Publications by authors named "Julie A Kiland"

24 Publications

  • Page 1 of 1

Development and validation of methods to visualize conventional aqueous outflow pathways in canine primary angle closure glaucoma.

Vet Ophthalmol 2022 May 28;25 Suppl 1:84-95. Epub 2021 Sep 28.

Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.

Purpose: Angle closure glaucoma (PACG) is highly prevalent in dogs and is often refractory to medical therapy. We hypothesized that pathology affecting the post-trabecular conventional aqueous outflow pathway contributes to persistent intraocular pressure (IOP) elevation in dogs with PACG. The goal of this study was to determine the potential for aqueous angiography (AA) and optical coherence tomography (OCT) to identify abnormalities in post-trabecular aqueous outflow pathways in canine PACG.

Methods: AA and anterior segment OCT (Spectralis HRA + OCT) were performed ex vivo in 19 enucleated canine eyes (10 normal eyes and 9 irreversibly blind eyes from canine patients enucleated for management of refractory PACG). Eyes were cannulated and maintained at physiologic IOP (10-20 mmHg) prior to intracameral infusion of fluorescent tracer. OCT scleral line scans were acquired in regions of high and low perilimbal AA signal. Eyes were then perfusion fixed and cryosections prepared from 10/10 normal and 7/9 PACG eyes and immunolabeled for a vascular endothelial marker.

Results: Normal canine eyes showed segmental, circumferential limbal AA signal, whereas PACG eyes showed minimal or no AA signal. AA signal correlated with scleral lumens on OCT in normal dogs, but lumens were generally absent or flattened in PACG eyes. Collapsed vascular profiles were identified in tissue sections from PACG eyes, including those in which no lumens were identified on AA and OCT.

Conclusions: In canine eyes with PACG, distal aqueous outflow channels are not identifiable by AA, despite normalization of their IOP, and intra-scleral vascular profiles are collapsed on OCT and histopathology.
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http://dx.doi.org/10.1111/vop.12943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8958177PMC
May 2022

Report: The effects of topical pleurotus tuberregium (PT) aqueous extract on intraocular pressure in monkeys.

PLoS One 2021 24;16(8):e0256422. Epub 2021 Aug 24.

Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States of America.

Purpose: In earlier experiments in Nigeria, aqueous extract of Pleurotus tuber-regium (PT) had been shown to lower intra ocular pressure (IOP) in a feline model. The aim of the current study was to determine whether PT had the same or a similar IOP-lowering effect in ocularly normal non-human primates.

Methods: Four monkeys were treated twice daily for 4 days with 2 x 20 μl drops of 50 mg/ml PT (pH = 4.3). The monkeys were sedated with 5-10 mg/kg ketamine HCl IM. PT was administered to the right eye and BSS to the left eye. Baseline IOP was measured just prior to beginning treatment, and on day 5 before treatment and then hourly for 3 hours, beginning 1 hour after treatment. SLEs were performed at baseline and on day 5 pre- and 3 hours post-treatment.

Results: There was no significant difference between IOP in treated vs control eyes in the protocol. There were no adverse effects or toxicity as seen by SLE.

Conclusions: The inability of the extract to lower IOP in monkeys, in contrast to ocular hypertensive cats in an earlier study, could be due to species differences or duration of treatment. Since no adverse effects were observed in the monkeys, further studies with varying durations and dosages are recommended.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256422PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384159PMC
December 2021

Validation and comparison of four handheld tonometers in normal ex vivo canine eyes.

Vet Ophthalmol 2021 Mar 1;24 Suppl 1:162-170. Epub 2020 Jun 1.

Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI, USA.

Objectives: To determine the accuracy and precision of the Icare TONOVET Plus rebound tonometer and the Tono-Pen AVIA Vet™ applanation tonometer for intraocular pressure (IOP) measurement in normal ex vivo canine eyes and comparison to earlier models of these tonometers.

Animals & Procedures: The anterior chambers of six normal dog eyes were cannulated ex vivo. IOP was measured with the TONOVET (TV01), TONOVET Plus, Tono-Pen Vet™, and Tono-Pen AVIA Vet™ at manometric IOPs ranging from 5 to 70 mm Hg. Data were analyzed by linear regression, ANOVA and Bland-Altman plots. A P value ≤ .05 was considered significant.

Results: Intraocular pressure values obtained using the TONOVET Plus and TV01 were significantly more accurate than with the Tono-Pen VET and Tono-Pen AVIA Vet, particularly at higher IOPs (30-70 mm Hg). Accuracy was not significantly different between any of the devices in the low to normal physiologic IOP range (5-25 mm Hg). Level of precision was high for all devices, though the TONOVET Plus was more precise than the Tono-Pen Vet in the 5-25 mmHg range and the TV01 was more precise than the Tono-Pen AVIA Vet over the whole IOP range.

Conclusions: All devices underestimated IOP, particularly at higher pressures. Rebound tonometers were more accurate over the full range of IOP tested and in the high IOP range; however, there were no significant differences in accuracy among devices in the physiologic IOP range. All tonometers can provide clinically useful IOP readings in dogs, but rebound and applanation tonometers should not be used interchangeably.
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http://dx.doi.org/10.1111/vop.12780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321415PMC
March 2021

Sub-region-Specific Optic Nerve Head Glial Activation in Glaucoma.

Mol Neurobiol 2020 Jun 7;57(6):2620-2638. Epub 2020 Apr 7.

