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Papers by Joel Schuman

CDKN2B-AS1 genotype-glaucoma feature correlations in primary open-angle glaucoma patients from the United States

American journal of ophthalmology, 2013

To assess the association between single nucleotide polymorphisms (SNPs) of the gene region conta... more To assess the association between single nucleotide polymorphisms (SNPs) of the gene region containing cyclin-dependent kinase inhibitor 2B antisense noncoding RNA (CDKN2B-AS1) and glaucoma features among primary open-angle glaucoma (POAG) patients. Retrospective observational case series. We studied associations between 10 CDKN2B-AS1 SNPs and glaucoma features among 976 POAG cases from the Glaucoma Genes and Environment (GLAUGEN) study and 1971 cases from the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium. For each patient, we chose the feature from the eye with the higher value. We created cohort-specific multivariable models for glaucoma features and then meta-analyzed the results. For 9 of the 10 protective CDKN2B-AS1 SNPs with minor alleles associated with reduced disease risk (eg, the G allele at rs2157719), POAG patients carrying these minor alleles had smaller cup-to-disc ratio (0.05 units smaller per G allele at diagnosis; 95% CI: -0.08, -0.03; P = 6.23E-05) despite having higher intraocular pressure (IOP) (0.70 mm Hg higher per G allele at DNA collection; 95% CI: 0.40, 1.00; P = 5.45E-06). For the 1 adverse rs3217992 SNP with minor allele A associated with increased disease risk, POAG patients with A alleles had larger cup-to-disc ratio (0.05 units larger per A allele at diagnosis; 95% CI: 0.02, 0.07; P = 4.74E-04) despite having lower IOP (-0.57 mm Hg per A allele at DNA collection; 95% CI: -0.84, -0.29; P = 6.55E-05). Alleles of CDKN2B-AS1 SNPs, which influence risk of developing POAG, also modulate optic nerve degeneration among POAG patients, underscoring the role of CDKN2B-AS1 in POAG.

PLoS genetics, 2012

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients a... more Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normalpressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86610 218 ), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87610 211 ). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17610 212 ) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88610 210 ).

Glaucoma care: the patients' perspective. What do patients want

The British journal of ophthalmology, 2008

The ophthalmic practice of the future

Archives of ophthalmology, 2012

How will the ophthalmologist of the future practice? What will be the effect of government policy... more How will the ophthalmologist of the future practice? What will be the effect of government policy? How will this impact the mix of health care providers responsible for the delivery of eye care to patients? What part will health record technology play in clinical practice? These topics were discussed at the Knapp Symposium of the 2011 Annual Meeting of the American Ophthalmological Society. The health care system within which ophthalmology will be practiced will be radically different, ruled by changes in collaboration, communication, and practice guidelines. Given the coming uncertainty of our professional lives, it is vital that we anticipate, contemplate, and plan for our futures.

OCT: a bright future

Ophthalmic surgery, lasers & imaging : the official journal of the International Society for Imaging in the Eye, 2011

Biglan Festschrift

Seminars in ophthalmology

Investigative ophthalmology & visual science, 2013

PURPOSE. To investigate the potential of human trabecular meshwork stem cells (TMSCs) for homing ... more PURPOSE. To investigate the potential of human trabecular meshwork stem cells (TMSCs) for homing to mouse TM tissue and survival in vivo.

Investigative ophthalmology & visual science, 2012

To isolate and characterize stem cells from human trabecular meshwork (TM) and to investigate the... more To isolate and characterize stem cells from human trabecular meshwork (TM) and to investigate the potential of these stem cells to differentiate into TM cells. METHODS. Human trabecular meshwork stem cells (TMSCs) were isolated as side population cells by fluorescence-activated cell sorting or isolated by clonal cultures. Passaged TMSCs were compared with primary TM cells by immunostaining and quantitative RT-PCR. TMSC purity was assessed by flow cytometry and TMSC multipotency was examined by induction of neural cells, adipocytes, keratocytes, or TM cells. Differential gene expression was detected by quantitative RT-PCR, immunostaining, and immunoblotting. TM cell function was evaluated by phagocytic assay using inactivated Staphylococcus aureus bioparticles. RESULTS. Side population and clonal isolated cells expressed stem cell markers ABCG2, Notch1, OCT-3/4, AnkG, and MUC1 but not TM markers AQP1, MGP, CHI3L1, or TIMP3. Passaged TMSCs are a homogeneous population with Ͼ95% cells positive to CD73, CD90, CD166, or Bmi1. TMSCs exhibited multipotent ability of differentiation into a variety of cell types with expression of neural markers neurofilament, ␤-tubulin III, GFAP; or keratocyte-specific markers keratan sulfate and keratocan; or adipocyte markers ap2 and leptin. TMSC readily differentiated into TM cells with phagocytic function and expression of TM markers AQP1, CHI3L1, and TIMP3. CONCLUSIONS. TMSCs, isolated as side population or as clones, express specific stem cell markers, are homogeneous and multipotent, with the ability to differentiate into phagocytic TM cells. These cells offer a potential for development of a novel stem cell-based therapy for glaucoma. (Invest Ophthalmol Vis Sci. 2012;53:1566 -1575

Journal of glaucoma, 2011

Purpose-To determine whether there are regional differences in the age-related changes in peripap... more Purpose-To determine whether there are regional differences in the age-related changes in peripapillary retinal nerve fiber layer thickness as measured by time-domain optical coherence tomography (OCT).

