bluuebunny/crossref_metadata_2025 huggingface dataset:
The relationship between ambient air pollution and glaucoma phenotypes in a large community cohort
Authors: Chua Sharon , Khawaja Anthony , Reisman Charles , Khaw Peng , Patel Praveen , Foster Paul
Published: December 2019

Purpose

Glaucoma is reportedly more frequent in people living in urban areas and more than 91% of the world’s population live in areas with air pollution above WHO recommended limits. However, few studies have examined the association between air pollution and risk of glaucoma.

Methods

UK Biobank participants aged 40–69 years old completed a detailed baseline questionnaire and underwent ophthalmic and air pollution assessments. Ambient particulate matter with an aerodynamic diameter <2.5 µm (PM2.5) concentration was estimated. Eye measures including self‐reported glaucoma status, corneal compensated intraocular pressure (IOPcc), Goldmann‐correlated intraocular pressure (IOPg) and thickness of retinal layers were collected. Total average thickness of the retinal nerve fibre layer (mRNFL), ganglion cell‐inner plexiform layer (mGC‐IPL), ganglion cell complex (mGCC) and total macular layer were obtained from spectral‐domain optical coherence tomography (SD‐OCT). Multivariable regression models were used to evaluate associations between PM2.5 concentration with self‐reported glaucoma, IOP and retinal layer thickness.

Results

In multivariable regression analysis, participants resident in areas with higher PM2.5 concentration were more likely to report a diagnosis of glaucoma (OR = 1.13, 95% CI 1.08 to 1.19, per interquartile range [IQR] increase). Higher PM2.5 concentration was associated with thinner mGC‐IPL (β = −0.47 µm, 95% CI −0.56 to −0.39, per IQR increase), mGCC (β = −0.21 µm, 95% CI −0.33 to −0.09, per IQR increase) and total macular thickness (β = ‐0.36 µm, 95% CI −0.56 to −0.15, per IQR increase), while a thicker mRNFL (β = 0.25 µm, 95% CI 0.18 to 0.32, per IQR increase) was observed. There was no relationship between PM2.5 concentration and IOP that was biologically relevant (IOP: β = 0.06 mmHg, 95% CI 0.03 to 0.09, per IQR increase; IOPcc (β = 0.08 mmHg, 95% CI 0.01 to 0.15, highest versus lowest quartile).

Conclusion

In this large adult population, higher PM2.5 concentration was associated with a self‐reported diagnosis of glaucoma, and thinner inner retinal layers, consistent with structural changes seen in glaucoma. No biologically relevant relationship was observed for either IOPcc and IOPg. This suggest that PM2.5 concentration may be a potential modifiable risk factor for glaucoma that is independent of IOP.
Nation‐wide survival outcomes of metastatic uveal melanoma with best supportive care
Authors: Rantala Elina , Hernberg Micaela , Kivelä Tero
Published: December 2019

Purpose

To report overall survival (OS) of patients with metastatic uveal melanoma who received best supportive care (BSC).

Methods

Retrospective cohort study of patients with primary uveal melanoma treated between January 1999 and December 2016 at a national referral center and diagnosed with metastasis before December 2016. The patients who received BSC as the only treatment were enrolled. Complete data for all patients was requested from all hospitals that had participated in management. Age, gender, time from primary tumour to metastasis, presence of symptoms, locations of metastases, largest metastasis diameter, WHO performance index, and liver function tests were collected. Predicted median survival time calculated according to the Ophthalmic Oncology Group (OOG)‐validated Helsinki University Hospital Working Formulation (HUCH‐WF) was used to assign patients to stages IVa, IVb, and IVc, which correspond to predicted survival times of >12, <12–6, and <6 months, respectively. Primary endpoint was OS estimated with Kaplan–Meier analysis.

Results

The median OS was 1.6 months (range 0–65.8, 95% CI 1.0–3.4) from the beginning of treatment in 84 patients. According to the HUCH‐WF, 20 (23%) patients with known survival time were assigned to stage IVa, 16 (19%) to IVb, 41 (49%) to IVc, and 7 (8%) were missing data. OS according to the HUCH‐WF was 11.1 months (95% CI 8.3–22.0) in stage IVa, 3.4 months (95% CI 1.0–10.0) in IVb, and 0.7 months (95% CI 0.4–0.9) in IVc.

