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202. Genetic Analysis of 'PAX6-Negative' Individuals with Aniridia or Gillespie Syndrome

Author

Ansari, Morad, Rainger, Jacqueline, Hanson, Isabel M, Williamson, Kathleen A, Sharkey, Freddie, Harewood, Louise, Sandilands, Angela, Clayton-Smith, Jill, Dollfus, Helene, Bitoun, Pierre, Meire, Francoise, Fantes, Judy, Franco, Brunella, Lorenz, Birgit, Taylor, David S, Stewart, Fiona, Willoughby, Colin E, McEntagart, Meriel, Khaw, Peng Tee, Clericuzio, Carol, Van Maldergem, Lionel, Williams, Denise, Newbury-Ecob, Ruth, Traboulsi, Elias I, Silva, Eduardo D, Madlom, Mukhlis M, Goudie, David R, Fleck, Brian W, Wieczorek, Dagmar, Kohlhase, Juergen, McTrusty, Alice D, Gardiner, Carol, Yale, Christopher, Moore, Anthony T, Russell-Eggitt, Isabelle, Islam, Lily, Lees, Melissa, Beales, Philip L, Tuft, Stephen J, Solano, Juan B, Splitt, Miranda, Hertz, Jens Michael, Prescott, Trine E, Shears, Deborah J, Nischal, Ken K, Doco-Fenzy, Martine, Prieur, Fabienne, Temple, I Karen, Lachlan, Katherine L, Damante, Giuseppe, Morrison, Danny A, van Heyningen, Veronica, FitzPatrick, David R, Ansari, Morad, Rainger, Jacqueline, Hanson, Isabel M., Williamson, Kathleen A., Sharkey, Freddie, Harewood, Louise, Sandilands, Angela, Clayton Smith, Jill, Dollfus, Helene, Bitoun, Pierre, Meire, Francoise, Fantes, Judy, Franco, Brunella, Lorenz, Birgit, Taylor, David S., Stewart, Fiona, Willoughby, Colin E., Mcentagart, Meriel, Khaw, Peng Tee, Clericuzio, Carol, Van Maldergem, Lionel, Williams, Denise, Newbury Ecob, Ruth, Traboulsi, Elias I., Silva, Eduardo D., Madlom, Mukhlis M., Goudie, David R., Fleck, Brian W., Wieczorek, Dagmar, Kohlhase, Juergen, Mctrusty, Alice D., Gardiner, Carol, Yale, Christopher, Moore, Anthony T., Russell Eggitt, Isabelle, Islam, Lily, Lees, Melissa, Beales, Philip L., Tuft, Stephen J., Solano, Juan B., Splitt, Miranda, Hertz, Jens Michael, Prescott, Trine E., Shears, Deborah J., Nischal, Ken K., Doco Fenzy, Martine, Prieur, Fabienne, Temple, I. Karen, Lachlan, Katherine L., Damante, Giuseppe, Morrison, Danny A., Van Heyningen, Veronica, and Fitzpatrick, David R.

Subjects
Male, Genetics and Molecular Biology (all), Eye Diseases, PAX6 Transcription Factor, Mutagenesis and Gene Deletion Techniques, Gene Identification and Analysis, Iris, lcsh:Medicine, Artificial Gene Amplification and Extension, Polymerase Chain Reaction, Biochemistry, axenfeld-rieger syndrome gtpase-activating protein linear skin defects cerebellar-ataxia mental-retardation pax6 gene missense mutations impaired accommodation pitx2 mutations phenotype Science & Technology - Other Topics, Medicine and Health Sciences, Pair 11, lcsh:Science, Aniridia, Comparative Genomic Hybridization, Medicine (all), GTPase-Activating Proteins, Forkhead Transcription Factors, Genomics, Deletion Mutation, Female, Anatomy, Research Article, Human, congenital, hereditary, and neonatal diseases and abnormalities, Cerebellar Ataxia, Ocular Anatomy, Research and Analysis Methods, Human Genomics, Chromosomes, Histone Deacetylases, Ocular System, Intellectual Disability, Genetics, Humans, Genetic Testing, Molecular Biology Techniques, Molecular Biology, Mutation Detection, Homeodomain Proteins, Chromosomes, Human, X, Biochemistry, Genetics and Molecular Biology (all), Chromosomes, Human, Pair 11, lcsh:R, Biology and Life Sciences, Glaucoma, Mutation, Transcription Factors, Agricultural and Biological Sciences (all), eye diseases, Ophthalmology, Mutational Analysis, Genetic Loci, lcsh:Q, sense organs
Abstract

We report molecular genetic analysis of 42 affected individuals referred with a diagnosis of aniridia who previously screened as negative for intragenic PAX6 mutations. Of these 42, the diagnoses were 31 individuals with aniridia and 11 individuals referred with a diagnosis of Gillespie syndrome (iris hypoplasia, ataxia and mild to moderate developmental delay). Array-based comparative genomic hybridization identified six whole gene deletions: four encompassing PAX6 and two encompassing FOXC1. Six deletions with plausible cis-regulatory effects were identified: five that were 3′ (telomeric) to PAX6 and one within a gene desert 5′ (telomeric) to PITX2. Sequence analysis of the FOXC1 and PITX2 coding regions identified two plausibly pathogenic de novo FOXC1 missense mutations (p.Pro79Thr and p. Leu101Pro). No intragenic mutations were detected in PITX2. FISH mapping in an individual with Gillespie-like syndrome with an apparently balanced X;11 reciprocal translocation revealed disruption of a gene at each breakpoint: ARHGAP6 on the X chromosome and PHF21A on chromosome 11. In the other individuals with Gillespie syndrome no mutations were identified in either of these genes, or in HCCS which lies close to the Xp breakpoint. Disruption of PHF21A has previously been implicated in the causation of intellectual disability (but not aniridia). Plausibly causative mutations were identified in 15 out of 42 individuals (12/32 aniridia; 3/11 Gillespie syndrome). Fourteen of these mutations presented in the known aniridia genes; PAX6, FOXC1 and PITX2. The large number of individuals in the cohort with no mutation identified suggests greater locus heterogeneity may exist in both isolated and syndromic aniridia than was previously appreciated.