Cystoid macular edema in retinitis pigmentosa patients without associated macular thickening

Seminars in ophthalmology, 2013

To describe the occurrence of cystoid macular edema (CME) in the setting of central foveal thickn... more To describe the occurrence of cystoid macular edema (CME) in the setting of central foveal thickness (CFT) under 250 μm as measured by optical coherence tomography (OCT) in patients with retinitis pigmentosa (RP). Stratus OCT was used to measure CFT in a total of 90 eyes from 46 patients with RP. Cross-sectional OCT images were also evaluated for CME, which was defined as cystoid changes in the macula seen on at least two linear scans. CME was identified in 13 of the 46 patients or in 22 of 90 eyes by OCT. In eyes with macular edema, CFT ranged from 224 to 718 μm (mean = 339 ± 137 μm). In eyes without macular edema, CFT ranged from 99 to 273 μm (mean = 184 ± 40 μm). Bilateral CME occurred in 9 of 13 patients (69%). CFT was considered "normal" in 7 of the 22 eyes (32%) with CME. Two patients had bilateral CME with normal CFTs, under 250 μm. We demonstrate the occurrence of CME in RP patients without associated thickening, which has not been described. This concept likely is applicable to other diseases with retinal thinning.

Investigative ophthalmology & visual science, 2010

PURPOSE. Time domain optical coherence tomography (TD-OCT) has been used commonly in clinical pra... more PURPOSE. Time domain optical coherence tomography (TD-OCT) has been used commonly in clinical practice, producing a large inventory of circular scan data for retinal nerve fiber layer (RNFL) assessment. Spectral domain (SD)-OCT produces three-dimensional (3-D) data volumes. The purpose of this study was to create a robust technique that makes TD-OCT circular scan RNFL thickness measurements comparable with those from 3-D SD-OCT volumes. METHODS. Eleven eyes of 11 healthy subjects and 7 eyes of 7 subjects with glaucoma were enrolled. Each eye was scanned with one centered and eight displaced TD-OCT scanning circles. One 3-D SD-OCT cube scan was obtained at the same visit. The matching location of the TD-OCT scanning circle was automatically detected within the corresponding 3-D SD-OCT scan. Algorithm performance was assessed by estimating the difference between the detected scanning circle location on 3-D SD-OCT volume and the TD-OCT circle location. Global and sectoral RNFL thickness measurement errors between the two devices were also compared. RESULTS. The difference (95% confidence interval) in scanning circle center locations between TD-and SD-OCT was 2.3 (1.5-3.2) pixels (69.0 [45.0 -96.0] m on the retina) for healthy eyes and 3.1 (2.0 -4.1) pixels (93.0 [60.0 -123.0] m on the retina) for glaucomatous eyes. The absolute RNFL thickness measure-ment difference was significantly smaller with the matched scanning circle.

Optics express, 2009

Optical coherence tomography has allowed unprecedented visualization of ocular structures, but th... more Optical coherence tomography has allowed unprecedented visualization of ocular structures, but the identity of some visible objects within slices remains unknown. This study reconstructs a number of those objects in 3D space, allowing their identification by observation of their 3D morphology. In the case mottling deep within image slices through the optic disc, C-mode imaging provided visualization of the appearance and distribution of laminar pores. In the case of white spots and streaks sometimes observed in image slices through the cornea, C-mode imaging contoured to the path of those white spots allowed their visual identification as nerves extending radially into the cornea from the limbus. White spots observed in ultrahigh resolution retinal image slices were identified as blood within retinal capillaries. C-mode contour-corrected imaging of three-dimensional structures provided the identification of previously unidentified structures visible in cross-sectional image slices.

Investigative ophthalmology & visual science, 2008

Purpose-To visualize, quantitatively assess, and interpret outer retinal morphology by using high... more Purpose-To visualize, quantitatively assess, and interpret outer retinal morphology by using highspeed, ultrahigh-resolution (UHR) OCT.