Conclusions

HUCH‐WF can differentiate by OS patients who receive BSC. The OS for stage IVa disease was similar to the median OS of 12.8 months reported in a meta‐analysis for all patients who receive active treatment. However, divided by HUCH‐WF, comparison with our data suggest that patients who receive active treatment for stage IVa and IVb disease might live on average 7 months longer (OS 18.6, 10.7, and 4.6 months for stage IVa, IVb, and IVc, respectively, in the OOG validation study).
Intravitreal kinetics of macromolecules in rats and rabbits: evaluation with ocular fluorophotometry
Authors: Sadeghi Amir , Toropainen Elisa , Valtari Annika , Puranen Jooseppi , Ruponen Marika , Ranta Veli‐Pekka , Urtti Arto
Published: December 2019

Purpose

Rats and rabbits are widely used in preclinical ocular pharmacodynamics and pharmacokinetics. Despite the wide application in the evaluation of intravitreally injected drugs, there is no information about scaling of vitreal kinetics between rats and rabbits. In this study, the vitreal kinetics of macromolecules in rats and rabbits were evaluated using in vivo fluorophotometry.

Methods

In order to elucidate the pharmacokinetics of macromolecules and drug delivery systems we used ocular fluorophotometry that is a noninvasive technique for non‐invasive and quantitative measurement of fluorescence signals from the eye. Molecules with different molecular weights (peptide 4.5 kD, FITC‐hyaluronic acid 770 kD, FITC‐dextran 500 kD and fluorescein 330 D, FITC‐dextran 10 kD and FITC‐dextran 150 kD) were injected to the vitreous of rabbits and rats. The concentrations of these molecules were quantified in the vitreous at various time.

Results and Discussion

The data were used to calculate kinetic parameter, such as vitreal elimination half‐life and clearance. For example, the vitreal elimination half‐lives of FITC‐hyaluronic acid 770 kD in rabbits and rats were about 280 hr and 9 hr, respectively. Overall the vitreal elimination half‐lives of the compounds in the rats were much faster than in the rabbits. Since rats are widely used in the retinal pharmacodynamics studies, the fast elimination of macromolecules from the rat vitreous should be taken into account when scaling the doses from rats to rabbits and man.
Inhibition of adaptor proteins MAVS and TXNIP reduces inflammasome activation in RPE cells
Authors: Ranta‐aho Sofia , Bhattarai Niina , Korhonen Eveliina , Piippo Niina , Hytti Maria , Kaarniranta Kai , Kauppinen Anu
Published: December 2019

NLRP3 inflammasome is one of the inflammatory factors linked to the development of age‐related macular degeneration (AMD). For its activation, several regulatory proteins are needed. Mitochondrial antiviral‐signaling protein (MAVS) recruits NLRP3 inflammasome to the surface of mitochondria, where it is activated. Another adaptor protein, thioredoxin (TRX)‐interacting protein (TXNIP) binds to NLRP3 promoting its activation. It has been shown that the silencing of MAVS or TXNIP leads to the reduced secretion of IL‐1β, which is a marker of NLRP3 activation. Here, we tested whether the silencing of MAVS or TXNIP reduces the activation of NLRP3 also on human retinal pigment epithelial cells (RPE). ARPE‐19 cells we tranfected with three different commercial MAVS and TXNIP siRNAs. The NLRP3 was primed with IL‐1α and activated by blocking proteasomal and autophagosomal clearance with MG‐132 and Bafilomycin A (BafA), respectively. Thereafter, the levels of IL‐1β and NLRP3 were detected using the ELISA method and cytotoxicity was measured by the lactate dehydrogenase (LDH) assay. Specific siRNAs to MAVS and TXNIP significantly reduced the secretion of IL‐1β from human RPE cells upon inflammasome activation by the blockade of intracellular clearance. Additionally, silencing of TXNIP protected from cell membrane rupturing and reduced the amount of extracellular NLRP3, which indicates attenuated inflammasome activity. In RPE cells, regulatory proteins TXNIP and MAVS are involved in the activation of NLRP3 inflammasome.
Complete blood cell count indexes in non‐arteritic anterior ischemic optic neuropathy
Authors: Pinna Antonio , Porcu Tiziana , Marzano Jacopo , Boscia Francesco , Paliogiannis Panagiotis , Carru Ciriaco , Zinellu Angelo
Published: December 2019