Published
2016

203. In vitro and in vivo delivery of a sustained release nanocarrier-based formulation of an MRTF/SRF inhibitor in conjunctival fibrosis

Author

Tagalakis, Aristides, Madaan, Shivam, Larsen, Scott D., Neubig, Richard R., Khaw, Peng T., Yu-Wai-Man, Cynthia, Tagalakis, Aristides, Madaan, Shivam, Larsen, Scott D., Neubig, Richard R., Khaw, Peng T., and Yu-Wai-Man, Cynthia

Abstract

Background: Sustained drug delivery is a great unmet clinical need in glaucoma. Here, we incorporated a Myocardin-Related Transcription Factor/Serum Response Factor inhibitor, CCG-222740, into slow release large unilamellar vesicles derived from the liposomes DOTMA (1,2-di-O-octadecenyl-3-trimethylammonium propane) and DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), and tested their effects in vitro and in vivo. Results: The vesicles were spherical particles of around 130 nm and were strongly cationic. A large amount of inhibitor could be incorporated into the vesicles. We showed that the nanocarrier CCG-222740 formulation gradually released the inhibitor over 14 days using high performance liquid chromatography. Nanocarrier CCG-222740 significantly decreased ACTA2 gene expression and was not cytotoxic in human conjunctival fibroblasts. In vivo, nanocarrier CCG-222740 doubled the bleb survival from 11.0 ± 0.6 days to 22.0 ± 1.3 days (p = 0.001), decreased conjunctival scarring and did not have any local or systemic adverse effects in a rabbit model of glaucoma filtration surgery. Conclusions: Our study demonstrates proof-of-concept that a nanocarrier-based formulation efficiently achieves a sustained release of a Myocardin-Related Transcription Factor/Serum Response Factor inhibitor and prevents conjunctival fibrosis in an established rabbit model of glaucoma filtration surgery.

Published
2018

208. Translating Minimally Invasive Glaucoma Surgery Devices.

Author

Lee, Richard M.H., Bouremel, Yann, Eames, Ian, Brocchini, Steve, and Khaw, Peng Tee

Subjects
MINIMALLY invasive procedures, OCULAR hypotony, TRABECULAR meshwork (Eye), INTRAOCULAR pressure, ARTIFICIAL implants, GLAUCOMA surgery, HUMAN body, SURGICAL robots
Abstract

Glaucoma is the leading cause of irreversible blindness with over 70 million people affected worldwide. The surgical management of glaucoma aims to lower intraocular pressure by increasing aqueous outflow facility. The latest manufacturing techniques have allowed for the development of a number of novel implantable devices to improve safety and outcomes of glaucoma surgery. These are collectively referred to as minimally invasive glaucoma surgery (MIGS) devices and are among the smallest devices implanted in the human body. This review discusses the design criterion and constraints as well as the user requirements for MIGS devices. We review how recent devices have attempted to meet these challenges and give our opinion as to the necessary characteristics for the development of future devices. [ABSTRACT FROM AUTHOR]

Published
2020
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217. Surgery versus epilation for the treatment of minor trichiasis in ethiopia: a randomised controlled noninferiority trial

Author

Rajak, Saul N., Habtamu, Esmael, Weiss, Helen A., Kello, Amir Bedri, Gebre, Teshome, Genet, Asrat, Bailey, Robin L., Mabey, David C.W., Khaw, Peng T., Gilbert, Clare E., Emerson, Paul M., and Burton, Matthew J.

Subjects
Trachoma -- Diagnosis -- Care and treatment -- Research, Surgery -- Health aspects, Biological sciences
Abstract

Background: Trachomatous trichiasis can cause corneal damage and visual impairment. WHO recommends surgery for all cases. However, in many regions surgical provision is inadequate and patients frequently decline. Self-epilation is common and was associated with comparable outcomes to surgery in nonrandomised studies for minor trichiasis ( Methods and Findings: 1,300 individuals with minor trichiasis from Amhara Regional State, Ethiopia were recruited and randomly assigned (1:1) to receive trichiasis surgery or epilation. The epilation group were given new forceps and epilation training. The surgical group received trichiasis surgery. Participants were examined every 6 months for 2 years by clinicians masked to allocation, with 93.5% follow-up at 24 months. The primary outcome measure ('failure') was ≥ five lashes touching the eye or receiving trichiasis surgery during 24 months of follow-up, and was assessed for noninferiority with a 10% prespecified noninferiority margin. Secondary outcomes included number of lashes touching, time to failure, and changes in visual acuity and corneal opacity. Cumulative risk of failure over 24 months was 13.2% in the epilation group and 2.2% in the surgical group (risk difference = 11%). The 95% confidence interval (8.1%-13.9%) includes the 10% noninferiority margin. Mean number of lashes touching the eye was greater in the epilation group than the surgery group (at 24 months 0.95 versus 0.09, respectively; p Conclusions: This trial was inconclusive regarding inferiority of epilation to surgery for the treatment of minor trichiasis, relative to the prespecified margin. Epilation had a comparable effect to surgery on visual acuity and corneal outcomes. We suggest that surgery be performed whenever possible but epilation be used for treatment of minor trichiasis patients without access to or declining surgery. Trial registration: http://ClinicalTrials.gov NCT00522912 Please see later in the article for the Editors' Summary., Introduction Trachoma is the leading infectious cause of blindness worldwide [1]. Recurrent episodes of ocular Chlamydia trachomatis infection in early childhood provoke chronic conjunctival inflammation (active trachoma). This inflammation can [...]