The British journal of ophthalmology, 2009

Glaucomatous damage typically causes retinal ganglion cell and retinal nerve fibre layer (RNFL) l... more Glaucomatous damage typically causes retinal ganglion cell and retinal nerve fibre layer (RNFL) loss that can occur diffusely and focally. Optical coherence tomography (OCT) is a non-invasive, non-contact technology that allows cross-sectional high-resolution in vivo imaging of intraretinal layers. Since structural abnormalities may precede functional abnormalities, it might be expected that an OCT RNFL abnormality would be observed when glaucomatous visual field (VF) loss is present. We report two patients who demonstrated clinically evident focal RNFL defects with corresponding VF loss that failed to be recognised as outside normal limits by OCT analysis.

The British journal of ophthalmology, 2011

Optical coherence tomography (OCT) techniques have been applied to develop a new generation of th... more Optical coherence tomography (OCT) techniques have been applied to develop a new generation of the technology, called spectral domain (SD) or Fourier domain (FD) OCT. The commercially available SD-OCT technology offers benefits over the conventional time domain (TD) OCT such as a scanning speed up to 200 times faster and higher axial resolution (3 to 6 μm). Overall, SD-OCT offers improved performance in terms of reproducibility. SD-OCT has a level of discriminating capability, between healthy and perimetric glaucoma eyes similar to that obtained with TD-OCT. Furthermore, the capabilities and features of SD-OCT are rapidly evolving, mainly due to three-dimensional imaging and image rendering. More sophisticated approaches for macular and optic disc assessment are expected to be employed in clinical practice. Analysis software should be further refined for interpretation of SD-OCT images in order to enhance the sensitivity and specificity of glaucoma diagnostics. Most importantly for SD-OCT is determination of its ability to diagnostic structural glaucomatous progression. Considering the recent launch time of the commercially available SD-OCT and slow progressing characteristic of glaucoma, we must wait for longitudinal SD-OCT data, with a long enough follow-up, to become available.

Clinical ophthalmology (Auckland, N.Z.), 2009

Purpose: To evaluate whether dexamethasone injected intracamerally at the conclusion of surgery c... more Purpose: To evaluate whether dexamethasone injected intracamerally at the conclusion of surgery can safely and effectively reduce postoperative inflammation and improve surgical outcomes in eyes with and without glaucoma. Methods: Retrospective chart review of 176 consecutive eyes from 146 patients receiving uncomplicated phacoemulsification (PE) (n = 118 total, 82 with glaucoma), glaucoma drainage device (GDD) (n = 35), combined PE/GDD (n = 11) and combined PE/endoscopic cyclophotocoagulation (n = 12). Ninety-one eyes from 76 patients were injected with 0.4 mg dexamethasone intracamerally at the conclusion of surgery. All eyes received standard postoperative prednisolone and ketorolac eyedrops. Outcomes were measured for four to eight weeks by subjective complaints, visual acuity (VA), slit-lamp biomicroscopy, intraocular pressure (IOP) and postoperative complications. Results: Dexamethasone significantly reduced the odds of having an increased anterior chamber (AC) cell score after PE (p = 0.0013). Mean AC cell score ± SD in nonglaucomatous eyes was 1.3 ± 0.8 in control and 0.8 ± 0.7 with dexamethasone; scores in glaucomatous eyes were 1.3 ± 0.7 in control and 0.9 ± 0.8 with dexamethasone. Treated nonglaucomatous eyes had significantly fewer subjective complaints after PE (22.2% vs 64.7% in control; p = 0.0083). Dexamethasone had no significant effects on VA, corneal changes, IOP one day and one month after surgery, or long-term complications. Conclusions: Intracameral dexamethasone given at the end of cataract surgery significantly reduces postoperative AC cells in eyes with and without glaucoma, and improves subjective reports of recovery in nonglaucomatous eyes. There were no statistically significant risks of IOP elevation or other complications in glaucomatous eyes.

Responses of cultured human keratocytes and myofibroblasts to ethyl pyruvate: a microarray analysis of gene expression

Investigative ophthalmology & visual science, 2010

Ethyl pyruvate (EP) has pharmacologic effects that remediate cellular stress. In the organ-cultur... more Ethyl pyruvate (EP) has pharmacologic effects that remediate cellular stress. In the organ-cultured murine lens, EP ameliorates oxidative stress, and in a rat cataract model, it attenuates cataract formation. However, corneal responses to EP have not been elucidated. In this study, the potential of EP as a therapeutic agent in corneal wound healing was determined by examining its effects on the transition of quiescent corneal stromal keratocytes into contractile myofibroblasts. Three independent preparations of cultured human keratocytes were treated with TGF-beta1, to elicit a phenotypic transition to myofibroblasts in the presence or absence of 10 or 15 mM EP. Gene expression profiles of the 12 samples (keratocytes +/- EP +/- TGF-beta1 for three preparations) were produced by using gene microarrays. TGF-beta1-driven twofold changes in at least two of three experiments defined a group of 1961 genes. Genes showing twofold modulation by EP in at least two experiments appeared exclusively in myofibroblasts (857 genes), exclusively in keratocytes (409 genes), or in both phenotypes (252 genes). Analysis of these three EP-modulated groups showed that EP (1) inhibited myofibroblast proliferation with concomitant modulation of some cell cycle genes, (2) augmented the NRF2-mediated antioxidant response in both keratocytes and myofibroblasts, and (3) modified the TGF-beta1-driven transition of keratocytes to myofibroblasts by inhibiting the upregulation of a subset of profibrotic genes. These EP-induced phenotypic changes in myofibroblasts indicate the potential of EP as a therapeutic agent in corneal wound healing.