Purpose

To investigate the role of some blood count‐derived inflammation biomarkers in non‐arteritic anterior ischemic optic neuropathy (NAION).

Methods

37 newly diagnosed NAION patients and 37 sex‐ and age‐matched subjects without NAION were recruited between January 2017 and December 2018. A blood sample was taken and complete blood cell count was performed. The following blood cell count‐derived indexes were evaluated: neutrophil/lymphocyte ratio (NLR), derived NLR [dNLR = neutrophils/(white blood cells‐neutrophils)], platelet/lymphocyte ratio (PLR).

Results

NAION patients had significantly higher median values of mean platelet volume (MPV; p = 0.01), red cell distribution width (RDW; p = 0.015), NLR (p = 0.03), and dNLR (p = 0.01). There were no significant differences in white blood cells, lymphocytes, neutrophils, and PLR.

Conclusion

Results suggest that MPV, RDW, NLR and dNLR may be disease biomarkers in NAION. Larger scale studies are necessary to confirm these findings.
Positive correlation of blood reflux in Schlemm’s canal and reduction of intraocular pressure after ab interno 360‐degree viscocanalostomy in primary open‐angle glaucoma
Authors: Grieshaber Matthias , Pienaar Ané , Stegmann Robert
Published: December 2019

Purpose

The aim was to investigate the association between blood reflux in Schlemm’s canal (SC) and the reduction of intraocular pressure (IOP) after ab interno viscocanalostomy in primary open‐angle glaucoma (POAG).

Methods

Non‐comparative study of consecutive patients with early to moderate POAG underwent ab interno viscocanalostomy with a follow‐up time of at least 12 months. Indications for glaucoma surgery were inadequate IOP and /or intolerance to eye drops. Through clear cornea incision, the IOP was lowered below episcleral venous pressure by aspiration of aqueous from the anterior chamber to provoke blood reflux into the SC. After a 1‐min waiting period, a goniolens was placed on the globe, and blood reflux was observed and classified into three filling patterns: no filling, partly filling and complete filling. Then, the anterior chamber was filled with viscoelastic material and ab interno viscocanalostomy was performed with a microcatheter system (Visco360).

Results

In provocative gonioscopy, 12 eyes had no blood reflux (group 1), 19 had patchy blood reflux (group 2), and 14 had complete blood reflux (group 3). For the different reflux patterns, the preoperative IOP was 17.0 mmHg (SD ± 2.8) mmHg for group 1, 18.4 mmHg (SD ± 2.0) for group 2, and 22.2 mmHg (SD ± 2.8) for group 3. The IOP difference between preoperative and 6 months postoperative was 1.8 mmHg (SD ± 1.2) group 1, 4.9 mmHg (SD ± 0.9) for group 2, and 9.9 mmHg (SD ± 2.5) for group 3 (p < 0.001). In a linear regression model, there were highly significant differences between the groups even after adjustment for preoperative IOP (p < 0.001).

Conclusions

Blood reflux in SC seems to be a significant positive prognostic indicator in uneventful ab interno viscocanalostomy concerning IOP reduction, possibly representing the patency of the physiologic aqueous outflow system.
Improvements of retinal sensitivity, visual acuity, and central retinal thickness after intravitreal injection of aflibercept in patients with wet age‐related macular degeneration
Authors: Nizawa Tomohiro , Kitahashi Masayasu , Baba Takayuki , Iwase Takehito , Kubota Mariko , Hattori Yoko , Kawasaki Yohei , Iwase Takayuki , Sato Takatoshi , Ogawa Shoko , Sugawara Takeshi , Yamamoto Shuichi
Published: December 2019

Purpose

To determine the retinal sensitivity, best‐corrected visual acuity (BCVA), and central retinal thickness (CRT) in patients with wet age‐related macular degeneration (wAMD) after intravitreal aflibercept (IVA).

