness with appendicular spasticity, and a diffuse brain malformation. In addition, the patient had poor visual acuity, nystagmus, optic nerve hypoplasia, bilateral retinal dysplasia and retinal dragging with a large vertical angle kappa, and an avascular peripheral retina. Genetic testing revealed two known heterozygous mutations in the POMGnT1 gene confirming MDDGA3. He was treated with botulinum toxin injections for his strabismus and continues to be followed, with planned laser ablation of the peripheral avascular retina.
Rubinfeld R, Stulting D, Gum G, Talamo J. Quantitative analysis of corneal stromal riboflavin concentration without epithelial removal. J Cataract Refract Surg. 2018;44(2):237–242.
PURPOSE: To compare the corneal stromal riboflavin concentration and distribution using 2 transepithelial corneal crosslinking (CXL) systems. SETTING: Absorption Systems, San Diego, California, USA. DESIGN: Experimental study. METHODS: The stromal riboflavin concentration of 2 transepithelial CXL systems was compared in rabbit eyes in vivo. The systems were the Paracel/Vibex Xtra, comprising riboflavin 0.25% solution containing TRIS and ethylenediaminetetraacetic acid and an isotonic solution of riboflavin 0.25%, (Group 1) and the CXLO system (Group 2). Manufacturers' Instructions For Use were followed. The intensity of riboflavin fluorescence by slitlamp observation 10, 15, and 20 minutes after instillation was graded on a scale of 0 to 5. The animals were humanely killed and the corneal stromal samples analyzed with liquid chromatography and mass spectrometry. RESULTS: The mean riboflavin fluorescence intensity grades in Group 1 (4 eyes) were 3.8, 4.8, and 4.8 at 10, 15, and 20 minutes, respectively. The mean grades in Group 2 (3 eyes) were 2.0, 2.3, and 2.0, respectively. The riboflavin distribution was uniform in Group 1 but not in Group 2. The mean riboflavin concentration by liquid chromatography and mass spectrometry was 27.0 μg/g stromal tissue in Group 1 and 6.7 μg/g in Group 2. A stromal riboflavin concentration theoretically adequate for CXL, 15 μg/g, was achieved in all eyes in Group 1 and no eyes in Group 2. Slitlamp grading correlated well with liquid chromatography and mass spectrometry concentration (R = 0.940). CONCLUSIONS: The system used in Group 1 produced corneal riboflavin concentrations that were theoretically adequate for effective transepithelial CXL (≥15 μg/g), while the system in Group 2 did not. Slitlamp grading successfully estimated the corneal riboflavin concentration and can be used to ensure an adequate concentration of riboflavin in the cornea for transepithelial CXL.
Sung Y, Winkler T, Las Fuentes L, Bentley A, Brown M, Kraja A, Schwander K, Ntalla I, Guo X, Franceschini N, Lu Y, Cheng CY, Sim X, Vojinovic D, Marten J, Musani S, Li C, Feitosa M, Kilpeläinen T, Richard M, Noordam R, Aslibekyan S, Aschard H, Bartz T, Dorajoo R, Liu Y, Manning A, Rankinen T, Smith AV, Tajuddin S, Tayo B, Warren H, Zhao W, Zhou Y, Matoba N, Sofer T, Alver M, Amini M, Boissel M, Chai JF, Chen X, Divers J, Gandin I, Gao C, Giulianini F, Goel A, Harris S, Hartwig FP, Horimoto A, Hsu FC, Jackson A, Kähönen M, Kasturiratne A, Kühnel B, Leander K, Lee WJ, Lin KH, Luan J, McKenzie C, Meian H, Nelson C, Rauramaa R, Schupf N, Scott R, Sheu W, Stančáková A, Takeuchi F, Most P, Varga T, Wang H, Wang Y, Ware E, Weiss S, Wen W, Yanek L, Zhang W, Zhao JH, Afaq S, Alfred T, Amin N, Arking D, Aung T, Barr G, Bielak L, Boerwinkle E, Bottinger E, Braund P, Brody J, Broeckel U, Cabrera C, Cade B, Caizheng Y, Campbell A, Canouil M, Chakravarti A, CHARGE Neurology Working Group, Chauhan G, Christensen K, Cocca M, COGENT-Kidney Consortium, Collins F, Connell J, Mutsert R, Silva J, Debette S, Dörr M, Duan Q, Eaton C, Ehret G, Evangelou E, Faul