Repeated, noninvasive, high resolution spectral domain optical coherence tomography imaging of zebrafish embryos

Molecular vision, 2008

To demonstrate a new imaging method for high resolution spectral domain optical coherence tomogra... more To demonstrate a new imaging method for high resolution spectral domain optical coherence tomography (SD-OCT) for small animal developmental imaging. Wildtype zebrafish that were 24, 48, 72, and 120 h post fertilization (hpf) and nok gene mutant (48 hpf) embryos were imaged in vivo. Three additional embryos were imaged twice, once at 72 hpf and again at 120 hpf. Images of the developing eye, brain, heart, whole body, proximal yolk sac, distal yolk sac, and tail were acquired. Three-dimensional OCT data sets (501 x 180 axial scans) were obtained as well as oversampled frames (8,100 axial scans) and repeated line scans (180 repeated frames). Scan volumes ranged from 750 x 750 microm to 3 x 3 mm, each 1.8 mm thick. Three-dimensional data sets allowed construction of C-mode slabs of the embryo. SD-OCT provided ultra-high resolution visualization of the eye, brain, heart, ear, and spine of the developing embryo as early as 24 hpf, and allowed development to be documented in each of these organ systems in consecutive sessions. Repeated line scanning with averaging optimized the visualization of static and dynamic structures contained in SD-OCT images. Structural defects caused by a mutation in the nok gene were readily observed as impeded ocular development, and enlarged pericardial cavities. SD-OCT allowed noninvasive, in vivo, ultra-high resolution, high-speed imaging of zebrafish embryos in their native state. The ability to measure structural and functional features repeatedly on the same specimen, without the need to sacrifice, promises to be a powerful tool in small animal developmental imaging.

Investigative ophthalmology & visual science, 2009

Three dimensional (3D) ophthalmic imaging using optical coherence tomography (OCT) has revolution... more Three dimensional (3D) ophthalmic imaging using optical coherence tomography (OCT) has revolutionized assessment of the eye, the retina in particular. Recent technological improvements have made the acquisition of 3D-OCT datasets feasible. However, while volumetric data can improve disease diagnosis and follow-up, novel image analysis techniques are now necessary in order to process the dense 3D-OCT dataset. Fundamental software improvements include methods for correcting subject eye motion, segmenting structures or volumes of interest, extracting relevant data post hoc and signal averaging to improve delineation of retinal layers. In addition, innovative methods for image display, such as C-mode sectioning, provide a unique viewing perspective and may improve interpretation of OCT images of pathologic structures. While all of these methods are being developed, most remain in an immature state. This review describes the current status of 3D-OCT scanning and interpretation, and discusses the need for standardization of clinical protocols as well as the potential benefits of 3D-OCT scanning that could come when software methods for fully exploiting these rich data sets are available clinically. The implications of new image analysis approaches include improved reproducibility of measurements garnered from 3D-OCT, which may then help improve disease discrimination and progression detection. In addition, 3D-OCT offers the potential for preoperative surgical planning and intraoperative surgical guidance.

Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference, 2011

Current standard quantitative 3D spectral-domain optical coherence tomography (SD-OCT) analyses o... more Current standard quantitative 3D spectral-domain optical coherence tomography (SD-OCT) analyses of various ocular diseases is limited in detecting structural damage at early pathologic stages. This is mostly because only a small fraction of the 3D data is used in the current method of quantifying the structure of interest. This paper presents a novel SD-OCT data analysis technique, taking full advantage of the 3D dataset. The proposed algorithm uses machine classifier to analyze SD-OCT images after grouping adjacent pixels into super pixel in order to detect glaucomatous damage. A 3D SD-OCT image is first converted into a 2D feature map and partitioned into over a hundred super pixels. Machine classifier analysis using boosting algorithm is performed on super pixel features. One hundred and ninety-two 3D OCT images of the optic nerve head region were tested. Area under the receiver operating characteristic (AUC) was computed to evaluate the glaucoma discrimination performance of the algorithm and compare it to the commercial software output. The AUC of normal vs glaucoma suspect eyes using the proposed method was statistically significantly higher than the current method (0.855 and 0.707, respectively, p=0.031). This new method has the potential to improve early detection of glaucomatous structural damages.