Published
2011
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218. Absorbable versus silk sutures for surgical treatment of trachomatous trichiasis in ethiopia: a randomised controlled trial

Author

Rajak, Saul N., Habtamu, Esmael, Weiss, Helen A., Kello, Amir Bedri, Gebre, Teshome, Genet, Asrat, Bailey, Robin L., Mabey, David C.W., Khaw, Peng T., Gilbert, Clare E., Emerson, Paul M., and Burton, Matthew J.

Subjects
Blindness -- Research -- Care and treatment -- Diagnosis, Prevalence studies (Epidemiology) -- Usage, Biological sciences
Abstract

Background: Trachoma causes blindness through an anatomical abnormality called trichiasis (lashes touching the eye). Trichiasis can recur after corrective surgery. We tested the hypothesis that using absorbable sutures instead of silk sutures might reduce the risk of recurrent disease among patients with major trichiasis in a randomised trial. Methods and Findings: 1,300 individuals with major trichiasis from rural villages in the Amhara Region of Ethiopia were recruited and assigned (1:1) by computer-generated randomisation sequence to receive trichiasis surgery using either an absorbable suture (polyglactin-910) or silk sutures (removed at 7-10 days) in an otherwise identical surgical technique. Participants were examined every 6 months for 2 years by clinicians masked to allocation. The primary outcome measure was recurrent trichiasis ([greater than or equal to] one lash touching the eye) at 1 year. There was no difference in prevalence of recurrent trichiasis at 1 year (114 [18.2%] in the absorbable suture group versus 120 [19.7%] in the silk suture group;odds ratio = 0.90, 95% CI 0.68-1.20). The two groups also did not differ in terms of corneal opacification, visual acuity, conjunctival inflammation, and surgical complications. Conclusions: There was no evidence that use of absorbable polyglactin-910 sutures was associated with a lower prevalence of trichiasis recurrence at 1 year postsurgery than silk sutures. However, from a programmatic perspective, polyglactin-910 offers the major advantage that patients do not have to be seen soon after surgery for suture removal. The postoperative review after surgery using absorbable polyglactin-910 sutures can be delayed for 3-6 months, which might allow us to better determine whether a patient needs additional surgery. Trial registration: http://ClinicalTrials.gov NCT00522860 Please see later in the article for the Editors' Summary., Introduction Trachoma is the leading infectious cause of blindness worldwide [1]. Recurrent episodes of ocular Chlamydia trachomatis infection in early childhood provoke chronic conjunctival inflammation (active trachoma). This inflammation leads [...]

Published
2011
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219. IL-6 and PRG4 are novel predictive and mechanistic tissue biomarkers in conjunctival fibrosis

Author

Yu-Wai-Man, Cynthia, Tagalakis, Aristides, Meng, Jinhong, Lee, Richard M H., Bouremel, Yann, Virasami, Alex, Hart, Stephen L., Khaw, Peng T., Yu-Wai-Man, Cynthia, Tagalakis, Aristides, Meng, Jinhong, Lee, Richard M H., Bouremel, Yann, Virasami, Alex, Hart, Stephen L., and Khaw, Peng T.

Abstract

IMPORTANCE: Postsurgical fibrosis is a critical determinant of the long-term success of glaucoma surgery, but no reliable biomarkers are currently available to stratify the risk of scarring. OBJECTIVE: To compare the clinical phenotype of patients with conjunctival fibrosis after glaucoma surgery with candidate gene expression tissue biomarkers of fibrosis. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, 42 patients were recruited at the time of glaucoma surgery at the Moorfields Eye Hospital from September 1, 2014, to September 1, 2016. The participants were divided into those with fibrosis and those without fibrosis. MAIN OUTCOMES AND MEASURES: Genotype-phenotype correlations of the IL6 or PRG4 gene and detailed clinical phenotype. The IL6 and PRG4 protein expression in conjunctival tissues was also assessed using in situ immunohistochemical analysis. Central bleb area, maximal bleb area, and bleb height were graded on a scale of 1 to 5 (1 indicating 0%; 2, 25%; 3, 50%; 4, 75%; and 5, 100%). Bleb vascularity was graded on a scale of 1 to 5 (1 indicating avascularity; 2, normal; 3, mild; 4, moderate; and 5, severe hyperemia). RESULTS: A total of 42 patients were recruited during the study period; 28 participants (67%) had previously undergone glaucoma surgery (fibrotic group) (mean [SD] age, 43.8 [3.6 years]; 16 [57%] female; 22 [79%] white), and 14 participants (33%) had not previously undergone glaucoma surgery (nonfibrotic group) (mean [SD] age, 47.7 [6.9] years; 4 [29%] female; 9 [64%] white). The fibrotic group had marked bleb scarring and vascularization and worse logMAR visual acuity. The mean (SD) grades were 1.4 (0.1) for central bleb area, 1.4 (0.1) for bleb height, and 3.4 (0.2) for bleb vascularity. The IL6 gene was upregulated in fibrotic cell lines (mean, 0.040) compared with nonfibrotic cell lines (mean, 0.011) (difference, 0.029; 95% CI, 0.015-0.043; P = .003). The PRG4 gene was also downregulated in fibrotic cell lines (0.002) com

Published
2017

220. Genome-wide RNA-Sequencing analysis reveals a distinct fibrosis gene signature in the conjunctiva after glaucoma surgery

Author

Yu-Wai-Man, Cynthia, Owen, Nicholas, Lees, Jonathan, Tagalakis, Aristides, Hart, Stephen L., Brocchini, S, Orengo, Christine, A., Khaw, Peng T., Yu-Wai-Man, Cynthia, Owen, Nicholas, Lees, Jonathan, Tagalakis, Aristides, Hart, Stephen L., Brocchini, S, Orengo, Christine, A., and Khaw, Peng T.

