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- Cardiakidis Myers, Anna, et al.
(author)
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Intravitreal Injection of Triamcinolone Acetonide into Healthy Rabbit Eyes Alters Retinal Function and Morphology
- 2013
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In: Current Eye Research. - : Informa UK Limited. - 0271-3683 .- 1460-2202. ; 38:6, s. 649-661
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Journal article (peer-reviewed)abstract
- Aim: To study the effects of intravitreally injected triamcinolone acetonide (TA) and/or its preservative benzyl alcohol (BA) in healthy rabbit retina. Methods: Forty-eight rabbits (aged 4 months, body weight approximate to 3 kg) were randomized into four groups (n=12). They were examined with electroretinography (ERG) prior to drug exposure, and then injected intravitreally with a combination of TA and BA, TA without BA, BA alone or a balanced saline solution (BSS). The electroretinograms were assessed 1 week and 7 weeks post-injection. The rabbits were euthanized and the sectioned retinas were studied. Immunohistochemical analysis was performed on rods, cones, rod bipolar cells, horizontal cells, amacrine cells and Muller cells. Results: Rabbits injected with BA showed a significantly lower rod-mediated b-wave amplitude than the controls 1 week after injection. TA-injected rabbits demonstrated significantly higher a- and b-wave amplitudes in the total retinal response than the controls 1 week post-injection. The rabbits injected with TA+BA demonstrated a significantly higher b-wave amplitude in the total retinal response than the controls 1 week after injection. The significantly higher a-wave amplitude in the total retinal response remained in the TA-injected rabbits 7 weeks after injection. Immunohistochemistry revealed that protein kinase C alpha (PKC alpha) was down-regulated in both the perikarya and the axons of bipolar cells in histological sections from rabbit retina injected with TA+BA, BA and TA. Conclusions: Intravitreal injection of the preservative BA reduces the isolated rod-mediated retinal response in the rabbit, transiently and selectively. Intravitreal injection of TA increases the total retinal response in the rabbit up to seven weeks after injection. The effects observed are not only limited to retinal function, but also include changes in the expression of PKC alpha in rod bipolar cells, indicating drug-related interference with normal retinal physiology in the healthy rabbit eye.
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| 2. |
- Cardiakidis Myers, Anna, et al.
(author)
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Retinal function and morphology in rabbit after intravitreal injection of VEGF inhibitors.
- 2012
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In: Current Eye Research. - : Informa UK Limited. - 0271-3683 .- 1460-2202. ; 37:5, s. 399-407
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Journal article (peer-reviewed)abstract
- Purpose/Aim: To explore changes in morphology and function in the rabbit retina after intravitreal high-dose injection of three commonly used VEGF inhibitors. Materials and methods: Forty-eight rabbits of mixed strain (6 months of age, body weight ≈ 3 kg) were randomized into four groups (n = 12). They were examined with full-field electroretinography (ERG) and with multifocal electroretinography (mf ERG) prior to drug exposure. The rabbits were then injected intravitreally with bevacizumab, ranibizumab, pegaptanib, or with a balanced saline solution. The dose of VEGF inhibitor was chosen to achieve a vitreous concentration approximately three times higher than the one clinically used in the adult human eye. ERG was then performed 8 weeks postinjection, and mf ERG 9 weeks postinjection. After 9 weeks, the rabbits were sacrificed and the sectioned retina was studied. Immunohistochemical analysis was performed of rods, cones, rod bipolar cells, horizontal cells, and amacrine cells. Results: Rabbits injected with VEGF inhibitors all showed significantly lower amplitude of the dark-adapted b-wave rod-mediated response to dim light, compared to the rabbits injected with BSS. The a wave (reflecting photoreceptor function) in the response to single flash white light was however not affected. Immunohistochemistry revealed a significant reduction in PKC labeling of rod bipolar cells in pegaptanib and ranibizumab injected eyes whereas bevacizumab injected eyes displayed normal PKC labeling. No apparent morphological change was seen with markers for remaining retinal cells. Conclusions: Our results indicate that the use of high-dose intravitreal VEGF inhibitors in the rabbit eye affects rod-mediated retinal function and PKC expression in rod bipolars cells for at least 9 weeks after drug administration. The three VEGF inhibitors influence the retina slightly differently. These results are important for the understanding of drug action and when devising therapeutical strategies in new areas such as retinopathy of prematurity where vitreous volume is significantly lower compared to the adult eye.