J, Fisher V, Forouhi N, Franco O, Friedlander Y, Gao H, GIANT Consortium, Gigante B, Graff M, Gu C, Gu D, Gupta P, Hagenaars S, Harris T, He J, Heikkinen S, Heng CK, Hirata M, Hofman A, Howard B, Hunt S, Irvin M, Jia Y, Joehanes R, Justice A, Katsuya T, Kaufman J, Kerrison N, Khor CC, Koh WP, Koistinen H, Komulainen P, Kooperberg C, Krieger J, Kubo M, Kuusisto J, Langefeld C, Langenberg C, Launer L, Lehne B, Lewis C, Li Y, LifeLines Cohort Study, Lim SH, Lin S, Liu CT, Liu J, Liu J, Liu K, Liu Y, Loh M, Lohman K, Long J, Louie T, Mägi R, Mahajan A, Meitinger T, Metspalu A, Milani L, Momozawa Y, Morris A, Mosley T, Munson P, Murray A, Nalls M, Nasri U, Norris J, North K, Ogunniyi A, Padmanabhan S, Palmas W, Palmer N, Pankow J, Pedersen N, Peters A, Peyser P, Polašek O, Raitakari O, Renström F, Rice T, Ridker P, Robino A, Robinson J, Rose L, Rudan I, Sabanayagam C, Salako B, Sandow K, Schmidt C, Schreiner P, Scott W, Seshadri S, Sever P, Sitlani C, Smith J, Snieder H, Starr J, Strauch K, Tang H, Taylor K, Teo YY, Tham YC, Uitterlinden A, Waldenberger M, Wang L, Wang Y, Wei WB, Williams C, Wilson G, Wojczynski M, Yao J, Yuan JM, Zonderman A, Becker D, Boehnke M, Bowden D, Chambers J, Chen YDI, Faire U, Deary I, Esko T, Farrall M, Forrester T, Franks P, Freedman B, Froguel P, Gasparini P, Gieger C, Horta BL, Hung YJ, Jonas J, Kato N, Kooner J, Laakso M, Lehtimäki T, Liang KW, Magnusson P, Newman A, Oldehinkel A, Pereira A, Redline S, Rettig R, Samani N, Scott J, Shu XO, Harst P, Wagenknecht L, Wareham N, Watkins H, Weir D, Wickremasinghe A, Wu T, Zheng W, Kamatani Y, Laurie C, Bouchard C, Cooper R, Evans M, Gudnason V, Kardia S, Kritchevsky S, Levy D, O’Connell J, Psaty B, Dam R, Sims M, Arnett D, Mook-Kanamori D, Kelly T, Fox E, Hayward C, Fornage M, Rotimi C, Province M, Duijn C, Tai S, Wong TY, Loos R, Reiner A, Rotter J, Zhu X, Bierut L, Gauderman J, Caulfield M, Elliott P, Rice K, Munroe P, Morrison A, Cupples A, Rao D, Chasman D. A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. Am J Hum Genet. 2018;102(3):375–400.
Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
Guhan S, Peng SL, Janbatian H, Saadeh S, Greenstein S, Al Bahrani F, Fadlallah A, Yeh TC, Melki S. Surgical adhesives in ophthalmology: history and current trends. Br J Ophthalmol. 2018;
Tissue adhesives are gaining popularity in ophthalmology, as they could potentially reduce the complications associated with current surgical methods. An ideal tissue adhesive should have superior tensile strength, be non-toxic and anti-inflammatory, improve efficiency and be cost-effective. Both synthetic and biological glues are available. The primary synthetic glues include cyanoacrylate and the recently introduced polyethylene glycol (PEG) derivatives, while most biological glues are composed of fibrin. Cyanoacrylate has a high tensile strength, but rapidly polymerises upon contact with any fluid and has been associated with histotoxicity. Fibrin induces less toxic and inflammatory reactions, and its polymerisation time can be controlled. Tensile strength studies have shown that fibrin is not as strong as cyanoacrylate. While more research is needed, PEG variants currently appear to have the most promise. These glues are non-toxic, strong and time-effective. Through MEDLINE and internet searches, this paper presents a systematic review of the current applications of surgical adhesives to corneal, glaucoma, retinal, cataract and strabismus surgeries. Our review suggests that surgical adhesives have promise to reduce problems in current ophthalmic surgical procedures.
Struebing F, King R, Li Y, Cooke Bailey J, NEIGHBORHOOD Consortium, Wiggs J, Geisert E. Genomic loci modulating retinal ganglion cell death following elevated IOP in the mouse. Exp Eye Res. 2018;169:61–67.