Methods

An observational study conducted at the Chiba University Hospital between October 2016 and March 2019. All patients were treatment‐naïve with wet AMD and received three monthly (induction phase) and bimonthly (maintenance phase) of IVA for 12 months. Each patient underwent spectral‐domain OCT, fundus autofluorescence, indocyanine green angiography, and microperimetry. The primary outcome was the change in the retinal sensitivity from the baseline at 6 months (6 M). The retinal sensitivity was determined by the average of 13 points within the central 2 degrees and measured by Macular Integrity Assessment (MAIA, CenterVue, Italy). The secondary outcomes were the changes in the BCVA, CRT, presence of subretinal exudations, and greatest linear dimension (GLD) at 12 M relative to the baseline.

Results

Thirty‐seven eyes of 37 patients were studied. The mean age was 72.8 ± 7.4 years (mean ± SD), and there were 26 men (72.2%). There were 18 eyes (49%) with typical wAMD and 19 eyes with PCV (51%). The mean retinal sensitivity was significantly improved from 15.4 ± 4.2 dB at the baseline to 19.9 ± 5.0 dB at 3M, 20.3 ± 4.5 dB at 6M, and 20.9 ± 4.6 dB at 12M (all p < 0.0001 relative to baseline). The mean BCVA at the baseline was 0.35 ± 0.23 logMAR units which improved to 0.22 ± 0.28 logMAR units at 12 months (p = 0.001). The BCVA was improved or maintained at 12M in 71% of the patients. The mean CRT and GLD were significantly reduced at 12M (p < 0.001). Twenty‐two eyes (71%) had a dry macula at 12M.

Conclusions

These results indicate that IVA applied with this protocol will improve not only the morphology (CRT) but also the physiology (BCVA, retinal sensitivity) of the retina at 12M.
Quantification of Bruch’s Membrane calcification in Pseudoxanthoma Elasticum: a proof‐of‐concept study using SD‐OCT
Authors: Risseeuw Sara , Bennink Edwin , Poirot Maarten , Imhof Saskia , van Leeuwen Redmer , Ossewaarde ‐ van Norel Jeanette
Published: December 2019

Purpose

Progressive calcification of Bruch’s membrane (BM) causes considerable visual morbidity in patients with pseudoxanthoma elasticum (PXE). Since calcification is hyperreflective in SD‐OCT imaging, our aim was to quantify BM calcification using SD‐OCT.

Methods

We performed a ‘proof of concept’ study with 45 PXE patients under 40 years and 25 age‐matched controls. Spectralis HRA‐OCT imaging was performed, consisting of 7 macular B‐scans with 250 µm distance in between. Retinal segmentation was performed using OCT Explorer (and visually verified per B‐scan on correct segmentation and an intact outer retinal layer). Matlab was used to extract and average z‐axis intensity profiles for each set of B‐scans. Mean layer intensities normalized to the GCL‐IPL layer were used for descriptive analysis. Intensity ratios, defined as the retinal pigment epithelium (RPE)‐BM peak intensity relative to another layer, were calculated to quantify RPE‐BM intensity. These ratios were compared with the control group to find a discriminative value using ROC analysis.

Results

The age of the groups were comparable, with a mean age of 27.0 years in PXE patients and 26.9 years in the control group. The median normalized intensity of the RPE‐BM was 34.0 (IQR 24.7–42.3) in patients with PXE, compared to 20.4 (IQR 17.2–24.4) in normal controls (p < 0.001). The RPE‐BM/ ellipsoid zone (EZ) ratio was the most discriminative with an AUC of 0.97 (95% CI 0.92–1). In PXE patients, the median ratio was 1.79 (IQR 1.33; 2.63) compared to 0.75 in controls (IQR 0.61; 0.97). The RPE‐BM/EZ ratio increased with age in PXE patients: 1.14 (IQR 1.01–1.32) in patients under 20 (n = 7), 1.81 (IQR 1.35–2.19) in patients aged 20–30 years (n = 22) and 2.35 (IQR 1.68–3.08) in patients aged 30–40 (n = 16) (p = 0.010).