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| 3. |
- Cardiakidis Myers, Anna, et al.
(author)
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Retinal Function and Morphology in the Rabbit Eye after Intravitreal Injection of the TNF Alpha Inhibitor Adalimumab.
- 2014
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In: Current Eye Research. - : Informa UK Limited. - 0271-3683 .- 1460-2202. ; 39:11, s. 1106-1116
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Journal article (peer-reviewed)abstract
- Abstract Aim: To study the effects of the tumor necrosis factor alpha inhibitor adalimumab on rabbit retina after injection into the vitreous body. Methods: Forty-eight rabbits of mixed strain (9-12 months old, weighing ≈ 3.5 kg) were randomized into four groups. Adalimumab was injected at one of two concentrations (1.25 mg or 2.5 mg) into the eyes of two groups, and balanced salt solution into the eyes of the third group. The fourth group acted as controls. Full-field electroretinography (ffERG) was performed before injection and 1 and 6 weeks post-injection. At 6 weeks post-injection the rabbits were euthanized and the sectioned retinas were studied. Retinal histology was studied with hematoxylin-eosin staining. Immunohistochemical analysis was performed on rods, cones, rod bipolar cells, horizontal cells, amacrine cells and Müller cells. Results: No significant difference in ffERG amplitudes or implicit times was observed between the four groups at any time point. Histological and immunohistochemical findings were similar in all groups. Conclusions: Injection of adalimumab into the vitreous body of healthy rabbits, at doses up to 2.5 mg, does not appear to be toxic to the rabbit retina.
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| 4. |
- Cardiakidis Myers, Anna, et al.
(author)
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Rifabutin accumulates in the lens and reduces retinal function in the rabbit eye
- 2009
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In: Retina. - 0275-004X. ; 29:1, s. 106-111
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Journal article (peer-reviewed)abstract
- PURPOSE: To study the toxicology of rifabutin in the rabbit eye with emphasis on retinal function and histopathology.METHODS: Seven rabbits received a daily dose of rifabutin during 15 months. Six rabbits receiving only the vehicle were used as controls. Repeated standardized full-field electroretinograms (ERG) were assessed. After discontinuing treatment, the rabbits were killed and the cornea, the lens, and the sectioned retina was studied. Immunhistochemistry directed against vimentin, glial fibrillaryacidic protein (GFAP), protein kinase C (PKC), and peanut agglutinin (PNA) was performed.RESULTS: Rifabutin was detected in serum of the treated rabbits. During treatment, the full-field ERG demonstrated significantly reduced b-wave amplitudes in the total rod-cone response as well as in the isolated rod and cone response compared with the recordings before treatment. The control rabbits did not demonstrate a reduction of the ERG amplitudes. The treated rabbits developed a discoloration of the lens, not seen in the control group. No retinal pathology was demonstrated using immunohistochemical methods.CONCLUSION: Rifabutin causes a discoloration of the lens and reduces both rod and cone function in rabbits, but does not alter retinal morphology. Previous reports on ocular side effects caused by rifabutin are supported by the results of this study.
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| 6. |
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| 7. |
- Molnar, Anna E. C., et al.