The present study was designed to identify genomic loci modulating the susceptibility of retinal ganglion cells (RGC) to elevated intraocular pressure (IOP) in the BXD recombinant inbred mouse strain set. IOP was elevated by injecting magnetic microspheres into the anterior chamber and blocking the trabecular meshwork using a handheld magnet to impede drainage. The IOP was then measured over the next 21 days. Only animals with IOP greater than 25 mmHg for two consecutive days or an IOP above 30 mmHg on a single day after microsphere-injection were used in this study. On day 21, mice were sacrificed and the optic nerve was processed for histology. Axons were counted for both the injected and the control eye in 49 BXD strains, totaling 181 normal counts and 191 counts associated with elevated IOP. The axon loss for each strain was calculated and the data were entered into genenetwork.org. The average number of normal axons in the optic nerve across all strains was 54,788 ± 16% (SD), which dropped to 49,545 ± 20% in animals with artificially elevated IOP. Interval mapping demonstrated a relatively similar genome-wide map for both conditions with a suggestive Quantitative Trait Locus (QTL) on proximal Chromosome 3. When the relative axon loss was used to generate a genome-wide interval map, we identified one significant QTL (p  0.05) on Chromosome 18 between 53.6 and 57 Mb. Within this region, the best candidate gene for modulating axon loss was Aldh7a1. Immunohistochemistry demonstrated ALDH7A1 expression in mouse RGCs. ALDH7A1 variants were not significantly associated with glaucoma in the NEIGHBORHOOD GWAS dataset, but this enzyme was identified as part of the butanoate pathway previously associated with glaucoma risk. Our results suggest that genomic background influences susceptibility to RGC degeneration and death in an inducible glaucoma model.
Shi L, Zhang N, Liu H, Zhao L, Liu J, Wan J, Wu W, Lei H, Liu R, Han M. Lysyl oxidase inhibition via β-aminoproprionitrile hampers human umbilical vein endothelial cell angiogenesis and migration in vitro. Mol Med Rep. 2018;17(4):5029–5036.
Lysyl oxidase (LOX) is an enzyme that oxidizes lysine residues in collagens and elastin. It stabilizes or remodels the extracellular matrix and basement membrane of blood vessels. Current oncology studies have revealed that LOX is upregulated in invasive cancer cells and bolstered cell movement, and LOX was observed to promote the angiogenesis and migration of endothelial cells. In the present study, angiogenesis and migration were examined in human umbilical vein endothelial cells (HUVECs). Following cell treatment with 0.1-0.4 mM β-aminoproprionitrile (BAPN), a specific inhibitor of LOX, angiogenesis was analyzed with a fibrin gel in vitro angiogenesis assay kit and migration was examined via a Boyden Chamber assay. Angiogenesis-associated gene expression was investigated with a microarray assay and confirmed with reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The results showed that HUVEC angiogenesis substantially increased in the presence of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and phorbol 12-myristate 13-acetate (PMA). In addition, LOX inhibition blocked the angiogenesis stimulated by VEGF bFGF and PMA, and the inhibition of LOX reduced the migration of HUVECs. Furthermore, the microarray and RT-qPCR revealed that BAPN downregulated myeloid progenitor inhibitory factor 1, and western blot analysis demonstrated that BAPN decreased the phosphorylation of MAPK and Akt, suggesting that the specific inhibitor of LOX, BAPN, may serve as an alternative strategy for preventing angiogenesis.
Wang M, Pasquale L, Shen L, Boland M, Wellik S, De Moraes CG, Myers J, Wang H, Baniasadi N, Li D, Silva RN, Bex P, Elze T. Reversal of Glaucoma Hemifield Test Results and Visual Field Features in Glaucoma. Ophthalmology. 2018;125(3):352–360.
PURPOSE: To develop a visual field (VF) feature model to predict the reversal of glaucoma hemifield test (GHT) results to within normal limits (WNL) after 2 consecutive outside normal limits (ONL) results. DESIGN: Retrospective cohort study. PARTICIPANTS: Visual fields of 44 503 eyes from 26 130 participants. METHODS: Eyes with 3 or more consecutive reliable VFs measured with the Humphrey Field Analyzer (Swedish interactive threshold algorithm standard 24-2) were included. Eyes with ONL GHT results for the 2 baseline VFs were selected. We extracted 3 categories of VF features from the baseline tests: (1) VF global indices (mean deviation [MD] and pattern standard deviation), (2) mismatch between baseline VFs, and (3) VF loss patterns (archetypes). Logistic regression was applied to predict the GHT results reversal. Cross-validation was applied to evaluate the model on testing data by the area under the receiver operating characteristic curve (AUC). We ascertained clinical glaucoma status on a patient subset (n = 97) to determine the usefulness of our model. MAIN OUTCOME MEASURES: Predictive models for GHT results reversal using VF features. RESULTS: For the 16 604 eyes with 2 initial ONL results, the prevalence of a subsequent WNL result increased from 0.1% for MD < -12 dB to 13.8% for MD ≥-3 dB. Compared with models with VF global indices, the AUC of predictive models increased from 0.669 (MD ≥-3 dB) and 0.697 (-6 dB ≤ MD < -3 dB) to 0.770 and 0.820, respectively, by adding VF mismatch features and computationally derived VF archetypes (P < 0.001 for both). The GHT results reversal was associated with a large mismatch between baseline VFs. Moreover, the GHT results reversal was associated more with VF archetypes of nonglaucomatous loss, severe widespread loss, and lens rim artifacts. For a subset of 97 eyes, using our model to predict absence of glaucoma based on clinical evidence after 2 ONL results yielded significantly better prediction accuracy (87.7%; P < 0.001) than predicting GHT results reversal (68.8%) with a prescribed specificity 67.7%. CONCLUSIONS: Using VF features may predict the GHT results reversal to WNL after 2 consecutive ONL results.