Conclusions

We demonstrated that BM calcification is quantifiable as hyperreflectivity in young PXE patients, that the RPE‐BM/EZ intensity ratio can discriminate between PXE and normal controls, and that this intensity ratio increases with age.
Etiologies and treatment of manifest vertical deviations: series of 95 patients
Authors: Boucenna William , Taright Nabil , Rahmania Nesrine , Morfeq Hussein , Jany Benjamin , Promelle Veronique , Bremond Gignac Dominique , Milazzo Solange
Published: December 2019

Purpose

Manifest vertical deviations (MVD) are permanent vertical misalignment of one or both eyes. A hypertropia is a form of vertical strabismus where one eye is deviated upwards in comparison to the fellow eye, as opposed to hypotropia, where one eye is deviated downwards. The aim of this study is to analyze the different etiologies associated with MVD and their management.

Methods

A retrospective analysis of patients referred to our center with MVD between September 2013 and February 2016 was done. A total of 95 patients were included. Each patient received an orthoptic and complete ophthalmological assessment. The outcomes studied were the age, sex of the patient, etiologies associated with MVD, angle of deviation in primary position at near and distance fixation as well as the proposed treatment.

Results

Fifty men (53%) and 45 women (47%) were included with a mean age of 33 years (range 2‐86 years), without statistically significant difference of affected eye or to gender. The mean deviation angle, at far and near distances, was 10 diopters. The majority of MVD were acquired (46%), congenital (35%), residual (13%) and consecutive (6%). The most common etiology was cranial nerves IV paralysis (29% n = 26). The other etiologies were cranial nerves III paralysis (20% n = 19), residual MVD (12% n = 10), strabismus (6% n = 5), consecutive MVD (5% n = 4),cranial nerves VI paralysis (3% n = 3), Graves’ disease (3% n = 3), orbital floor fracture (1% n = 1), other etiologies (21% n = 24). Treatment was surgical for 52% of patients, prism correction (25%), eye occlusion (4%), optical correction alone (5%). Eleven per cent are regressed spontaneously and treatment was not specified for the remaining 3%.

Conclusions

MVD are the most common finding in acquired oculomotor palsy. The variability of the clinical forms and etiologies makes their proper diagnosis and testing challenging. Indications of the treatment are guided by functional repercussion.
Diabetes exacerbates the early RGCs loss of function in the DBA/2J inherited mouse model of Glaucoma
Authors: Amato Rosario , Lazzara Francesca , Chou Tsung Han , Porciatti Vittorio , Dal Monte Massimo , Casini Giovanni
Published: December 2019

Purpose

Glaucoma is a multifactorial disease that progressively determines the dysfunction and the subsequent death of retinal ganglion cells (RGCs), depending or not by the intraocular pressure (IOP) elevation. The possible influence of diabetes as a risk and/or exacerbating factor for glaucoma has been postulated, but the relationship between diabetes and glaucoma remains controversial. The purpose of this study is to clarify the effect of diabetes in the early progression of glaucoma during the RGCs dysfunction stage preceding the IOP elevation and the cell death.

Methods

DBA/2J glaucomatous mice were injected with streptozotocin (STZ) to obtain a combined model of diabetes and glaucoma. In addition, non‐treated DBA/2J mice and STZ‐injected C57BL/6J were analyzed respectively as glaucomatous and diabetic only controls. RGCs and outer retina activities were evaluated performing respectively pattern electroretinogram (PERG) and flash electroretinogram (FERG) from 4 to 6 month of age. Additionally, IOP and glycaemia were followed up to monitor the progression of the disease.

