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Variants in the chromosomal region 10q26 are strongly associated with an increased risk for age-related macular degeneration (AMD). Two potential AMD genes are located in this region: ARMS2 and HTRA1 (high-temperature requirement A1). Previous studies have suggested that polymorphisms in the promotor region of HTRA1 result in overexpression of HTRA1 protein. This study investigated the role of HTRA1 overexpression in the pathogenesis of AMD. Transgenic Htra1 mice overexpressing the murine protein in the retinal pigment epithelium (RPE) layer of the retina were generated and characterized by transmission electron microscopy, immunofluorescence staining and Western Blot analysis. The elastic layer of Bruch's membrane (BM) in the Htra1 transgenic mice was fragmented and less continuous than in wild type (WT) controls. Recombinant HTRA1 lacking the N-terminal domain cleaved various extracellular matrix (ECM) proteins. Subsequent Western Blot analysis revealed an overexpression of fibronectin fragments and a reduction of fibulin 5 and tropoelastin in the RPE/choroid layer in transgenic mice compared to WT. Fibulin 5 is essential for elastogenesis by promoting elastic fiber assembly and maturation. Taken together, our data implicate that HTRA1 overexpression leads to an altered elastogenesis in BM through fibulin 5 cleavage. It highlights the importance of ECM related proteins in the development of AMD and links HTRA1 to other AMD risk genes such as fibulin 5, fibulin 6, ARMS2 and TIMP3.

AimTo determine clinical correlations to intraocular vascular endothelial growth factor A (VEGF-A) suppression times (VSTs) on the treatment of neovascular age-related macular degeneration (nAMD) with ranibizumab (Lucentis) or aflibercept (Eylea).MethodsSeven of 89 treatment-naïve nAMD eyes showed persistent choroidal neovascular membrane (CNV) activity throughout a spectral domain optical coherence tomography (SD-OCT)-driven pro re nata (PRN) regimen of intravitreal ranibizumab injections over 28±4 months. The treatment was switched to PRN aflibercept injections and patients were followed for another 15±2 months. A total of 160 aqueous humour specimens were collected before the intravitreal injections, and their VEGF-A concentrations were assayed by Luminex multiplex bead analysis (Luminex, Austin, Texas, USA). Intraocular VEGF-A concentrations were correlated to CNV activity shown by SD-OCT.ResultsThe mean duration of suppression of VEGF-A concentrations in aqueous humour below the lower limit of quantification of our assay was 34±5 (26–69) days for ranibizumab and 67±14 (49–89) days for aflibercept (p<0.001). The percentual reduction of central retinal volume (CRV) 6 weeks after injection was higher for aflibercept compared with ranibizumab (p=0.009). The time point of clinical re-activity occurred about 50% earlier than the respective VST for each ranibizumab and aflibercept.ConclusionsThe VST under aflibercept treatment exceeded that under ranibizumab treatment by a factor of 2. This difference correlated with differential clinical CRV reduction 6 weeks after the respective injection. For both medications, clinical activity was found at a time point as early as 50% of the individual VST.Trial registration numberNCT01213667, post-results

Background To identify factors and problems influencing treatment adherence in patients undergoing anti-VEGF therapy for neovascular age-related macular degeneration (AMD) under real-life conditions. Methods Cross-sectional study was conducted of 95 patients receiving ranibizumab therapy on a pro re nata (PRN) regimen with monthly controls in a tertiary health care clinic. Monthly controls included best corrected visual acuity, slit-lamp examination and spectral-domain optical coherence tomography. Adherence was measured using Kaplan–Meier time-to-discontinuation analysis. Patients were asked to respond to a 16-item questionnaire covering items such as anxiety, subjective benefit, and financial issues of therapy. Results Forty-two men and 53 women were included. After a mean follow-up time of 675 days (range 63–1008), adherence was 81.1 % (77/95). The mean number of follow-up visits was 19 (3–30), the mean number of intravitreal injections was ten (3–23). Seven patients withdrew from treatment due to subjective dissatisfaction with benefit. Other reasons for loss to follow-up were death in one case, serious general disease in three patients, and treatment options closer to home in five cases. Two patients cancelled further follow-up after treatment cessation due to terminal fibrosis. 62.1 % of patients were afraid of a negative examination result, whereas 19.0 % were afraid of intravitreal injections. A major problem was travel to and from the hospital (46.3 %), with 61.5 % of patients requiring escort. Conclusion Despite necessary monthly visits, patients showed a high adherence to therapy. The major problem was travel to and from the hospital. From the patients’ point of view, anxiety of a negative examination result was more pronounced than fear of intraocular injections, which would be an argument for continuous injections rather than for a PRN regimen.