Hellgren G, Löfqvist C, Hansen-Pupp I, Gram M, Smith L, Ley D, Hellström A. Increased postnatal concentrations of pro-inflammatory cytokines are associated with reduced IGF-I levels and retinopathy of prematurity. Growth Horm IGF Res. 2018;39:19–24.
OBJECTIVE: Retinopathy of prematurity (ROP) is a multifactorial disease linked to low insulin-like growth factor (IGF)-I levels and perhaps to postnatal inflammation. Here, we investigated the longitudinal postnatal serum concentrations of pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α in relation to IGF-I levels and ROP. DESIGN: The study cohort included 52 infants born before 31 gestational weeks. The infants were screened for ROP and classified as non-ROP (n=33), non-proliferative ROP (stages 1 and 2; n=10), or proliferative ROP (stage 3, all treated for ROP; n=9). Blood samples were collected at birth, 24h after birth, and then weekly until at least 36weeks postmenstrual age (PMA) (i.e., up to 13weeks after birth). Circulating levels of IL-6 and TNF-α were evaluated in relation to circulating IGF-I levels and ROP. RESULTS: IL-6 levels negatively correlated with IGF-I levels between 5 and 8weeks after birth, (p<0.01 to p<0.05). At birth, the IL-6 and TNF-α levels were similar independent of later ROP. Twenty-four hours after birth, both IL-6 and TNF-α levels had increased in infants later treated for ROP (p<0.05). Postnatal, infants treated for ROP had higher IL-6 levels than infants without ROP. CONCLUSIONS: The pro-inflammatory response is associated with low IGF-I levels and the development of ROP.
Bourne R, Jonas J, Bron A, Cicinelli MV, Das A, Flaxman S, Friedman D, Keeffe J, Kempen J, Leasher J, Limburg H, Naidoo K, Pesudovs K, Peto T, Saadine J, Silvester A, Tahhan N, Taylor H, Varma R, Wong T, Resnikoff S, Study VLEGGBD. Prevalence and causes of vision loss in high-income countries and in Eastern and Central Europe in 2015: magnitude, temporal trends and projections. Br J Ophthalmol. 2018;102(5):575–585.
BACKGROUND: Within a surveillance of the prevalence and causes of vision impairment in high-income regions and Central/Eastern Europe, we update figures through 2015 and forecast expected values in 2020. METHODS: Based on a systematic review of medical literature, prevalence of blindness, moderate and severe vision impairment (MSVI), mild vision impairment and presbyopia was estimated for 1990, 2010, 2015, and 2020. RESULTS: Age-standardised prevalence of blindness and MSVI for all ages decreased from 1990 to 2015 from 0.26% (0.10-0.46) to 0.15% (0.06-0.26) and from 1.74% (0.76-2.94) to 1.27% (0.55-2.17), respectively. In 2015, the number of individuals affected by blindness, MSVI and mild vision impairment ranged from 70 000, 630 000 and 610 000, respectively, in Australasia to 980 000, 7.46 million and 7.25 million, respectively, in North America and 1.16 million, 9.61 million and 9.47 million, respectively, in Western Europe. In 2015, cataract was the most common cause for blindness, followed by age-related macular degeneration (AMD), glaucoma, uncorrected refractive error, diabetic retinopathy and cornea-related disorders, with declining burden from cataract and AMD over time. Uncorrected refractive error was the leading cause of MSVI. CONCLUSIONS: While continuing to advance control of cataract and AMD as the leading causes of blindness remains a high priority, overcoming barriers to uptake of refractive error services would address approximately half of the MSVI burden. New data on burden of presbyopia identify this entity as an important public health problem in this population. Additional research on better treatments, better implementation with existing tools and ongoing surveillance of the problem is needed.