Abstract

Fibrosis-related events play a part in most blinding diseases worldwide. However, little is known about the mechanisms driving this complex multifactorial disease. Here we have carried out the first genome-wide RNA-Sequencing study in human conjunctival fibrosis. We isolated 10 primary fibrotic and 7 non-fibrotic conjunctival fibroblast cell lines from patients with and without previous glaucoma surgery, respectively. The patients were matched for ethnicity and age. We identified 246 genes that were differentially expressed by over two-fold and p < 0.05, of which 46 genes were upregulated and 200 genes were downregulated in the fibrotic cell lines compared to the non-fibrotic cell lines. We also carried out detailed gene ontology, KEGG, disease association, pathway commons, WikiPathways and protein network analyses, and identified distinct pathways linked to smooth muscle contraction, inflammatory cytokines, immune mediators, extracellular matrix proteins and oncogene expression. We further validated 11 genes that were highly upregulated or downregulated using real-time quantitative PCR and found a strong correlation between the RNA-Seq and qPCR results. Our study demonstrates that there is a distinct fibrosis gene signature in the conjunctiva after glaucoma surgery and provides new insights into the mechanistic pathways driving the complex fibrotic process in the eye and other tissues.

Published
2017

222. Associations with Intraocular Pressure in a Large Cohort:Results from the UK Biobank

Author

Chan, Michelle P Y, Grossi, Carlota M, Khawaja, Anthony P, Yip, Jennifer L Y, Khaw, Kay-Tee, Patel, Praveen J, Khaw, Peng T, Morgan, James E, Vernon, Stephen A, and Foster, Paul J

Subjects
Adult, Male, Aging, genetic structures, Databases, Factual, National Health Programs, Research Support, Non-U.S. Gov't, Blood Pressure, Middle Aged, Refraction, Ocular, United Kingdom, Body Mass Index, Cohort Studies, Cornea, Multicenter Study, Tonometry, Ocular, Cross-Sectional Studies, Heart Rate, Surveys and Questionnaires, Journal Article, Humans, Female, Prospective Studies, Intraocular Pressure, Aged
Abstract

PURPOSE: To describe the associations of physical and demographic factors with Goldmann-correlated intraocular pressure (IOPg) and corneal-compensated intraocular pressure (IOPcc) in a British cohort.DESIGN: Cross-sectional study within the UK Biobank, a large-scale multisite cohort study in the United Kingdom.PARTICIPANTS: We included 110 573 participants from the UK Biobank with intraocular pressure (IOP) measurements available. Their mean age was 57 years (range, 40-69 years); 54% were women, and 90% were white.METHODS: Participants had 1 IOP measurement made on each eye using the Ocular Response Analyzer noncontact tonometer. Linear regression models were used to assess the associations of IOP with physical and demographic factors.MAIN OUTCOME MEASURES: The IOPg and IOPcc.RESULTS: The mean IOPg was 15.72 mmHg (95% confidence interval [CI], 15.70-15.74 mmHg), and the mean IOPcc was 15.95 mmHg (15.92-15.97 mmHg). After adjusting for covariates, IOPg and IOPcc were both significantly associated with older age, male sex, higher systolic blood pressure (SBP), faster heart rate, greater myopia, self-reported glaucoma, and colder season (all P < 0.001). The strongest determinants of both IOPg and IOPcc were SBP (partial R(2): IOPg 2.30%, IOPcc 2.26%), followed by refractive error (IOPg 0.60%, IOPcc 1.04%). The following variables had different directions of association with IOPg and IOPcc: height (-0.77 mmHg/m IOPg; 1.03 mmHg/m IOPcc), smoking (0.19 mmHg IOPg, -0.35 mmHg IOPcc), self-reported diabetes (0.41 mmHg IOPg, -0.05 mmHg IOPcc), and black ethnicity (-0.80 mmHg IOPg, 0.77 mmHg IOPcc). This suggests that height, smoking, diabetes, and ethnicity are related to corneal biomechanical properties. The increase in both IOPg and IOPcc with age was greatest among those of mixed ethnicities, followed by blacks and whites. The same set of covariates explained 7.4% of the variability of IOPcc but only 5.3% of the variability of IOPg.CONCLUSIONS: This analysis of associations with IOP in a large cohort demonstrated that some variables clearly have different associations with IOPg and IOPcc, and that these 2 measurements may reflect different biological characteristics.

Published
2016

223. Study of Optimal Perimetric Testing In Children (OPTIC): developing consensus and setting research priorities for perimetry in the management of children with glaucoma

Author

Patel, Dipesh E., Cumberland, Phillippa M., Walters, Bronwen C., Abbott, Joseph, Brookes, John, Edmunds, Beth, Khaw, Peng Tee, Lloyd, Ian Christopher, Papadopoulos, Maria, Sung, Velota, Cortina-Borja, Mario, and Rahi, Jugnoo S.

Abstract

Background: Perimetry is important in the management of children with glaucoma, but there is limited evidence-based guidance on its use. We report an expert consensus-based study to update guidance and identify areas requiring further research. Methods: Experts were invited to participate in a modified Delphi consensus process. Panel selection was based on clinical experience of managing children with glaucoma and UK-based training to minimise diversity of view due to healthcare setting. Questionnaires were delivered electronically, and analysed to establish ‘agreement’. Divergence of opinions was investigated and resolved where possible through further iterations. Results: 7/9 experts invited agreed to participate. Consensus (≥5/7 (71%) in agreement) was achieved for 21/26 (80.8%) items in 2 rounds, generating recommendations to start perimetry from approximately 7 years of age (IQR: 6.75–7.25), and use qualitative methods in conjunction with automated reliability indices to assess test quality. There was a lack of agreement about defining progressive visual field (VF) loss and methods for implementing perimetry longitudinally. Conclusions: There is commonality of expert views in relation to implementing perimetry and interpreting test quality in the management of children with glaucoma. However, there remains a lack of agreement about defining progressive VF loss, and utilising perimetry over an individuals’ lifetime, highlighting the need for further research.