CDKN2B-AS1 genotype-glaucoma feature correlations in primary open-angle glaucoma patients from the United States

American journal of ophthalmology, 2013

To assess the association between single nucleotide polymorphisms (SNPs) of the gene region conta... more To assess the association between single nucleotide polymorphisms (SNPs) of the gene region containing cyclin-dependent kinase inhibitor 2B antisense noncoding RNA (CDKN2B-AS1) and glaucoma features among primary open-angle glaucoma (POAG) patients. Retrospective observational case series. We studied associations between 10 CDKN2B-AS1 SNPs and glaucoma features among 976 POAG cases from the Glaucoma Genes and Environment (GLAUGEN) study and 1971 cases from the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium. For each patient, we chose the feature from the eye with the higher value. We created cohort-specific multivariable models for glaucoma features and then meta-analyzed the results. For 9 of the 10 protective CDKN2B-AS1 SNPs with minor alleles associated with reduced disease risk (eg, the G allele at rs2157719), POAG patients carrying these minor alleles had smaller cup-to-disc ratio (0.05 units smaller per G allele at diagnosis; 95% CI: -0.08, -0.03; P = 6.23E-05) despite having higher intraocular pressure (IOP) (0.70 mm Hg higher per G allele at DNA collection; 95% CI: 0.40, 1.00; P = 5.45E-06). For the 1 adverse rs3217992 SNP with minor allele A associated with increased disease risk, POAG patients with A alleles had larger cup-to-disc ratio (0.05 units larger per A allele at diagnosis; 95% CI: 0.02, 0.07; P = 4.74E-04) despite having lower IOP (-0.57 mm Hg per A allele at DNA collection; 95% CI: -0.84, -0.29; P = 6.55E-05). Alleles of CDKN2B-AS1 SNPs, which influence risk of developing POAG, also modulate optic nerve degeneration among POAG patients, underscoring the role of CDKN2B-AS1 in POAG.

PLoS genetics, 2012

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients a... more Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normalpressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86610 218 ), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87610 211 ). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17610 212 ) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88610 210 ).

Glaucoma care: the patients' perspective. What do patients want

The British journal of ophthalmology, 2008

The ophthalmic practice of the future

Archives of ophthalmology, 2012

How will the ophthalmologist of the future practice? What will be the effect of government policy... more How will the ophthalmologist of the future practice? What will be the effect of government policy? How will this impact the mix of health care providers responsible for the delivery of eye care to patients? What part will health record technology play in clinical practice? These topics were discussed at the Knapp Symposium of the 2011 Annual Meeting of the American Ophthalmological Society. The health care system within which ophthalmology will be practiced will be radically different, ruled by changes in collaboration, communication, and practice guidelines. Given the coming uncertainty of our professional lives, it is vital that we anticipate, contemplate, and plan for our futures.

OCT: a bright future

Ophthalmic surgery, lasers & imaging : the official journal of the International Society for Imaging in the Eye, 2011

Biglan Festschrift

Seminars in ophthalmology

Investigative ophthalmology & visual science, 2013

PURPOSE. To investigate the potential of human trabecular meshwork stem cells (TMSCs) for homing ... more PURPOSE. To investigate the potential of human trabecular meshwork stem cells (TMSCs) for homing to mouse TM tissue and survival in vivo.

Investigative ophthalmology & visual science, 2012

To isolate and characterize stem cells from human trabecular meshwork (TM) and to investigate the... more To isolate and characterize stem cells from human trabecular meshwork (TM) and to investigate the potential of these stem cells to differentiate into TM cells. METHODS. Human trabecular meshwork stem cells (TMSCs) were isolated as side population cells by fluorescence-activated cell sorting or isolated by clonal cultures. Passaged TMSCs were compared with primary TM cells by immunostaining and quantitative RT-PCR. TMSC purity was assessed by flow cytometry and TMSC multipotency was examined by induction of neural cells, adipocytes, keratocytes, or TM cells. Differential gene expression was detected by quantitative RT-PCR, immunostaining, and immunoblotting. TM cell function was evaluated by phagocytic assay using inactivated Staphylococcus aureus bioparticles. RESULTS. Side population and clonal isolated cells expressed stem cell markers ABCG2, Notch1, OCT-3/4, AnkG, and MUC1 but not TM markers AQP1, MGP, CHI3L1, or TIMP3. Passaged TMSCs are a homogeneous population with Ͼ95% cells positive to CD73, CD90, CD166, or Bmi1. TMSCs exhibited multipotent ability of differentiation into a variety of cell types with expression of neural markers neurofilament, ␤-tubulin III, GFAP; or keratocyte-specific markers keratan sulfate and keratocan; or adipocyte markers ap2 and leptin. TMSC readily differentiated into TM cells with phagocytic function and expression of TM markers AQP1, CHI3L1, and TIMP3. CONCLUSIONS. TMSCs, isolated as side population or as clones, express specific stem cell markers, are homogeneous and multipotent, with the ability to differentiate into phagocytic TM cells. These cells offer a potential for development of a novel stem cell-based therapy for glaucoma. (Invest Ophthalmol Vis Sci. 2012;53:1566 -1575

Journal of glaucoma, 2011

Purpose-To determine whether there are regional differences in the age-related changes in peripap... more Purpose-To determine whether there are regional differences in the age-related changes in peripapillary retinal nerve fiber layer thickness as measured by time-domain optical coherence tomography (OCT).