Department of Surgical Sciences, University of Wisconsin-Madison, Madison, WI, USA.

Glaucoma, a multifactorial neurodegenerative disease characterized by progressive loss of retinal ganglion cells and their axons in the optic nerve, is a leading cause of irreversible vision loss. Intraocular pressure (IOP) is a risk factor for axonal damage, which initially occurs at the optic nerve head (ONH). Complex cellular and molecular mechanisms involved in the pathogenesis of glaucomatous optic neuropathy remain unclear. Here we define early molecular events in the ONH in an inherited large animal glaucoma model in which ONH structure resembles that of humans. Gene expression profiling of ONH tissues from rigorously phenotyped feline subjects with early-stage glaucoma and precisely age-matched controls was performed by RNA-sequencing (RNA-seq) analysis and complementary bioinformatic approaches applied to identify molecular processes and pathways of interest. Immunolabeling supported RNA-seq findings while providing cell-, region-, and disease stage-specific context in the ONH in situ. Transcriptomic evidence for cell proliferation and immune/inflammatory responses is identifiable in early glaucoma, soon after IOP elevation and prior to morphologically detectable axon loss, in this large animal model. In particular, proliferation of microglia and oligodendrocyte precursor cells is a prominent feature of early-stage, but not chronic, glaucoma. ONH microgliosis is a consistent hallmark in both early and chronic stages of glaucoma. Molecular pathways and cell type-specific responses strongly implicate toll-like receptor and NF-κB signaling in early glaucoma pathophysiology. The current study provides critical insights into molecular pathways, highly dependent on cell type and sub-region in the ONH even prior to irreversible axon degeneration in glaucoma.
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http://dx.doi.org/10.1007/s12035-020-01910-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282894PMC
June 2020

Vigabatrin-Induced Retinal Functional Alterations and Second-Order Neuron Plasticity in C57BL/6J Mice.

Invest Ophthalmol Vis Sci 2020 02;61(2):17

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Purpose: Vigabatrin (VGB) is an effective antiepileptic that increases concentrations of inhibitory γ-aminobutyric acid (GABA) by inhibiting GABA transaminase. Reports of VGB-associated visual field loss limit its clinical usefulness, and retinal toxicity studies in laboratory animals have yielded conflicting results.

Methods: We examined the functional and morphologic effects of VGB in C57BL/6J mice that received either VGB or saline IP from 10 to 18 weeks of age. Retinal structure and function were assessed in vivo by optical coherence tomography (OCT), ERG, and optomotor response. After euthanasia, retinas were processed for immunohistochemistry, and retinal GABA, and VGB quantified by mass spectrometry.

Results: No significant differences in visual acuity or total retinal thickness were identified between groups by optomotor response or optical coherence tomography, respectively. After 4 weeks of VGB treatment, ERG b-wave amplitude was enhanced, and amplitudes of oscillatory potentials were reduced. Dramatic rod and cone bipolar and horizontal cell remodeling, with extension of dendrites into the outer nuclear layer, was observed in retinas of VGB-treated mice. VGB treatment resulted in a mean 3.3-fold increase in retinal GABA concentration relative to controls and retinal VGB concentrations that were 20-fold greater than brain.

Conclusions: No evidence of significant retinal thinning or ERG a- or b-wave deficits were apparent, although we describe significant alterations in ERG b-wave and oscillatory potentials and in retinal cell morphology in VGB-treated C57BL/6J mice. The dramatic concentration of VGB in retina relative to the target tissue (brain), with a corresponding increase in retinal GABA, offers insight into the pathophysiology of VGB-associated visual field loss.
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http://dx.doi.org/10.1167/iovs.61.2.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326505PMC
February 2020

Evoked potentials as a biomarker of remyelination.

Proc Natl Acad Sci U S A 2019 Dec 16. Epub 2019 Dec 16.

Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706;

Multiple sclerosis (MS) is a common cause of neurologic disease in young adults that is primarily treated with disease-modifying therapies which target the immune and inflammatory responses. Promotion of remyelination has opened a new therapeutic avenue, but how best to determine efficacy of remyelinating drugs remains unresolved. Although prolongation and then shortening of visual evoked potential (VEP) latencies in optic neuritis in MS may identify demyelination and remyelination, this has not been directly confirmed. We recorded VEPs in a model in which there is complete demyelination of the optic nerve, with subsequent remyelination. We examined the optic nerves microscopically during active disease and recovery, and quantitated both demyelination and remyelination along the length of the nerves. Latencies of the main positive component of the control VEP demonstrated around 2-fold prolongation during active disease. VEP waveforms were nonrecordable in a few subjects or exhibited a broadened profile which precluded peak identification. As animals recovered neurologically, the VEP latencies decreased in association with complete remyelination of the optic nerve but remained prolonged relative to controls. Thus, it has been directly confirmed that VEP latencies reflect the myelin status of the optic nerve and will provide a surrogate marker in future remyelination clinical trials.
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http://dx.doi.org/10.1073/pnas.1906358116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936696PMC
December 2019

Imaging Distal Aqueous Outflow Pathways in a Spontaneous Model of Congenital Glaucoma.

Transl Vis Sci Technol 2019 Sep 9;8(5):22. Epub 2019 Oct 9.

Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, WI, USA.

Purpose: To validate the use of aqueous angiography (AA) in characterizing distal aqueous outflow pathways in normal and glaucomatous cats.