Published
2021
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232. Pathogenesis of Progressive Scarring Trachoma in Ethiopia and Tanzania and Its Implications for Disease Control: Two Cohort Studies

Author

Burton, Matthew J, Rajak, Saul N, Hu, Victor H, Ramadhani, Athumani, Habtamu, Esmael, Massae, Patrick, Tadesse, Zerihun, Callahan, Kelly, Emerson, Paul M, Khaw, Peng T, Jeffries, David, Mabey, David CW, Bailey, Robin L, Weiss, Helen A, and Holland, Martin J

Subjects
Adult, Male, Trichiasis, lcsh:Arctic medicine. Tropical medicine, lcsh:RC955-962, Chlamydia trachomatis, Blindness, GPI-Linked Proteins, Polymerase Chain Reaction, Tanzania, S100 Calcium Binding Protein A7, Cohort Studies, Cicatrix, Humans, Inflammation, Trachoma, lcsh:Public aspects of medicine, Interleukin-17, S100 Proteins, Connective Tissue Growth Factor, lcsh:RA1-1270, Middle Aged, Carcinoembryonic Antigen, Matrix Metalloproteinase 7, Disease Progression, Cytokines, Female, Ethiopia, Conjunctiva, Research Article
Abstract

Background Trachoma causes blindness through a conjunctival scarring process initiated by ocular Chlamydia trachomatis infection; however, the rates, drivers and pathophysiological determinants are poorly understood. We investigated progressive scarring and its relationship to conjunctival infection, inflammation and transcript levels of cytokines and fibrogenic factors. Methodology/Principal Findings We recruited two cohorts, one each in Ethiopia and Tanzania, of individuals with established trachomatous conjunctival scarring. They were followed six-monthly for two years, with clinical examinations and conjunctival swab sample collection. Progressive scarring cases were identified by comparing baseline and two-year photographs, and compared to individuals without progression. Samples were tested for C. trachomatis by PCR and transcript levels of S100A7, IL1B, IL13, IL17A, CXCL5, CTGF, SPARCL1, CEACAM5, MMP7, MMP9 and CD83 were estimated by quantitative RT-PCR. Progressive scarring was found in 135/585 (23.1%) of Ethiopian participants and 173/577 (30.0%) of Tanzanian participants. There was a strong relationship between progressive scarring and increasing inflammatory episodes (Ethiopia: OR 5.93, 95%CI 3.31–10.6, p, Author Summary Blinding trachoma is believed to be the end result of a long-term progressive scarring process that is initiated by recurrent infection by the bacterium Chlamydia trachomatis starting in childhood. Scar tissue predominantly develops on the inner surface of the upper eyelids (conjunctiva). However, the rates, drivers and pathophysiological determinants are poorly understood. We investigated progressive scarring and its relationship to conjunctival infection, inflammation and transcript levels of cytokines and fibrogenic factors in two cohorts of adults in Tanzania and Ethiopia. These groups of people already had a degree of scarring and were regularly followed-up with over a two-year period. We found scarring progressed in about a quarter of people over this time. The progression was closely associated with episodes of conjunctival inflammation but not to the detection of C. trachomatis infection. This raises uncertainty about the primary drivers of late-stage trachoma. Chronic conjunctival inflammation appears to be central and is associated with enriched expression of pro-inflammatory factors and altered expression of extracellular matrix regulators. Host determinants of scarring progression appear more complex and subtle than the features of inflammation. Overall this indicates the likely need for trichiasis disease surveillance and surgery long after chlamydial infection has been controlled at community level.

Published
2015

233. Epilation for minor trachomatous trichiasis: four-year results of a randomised controlled trial

Author

Habtamu, Esmael, Rajak, Saul N, Tadesse, Zerihun, Wondie, Tariku, Zerihun, Mulat, Guadie, Birhan, Gebre, Teshome, Kello, Amir Bedri, Callahan, Kelly, Mabey, David CW, Khaw, Peng T, Gilbert, Clare E, Weiss, Helen A, Emerson, Paul M, and Burton, Matthew J

Subjects
lcsh:Arctic medicine. Tropical medicine, lcsh:RC955-962, lcsh:Public aspects of medicine, lcsh:RA1-1270
Abstract

BACKGROUND: Trachomatous trichiasis (TT) needs to be managed to reduce the risk of vision loss. The long-term impact of epilation (a common traditional practice of repeated plucking of lashes touching the eye) in preventing visual impairment and corneal opacity from TT is unknown. We conducted a randomized controlled trial of epilation versus surgery for the management of minor TT (fewer than six lashes touching the eye) in Ethiopia. Here we report the four-year outcome and the effect on vision and corneal opacity. METHODOLOGY/ PRINCIPAL FINDINGS: 1300 individuals with minor TT were recruited and randomly assigned to quality trichiasis surgery or repeated epilation using high quality epilation forceps by a trained person with good near vision. Participants were examined six-monthly for two-years, and then at four-years after randomisation. At two-years all epilation arm participants were offered free surgery. At four-years 1151 (88.5%) were re-examined: 572 (88%) and 579 (89%) from epilation and surgery arms, respectively. At that time, 21.1% of the surgery arm participants had recurrent TT; 189/572 (33%) of the epilation arm had received surgery, while 383 (67%) declined surgery and had continued epilating ("epilation-only"). Among the epilation-only group, 207 (54.1%) fully controlled their TT, 166 (43.3%) had minor TT and 10 (2.6%) had major TT (>5 lashes). There were no differences between participants in the epilation-only, epilation-to-surgery and surgery arm participants in changes in visual acuity and corneal opacity between baseline and four-years. CONCLUSIONS/ SIGNIFICANCE: Most minor TT participants randomised to the epilation arm continued epilating and controlled their TT. Change in vision and corneal opacity was comparable between surgery and epilation-only participants. This suggests that good quality epilation with regular follow-up is a reasonable second-line alternative to surgery for minor TT for individuals who either decline surgery or do not have immediate access to surgical treatment.