Cystoid macular edema in retinitis pigmentosa patients without associated macular thickening

Seminars in ophthalmology, 2013

To describe the occurrence of cystoid macular edema (CME) in the setting of central foveal thickn... more To describe the occurrence of cystoid macular edema (CME) in the setting of central foveal thickness (CFT) under 250 μm as measured by optical coherence tomography (OCT) in patients with retinitis pigmentosa (RP). Stratus OCT was used to measure CFT in a total of 90 eyes from 46 patients with RP. Cross-sectional OCT images were also evaluated for CME, which was defined as cystoid changes in the macula seen on at least two linear scans. CME was identified in 13 of the 46 patients or in 22 of 90 eyes by OCT. In eyes with macular edema, CFT ranged from 224 to 718 μm (mean = 339 ± 137 μm). In eyes without macular edema, CFT ranged from 99 to 273 μm (mean = 184 ± 40 μm). Bilateral CME occurred in 9 of 13 patients (69%). CFT was considered "normal" in 7 of the 22 eyes (32%) with CME. Two patients had bilateral CME with normal CFTs, under 250 μm. We demonstrate the occurrence of CME in RP patients without associated thickening, which has not been described. This concept likely is applicable to other diseases with retinal thinning.

Investigative ophthalmology & visual science, 2010

PURPOSE. Time domain optical coherence tomography (TD-OCT) has been used commonly in clinical pra... more PURPOSE. Time domain optical coherence tomography (TD-OCT) has been used commonly in clinical practice, producing a large inventory of circular scan data for retinal nerve fiber layer (RNFL) assessment. Spectral domain (SD)-OCT produces three-dimensional (3-D) data volumes. The purpose of this study was to create a robust technique that makes TD-OCT circular scan RNFL thickness measurements comparable with those from 3-D SD-OCT volumes. METHODS. Eleven eyes of 11 healthy subjects and 7 eyes of 7 subjects with glaucoma were enrolled. Each eye was scanned with one centered and eight displaced TD-OCT scanning circles. One 3-D SD-OCT cube scan was obtained at the same visit. The matching location of the TD-OCT scanning circle was automatically detected within the corresponding 3-D SD-OCT scan. Algorithm performance was assessed by estimating the difference between the detected scanning circle location on 3-D SD-OCT volume and the TD-OCT circle location. Global and sectoral RNFL thickness measurement errors between the two devices were also compared. RESULTS. The difference (95% confidence interval) in scanning circle center locations between TD-and SD-OCT was 2.3 (1.5-3.2) pixels (69.0 [45.0 -96.0] m on the retina) for healthy eyes and 3.1 (2.0 -4.1) pixels (93.0 [60.0 -123.0] m on the retina) for glaucomatous eyes. The absolute RNFL thickness measure-ment difference was significantly smaller with the matched scanning circle.

Optics express, 2009

Optical coherence tomography has allowed unprecedented visualization of ocular structures, but th... more Optical coherence tomography has allowed unprecedented visualization of ocular structures, but the identity of some visible objects within slices remains unknown. This study reconstructs a number of those objects in 3D space, allowing their identification by observation of their 3D morphology. In the case mottling deep within image slices through the optic disc, C-mode imaging provided visualization of the appearance and distribution of laminar pores. In the case of white spots and streaks sometimes observed in image slices through the cornea, C-mode imaging contoured to the path of those white spots allowed their visual identification as nerves extending radially into the cornea from the limbus. White spots observed in ultrahigh resolution retinal image slices were identified as blood within retinal capillaries. C-mode contour-corrected imaging of three-dimensional structures provided the identification of previously unidentified structures visible in cross-sectional image slices.

Investigative ophthalmology & visual science, 2008

Purpose-To visualize, quantitatively assess, and interpret outer retinal morphology by using high... more Purpose-To visualize, quantitatively assess, and interpret outer retinal morphology by using highspeed, ultrahigh-resolution (UHR) OCT.