Methods: Ex vivo AA and optical coherence tomography (OCT) were performed in nine adult cat eyes (5 feline congenital glaucoma [FCG] and 4 normal), following intracameral infusion of 2.5% fluorescein and/or 0.4% indocyanine green (ICG) at physiologic intraocular pressure (IOP). Scleral OCT line scans were acquired in areas of high- and low-angiographic signal. Tissues dissected in regions of high- and low-AA signal, were sectioned and hematoxylin and eosin (H&E)-stained or immunolabeled (IF) for vascular endothelial and perivascular cell markers. Outflow vessel numbers and locations were compared between groups by Student's -test.

Results: AA yielded circumferential, high-quality images of distal aqueous outflow pathways in normal and FCG eyes. No AA signal or scleral lumens were appreciated in one buphthalmic FCG eye, though collapsed vascular profiles were identified on IF. The remaining eight of nine eyes all showed segmental AA signal, distinguished by differences in time of signal onset. AA signal always corresponded with lumens seen on OCT. Numbers of intrascleral vessels were not significantly different between groups, but scleral vessels were significantly more posteriorly located relative to the limbus in FCG.

Conclusions: A capacity for distal aqueous humor outflow was confirmed by AA in FCG eyes ex vivo but with significant posterior displacement of intrascleral vessels relative to the limbus in FCG compared with normal eyes.

Translational Relevance: This report provides histopathologic correlates of advanced diagnostic imaging findings in a spontaneous model of congenital glaucoma.
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http://dx.doi.org/10.1167/tvst.8.5.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788461PMC
September 2019

Validation of the Icare TONOVET plus rebound tonometer in normal rabbit eyes.

Exp Eye Res 2019 08 12;185:107698. Epub 2019 Jun 12.

Department of Ophthalmology & Visual Sciences, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA; McPherson Eye Research Institute, University of Wisconsin, Madison, WI, USA; Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI, USA. Electronic address:

To determine the accuracy and precision of the Icare TONOVET Plus rebound tonometer for measuring intraocular pressure (IOP) in normal rabbit eyes, as well as compare it to three other commercially available tonometers: the Icare TONOVET (TV01), Tono-Pen Vet™, and Tono-Pen AVIA Vet™. The anterior chambers of both eyes of three New Zealand White rabbits were cannulated, post-mortem. IOP was measured using each of the above four tonometers at manometric pressures ranging between 5 mmHg and 70 mmHg. Data were analyzed by linear regression, ANOVA, and Bland-Altman plots. A p-value of ≤0.05 was considered significant for all statistical tests. IOP values obtained with the TONOVET Plus (in 'lapine' mode) were significantly closer to manometric IOP than those obtained with the other tonometers tested. The TV01 (in 'd' dog setting) and Tono-Pen AVIA Vet™ were significantly more accurate compared to the Tono-Pen Vet™. All tonometers had high levels of precision, though the TONOVET Plus and TV01 were significantly more precise compared to the Tono-Pen AVIA Vet™. All tonometers tended to underestimate IOP, particularly at high pressures, however the TONOVET Plus was highly correlated with manometric IOP in the clinically relevant range of 5-50 mmHg. The TONOVET Plus is an appropriate choice of instrument for measuring IOP in rabbit eyes in both research and clinical settings.
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http://dx.doi.org/10.1016/j.exer.2019.107698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698397PMC
August 2019

Relationship between corneal sensitivity, corneal thickness, corneal diameter, and intraocular pressure in normal cats and cats with congenital glaucoma.

Vet Ophthalmol 2019 Jan 8;22(1):4-12. Epub 2018 Mar 8.

Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA.

Objective: To determine the effect of feline congenital glaucoma (FCG) on corneal sensitivity, and relationships between corneal sensitivity, central corneal thickness (CT), and corneal diameter (CD).

Animals And Procedures: Corneal sensitivity (estimated by corneal touch threshold [CTT] using Cochet-Bonnet esthesiometry); CT using ultrasonic pachymetry; intraocular pressure (IOP) using rebound tonometry; and maximal horizontal CD were measured in 16 normal and 14 FCG cats, both males and females, aged 7 months-3.5 years. All procedures complied with an Institutional Animal Care and Use Committee-approved protocol. Data were analyzed by linear regression: paired Student's t tests for between-eye comparisons, and unpaired Student's t tests for comparisons between groups. Relationships between parameters were evaluated by Pearson correlation coefficients and linear mixed effects modeling. For statistical tests, with the exception of values that were Benjamini-Hochberg adjusted for multiple comparisons, P-values < 0.05 were considered significant.

Results: Mean CTT and CT values were lower in FCG eyes relative to normal eyes, but differences were not statistically significant. Mean CD was significantly larger in FCG eyes relative to normal eyes, and there was a significant negative correlation between CD and CTT in FCG (r = -0.8564, corrected P = 0.005). These associations were confirmed in linear mixed effects models.

Conclusions: Eyes with FCG have significantly larger CDs when compared with normal eyes, and larger CDs correlated with decreased corneal sensitivity in this group. Further studies are warranted to explore the effect of buphthalmos and corneal enlargement on corneal sensitivity and innervation in feline subjects with chronic glaucoma.
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http://dx.doi.org/10.1111/vop.12558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129219PMC
January 2019

The post-natal development of intraocular pressure in normal domestic cats (Felis catus) and in feline congenital glaucoma.

Exp Eye Res 2018 01 17;166:70-73. Epub 2017 Oct 17.