(author)
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Macular function measured by binocular mfERG and compared with macular structure in healthy children
- 2015
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In: Documenta Ophthalmologica. - : Springer Science and Business Media LLC. - 0012-4486 .- 1573-2622. ; 131:3, s. 169-176
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Journal article (peer-reviewed)abstract
- To create normative data in children from binocular multifocal ERG (mfERG) recordings and compare results with the macular thickness. Forty-nine 5- to 15-year-old healthy, full-term children were examined with Espion Multifocal System, using DTL electrodes. The stimulus matrix consisted of 37 hexagonal elements. Amplitudes, implicit times and response densities (presented in three rings) of the first-order component P1 were analyzed. Measurements of macular thickness were performed with spectral-domain Cirrus OCT. There were no significant differences between right and left eyes regarding mfERG recordings. Median P1 implicit times of Rings 1-3 of the 46 right eyes were 30.0, 30.0 and 30.8 ms and response densities 20.5, 10.9 and 7.6 nV/deg(2), respectively. Implicit time was longer in boys than in girls (p = 0.009, 0.039, 0.005 in Rings 1-3) and was correlated with age (r (s) = 0.417, 0.316, 0.274 in Rings 1-3). Implicit time in Ring 1 correlated significantly with the inner circle of the OCT measurements (p = 0.014). Binocular mfERG with DTL electrodes is a reliable test of the central macular function in children and correlates with macular structure. As previously not shown, there was a significant difference in implicit time between boys and girls.
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| 8. |
- Molnar, Anna E. C., et al.
(author)
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Reduction of rod and cone function in 6.5-year-old children born extremely preterm
- 2017
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In: JAMA Ophthalmology. - : American Medical Association (AMA). - 2168-6165 .- 2168-6173. ; 135:8, s. 854-861
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Journal article (peer-reviewed)abstract
- OBJECTIVE To compare retinal function via full-field electroretinographic (ffERG) recordings in 6.5-year-old children born extremely preterm with children born at term. DESIGN, SETTING, AND PARTICIPANTS A subcohort studywas conducted from July 1, 2010, to January 15, 2014, of the national Extremely Preterm Infants in Sweden Study, including preterm children (<27 weeks' gestational age) and children born at term, at 6.5 years of age and living in the Uppsala health care region in Sweden. Full-field electroretinography was performed binocularly, using DTL electrodes and electroretinographic (ERG) protocols with flash strengths of 0.009, 0.17, 3.0, and 12.0 candelas (cd)/s/m2, together with 30-Hz flicker and 3.0 cd/s/m2 single-cone flash. MAIN OUTCOMES AND MEASURES The ffERG recordingswere analyzed, and their associations with gestational age and retinopathy of prematurity were examined. RESULTS Adequate ffERG recordings were obtained from 52 preterm children (19 girls and 33 boys; mean [SD] age at examination, 6.6 [0.1] years) and 45 children born at term (22 girls and 23 boys; mean [SD] age at examination, 6.6 [0.1] years). Lower amplitudes of the combined rod and cone responses (the a-wave of the dark-adapted ERG protocol of 3.0 cd/s/m2: Mean difference, -48.9 μV [95%CI, -80.0 to -17.9 μV]; P=.003; the a-wave of the dark-adapted ERG protocol of 12.0 cd/s/m2: Mean difference, -55.7 μV [95%CI, -92.5 to -18.8 μV]; P = .004), as well as of the isolated cone response (30-Hz flicker ERG: Mean difference, -12.1 μV [95%CI, -22.5 to -1.6 μV]; P = .03), were found in the preterm group in comparison with the group born at term. The implicit time of the combined rod and cone responses (the a-wave of the dark-adapted ERG protocol of 12.0 cd/s/m2) was longer (mean difference, 1.2 milliseconds [95%CI, 0.3-2.0 milliseconds]; P = .01) in the preterm group, as were the isolated cone responses (30-Hz flicker ERG: Mean difference, 1.2 milliseconds [95%CI, 0.5-1.8 milliseconds]; P < .001), than in the group born at term. No association was found between the ffERG recordings and gestational age or retinopathy of prematurity in the preterm group. CONCLUSIONS AND RELEVANCE Both rod function and cone function were reduced in children born extremely preterm when compared with children born at term. There was no association with retinopathy of prematurity in the preterm group, which suggests that being born extremely preterm may be one of the main reasons for a general retinal dysfunction.