The British journal of ophthalmology, 2009

Glaucomatous damage typically causes retinal ganglion cell and retinal nerve fibre layer (RNFL) l... more Glaucomatous damage typically causes retinal ganglion cell and retinal nerve fibre layer (RNFL) loss that can occur diffusely and focally. Optical coherence tomography (OCT) is a non-invasive, non-contact technology that allows cross-sectional high-resolution in vivo imaging of intraretinal layers. Since structural abnormalities may precede functional abnormalities, it might be expected that an OCT RNFL abnormality would be observed when glaucomatous visual field (VF) loss is present. We report two patients who demonstrated clinically evident focal RNFL defects with corresponding VF loss that failed to be recognised as outside normal limits by OCT analysis.

The British journal of ophthalmology, 2011

Optical coherence tomography (OCT) techniques have been applied to develop a new generation of th... more Optical coherence tomography (OCT) techniques have been applied to develop a new generation of the technology, called spectral domain (SD) or Fourier domain (FD) OCT. The commercially available SD-OCT technology offers benefits over the conventional time domain (TD) OCT such as a scanning speed up to 200 times faster and higher axial resolution (3 to 6 μm). Overall, SD-OCT offers improved performance in terms of reproducibility. SD-OCT has a level of discriminating capability, between healthy and perimetric glaucoma eyes similar to that obtained with TD-OCT. Furthermore, the capabilities and features of SD-OCT are rapidly evolving, mainly due to three-dimensional imaging and image rendering. More sophisticated approaches for macular and optic disc assessment are expected to be employed in clinical practice. Analysis software should be further refined for interpretation of SD-OCT images in order to enhance the sensitivity and specificity of glaucoma diagnostics. Most importantly for SD-OCT is determination of its ability to diagnostic structural glaucomatous progression. Considering the recent launch time of the commercially available SD-OCT and slow progressing characteristic of glaucoma, we must wait for longitudinal SD-OCT data, with a long enough follow-up, to become available.

Clinical ophthalmology (Auckland, N.Z.), 2009

Purpose: To evaluate whether dexamethasone injected intracamerally at the conclusion of surgery c... more Purpose: To evaluate whether dexamethasone injected intracamerally at the conclusion of surgery can safely and effectively reduce postoperative inflammation and improve surgical outcomes in eyes with and without glaucoma. Methods: Retrospective chart review of 176 consecutive eyes from 146 patients receiving uncomplicated phacoemulsification (PE) (n = 118 total, 82 with glaucoma), glaucoma drainage device (GDD) (n = 35), combined PE/GDD (n = 11) and combined PE/endoscopic cyclophotocoagulation (n = 12). Ninety-one eyes from 76 patients were injected with 0.4 mg dexamethasone intracamerally at the conclusion of surgery. All eyes received standard postoperative prednisolone and ketorolac eyedrops. Outcomes were measured for four to eight weeks by subjective complaints, visual acuity (VA), slit-lamp biomicroscopy, intraocular pressure (IOP) and postoperative complications. Results: Dexamethasone significantly reduced the odds of having an increased anterior chamber (AC) cell score after PE (p = 0.0013). Mean AC cell score ± SD in nonglaucomatous eyes was 1.3 ± 0.8 in control and 0.8 ± 0.7 with dexamethasone; scores in glaucomatous eyes were 1.3 ± 0.7 in control and 0.9 ± 0.8 with dexamethasone. Treated nonglaucomatous eyes had significantly fewer subjective complaints after PE (22.2% vs 64.7% in control; p = 0.0083). Dexamethasone had no significant effects on VA, corneal changes, IOP one day and one month after surgery, or long-term complications. Conclusions: Intracameral dexamethasone given at the end of cataract surgery significantly reduces postoperative AC cells in eyes with and without glaucoma, and improves subjective reports of recovery in nonglaucomatous eyes. There were no statistically significant risks of IOP elevation or other complications in glaucomatous eyes.

Responses of cultured human keratocytes and myofibroblasts to ethyl pyruvate: a microarray analysis of gene expression

Investigative ophthalmology & visual science, 2010

Ethyl pyruvate (EP) has pharmacologic effects that remediate cellular stress. In the organ-cultur... more Ethyl pyruvate (EP) has pharmacologic effects that remediate cellular stress. In the organ-cultured murine lens, EP ameliorates oxidative stress, and in a rat cataract model, it attenuates cataract formation. However, corneal responses to EP have not been elucidated. In this study, the potential of EP as a therapeutic agent in corneal wound healing was determined by examining its effects on the transition of quiescent corneal stromal keratocytes into contractile myofibroblasts. Three independent preparations of cultured human keratocytes were treated with TGF-beta1, to elicit a phenotypic transition to myofibroblasts in the presence or absence of 10 or 15 mM EP. Gene expression profiles of the 12 samples (keratocytes +/- EP +/- TGF-beta1 for three preparations) were produced by using gene microarrays. TGF-beta1-driven twofold changes in at least two of three experiments defined a group of 1961 genes. Genes showing twofold modulation by EP in at least two experiments appeared exclusively in myofibroblasts (857 genes), exclusively in keratocytes (409 genes), or in both phenotypes (252 genes). Analysis of these three EP-modulated groups showed that EP (1) inhibited myofibroblast proliferation with concomitant modulation of some cell cycle genes, (2) augmented the NRF2-mediated antioxidant response in both keratocytes and myofibroblasts, and (3) modified the TGF-beta1-driven transition of keratocytes to myofibroblasts by inhibiting the upregulation of a subset of profibrotic genes. These EP-induced phenotypic changes in myofibroblasts indicate the potential of EP as a therapeutic agent in corneal wound healing.