Department of Ophthalmology & Visual Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, WI, USA; Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, WI, USA; McPherson Eye Research Institute, University of Wisconsin-Madison, WI, USA. Electronic address:

Intraocular pressure (IOP) is the most consistent risk factor for progressive vision loss in glaucoma. Cats with recessively inherited feline congenital glaucoma (FCG) exhibit elevated IOP with gradual, painless progression of glaucoma similar to humans and are studied as a model of glaucoma in humans and animals. Here, post-natal development of IOP was characterized in normal domestic cats and in cats with FCG caused by a homozygous LTBP2 mutation. Rebound tonometry (TonoVet, ICare Oy, Finland) was used to measure IOP non-invasively, 2-3 times weekly in 63 FCG and 33 normal kittens, of both sexes, from eyelid opening until 3-6 months of age. IOPs in the left and right eyes of both FCG and normal kittens were compared by paired t-test and linear regression. One-way ANOVA and Tukey-Kramer post-tests were used to compare IOP of cats grouped by age and disease status. A p-value <0.05 was considered significant. In the second week of life, mean IOP was 7.16 mmHg (SD = 1.3) in normal kittens and 8.72 mmHg (SD = 1.4) in kittens with FCG. Mean IOP at age 10 weeks was significantly higher in FCG (19.8 mmHg; 95% CI = 17.7, 21.9  mmHg) than in normal kittens (13.2 mmHg; 95% CI = 11.9, 14.5  mmHg). At 3 months of age, IOP in normal cats reached adult values while IOP in FCG cats continued to increase through at least six months of age. These results provide ranges for normal IOP values in young kittens and confirm that IOP is significantly higher than normal by 10wks of age in this spontaneous feline glaucoma model.
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http://dx.doi.org/10.1016/j.exer.2017.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756501PMC
January 2018

Effect of timolol maleate gel-forming solution on intraocular pressure, pupil diameter, and heart rate in normal and glaucomatous cats.

Vet Ophthalmol 2016 Jul 18;19 Suppl 1:91-6. Epub 2016 Mar 18.

Department of Ophthalmology & Visual Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA.

Objective: To determine the effects of once-daily topical treatment with timolol maleate gel-forming solution (GFS) on intraocular pressure (IOP), pupil diameter (PD), and heart rate (HR) in normal cats and cats with feline primary congenital glaucoma (FCG).

Animals Studied And Procedures: A single drop of timolol maleate 0.5% GFS was administered topically to one randomly assigned eye of 18 adult cats (8 normal, 10 FCG) at 8 am for 8 days; the opposite eye served as the untreated control. IOP was measured in both eyes (OU) every 2 h (PD and HR were measured every 4 h), for 14 h total, 1 day prior to and on days 1 and 8 of treatment. In a second treatment phase, a single drop of timolol was administered at 8 pm for 3 nights and IOP, PD, and HR were measured, as above, beginning at 8 am on day 4. Slit-lamp examinations were conducted prior to and after treatment phases. Comparisons of mean IOP, PD, and HR were made at each time point and between treated and untreated eyes by repeated-measures ANOVA and Tukey-Kramer post hoc test, with P < 0.05 considered significant.

Results: Timolol maleate 0.5% GFS had an inconsistent effect on IOP, with maximum IOP-lowering effect (mean = 5.6 mmHg, 17.4%) observed 6 h post-treatment in FCG. The drug caused significant miosis (from 4 to 8 h post-treatment), but had no effect on HR.

Conclusion: Once-daily application of timolol maleate 0.5% GFS may be of limited clinical benefit in the management of feline congenital glaucoma.
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http://dx.doi.org/10.1111/vop.12376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930696PMC
July 2016

Effects of topical corticosteroid administration on intraocular pressure in normal and glaucomatous cats.

Vet Ophthalmol 2016 Jul 15;19 Suppl 1:69-76. Epub 2016 Feb 15.

Department of Surgical Sciences, University of Wisconsin-Madison, Madison, WI, USA.

Objective: The objective of this study was to determine the effect of topical corticosteroid (CCS) therapy on intraocular pressure (IOP) in normal cats and cats with primary feline congenital glaucoma (FCG).

Animals Studied: Five normal and 11 FCG cats were studied in two cohorts.

Procedures: IOP was measured by a single, masked observer, once daily, 3-5 days/week throughout the course of CCS treatment and for up to 11 days after treatment discontinuation. One eye per cat was randomly assigned for treatment twice daily with CCS; balanced salt solution (BSS) applied to the contralateral eye served as a control. Differences between eyes and between weeks of the study period were calculated for each cat. A positive response to CCS was defined as a consistent >15% or >25% higher IOP in the treated relative to control eye in normal and FCG cats, respectively.

Results: A total of 8 of 11 FCG cats responded to topical CCS after 1-5 weeks of treatment with an increase in IOP relative to the untreated eye (maximum IOP discrepancy of 56 mmHg). Two of five normal cats responded to topical CCS with an appreciable, but clinically unimportant increase in IOP in the treated eye (maximum IOP discrepancy of 6.4 mmHg).

Conclusions: Our data indicate that the incidence of steroid-induced IOP elevation in cats is lower than that of previously published feline studies. Cats with preexisting compromise in aqueous humor outflow may show a greater, clinically relevant response to topical CCS than normal cats.
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http://dx.doi.org/10.1111/vop.12355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930713PMC
July 2016

Effect of topical latanoprost 0.005% on intraocular pressure and pupil diameter in normal and glaucomatous cats.

