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Ophthalmic research [journal]
- Thrombospondin-1 Is Produced by Retinal Glial Cells and Inhibits the Growth of Vascular Endothelial Cells. [JOURNAL ARTICLE]
- Ophthalmic Res 2014 Aug 14; 52(2):81-88.
Background/Aims: By the release of antiangiogenic factors, Müller glial cells provide an angiostatic environment in the normal and ischemic retina. We determined whether Müller cells produce thrombospondin-1 (TSP-1), a known inhibitor of angiogenesis. Methods: Secretion of TSP-1 by cultured Müller cells was determined with ELISA. Slices of rat retinas and surgically excised retinal membranes of human subjects were immunostained against TSP-1 and the glial marker vimentin. The effects of TSP-1 on the growth of bovine retinal endothelial cells (BRECs) and activation of ERK1/2 were determined with DNA synthesis and migration assays, and Western blotting, respectively. Results: Cultured Müller cells secrete TSP-1 under normoxic and hypoxic (0.2% O2) conditions. Secretion of TSP-1 was increased in hypoxia compared to normoxia. In rat retinal slices, glial, retinal ganglion, and possibly horizontal cells were stained for TSP-1. Retinal glial cells in preretinal membranes from human subjects with nonhypoxic epiretinal gliosis (macular pucker) and proliferative diabetic retinopathy, respectively, were immunopositive for TSP-1. Exogenous TSP-1 reduced the VEGF-induced proliferation and migration of BRECs and decreased the phosphorylation level of ERK1/2 in BRECs. Conclusion: The data suggest that Müller cells are one major source of TSP-1 in the normal and ischemic retina. Glia-derived TSP1 may inhibit angiogenic responses in the ischemic retina. © 2014 S. Karger AG, Basel.
- Intravitreal Functional Plasminogen in Eyes with Branch Retinal Vein Occlusion. [JOURNAL ARTICLE]
- Ophthalmic Res 2014 Jul 23; 52(2):74-80.
Purpose: To evaluate whether intravitreal functional plasminogen is elevated in eyes with branch retinal vein occlusion (BRVO) and to discover whether intravitreal plasminogen activities are correlated with the extent of blood-retina barrier (BRB) breakdown. Methods: Our study is a prospective case series of 20 consecutive patients with BRVO and 10 consecutive patients serving as controls. Vitreous taps were extracted from the central vitreous body and plasminogen was functionally determined in an innovative, ultrasensitive p-nitroanilide reaction after activation with streptokinase (100% of normal, %N = functional plasminogen in pooled normal citrated plasma). Intravitreal VEGF levels were assayed to estimate BRB breakdown. Results: Intravitreal functional plasminogen was detected in all analyzed samples (n = 30) and mean (±SD) plasminogen activities were found to be 0.97 ± 1.06%N (range: 0.03-3.9%N). Patients suffering from BRVO exhibited significantly higher intravitreal plasminogen (1.35 ± 1.11%N) in comparison with controls (0.20 ± 0.21%N, p < 0.001). Intravitreal VEGF concentrations in the BRVO group (576 ± 547 pg/ml) were significantly higher than these in controls (111 ± 120 pg/ml, p = 0.003). There was a significant correlation between intravitreal functional plasminogen and intravitreal VEGF levels (r = 0.519, p = 0.003). Conclusions: Intravitreal functional plasminogen is significantly elevated in eyes suffering from BRVO and correlates with the extent of BRB breakdown. The induction of posterior vitreous detachment by using intravitreally administered recombinant tissue plasminogen activator (enzymatic vitreolysis) should be explored in further investigations. © 2014 S. Karger AG, Basel.
- Detection of Fovea-Threatening Diabetic Macular Edema by Optical Coherence Tomography to Maintain Good Vision by Prophylactic Treatment. [JOURNAL ARTICLE]
- Ophthalmic Res 2014 Jul 18; 52(2):65-73.