Repeated, noninvasive, high resolution spectral domain optical coherence tomography imaging of zebrafish embryos

Molecular vision, 2008

To demonstrate a new imaging method for high resolution spectral domain optical coherence tomogra... more To demonstrate a new imaging method for high resolution spectral domain optical coherence tomography (SD-OCT) for small animal developmental imaging. Wildtype zebrafish that were 24, 48, 72, and 120 h post fertilization (hpf) and nok gene mutant (48 hpf) embryos were imaged in vivo. Three additional embryos were imaged twice, once at 72 hpf and again at 120 hpf. Images of the developing eye, brain, heart, whole body, proximal yolk sac, distal yolk sac, and tail were acquired. Three-dimensional OCT data sets (501 x 180 axial scans) were obtained as well as oversampled frames (8,100 axial scans) and repeated line scans (180 repeated frames). Scan volumes ranged from 750 x 750 microm to 3 x 3 mm, each 1.8 mm thick. Three-dimensional data sets allowed construction of C-mode slabs of the embryo. SD-OCT provided ultra-high resolution visualization of the eye, brain, heart, ear, and spine of the developing embryo as early as 24 hpf, and allowed development to be documented in each of these organ systems in consecutive sessions. Repeated line scanning with averaging optimized the visualization of static and dynamic structures contained in SD-OCT images. Structural defects caused by a mutation in the nok gene were readily observed as impeded ocular development, and enlarged pericardial cavities. SD-OCT allowed noninvasive, in vivo, ultra-high resolution, high-speed imaging of zebrafish embryos in their native state. The ability to measure structural and functional features repeatedly on the same specimen, without the need to sacrifice, promises to be a powerful tool in small animal developmental imaging.

Investigative ophthalmology & visual science, 2009

Three dimensional (3D) ophthalmic imaging using optical coherence tomography (OCT) has revolution... more Three dimensional (3D) ophthalmic imaging using optical coherence tomography (OCT) has revolutionized assessment of the eye, the retina in particular. Recent technological improvements have made the acquisition of 3D-OCT datasets feasible. However, while volumetric data can improve disease diagnosis and follow-up, novel image analysis techniques are now necessary in order to process the dense 3D-OCT dataset. Fundamental software improvements include methods for correcting subject eye motion, segmenting structures or volumes of interest, extracting relevant data post hoc and signal averaging to improve delineation of retinal layers. In addition, innovative methods for image display, such as C-mode sectioning, provide a unique viewing perspective and may improve interpretation of OCT images of pathologic structures. While all of these methods are being developed, most remain in an immature state. This review describes the current status of 3D-OCT scanning and interpretation, and discusses the need for standardization of clinical protocols as well as the potential benefits of 3D-OCT scanning that could come when software methods for fully exploiting these rich data sets are available clinically. The implications of new image analysis approaches include improved reproducibility of measurements garnered from 3D-OCT, which may then help improve disease discrimination and progression detection. In addition, 3D-OCT offers the potential for preoperative surgical planning and intraoperative surgical guidance.

Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference, 2011

Current standard quantitative 3D spectral-domain optical coherence tomography (SD-OCT) analyses o... more Current standard quantitative 3D spectral-domain optical coherence tomography (SD-OCT) analyses of various ocular diseases is limited in detecting structural damage at early pathologic stages. This is mostly because only a small fraction of the 3D data is used in the current method of quantifying the structure of interest. This paper presents a novel SD-OCT data analysis technique, taking full advantage of the 3D dataset. The proposed algorithm uses machine classifier to analyze SD-OCT images after grouping adjacent pixels into super pixel in order to detect glaucomatous damage. A 3D SD-OCT image is first converted into a 2D feature map and partitioned into over a hundred super pixels. Machine classifier analysis using boosting algorithm is performed on super pixel features. One hundred and ninety-two 3D OCT images of the optic nerve head region were tested. Area under the receiver operating characteristic (AUC) was computed to evaluate the glaucoma discrimination performance of the algorithm and compare it to the commercial software output. The AUC of normal vs glaucoma suspect eyes using the proposed method was statistically significantly higher than the current method (0.855 and 0.707, respectively, p=0.031). This new method has the potential to improve early detection of glaucomatous structural damages.