Vet Ophthalmol 2016 Jul 16;19 Suppl 1:13-23. Epub 2015 Jul 16.

Department of Ophthalmology & Visual Sciences, University of Wisconsin - Madison, Madison, WI, 53792, USA.

Objective: To determine the effects of latanoprost on intraocular pressure (IOP) and pupil diameter (PD) in cats with inherited primary congenital glaucoma (PCG) and normal cats.

Animals Studied And Procedures: IOP and PD were measured in both eyes (OU) of 12 adult cats (six normal, six PCG), three times per week for 3 weeks prior to, for 3 weeks during, and for 2 weeks following twice-daily treatment with 0.005% latanoprost to the right eye (OD) and vehicle to the left (control) eye (OS). IOP and PD were measured hourly, for 8 h, 1 day prior to, and on the first and last days of treatment. Aqueous humor flow rate (AHF) was determined at baseline and at the end of the treatment phase in six normal cats.

Results: Mean IOP was significantly lower in treated vs. control eyes of PCG cats, for up to 8 h following a single latanoprost treatment, and a maximal IOP reduction of 63% occurred in treated eyes at 3 h. Latanoprost acutely lowered IOP in cats with PCG, but this effect appeared to diminish over 3 weeks of treatment. AHF was modestly increased in the treated eyes of normal cats after 3 weeks of latanoprost treatment, although IOP was not significantly affected. Latanoprost caused miosis, with rebound mydriasis at 24 h posttreatment, in the treated eyes of all cats.

Conclusions: Further research is needed to determine the suitability and efficacy of latanoprost treatment for long-term IOP-lowering in cats with PCG or other forms of glaucoma.
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http://dx.doi.org/10.1111/vop.12292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755930PMC
July 2016

Identification of adult stem cells in Schwalbe's line region of the primate eye.

Invest Ophthalmol Vis Sci 2014 Oct 16;55(11):7499-507. Epub 2014 Oct 16.

Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany.

Purpose: To identify stem cells in the chamber angle of the monkey eye by detection of 5-bromo-2'-deoxyuridine (BrdU) long-term retention.

Methods: Four cynomolgus monkeys were treated with BrdU via subcutaneous pumps for 4 weeks. The eyes of two animals were processed immediately thereafter (group 1) while in the other animals, BrdU treatment was discontinued for 4 weeks to allow identification of cells with long-term BrdU retention (group 2). The number of BrdU-positive nuclei was quantified, and the cells were characterized by immunohistochemistry and transmission electron microscopy (TEM).

Results: The number of BrdU-positive cells was higher at Schwalbe's line covering the peripheral end of Descemet's membrane than in Schlemm's canal (SC) endothelium, trabecular meshwork (TM), and scleral spur (SS). Labeling with BrdU in SC, TM, and SS was less intense and the number of labeled cells was smaller in group 2 than in group 1. In contrast, in cells of Schwalbe's line the intensity of BrdU staining and the number of BrdU-positive cells was similar when group 1 and 2 monkeys were compared with each other, indicating long-term BrdU retention. Cells that were BrdU-positive in Schwalbe's line region stained for the stem cell marker OCT4. Details of a stem cell niche in Schwalbe's line region were identified by TEM.

Conclusions: We provide evidence for a niche in the Schwalbe's line region harboring cells with long-term BrdU retention and OCT4 immunoreactivity. The cells likely constitute a population of adult stem cells with the capability to compensate for the loss of TM and/or corneal endothelial cells.
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http://dx.doi.org/10.1167/iovs.14-14872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575086PMC
October 2014

Benzalkonium chloride and glaucoma.

J Ocul Pharmacol Ther 2014 Mar-Apr;30(2-3):163-9. Epub 2013 Nov 8.

Department of Ophthalmology & Visual Sciences, School of Medicine & Public Health, University of Wisconsin-Madison , Madison, Wisconsin.

Glaucoma patients routinely take multiple medications, with multiple daily doses, for years or even decades. Benzalkonium chloride (BAK) is the most common preservative in glaucoma medications. BAK has been detected in the trabecular meshwork (TM), corneal endothelium, lens, and retina after topical drop installation and may accumulate in those tissues. There is evidence that BAK causes corneal and conjunctival toxicity, including cell loss, disruption of tight junctions, apoptosis and preapoptosis, cytoskeleton changes, and immunoinflammatory reactions. These same effects have been reported in cultured human TM cells exposed to concentrations of BAK found in common glaucoma drugs and in the TM of primary open-angle glaucoma donor eyes. It is possible that a relationship exists between chronic exposure to BAK and glaucoma. The hypothesis that BAK causes/worsens glaucoma is being tested experimentally in an animal model that closely reflects human physiology.
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http://dx.doi.org/10.1089/jop.2013.0174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991986PMC
November 2014

Effect of nitric oxide on anterior segment physiology in monkeys.

Invest Ophthalmol Vis Sci 2013 Jul 30;54(7):5103-10. Epub 2013 Jul 30.

Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, USA.

Purpose: To determine the effect of the nitric oxide donor, sodium nitroprusside (SNP), and the nitric oxide synthase (NOS) inhibitor, L-nitro-arginine-methylester (L-NAME), on IOP, mean arterial pressure (MAP), pupil diameter (PD), refraction (Rfx), aqueous humor formation (AHF), and outflow facility (OF) in monkeys.