Background/Aims: To establish a screening and treatment method for fovea-threatening diabetic macular edema (DME) using spectral-domain optical coherence tomography (SD-OCT). In order to maintain good visual acuity (VA), focal/grid laser treatment for screened fovea-threatening DME was evaluated based on macular thickness map images produced by SD-OCT. Methods: In 66 diabetic eyes with no visual deterioration, the sensitivity and the specificity of SD-OCT without the use of mydriatics for the detection of fovea-threatening DME were determined. A definite diagnosis of DME was made under mydriasis, using slitlamp biomicroscopy with a contact lens. Eyes with fovea-threatening DME then underwent prophylactic focal/grid laser treatment. The main outcome measures were corrected VA and central macular thickness (CMT). Results: A definitive diagnosis of DME was made in 5 of the 66 eyes, while macular thickening above the 99th percentile was detected in 11 (Cirrus®) or 13 (RS-3000®) eyes by SD-OCT. The focal/grid laser treatment of the 5 eyes with fovea-threatening DME successfully maintained good VA, which was 0.91 ± 0.76 (average: 20/22; 0.04 ± 0.12 logMAR) before treatment and 0.89 ± 0.70 (average: 20/22; 0.05 ± 0.15 logMAR; p = 0.88) 1 year afterwards. The average CMT was stable before and after focal/grid lasering at 302 ± 29 and 329 ± 55 µm, respectively (p = 0.99). Conclusions: The detection of fovea-threatening DME is feasible by SD-OCT without using mydriatics. Prophylactic treatment, such as with focal/grid lasers, was effective in maintaining good VA by avoiding an otherwise highly likely foveal involvement. © 2014 S. Karger AG, Basel.
- Host-Derived Endothelial Regeneration of Corneal Transplants in a Rat Keratoplasty Model. [JOURNAL ARTICLE]
- Ophthalmic Res 2014 Jul 1; 52(2):60-64.
Background: It has been observed that formerly rejected opaque corneal transplants can regain clarity in the rat. We hypothesized that graft endothelium is regenerated by the host. Therefore, we used green fluorescent protein (GFP) transgenic rats to assess the origin of cells following keratoplasty. Methods: Allogeneic corneal transplantations were carried out between Fischer strain rats as graft donors and GFP-transgenic Lewis rats as recipients. In a second group, syngeneic transplantations were performed between GFP-negative Lewis donors and GFP-positive Lewis recipients, where endothelial-cell-free grafts after mechanical endothelial debridement were used. All grafts were followed up clinically for signs of opacity and rejection. After 6 weeks, corneal flatmounts counterstained with DAPI were analyzed by confocal microscopy. Results: Syngeneic transplantation of endothelial-cell-free grafts led to medium opacity levels without rejection and to subsequent clearing. All grafts showed a population of GFP-positive, host-derived endothelial cells on the graft after 6 weeks. In the allogeneic transplantation group, all grafts but one were rejected after a median of 17 days. While the graft that was not rejected maintained the GFP-negative transplant endothelium, all formerly rejected grafts showed GFP-positive endothelium on the transplant after 6 weeks, accompanied by clinical clearing of the graft. Conclusion: GPF positivity shows that in both a syngeneic and an allogeneic setting, the host-derived corneal endothelium can compensate for the endothelial cell loss of the graft. Following rejection, the grafts are repopulated by host-derived endothelial cells in the rat. This finding demonstrates a high regenerative capacity of the peripheral corneal endothelium in the rat, which should be considered whenever interpreting rat keratoplasty results. © 2014 S. Karger AG, Basel.
- Geographic Atrophy Progression in Eyes with Age-Related Macular Degeneration: Role of Fundus Autofluorescence Patterns, Fellow Eye and Baseline Atrophy Area. [JOURNAL ARTICLE]
- Ophthalmic Res 2014 Jun 27; 52(2):53-59.
Background/Objective: To evaluate if fundus autofluorescence (FAF) patterns around geographic atrophy (GA) and the status of the fellow eye have an impact on GA progression. Methods: We included 54 eyes of 35 patients with GA. Areas of GA were quantified by RegionFinder software. Results: GA progression rates in eyes with a diffuse trickling pattern (median 1.42 mm(2)/year) were significantly higher than in normal eyes (median 0.22 mm(2)/year) and eyes with other diffuse FAF patterns (median 0.46 mm(2)/year). Eyes with a banded pattern had a significantly higher progression rate (median 0.81 mm(2)/year) than those without any FAF abnormalities (p = 0.038). The group with baseline total atrophy of the eyes <1 disk area (DA; median 0.42 mm(2)) had an inverse relation with GA progression compared to the groups with baseline atrophy >1 DA (p < 0.05). Conclusion: Diffuse trickling and banded patterns may have an impact on GA progression and may serve as prognostic factors. © 2014 S. Karger AG, Basel.