Background Limited data exist collating most of the associated factors for strabismus in one analysis. The aim of this study was to assess the prevalence of strabismus and to analyse associated factors in former preterm and full-term infants. Methods In this cross-sectional study, 239 former preterm infants with gestational age (GA) ≤ 32 weeks and 264 former full-term born infants with GA ≥ 37 weeks underwent detailed ophthalmologic examination in the age of 4–10 years and perinatal data assessment for risk factor analysis. Ophthalmologic examinations included cover testing, best corrected visual acuity, cycloplegic objective refraction, slit lamp as well as fundus examinations. For association analysis with strabismus, the following data was collected and included in multivariable analysis: sex, age at examination, anisometropia, myopic and hyperopic refractive error (≥ 3 dioptres), astigmatism, birth weight percentile, gestational age, retinopathy of prematurity occurrence, maternal age at childbirth, mother smoking, breastfeeding < 3 months, artificial ventilation, intraventricular bleeding, and other perinatal adverse events. Results Overall, 4/264 (2%) full-term infants, 15/125 (12%) preterm-infants with GA 29–32 weeks without ROP, 13/59 (22%) preterm infants with GA ≤ 28 weeks without ROP and 14/55 (26%) with GA ≤ 32 weeks with retinopathy of prematurity were affected by strabismus. In the multivariable regression model strabismus was associated with GA (OR = 0.84 per week; p  = 0.001), hyperopic refractive error (OR = 4.22; p  = 0.002) and astigmatism (OR = 1.68; p  = 0.02). Conclusion This investigation highlights that low gestational age and refraction of the eye are independent risk factors for strabismus, while the other factors show less independent influence.

Purpose Pre-operative antisepsis of the conjunctiva is indicated prior to intraocular surgery to prevent post-interventional endophthalmitis. In Germany, antisepsis with 5% povidone-iodine (PI) aqueous solution is explicitly required prior to intravitreal injections (IVI), and also generally recommended for intraocular surgery. However, this concentration often leads to a foreign body sensation and an unpleasant burning in combination with dry eye symptoms. Postoperative eye pain, persistent corneal epithelial defects, and a risk of keratitis are further side effects. Due to the repetitive nature of IVI, these symptoms are particularly present in IVI patients. A reduced concentration may be favorable to decrease patient discomfort. A 1.25% PI solution does not increase the iodine concentration in the aqueous humor and is also used for prophylaxis of ophthalmia neonatorum and for preoperative antisepsis; in both cases the renal iodine excretion stays in a physiological range thus thyroid diseases are no contraindication for its use. Thus, the efficacy of reduced concentrations of PI should be evaluated in vitro. Methods PI with dilutions below 5% (0.625 − 2.5% serial 1:2 dilution) was tested in vitro in a quantitative suspension assay and in a quantitative carrier test without and with addition of matrices to identify their antimicrobial effect against Staphylococcus epidermidis , Pseudomonas aeruginosa , Cutibacterium acnes and Candida albicans . Results No differences in the antimicrobial effect was seen due to reduced concentrations of PI in comparison to a 5% solution. However, a trend was seen regarding the required contact time of the antiseptic solution. Conclusion The in-vitro tests have shown adequate antisepsis of 1.25% PI prior to intraocular surgery. However, it is important to pay attention to a sufficient contact time of the antiseptic of about 1 min before ophthalmologic intervention. In order to give final recommendations, in vivo testing is needed to build a robust data foundation. Highlights 5% PVP-Iodine solution prior IVI leads to unpleasant side effects. In vitro, antimicrobial effect of 5% PI is comparable to that of 1.25% PI. Addition of matrices had no visible effects on antimicrobial activity. Contact time of 1 min is necessary.