Methods: Monkeys were treated with single or multiple topical treatments of 500 μg SNP or L-NAME to one eye. IOP was determined by Goldmann applanation tonometry, PD with vernier calipers in room light, Rfx by Hartinger coincidence refractometry, AHF by fluorophotometry, and MAP with a blood pressure monitor. OF was determined by two-level constant pressure perfusion following anterior chamber exchange.

Results: Following four topical treatments with 500 μg SNP, 30 minutes apart, IOP was significantly decreased from 2 to 6 hours compared with the contralateral control with the maximum IOP reduction of 20% at 3 hours (P < 0.001). PD, Rfx, and AHF were unchanged. Effects on MAP were variable. OF after SNP exchange was significantly increased by 77% (P < 0.05) at 10(-3) M. Topical L-NAME had no effect on IOP, PD, Rfx, or MAP.

Conclusions: Enhancement of nitric oxide concentration at targeted tissues in the anterior segment may be a useful approach for IOP reduction for glaucoma therapy. Additional studies are warranted before conclusions can be made regarding the effect of NOS inhibition on ocular physiology in nonhuman primates.
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http://dx.doi.org/10.1167/iovs.12-11491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729238PMC
July 2013

Validation of the TonoVet® rebound tonometer in normal and glaucomatous cats.

Vet Ophthalmol 2013 Mar 6;16(2):111-8. Epub 2012 Jun 6.

Department of Ophthalmology & Visual Sciences, University of Wisconsin, Madison, WI 53792, USA.

Objective  To validate intraocular pressure (IOP) readings obtained in cats with the TonoVet(®) tonometer. Animals studied  IOP readings obtained with the TonoVet(®) were compared to IOP readings determined by manometry and by the Tono-Pen XL(™) in 1 normal cat and two glaucomatous cats. TonoVet(®) and Tono-Pen XL(™) readings were also compared in a further six normal and nine glaucomatous cats. Procedures  The anterior chambers of both eyes of three anesthetized cats were cannulated and IOP was varied manometrically, first increasing from 5 to 70 mmHg in 5 mmHg increments, then decreasing from 70 to 10 mmHg in 10 mmHg decrements. At each point, two observers obtained three readings each from both eyes, with both the TonoVet(®) and Tono-Pen XL(™) . IOP was measured weekly for 8 weeks with both tonometers in six normal and nine glaucomatous unsedated cats. Data were analyzed by linear regression. Comparisons between tonometers and observers were made by paired student t-test. Results  The TonoVet(®) was significantly more accurate than the Tono-Pen XL(™) (P = 0.001), correlating much more strongly with manometric IOP. In the clinical setting, the Tono-Pen XL(™) underestimated IOP when compared with the TonoVet(®) . Conclusions  Both the TonoVet(®) and Tono-Pen XL(™) provide reproducible IOP measurements in cats; however, the TonoVet(®) provides readings much closer to the true IOP than the Tono-Pen XL(™) . The TonoVet(®) is superior in accuracy to the Tono-Pen XL(™) for the detection of ocular hypertension and/or glaucoma in cats in a clinical setting.
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http://dx.doi.org/10.1111/j.1463-5224.2012.01038.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3443498PMC
March 2013

1α,25-Dihydroxyvitamin D(3) and its analog, 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D(3) (2MD), suppress intraocular pressure in non-human primates.

Arch Biochem Biophys 2012 Feb 16;518(1):53-60. Epub 2011 Dec 16.

Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706-1544, United States.

Ocular hypertension is the greatest known risk factor for glaucoma that affects an estimated 70 million people worldwide. Lowering intraocular pressure (IOP) remains the mainstay of therapy in the management of glaucoma. By means of microarray analysis, we have discovered that 1α,25-dihydroxyvitamin D(3) (1α,25-(OH)(2)D(3)) regulates genes that are known to be involved in the determination of intraocular pressure (IOP). Topical administration of 1α,25-(OH)(2)D(3) or its analog, 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D(3) (2MD), markedly reduces IOP in non-human primates. The reduction in IOP is not the result of reduced aqueous humor formation, while a 35% increase in aqueous humor drainage by 1α,25-(OH)(2)D(3) was found but this increase did not achieve significance. Nevertheless, our results suggest that 1α,25-(OH)(2)D(3), or an analog thereof, may present a new approach to the treatment of glaucoma.
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http://dx.doi.org/10.1016/j.abb.2011.10.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390938PMC
February 2012

Relationship of aqueous outflow resistance to age and total volume perfused in rhesus and cynomolgus monkeys.

Invest Ophthalmol Vis Sci 2011 Aug 29;52(9):6820-4. Epub 2011 Aug 29.

Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA.

Purpose: The effect of total volume perfused on outflow resistance (the reciprocal of outflow facility) and the effect of age on the rate of change in resistance as a function of total volume were determined in rhesus and cynomolgus monkeys.

Methods: Outflow facility was measured under general anesthesia by two-level constant pressure perfusion in one eye of 22 rhesus and 17 cynomolgus monkeys (ranging in age, respectively, from 4 to 25 and from 3 to 12 years). Total volume perfused was calculated from data obtained during the perfusion.