- Effects of multiple doses of voriconazole on the vision of healthy volunteers: a double-blind, placebo-controlled study. [Journal Article]
- Ophthalmic Res 2014; 52(1):43-52.
Purpose:To investigate the effects, and their reversibility, of multiple oral voriconazole doses on a variety of visual tests in healthy male volunteers.
Methods:Single-center, double-blind, randomized, placebo-controlled, parallel-group study in 36 volunteers who received voriconazole (n = 18, 400 mg every 12 h on day 1, then 300 mg every 12 h for 27.5 days) or matched placebo (n = 18). Electroretinograms (ERGs) and ophthalmological examinations were performed at screening, throughout the study and at follow-up.
Results:Fifteen (83.3%) volunteers treated with voriconazole experienced ≥1 treatment-related visual adverse events (AEs); these included enhanced visual perceptions, blurred vision, color vision changes and photophobia. No serious AEs were reported. Voriconazole reduced from baseline scotopic maximal a- and b-wave amplitude, shortened implicit time and decreased oscillatory potential amplitude compared with placebo. Under photopic conditions, the 30-Hz flicker response amplitude was significantly reduced and was accompanied by a slight but nonsignificant prolongation of peak time. These effects did not progress in degree over the treatment period, and mean changes from baseline in ERG parameters were similar to placebo by day 43 (14 days after end of treatment). In the first week, color vision discrimination was impaired in the tritan axis, although this resolved by end of treatment and was similar to placebo by day 43. Mean deviation in the static visual field indicated increased sensitivity following voriconazole treatment, correlating with decreased amplitude in conjunction with shortened implicit time.
Conclusions:Effects of voriconazole on altered visual perception, ERG, color vision and static visual field thresholds are nonprogressive over a treatment period and reversible. It is hypothesized that voriconazole has a pharmacological effect on rod and cone pathways including a possible mechanism of disinhibition that reversibly puts the retina in a more light-adapted state and leads to increased relative contrast sensitivity. © 2014 S. Karger AG, Basel.
- Cytokines in Tears during the Secondary Keratoconjunctival Responses Induced by Allergic Reaction in the Nasal Mucosa. [JOURNAL ARTICLE]
- Ophthalmic Res 2014 Jun 4; 52(1):32-42.
Background: Allergic keratoconjunctivitis (KC) can occur in a primary form due to an allergic reaction taking place in the conjunctivae or in a secondary form induced by nasal allergy. Objectives: To search for the cytokine changes in tears accompanying the secondary keratoconjunctival response types (SKCR), caused by the nasal allergy. Methods: In 43 KC patients developing 15 immediate (SIKCR), 16 late (SLKCR) and 12 delayed (SDYKCR) responses to nasal provocation tests with allergens (NPT), the NPTs were repeated with subsequent recording of cytokine concentrations in tears up to 72 h. Results: The SIKCRs (p < 0.001), occurring 10-120 min after the NPT, were accompanied by significant changes (p < 0.05) of interleukin (IL)-4, IL-6, IL-10, IL-12p70 and granulocyte-macrophage colony-stimulating factor (GM-CSF). The SLKCRs (p < 0.01), appearing 5-12 h after the NPT, were associated with significant changes (p < 0.05) of IL-3, IL-4, IL-5, IL-8, IL-10, tumor necrosis factor (TNF)-α, GM-CSF and granulocyte colony-stimulating factor. The SDYKCRs (p < 0.01), occurring 24-48 h after the NPT, were accompanied by significant changes (p < 0.05) of IL-2, IL-8, IL-10, interferon-γ, transforming growth factor-β and TNF-α. Conclusions: The particular SKCR types, induced by an allergic reaction in the nasal mucosa, were accompanied by different cytokine profiles in the tears, suggesting involvement of different hypersensitivity mechanisms. These results also stress the diagnostic usefulness of NPTs combined with monitoring of ocular features in KC patients who did not respond satisfactorily to the topical ophthalmological treatment. © 2014 S. Karger AG, Basel.
- Fluorescein angiography and spectral-domain optical coherence tomography for monitoring anti-VEGF therapy in myopic choroidal neovascularization. [Journal Article]
- Ophthalmic Res 2014; 52(1):25-31.