Background Intravitreal injections of ranibizumab are the standard of care for neovascular age-related macular degeneration (AMD). In clinical trials, comparable efficacy has been shown for either monthly injections or as needed injections upon monthly controls. Unlike in trial settings, treatment in clinical routine is often delayed by complex approval procedures of health insurance and limited short-term surgical capacities. Methods Eighty-nine patients with neovascular AMD were followed for 12 months. Early treatment diabetic retinopathy study (ETDRS) visual acuity (VA), Radner reading VA and spectral domain optical coherence tomography were performed monthly, with additional fluorescein angiography if needed. After an initial loading phase of three consecutive monthly intravitreal injections with ranibizumab, re-injections were performed when recurrent activity of choroidal neovascularization (CNV) was detected. Results After an initial increase to a value of +5.0 ± 11.87 ETDRS letters from baseline, VA constantly decreased over 12 months to a value of −0.66 ± 16.82 ETDRS letters below baseline. Central retinal thickness (CRT) decreased from a value of 438.1 ± 191.4 μm at baseline to a value of 289.9 ± 138.6 μm after initial therapy and stabilized at a value of 322.4 ± 199.5 μm. Loss of VA during latency between indication to treat and treatment was significantly greater than re-gain of VA after re-initiation of therapy (−2.2 ± 5.0 versus 0.4 ± 7.4 letters; p  = 0.046). Conclusions Latency between indication to treat and treatment is responsible for irreversible VA deterioration. A successful PRN treatment regimen for neovascular AMD requires immediate access to therapy after indication.

Purpose To evaluate cytokine expression in the aqueous humor of patients with primary open-angle glaucoma (POAG) after previous glaucomatous and/or cataract surgery, and to determine the effect of intraocular pressure (IOP)-lowering eye drops on cytokine expression. Methods This prospective consecutive case study included 32 eyes diagnosed with POAG (19 with previous surgery and 13 without previous surgery, treated with topical antiglaucoma medication) and 12 eyes without signs of glaucoma. The Luminex 200 multiplex bead immunoassay was used to measure 27 cytokines in aqueous humor. Results Eyes suffering from POAG, with previous surgery, had significantly elevated concentrations of IL-6, IL-8, CCL2, CXCL9, and HGF, and a significantly lower concentration of CCL5, compared to POAG eyes without previous surgery, treated only with topical antiglaucoma medication. When compared with cataract controls, eyes with POAG and previous surgery had significantly elevated levels of G-CSF, IL-8, IL-12, CXCL10, and HGF, and significantly decreased concentrations of IL-17, CCL5, and VEGF in aqueous humor. In a comparison between POAG eyes without previous surgery and cataract controls, the cataract control eyes had significantly higher levels of IL-6 and CCL2, as the only significant difference. Conclusions POAG is associated with an aqueous inflammatory response in the aqueous humor, which is significantly elevated in eyes with previous surgery. In contrast, preoperative IOP-lowering eye drops did not significantly alter the anterior chamber milieu. The results of the current study indicate that filtration surgery has a higher success rate in eyes that have not experienced previous surgery.