Results: Resistance decreased in both cynomolgus and rhesus monkeys as total volume perfused increased (-0.085 ± 0.021 and -0.022 ± 0.011 mm Hg/μL/min/μL(tot); P = 0.001 and P = 0.047, respectively). Rate of change in resistance significantly increased in cynomolgus monkeys as total volume perfused increased (0.0018 ± 0.0.0007 mm Hg/μL/min/μL(tot), P = 0.033); however, this was not the case in rhesus monkeys. After accounting for total volume perfused, the rate of change in resistance significantly decreased with increasing age in rhesus monkeys (-0.0068 ± 0.0026 [mm Hg/μL/min]/μL(tot)/y, P = 0.017). There was no significant difference in rate of change in resistance with age, after accounting for total volume, in the cynomolgus monkeys.

Conclusions: The present study supports previous findings indicating that total washout is largely dependent on perfusion volume. However, in populations with old/elderly animals, such as our rhesus group, we found that age does play a significant role in rate of change in resistance, and may be an even more important factor to consider in the rate of resistance change than volume perfused in aged animals.
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http://dx.doi.org/10.1167/iovs.11-7811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3176014PMC
August 2011

Evaluation of rebound tonometry in non-human primates.

Exp Eye Res 2011 Apr 16;92(4):268-73. Epub 2011 Feb 16.

Dept. of Ophthalmology & Visual Sciences, University of Wisconsin-Madison, Madison, WI 53792, USA.

To determine the accuracy and reproducibility of intraocular pressure (IOP) measurements obtained with the TonoVet® rebound tonometer in cynomolgus macaques and to determine the effects of corneal thickness on measurements obtained by the TonoVet®. The anterior chambers of both eyes of anesthetized monkeys were cannulated with branched 23-G needles; one branch was connected to a vertically adjustable reservoir and the other to a pressure transducer. IOP was increased by 5 mmHg increments and then decreased by 10 mmHg decrements. IOP was measured using the TonoVet® at each increment and decrement by 2 independent observers and at every other increment and every decrement by a single observer using 'minified' Goldmann applanation tonometry. Central corneal thickness was measured with a PachPen(TM) ultrasonic pachymeter. TonoVet® readings correlated well with manometric IOP (slope = 0.972, r(2) coefficient = 0.955). No significant differences were observed when comparing eyes or operators; however there was a non-significant trend for TonoVet® readings taken in right eyes to be closer to manometric IOP than those taken in left eyes. The TonoVet® had a non-significant tendency to underestimate manometric IOP. TonoVet® readings obtained during the decremental phase of the experiment were significantly closer (p < 0.004) to manometric IOP than those obtained during the incremental phase. Central corneal thickness significantly increased (p < 0.0001) over the course of the experiment. The TonoVet® rebound tonometer is a reliable and accurate tool for the measurement of IOP in cynomolgus macaques. This tonometer has several advantages, including portability, ease of use, and brief contact with the corneal surface making topical anesthetics unnecessary.
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http://dx.doi.org/10.1016/j.exer.2011.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060952PMC
April 2011

Sodium orthovanadate effect on outflow facility and intraocular pressure in live monkeys.

Exp Eye Res 2010 Oct 8;91(4):486-90. Epub 2010 Jul 8.

Department of Ophthalmology, University of Southern California, Los Angeles, CA 90033, USA.

Sodium orthovanadate (Na(3)VO(4)) is reported to reduce IOP by affecting aqueous formation, but whether it also affects outflow facility (OF) is unclear. We tested the effect of Na(3)VO(4) on OF and intraocular pressure (IOP) in live cynomolgus monkeys, and on actin and cell adhesion organization in cultured human trabecular meshwork (HTM) cells. Total OF (n = 12) was measured by 2-level constant pressure perfusion of the monkey anterior chamber (AC) before and after exchange with 1 mM Na(3)VO(4) or vehicle in opposite eyes. Topical 1% Na(3)VO(4) or vehicle only was given twice daily (each 2 × 20 μL drops) for 4 days to opposite eyes (n = 8), and Goldmann IOP was measured before and hourly after treatment for 6 h on Days 1 and 4. Filamentous actin and vinculin-containing cell adhesions were examined by epifluorescence microscopy after the cells had been incubated with 1 mM Na(3)VO(4) for 24 h. A) In monkeys, Na(3)VO(4) increased OF by 29.3 ± 8.8% (mean ± s.e.m.) over the perfusion interval when adjusted for baseline and contralateral eye washout (p = 0.01; n = 12). B) Day 1 baseline IOP was 16.2 ± 1.5 mmHg in treated eyes and 15.9 ± 1.3 mmHg in the contralateral control eyes. Following treatment on Day 1, IOP was no different (p > 0.05) between treated eyes and control eyes at any time-point or compared to baseline. Day 4 mean IOP averaged over hours 2-6 was 13.5 ± 0.8 mmHg in treated eyes and 16.1 ± 0.2 mmHg in control eyes. Treated eye IOP was lower than its Day 4 baseline (p < 0.005), lower than control eyes for the same Day 4 interval (p = 0.009), and lower than the Day 1 baseline (p = 0.0000). Control eye IOP on Day 4 was not significantly different from baseline on Day 1. C) Incubation of HTM cells with 1 mM Na(3)VO(4) for 24 h caused a loss of actin stress fibers and vinculin-containing adhesions. Cell retraction and separation was also observed in vanadate-treated cultures. Reformation of actin stress fibers, vinculin-containing adhesions and confluent monolayers occurred within 24 h after Na(3)VO(4)-containing culture medium was replaced with Na(3)VO(4)-free medium. Ocular administration of Na(3)VO(4) to live monkeys significantly increases OF and reduces IOP. Na(3)VO(4) reversibly disrupts actin and cell adhesion organization and causes retraction and separation of cultured HTM cells. Na(3)VO(4) increases pressure-dependent outflow in live monkeys. Altered actin architecture in the TM may play a part in this increased OF.
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http://dx.doi.org/10.1016/j.exer.2010.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946324PMC
October 2010

Effect of the age cross-link breaker alagebrium on anterior segment physiology, morphology, and ocular age and rage.