Published
2015

234. Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia

Author

Hysi, Pirro G., Choquet, Hélène, Khawaja, Anthony P., Wojciechowski, Robert, Tedja, Milly S., Yin, Jie, Simcoe, Mark J., Patasova, Karina, Mahroo, Omar A., Thai, Khanh K., Cumberland, Phillippa M., Melles, Ronald B., Verhoeven, Virginie J. M., Vitart, Veronique, Segre, Ayellet, Stone, Richard A., Wareham, Nick, Hewitt, Alex W., Mackey, David A., Klaver, Caroline C. W., MacGregor, Stuart, Khaw, Peng T., Foster, Paul J., Guggenheim, Jeremy A., Rahi, Jugnoo S., Jorgenson, Eric, and Hammond, Christopher J.

Abstract

Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (area under the curve (AUC) = 0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may enable the prediction of refractive error and the development of personalized myopia prevention strategies in the future.

Published
2020
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235. Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression

Author

Craig, Jamie E., Han, Xikun, Qassim, Ayub, Hassall, Mark, Cooke Bailey, Jessica N., Kinzy, Tyler G., Khawaja, Anthony P., An, Jiyuan, Marshall, Henry, Gharahkhani, Puya, Igo, Robert P., Graham, Stuart L., Healey, Paul R., Ong, Jue-Sheng, Zhou, Tiger, Siggs, Owen, Law, Matthew H., Souzeau, Emmanuelle, Ridge, Bronwyn, Hysi, Pirro G., Burdon, Kathryn P., Mills, Richard A., Landers, John, Ruddle, Jonathan B., Agar, Ashish, Galanopoulos, Anna, White, Andrew J. R., Willoughby, Colin E., Andrew, Nicholas H., Best, Stephen, Vincent, Andrea L., Goldberg, Ivan, Radford-Smith, Graham, Martin, Nicholas G., Montgomery, Grant W., Vitart, Veronique, Hoehn, Rene, Wojciechowski, Robert, Jonas, Jost B., Aung, Tin, Pasquale, Louis R., Cree, Angela Jane, Sivaprasad, Sobha, Vallabh, Neeru A., Viswanathan, Ananth C., Pasutto, Francesca, Haines, Jonathan L., Klaver, Caroline C. W., van Duijn, Cornelia M., Casson, Robert J., Foster, Paul J., Khaw, Peng Tee, Hammond, Christopher J., Mackey, David A., Mitchell, Paul, Lotery, Andrew J., Wiggs, Janey L., Hewitt, Alex W., and MacGregor, Stuart

Abstract

Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOCvariant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P= 0.004) and surgical intervention in advanced disease (P= 3.6 × 10−6). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.

Published
2020
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236. Molecular Dynamic Simulations of Ocular Tablet Dissolution

Author

Ru, Qian, Fadda, Hala M., Li, Chung, Paul, Daniel, Khaw, Peng T., Brocchini, Steve, and Zloh, Mire

Abstract

Small tablets for implantation into the subconjunctival space in the eye are being developed to inhibit scarring after glaucoma filtration surgery (GFS). There is a need to evaluate drug dissolution at the molecular level to determine how the chemical structure of the active may correlate with dissolution in the nonsink conditions of the conjunctival space. We conducted molecular dynamics simulations to study the dissolution process of tablets derived from two drugs that can inhibit fibrosis after GFS, 5-fluorouracil (5-FU) and the matrix metalloprotease inhibitor (MMPi), ilomastat. The dissolution was simulated in the presence of simple point charge (SPC) water molecules, and the liquid turnover of the aqueous humor in the subconjunctival space was simulated by removal of the dissolved drug molecules at regular intervals and replacement by new water molecules. At the end of the simulation, the total molecular solvent accessible surface area of 5-FU tablets increased by 60 times more than that of ilomastat as a result of tablet swelling and release of molecules into solution. The tablet dissolution pattern shown in our molecular dynamic simulations tends to correlate with experimental release profiles. This work indicates that a series of molecular dynamic simulations can be used to predict the influence of the molecular properties of a drug on its dissolution profile and could be useful during preformulation where sufficient amounts of the drug are not always available to perform dissolution studies.

Published
2024
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237. Receptor-targeted liposome-peptide-siRNA nanoparticles represent a novel and efficient therapeutic approach to prevent conjunctival fibrosis.

Author

Yu-Wai-Man, Cynthia, Tagalakis, Aristides, Manunta, Maria D., Bailly, M, Hart, Stephen L., Khaw, Peng T., Yu-Wai-Man, Cynthia, Tagalakis, Aristides, Manunta, Maria D., Bailly, M, Hart, Stephen L., and Khaw, Peng T.

Abstract

There is increasing evidence that the Myocardin-related transcription factor/Serum response factor (MRTF/SRF) pathway plays a key role in fibroblast activation and that knocking down MRTF can lead to reduced scarring and fibrosis. Here, we have developed a receptor-targeted liposome-peptide-siRNA nanoparticle as a non-viral delivery system for MRTF-B siRNA in conjunctival fibrosis. Using 50 nM siRNA, the MRTF-B gene was efficiently silenced by 76% and 72% with LYR and LER nanoparticles, respectively. The silencing efficiency was low when non-targeting peptides or siRNA alone or liposome-siRNA alone were used. LYR and LER nanoparticles also showed higher silencing efficiency than PEGylated LYR-P and LER-P nanoparticles. The nanoparticles were not cytotoxic using different liposomes, targeting peptides, and 50 nM siRNA. Three-dimensional fibroblast-populated collagen matrices were also used as a functional assay to measure contraction in vitro, and showed that MRTF-B LYR nanoparticles completely blocked matrix contraction after a single transfection treatment. In conclusion, this is the first study to develop and show that receptor-targeted liposome-peptide-siRNA nanoparticles represent an efficient and safe non-viral siRNA delivery system that could be used to prevent fibrosis after glaucoma filtration surgery and other contractile scarring conditions in the eye.

