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2018

Sahu S, Mittal S, Foulsham W, Li M, Sangwan V, Chauhan S. Mast Cells Initiate the Recruitment of Neutrophils Following Ocular Surface Injury. Invest Ophthalmol Vis Sci. 2018;59(5):1732–1740.
Purpose: The purpose of this study was to investigate the contribution of mast cells to early neutrophil recruitment during ocular inflammation. Methods: In a murine model of corneal injury, the epithelium and anterior stroma were removed using a handheld motor brush. Cromolyn sodium (2% in PBS) eye drops were administered topically for mast cell inhibition. In vitro, bone marrow-derived mast cells were cultured alone or with corneal tissue. The frequencies of CD45+ inflammatory cells, CD11b+Ly6G+ neutrophils, and ckit+FcεR1+ mast cells in the cornea were assessed by flow cytometry. mRNA expression of CXCL2 was evaluated by real-time PCR and protein expression by ELISA. β-Hexosaminidase assays were performed to gauge mast cell activation. Results: Neutrophil infiltration of the cornea was observed within 1 hour of injury, with neutrophil frequencies increasing over subsequent hours. Concurrent expansion of mast cell frequencies at the cornea were observed, with mast cell activation (assessed by β-hexosaminidase levels) peaking at 6 hours after injury. Evaluation of CXCL2 mRNA and protein expression levels demonstrated augmented expression by injured corneal tissue relative to naïve corneal tissue. Mast cells were observed to constitutively express CXCL2, with significantly higher expression of CXCL2 protein compared with naïve corneal tissue. Culture with harvested injured corneas further amplified CXCL2 expression by mast cells. In vivo, mast cell inhibition was observed to decrease CXCL2 expression, limit early neutrophil infiltration, and reduce inflammatory cytokine expression by the cornea. Conclusions: Our data suggest that mast cell activation after corneal injury amplifies their secretion of CXCL2 and promotes the initiation of early neutrophil recruitment.
Kim W, Zhu W, Hendricks GL, Van Tyne D, Steele A, Keohane C, Fricke N, Conery A, Shen S, Pan W, Lee K, Rajamuthiah R, Fuchs BB, Vlahovska P, Wuest W, Gilmore M, Gao H, Ausubel F, Mylonakis E. A new class of synthetic retinoid antibiotics effective against bacterial persisters. Nature. 2018;556(7699):103–107.
A challenge in the treatment of Staphylococcus aureus infections is the high prevalence of methicillin-resistant S. aureus (MRSA) strains and the formation of non-growing, dormant 'persister' subpopulations that exhibit high levels of tolerance to antibiotics and have a role in chronic or recurrent infections. As conventional antibiotics are not effective in the treatment of infections caused by such bacteria, novel antibacterial therapeutics are urgently required. Here we used a Caenorhabditis elegans-MRSA infection screen to identify two synthetic retinoids, CD437 and CD1530, which kill both growing and persister MRSA cells by disrupting lipid bilayers. CD437 and CD1530 exhibit high killing rates, synergism with gentamicin, and a low probability of resistance selection. All-atom molecular dynamics simulations demonstrated that the ability of retinoids to penetrate and embed in lipid bilayers correlates with their bactericidal ability. An analogue of CD437 was found to retain anti-persister activity and show an improved cytotoxicity profile. Both CD437 and this analogue, alone or in combination with gentamicin, exhibit considerable efficacy in a mouse model of chronic MRSA infection. With further development and optimization, synthetic retinoids have the potential to become a new class of antimicrobials for the treatment of Gram-positive bacterial infections that are currently difficult to cure.
Amparo F, Dana R. Web-based longitudinal remote assessment of dry eye symptoms. Ocul Surf. 2018;16(2):249–253.
PURPOSE: To investigate the feasibility of remote assessment and follow-up of dry eye symptoms using electronic versions of two validated questionnaires. METHODS: We conducted a prospective study of consecutive patients with dry eye disease (DED). Patients were enrolled during a clinical visit and were explained how to respond electronic versions of the Ocular surface Disease Index (OSDI) and the Symptom Assessment in Dry Eye (SANDE) questionnaires using a computer in the presence of investigators. A secure link to both questionnaires was sent to each patient every 2 weeks in order to respond and submit their symptoms over a 3-month period. We analyzed the number of patients who responded to both questionnaires, the recurrence, and the symptoms scores reported. RESULTS: A total of 1121 questionnaires were collected; 103 patients (85%) reported their symptoms at least once during the 3-month study duration. The majority of participants who completed the study (71.6%) responded remotely at least once per month during the 3-month duration of the study. The mean OSDI and SANDE scores from the total of remote evaluations were 34.9 ± 21.9 (range 0-97.5) and 50.3 ± 24.9 (range 0-100), respectively. There was a statistically significant correlation between the total scores collected with the two questionnaires (R = 0.67, P < 0.001). CONCLUSIONS: Patients are motivated to report DED symptoms while away from the clinic. Distance-based evaluation of DED symptoms is both feasible and convenient, and can be implemented to follow symptoms in large populations with chronic dry eye.
Foulsham W, Coco G, Amouzegar A, Chauhan S, Dana R. When Clarity Is Crucial: Regulating Ocular Surface Immunity. Trends Immunol. 2018;39(4):288–301.
The ocular surface is a unique mucosal immune compartment in which anatomical, physiological, and immunological features act in concert to foster a particularly tolerant microenvironment. These mechanisms are vital to the functional competence of the eye, a fact underscored by the devastating toll of excessive inflammation at the cornea - blindness. Recent data have elucidated the contributions of specific anatomical components, immune cells, and soluble immunoregulatory factors in promoting homeostasis at the ocular surface. We highlight research trends at this distinctive mucosal barrier and identify crucial gaps in our current knowledge.
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.