Trans Am Ophthalmol Soc 2009 Dec;107:146-58

Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, USA.

Purpose: To determine the effects of the advanced glycation end product (AGE) cross-link breaker alagebrium on intraocular pressure (IOP), accommodation (ACC), outflow facility (OF), anterior segment morphology, and ocular AGE and receptors for AGE (RAGE) in older rhesus monkeys.

Methods: Six rhesus monkeys (aged 19 to 20 years) received 3 or 4 intracameral and intravitreal (final concentration, 1 mM) injections of alagebrium to one eye over 2.5 to 3 weeks and vehicle to the opposite eye. ACC and OF responses to intramuscular or intravenous pilocarpine were measured at baseline and at 1 to 2 weeks and 2, 4, and 6 months postinjection. IOP was measured prior to all injections, ACC, and OF measurements. Monkeys were euthanized 3 to 6 months after the last injection, the eyes were enucleated, and anterior and posterior segments were examined by electron microscopy or immunohistochemistry.

Results: No significant differences were found in ACC or IOP at any time point after alagebrium treatment. Baseline OF was higher (37.0 +/- 6.0%; P < or = .005) in alagebrium-treated vs control eyes at 6 months postinjection. In 3 monkeys, alagebrium-treated eyes, compared to control eyes, showed greater focal plaque formation, similar to that seen in primary open-angle glaucoma, in the juxtacanalicular meshwork/inner wall of Schlemm's canal. No changes in anterior segment AGE or RAGE were detectable. However, some areas of the retina and optic nerve head exhibited decreased AGE and increased RAGE immunostaining.

Conclusions: Intraocular injection of AGE cross-link breakers is an unlikely approach for glaucoma therapy. However, it may generate a model for further study of glaucomatous-like plaque formation. Immunohistochemical changes in the posterior segment in response to alagebrium warrant further functional studies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2814573PMC
December 2009

Corneal decompensation following bleb revision with absolute alcohol: clinical pathological correlation.

Arch Ophthalmol 2006 May;124(5):738-41

Dept. of Ophthalmology and Visual Sciences, University of Wisconsin, 2870 University Avenue, Madison, WI 53705-3631, USA.

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http://dx.doi.org/10.1001/archopht.124.5.738DOI Listing
May 2006

Adenovirus-mediated gene therapy using human p21WAF-1/Cip-1 to prevent wound healing in a rabbit model of glaucoma filtration surgery.

Arch Ophthalmol 2002 Jul;120(7):941-9

Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, 1300 University Ave, Room 6640 MSC, Madison, WI 53706-1532, USA.

Objective: To determine if adenovirus-mediated p21(WAF-1/Cip-1) (p21) gene therapy can prevent fibroproliferation and wound healing in a rabbit model of glaucoma filtration surgery.

Methods: In vitro studies were performed using rabbit Tenon fibroblasts harvested from fresh tissue. In vivo studies were conducted in New Zealand white rabbits. A full-thickness sclerotomy was performed under a limbal-based conjunctival flap. Reagents tested included a replication-deficient recombinant adenovirus containing the human p21 gene (rAd.p21); the nonspecific marker gene for green fluorescent protein or beta-galactosidase; mitomycin, 0.5 mg/mL; and balanced saline solution. Each treatment was applied episclerally for 5 minutes before the sclerotomy using a soaked cellulose sponge placed under the surgically created conjunctival flap. Independent experiments were conducted to (1) monitor changes in intraocular pressure during a 30-day period after treatment and examine surgical site histological features, (2) examine changes in bleb morphologic features over 30 days, (3) determine outflow facility 14 days after treatment, and (4) examine the localization and persistence of rAd.p21 expression between 3 and 60 days after treatment.

Results: Treatment of Tenon fibroblasts with rAd.p21 resulted in a dose-dependent inhibition of DNA synthesis and cell growth in vitro. In vivo, rAd.p21 inhibited wound healing and fibroproliferation after filtration surgery, comparably to mitomycin. Mitomycin caused notable thinning of the bleb wall. In addition, 2 of the 5 mitomycin-treated eyes exhibited an abscess with hypopyon and hyalitis 30 days after surgery, which was not observed in any of the rAd.p21-treated eyes. None of the treatments resulted in a significantly sustained decrease in intraocular pressure during the 30-day period, although mitomycin treatment resulted in a significant (P =.02) increase in outflow facility 2 weeks after surgery in separate animals. Mitomycin- and rAd.p21-treated eyes had functioning blebs at the end of the experiment based on slitlamp examination.

Conclusions: Mitomycin and rAd.p21 were effective in preventing fibroproliferation and wound healing in a rabbit model of glaucoma surgery. Mitomycin treatment increased outflow facility in normal-pressure eyes.

Clinical Relevance: Gene therapy with rAd.p21 may provide an effective antiproliferative for glaucoma filtration surgery, without the complications associated with mitomycin.
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http://dx.doi.org/10.1001/archopht.120.7.941DOI Listing
July 2002
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