Background Proliferative vitreoretinopathy (PVR) is characterized by epithelial to mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells and consecutive formation of fibrous membranes, leading to retinal redetachment. Transforming growth factor beta (TGF-ß) has been suggested to play an important role in this process, but the role of TGF-ß isoforms is unknown. Methods In pigmented rabbits ( n  = 14), PVR was induced by cryopexy and a full-thickness limbus-parallel incision. PVR was evaluated by indirect ophthalmoscopy. Concentrations of TGF-ß isoforms were determined by multiplex bead assay analysis in aqueous humor (AH) and vitreous samples. EMT marker vimentin was analyzed by western blot. Masson’s-trichrome, haematoxilin and eosine (H&E), and immunohistochemical analysis for EMT marker alpha SMA were performed on cross-sections of eyes. Results PVR was induced in all treated eyes. The number of quadrants affected by PVR was 1 ( n  = 5), 2 ( n  = 2), 3 ( n  = 2), 4 ( n  = 5). Vimentin and alpha SMA were expressed during PVR development. During PVR development, both TGF-ß1 levels (AH: p  = 0.001; vitreous: p  = 0.002) and TGF-ß2 levels increased (AH: p  = 0.027; vitreous: p  = 0.02), while TGF-ß3 was not detected at any timepoint. The increase was more pronounced for TGF-ß1 than for TGF- ß2 (AH: p  = 0.002; vitreous: p  = 0.0005), and only TGF-ß1 correlated with the amount of PVR ( p  = 0.024, r  = 0,723). Conclusions Development of PVR membranes was accompanied by a pronounced upregulation of TGF-ß1, rather than TGF-ß2. Therefore TGF-ß1 could be a promising target for inhibition of PVR.

Background Retinal argon laser coagulation is an established procedure for induction of choroidal neovascularization (CNV) in rodents. This study aimed to evaluate the in-vivo and ex-vivo morphology and variability of laser-induced CNV spots over time. Methods Female C57/Bl/6 mice, 3–6 months of age, were treated with five spots of retinal argon laser coagulation per eye (150 mW, 100 ms, 50 μm). In-vivo fluorescein angiography (FA) and standard high-resolution spectral-domain optical coherence tomography (SD-OCT) were performed on day (d) 0, d1, d4, d7, d14 and d21. Ex-vivo histology, CD31 immunostaining, flatmount and confocal microscopy were also conducted. CNV size in the retinal and choroidal focus, CNV morphology, central retinal thickness (CRT) and FA CNV activity grading were assessed in-vivo at all times and compared to the ex-vivo assessments. Results SD-OCT revealed sub-retinal and intra-retinal fluid, and permitted evaluation of longitudinal morphologic changes of the induced CNV. Laser spot area in FA and CRT in SD-OCT did not differ in longitudinal evaluation. CNV could not be consistently outlined on SD-OCT images, and CNV volume as assessed on SD-OCT did not change over time. Significant CNV activity changes were only found in FA CNV activity grading, peaking on d4 and decreasing by d7. Conclusions Non-invasive SD-OCT provides additional morphological information on laser-induced CNV. However, reliable evaluation of CNV requires FA. Spontaneous regression of CNV activity within 14 days after induction has to be taken into account when utilizing this model for testing the efficacies of potential future treatments.

Objective To analyse macular retinal and choroidal layer thickness in former preterm and full-term infants and to assess associated perinatal influence factors and functional correlation. Methods This prospective controlled, cross-sectional, hospital-based study in a tertiary center of maximum care examined former preterm infants with a gestational age (GA) ≤ 32 weeks and full-term neonates currently aged 4 to 10 years. We investigated data from 397 infants, analysing total foveal retinal thickness and six distinct macular retinal layer and choroidal layer measurements via spectral-domain optical coherence tomography. Multivariable linear regression analysis was performed to investigate associations of layer thickness with GA and retinopathy of prematurity (ROP). Results Total retinal thickness in the fovea was thicker in former preterm infants with GA ≤ 28 weeks and in those with GA between 29–32 weeks compared to full-term infants independently of ROP. Occurrence of ROP was also associated with increased foveal thickness. Ganglion cell layer together with inner plexiform layer (GCL+IPL) was thinner in infants with GA ≤ 28 weeks than in full-term infants at 1000 and 2000μm distance from the fovea, but no association with ROP was present. Similar results were found for the photoreceptor layer. Total foveal retinal thickness was associated with low visual function. Conclusion This study identified low gestational age and ROP occurrence as main determinants for foveal thickening. Furthermore, thinned GCL+IPL measurements were associated with lower gestational age. This study highlights the prognostic value of these maturity parameters influencing retinal morphology, which may affect visual function.