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| 9. |
- Molnar, Anna
(author)
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Structure and Function of the Retina in Children Born Extremely Preterm and in Children Born At Term
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Background: Optical coherence tomography (OCT), multifocal electroretinography (mfERG) and full-field electroretinography (ffERG) give important information about retinal structure and function.Purpose: To collect normative data of macular Cirrus Spectral domain (SD)-OCT assessments and of mfERG measurements of healthy children (papers I and II). To assess the macular thickness with Cirrus SD-OCT and the retinal function with ffERG in 6.5-year-old children born extremely preterm and in children born at term (papers III and IV).Methods: Study participants aged 5-15 years and living in Uppsala County were randomly chosen from the Swedish Birth Register (papers I and II). In papers III and IV, the study participants consisted of children born extremely preterm and children born at term – all were aged 6.5 years. In paper III, the children were living in Stockholm and Uppsala health care regions and, in paper IV, in Uppsala health care region only. Macular thickness was assessed with Cirrus SD-OCT and macular function with mfERG, using the Espion Multifocal system and DTL-electrodes. The retinal function was assessed with ffERG and DTL-electrodes, using the Espion Ganzfield system.Results: Altogether, 58 children participated in paper I and 49 children in paper II. In paper I, the repeatability and reproducibility of the OCT assessments were good. In paper II, the results of the mfERG measurements were in accordance with retinal cone density and there were no significant differences between the right and left eyes. In paper III, 134 preterm children and 145 children born at term constituted the study population. The central macular thickness was significantly thicker in the preterm group than in the control group. Within the preterm group, gestational age (GA), former retinopathy of prematurity (ROP) and male gender were all important risk factors for an increased macular thickness. In paper IV, 52 preterm children and 45 control children constituted the study population. Significantly lower amplitudes and prolonged implicit times of the combined rod and cone responses, as well as of the isolated cone responses, were found in the preterm group when compared with the control group. In paper IV, there was no association between GA, ROP or male gender and the ffERG assessments.Conclusion: Normative data of Cirrus SD-OCT and mfERG assessments were reported. The results of the assessments were reliable. Children aged 6.5 years, born extremely preterm, had a significantly thicker central macula and both rod and cone function were significantly reduced in comparison to children born at term. ROP had an influence on retinal structure but not retinal function in the present cohorts. Our results suggest that retinal development is abnormal in children born extremely preterm. Long-term follow-up studies are necessary in order to evaluate the functional ophthalmological outcome in this vulnerable population of children growing up today.
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| 10. |
- Panneman, Daan M., et al.
(author)
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Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis
- 2023
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In: Frontiers in Cell and Developmental Biology. - : Frontiers Media SA. - 2296-634X. ; 11
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Journal article (peer-reviewed)abstract
- Introduction: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are two groups of inherited retinal diseases (IRDs) where the rod photoreceptors degenerate followed by the cone photoreceptors of the retina. A genetic diagnosis for IRDs is challenging since >280 genes are associated with these conditions. While whole exome sequencing (WES) is commonly used by diagnostic facilities, the costs and required infrastructure prevent its global applicability. Previous studies have shown the cost-effectiveness of sequence analysis using single molecule Molecular Inversion Probes (smMIPs) in a cohort of patients diagnosed with Stargardt disease and other maculopathies. Methods: Here, we introduce a smMIPs panel that targets the exons and splice sites of all currently known genes associated with RP and LCA, the entire RPE65 gene, known causative deep-intronic variants leading to pseudo-exons, and part of the RP17 region associated with autosomal dominant RP, by using a total of 16,812 smMIPs. The RP-LCA smMIPs panel was used to screen 1,192 probands from an international cohort of predominantly RP and LCA cases. Results and discussion: After genetic analysis, a diagnostic yield of 56% was obtained which is on par with results from WES analysis. The effectiveness and the reduced costs compared to WES renders the RP-LCA smMIPs panel a competitive approach to provide IRD patients with a genetic diagnosis, especially in countries with restricted access to genetic testing.
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