Published
2016

238. List of Contributors

Author

Acera, Erika C., Afshari, Natalie A., Agarwal, Anita, Agranat, Joshua S., Ajlan, Radwan S., Akhlaq, Anam, Albini, Thomas A., Al-Ghoul, Ahmed, Ali, Ferhina S., Alió, Jorge L., Allemann, Norma, Allen, David, Allman, Keith G., Alvi, Nishat P., Ang, Leonard P.K., Apple, David J., Aquino, Maria Cecilia D., Arnold, Anthony C., Arshinoff, Steve A., Asbell, Penny A., Assil, Kerry K., Atebara, Neal H., Augsburger, James J., Aylward, G. William, Azar, Dimitri T., Bakri, Sophie J., Balcer, Laura J., Balducci, Nicole, Barboni, Piero, Barnett, Cullen J., Basu, Soumyava, Batta, Priti, Baumal, Caroline R., Bearelly, Srilaxmi, Berry, Jesse L., Bessette, Angela P., Bhatt, Nirali, Birdsong, Orry C., Biswas, Jyotirmay, Bodaghi, Bahram, Bose, Swaraj, Bouchard, Charles S., Boulton, Michael E., Brandt, James D., Brodie, Scott E., Brodsky, Michael C., Brooks, Cassandra C., Brumm, Matthew V., Budenz, Donald L., Bussel, Igor I., Cantor, Louis B., Capó, Hilda, Capone, Antonio, Jr, Carruthers, Alastair, Carruthers, Jean, Carter, Keith D., Caruso, Rafael C., Chahal, Harinderpal S., Chamon, Wallace, Chan, Chi-Chao, Chang, Melinda Y., Chang, Stanley, Chang, Victoria S., Charteris, David G., Chee, Soon-Phaik, Chen, John J., Chen, Xuejing, Chew, Paul T.K., Chiu, Bing, Chow, Clement C., Civan, Mortimer M., Clark, Abbot (Abe), Clarke, Jonathan C.K., Codère, François, Conner, Ian P., Coombs, Peter, Corrêa, Zélia M., Couch, Steven M., Coupland, Stuart G., Cowan, Claude L., Jr, Craven, E. Randy, Cukras, Catherine A., Dagi, Linda R., Dahan, Elie, Damgaard, Iben Bach, Damji, Karim F., Das, Dipankar, DeBusk, Adam, de la Cruz, Jose, Demer, Joseph L., Desai, Shilpa J., Dhaliwal, Deepinder K., Diamond, Gary R., Diniz, Daniel, Do, Diana V., Dolman, Peter J., Donahue, Sean P., Dortzbach, Richard K., Drenser, Kimberly A., Duker, Jacob S., Duker, Jay S., Durairaj, Vikram D., Dutton, Jonathan J., Edgington, Bryan, Eggers, Howard M., Eliott, Dean, Ellis, George S., Jr, Engelbert, Michael, Englander, Miriam, Esmaeli, Bita, Evans, Joshua W., Evans, Monica, Fahd, Daoud S., Faia, Lisa J., Fallano, Katherine A., Farjo, Ayad A., Feinstein, Eric, Fernandez, Karen B., Fisher, Yale L., Fishman, Gerald A., Fortun, Jorge A., Fragoso, Veronica Vargas, Freeman, Nicola, Friedman, David S., Friedman, Deborah I., Friedman, Neil J., Fynn-Thompson, Nicoletta, Gadaria-Rathod, Neha, Garcia-Zalisnak, Debora E., Gayre, Gregg S., Gedde, Steven J., Gery, Igal, Ghanem, Ramon C., Ghanem, Vinícius C., Ghosh, Saurabh, Gibbons, Allister, Gigantelli, James W., Giri, Pushpanjali, Goldberg, Ivan, Goldberg, Jeffrey L., Goldstein, Debra A., Goldstein, Michael H., Gonzales, John A., Granet, David B., Gray, Matthew J., Green, Kyle M., Greven, Craig M., Greven, Margaret A., Gross, Josh C., Gross, Ronald L., Grover, Sandeep, Guercio, Jason R., Gueudry, Julie, Gündüz, Ahmet Kaan, Hallak, Joelle A., Haller, Julia A., Hamrah, Pedram, Hardten, David R., Harris, Alon, Heier, Jeffrey S., Herndon, Leon W., Jr, Ho, Allen C., Hood, Christopher T., Hou, Joshua H., Houghton, Odette M., Houser, Kourtney, Howes, Frank W., Hsu, Jason, Hurwitz, Jeffrey J., Irochima, Francisco, Isteitiya, Jihad, Izak, Andrea M., Jacobs, Deborah S., Jain, Sandeep, Jampel, Henry D., Jampol, Lee M., Jap, Aliza, Johnson, Chris A., Johnson, Mark W., Johnson, T. Mark, Kaehr, Mark M., Kahook, Malik Y., Kaiser, Peter K., Kalarn, Sachin P., Kalevar, Ananda, Kane, Steven, Kanner, Elliott M., Kaplowitz, Kevin, Kapusta, Michael A., Karanjia, Rustum, Kardon, Randy H., Karp, Carol L., Kashani, Amir H., Kass, Michael A., Kataguiri, Paula, Katz, L. Jay, Kaufman, Paul L., Keenan, Jeremy D., Kenyon, Kenneth R., Khaw, Peng Tee, Kim, Gene, Kim, Ivana K., Kimura, Alan E., Kinori, Michael, Kirwan, Caitriona, Kiss, Szilárd, Kitchens, John W., Klein, Kendra, Koch, Douglas