To evaluate the agreement between fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD-OCT) in detecting myopic choroidal neovascularization (CNV) activity during bevacizumab treatment.Thirty-four patients with subfoveal myopic CNV were prospectively enrolled. FA and SD-OCT were performed at baseline and at all planned monthly visits. After the first injection, additional treatments were administered following detection of fluid on SD-OCT and/or leakage on FA. κ-Analysis was performed to examine the agreement between FA and SD-OCT.At baseline, FA and SD-OCT agreed in 26/34 cases (κ=0.23); sensitivity and specificity were 77.4 and 66.7%, respectively. Seven eyes presented leakage on FA with no fluid on SD-OCT, 1 case showed intraretinal fluid on SD-OCT and no leakage on FA. At the 1-month examination, specificity and κ-value improved, and 30/34 cases showed complete concordance. At the 3- and 4-month examinations, a discordance was noted in 6 cases. From the 5-month examination on, a correspondence was achieved in at least 30/34 cases and reached a perfect match in 11 sessions.Our study confirms the key role of FA in diagnosing myopic CNV. It seems possible there may be a role for SD-OCT in assisting FA to monitor the myopic CNV activity during anti-vascular endothelial growth factor antibody treatment.
- The Effect of TC14012 on Alkali Burn-Induced Corneal Neovascularization in Mice. [JOURNAL ARTICLE]
- Ophthalmic Res 2014 May 14; 52(1):17-24.
Aims: To observe the effect of TC14012 (a CXCR4 antagonist and CXCR7 agonist) on alkali burn-induced corneal neovascularization (CNV) in a mouse model. Methods: CNV was induced in vivo by alkali burns on the corneas of BALB/c mice. A total of 54 mice treated with alkali burns were randomly divided into 3 groups, each of which received one of the following treatments: bilateral subconjunctival injections of TC14012 for 3 consecutive days, bilateral subconjunctival injections of balanced saline (BS) for 3 consecutive days or no treatment (blank control). The areas of CNV were measured on days 3, 7 and 14 after the alkali burns. CXCR4, CXCR7, vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP) mRNAs were detected and quantified by real-time reverse transcription PCR on days 7 and 14. Additionally, the expression of the proteins CXCR4, CXCR7, VEGF, β-arrestin 2, total ERK1/2 and phospho-ERK1/2 was determined by Western blotting. Results: On day 7 after the alkali burns, the CNV area, VEGF, MMP-2 and MMP-9 mRNA levels, and VEGF, β-arrestin 2 and phospho-ERK1/2 protein levels were increased in the TC14012 group compared with the nontreatment and BS groups. However, on day 14, the CNV area, CXCR4, CXCR7, VEGF, MMP-2 and MMP-9 mRNA levels, and the CXCR4, CXCR7, VEGF and β-arrestin 2 protein levels were significantly decreased in the TC14012 group. Conclusions: TC14012 initially enhanced alkali burn-induced CNV but reduced CNV in later stages. In addition to CXCR4, CXCR7 is involved in the pathogenesis of CNV. © 2014 S. Karger AG, Basel.
- Influence of Primary Diagnosis and Complications on Visual Outcome in Patients Receiving a Boston Type 1 Keratoprosthesis. [JOURNAL ARTICLE]
- Ophthalmic Res 2014 May 14; 52(1):9-16.
Purpose: To analyse how primary diagnosis and complications affect the evolution of post-operative visual acuity (VA). Methods: We performed retrospective chart analysis on 59 eyes in 57 patients with various diagnoses, most of which were non-standard indications for Boston type 1 keratoprosthesis (Kpro) implantation. The follow-up period was at least 3 months. Patients were classified based on the evolution of post-operative VA: group A demonstrated stable VA improvement, group B lost VA improvement and group C no significant VA improvement. Results: We assigned 46% of our cases to group A with stable VA improvement, 32% to group B with lost VA improvement, and 22% to group C with no VA improvement. The number of graft failures before Kpro implantation did not influence VA outcome. Except for the relatively good VA outcome in chemical burn and radiation injury patients, there seems to be no association between primary diagnosis and positive or negative VA outcome. Only 9% of patients with posterior segment complications and 20% with infections and associated pathologies were assigned to group A. Conclusion: Most cases (78%) showed improvement in VA after Boston type 1 Kpro (groups A and B). Posterior segment complications and infections mostly resulted in persistent loss of vision. These complications should be prevented and carefully treated. © 2014 S. Karger AG, Basel.