D., Koh, Victor T.C., Kohnen, Thomas, Koustenis, Andrew, Lane, Stephen S., Lavin, Patrick J.M., Lavinsky, Fabio, Lawton, Andrew W., Lee, Bryan S., Lee, Daniel, Lee, Gregory D., Lee, Olivia L., Lee, Paul P., Lee, Richard M.H., Lim, Dawn K.A., Lim, Jennifer I., Lim, Ridia, Lin, Tony K.Y., Lind, John T., Liu, Yao, Liyanage, Sidath E., Lockwood, Alastair J., Loewen, Nils A., Longmuir, Reid A., Lopez, Pedro F., Lundström, Mats, Maamari, Robi N., Madu, Assumpta, Maloney, Maya H., Mandava, Naresh, Marmor, Michael F., Mathura, Jeevan R., Jr, Mattox, Cynthia, McClatchey, Scott K., McLeod, Stephen D., McMillan, Brian D., McNab, Alan A., Mehta, Jodhbir S., Mejico, Luis J., Mercado, Carolina L., Mian, Shahzad I., Mieler, William F., Miller, David, Miller, Kyle E., Mimura, Tatsuya, Mirza, Rukhsana G., Mititelu, Mihai, Moorthy, Ramana S., Moshfeghi, Andrew A., Moshirfar, Majid, Moss, Heather E., Moster, Mark L., Muir, Kelly W., Neff, Ann G., Nerad, Jeffrey A., Nikpoor, Neda, Noecker, Robert J., Nosé, Ricardo, Okada, Annabelle A., O'Keefe, Michael, Olson, Jeffrey L., Olver, Jane M., Opalinski, Yvonne A.V., Örge, Faruk H., Packer, Mark, Pandey, Suresh K., Parikh, Vishal S., Pasquale, Louis R., Patel, Sarju S., Patel, Vivek R., Pavesio, Carlos E., Perez, Victor L., Perez-Straziota, Claudia E., Phillips, Lauren T., Piltz-Seymour, Jody R., Piva, Alfio P., Podbielski, Dominik W., Pondelis, Nicolas J., Price, Francis W., Jr, Price, Marianne O., Pritchard, Cindy, Quiros, Peter A., Rachitskaya, Aleksandra V., Ramulu, Pradeep Y., Randleman, J. Bradley, Rao, Narsing A., Rao, Naveen K., Rao, P. Kumar, Rao, Rajesh C., Rathinam, Sivakumar, Read, Russell W., Saito Regatieri, Caio Vinicius, Regillo, Carl D., Reichel, Elias, Rhee, Douglas J., Ringeisen, Alexander L., Ritch, Robert, Robbins, Shira L., Rodger, Damien C., Roh, Miin, Roh, Shiyoung, Rosado-Adames, Noel, Rosen, Emanuel S., Rubenstein, Jonathan B., Rubin, Richard M., Rubin, Steven E., Rubsamen, Patrick E., Rupp, Jason D., Saadati, Hossein G., Sadun, Alfredo A., Saeedi, Osamah J., Salchow, Daniel J., Salim, Sarwat, Samuelson, Thomas W., Sandhu, Simrenjeet, Santhiago, Marcony R., Savini, Giacomo, Sayed-Ahmed, Ibrahim O., Scheffler, Amy C., Schor, Paulo, Schubert, Hermann D., Schuman, Joel S., Schwartz, Gary S., Sebag, J., Sebrow, Dov B., Sen, H. Nida, Shah, Gaurav K., Shields, Carol L., Shildkrot, Yevgeniy (Eugene), Shingleton, Bradford J., Shtein, Roni M., Shultz, Ryan W., Sierra, Patricia B., Siesky, Brent, Sieving, Paul A., Skondra, Dimitra, Small, Kent W., Smiddy, William E., Somogyi, Marie, Soong, H. Kaz, Soukiasian, Sarkis H., Spaide, Richard F., Spektor, Tatyana, Spoor, Thomas C., Srivastava, Sunil K., Stagg, Brian C., Steel, David H.W., Stein, Joshua D., Strominger, Mitchell B., Sugar, Alan, Sugar, Joel, Sychev, Yevgeniy V., Tania Tai, Tak Yee, Tan, James C., Tanenbaum, Myron, Taneri, Suphi, Tasman, William, Telander, David G., Thall, Edmond H., Thanos, Aristomenis, Theophanous, Christos N., Thomas, Benjamin J., Thulasi, Praneetha, Tibbetts, Michael D., Tingey, David P., Tobaigy, Faisal M., Todorich, Bozho, Tompson, Stuart W., Tsai, James C., Tsai, Julie H., Tucker, Nancy, Tuli, Sonal S., Vargason, Caroline W., Vasaiwala, Roshni A., Vasconcelos-Santos, Daniel Vitor, Vaughn, Gregory J., Venkat, Arthi, Villarreal, Guadalupe, Jr, Vinod, Kateki, Vislisel, Jesse M., Vrcek, Ivan, Wadia, Hormuz P., Walker, Brian D., Walton, David S., Wang, Li, Wang, Michelle Y., Wang, Robert C., Wax, Martin, Weinstein, Joel M., Weiter, John J., Werner, Liliana, Wevill, Mark, Wiggs, Janey L., Williams, Andrew M., Williams, George A., Witmer, Matthew T., Wollstein, Gadi, Woodward, Maria A., Wride, Nicholas K., Wu, Albert, Xu, David, Young, Joshua A., Yung, Edward S., Yu-Wai-Man, Cynthia, Zein, Wadih M., and Zhu, Ivy

Published
2019
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