Results

As expected, non‐treated DBA/2J mice didn’t show any elevation of IOP nor alteration of FERG response during this time window. However, this group showed an age‐dependent worsening of the amplitude and the latency related to the PERG response. C57BL/6J mice treated with STZ showed an IOP‐independent decrease in PERG response preceding alterations of FERG. Interestingly, hyperglycemia determined the exacerbation of the PERG response in STZ‐treated DBA/2J compared to both diabetic and glaucomatous only groups starting from the very beginning of the diabetic condition independently from both IOP and FERG changings.

Conclusion

Our results show that diabetes act as an exacerbating factor for the progression of glaucoma. Indeed, hyperglycemic condition act as a further stressor which leads to a quicker loss of RGCs function and cell death.
The effect of stimulus contrast on the harmonic components of steady state visual evoked potentials
Authors: Solf Benjamin , Klee Sascha
Published: December 2019

Purpose

Steady state visual evoked potentials (ssVEP) are widely used for objective functional diagnostics. Due to stimulation with intermittent stimuli, the evoked response contains frequency components related to the stimulation frequency and its harmonics. In general, the evoked amplitude at stimulation frequency is used for functional diagnostics. However, clinicals trails also reported main components at harmonic frequencies. The origin of the harmonic frequency components is not fully understood. This work aims to analyze the influence of the stimulation contrast on harmonic components of ssVEP.

Methods

We studied 10 healthy subjects (mean age 27.2 ± 5.8 years) using checkerboard stimuli (d = 7.2°) with a check size of 0.35°. Stimuli were presented in pattern‐reversal mode (7.5 changes per second) for 5 contrast levels (98%, 50%, 25%, 12.5%, 10%) at mean luminance of 50 cd/m2 and 20 cd/m2 in a random order. The active electrode was placed at Oz, reference electrode at FCz and ground electrode at FPz. The stimulations were performed monocularly in a dimmed room. The recorded ssVEP were transformed using Fourier Analysis. The normalized ratio of the amplitudes at stimulation frequency (7.5 Hz) and first harmonic (15 Hz) were calculated. For statistical analysis Wilcoxon test for paired samples were used.

Results

In our investigation, all 10 subjects exhibited the main component at stimulation frequency (7.5 Hz). The normalized ratio of the amplitudes showed no significant differences between the 5 contrast levels for the mean luminance of 50 cd/m2 and 20 cd/m2.

Conclusion

The presented work revealed, that main components at harmonic frequencies are not dependent on the stimulation contrast. The stimulation contrast has no significant effect on the harmonic responses of ssVEP.
Retrospective descriptive study on diagnosed patients of choroidal metastases
Authors: Montes Paula , Karlsruher Gisela , Boned Ana , Díaz María Dolores , Marco Sara , López Isabel , Pérez Diana , Ascaso Francisco Javier
Published: December 2019

Purpose

The most frequent intraocular tumour are metastatic carcinomas. Although it is a rare entity, choroidal involvement is considered the most frequent intraocular malignancy due in part to its abundant vascularization. Although they are often the first manifestation of the tumour, they usually appear late in the course of a tumour disease and are associated with poor prognosis. The most frequent primary origin in the case of women is the breast and in the male the lung. Blurred vision or visual loss is the most common form of presentation. The therapeutic options include systemic treatments and local therapies such as radiotherapy or surgery among others.

Methods

Retrospective descriptive study conducted in our centre from May 2009 to May 2019 on patients diagnosed with choroidal metastases. We analysed the primary tumour origin, clinic at the beginning, initial presentation of neoplastic disease, therapeutic attitude and median survival.

Results

Of the 10 patients studied there were four males (40%) and six females (60%). The average age was 63.6 years. The initial presentation clinic was headache in four patients (40%), exophthalmos in two (20%), visual field reduction in one (1%), blurred vision in one (10%), retinal detachment in one (10%) and seizure in one (10%). As a primary source, pulmonary neoplasia was identified in four patients (40%) (two adenocarcinomas, one squamous and one small cell carcinoma), breast cancer in three patients (30%), adenocarcinoma of the pancreas in one patient (10%), papillary carcinoma of thyroid in one (10%) and high‐grade undifferentiated carcinoma in one (10%). Regarding the treatment received, six patients were candidates for palliative chemotherapy, one for radioactive iodine, one patient could not receive any type of treatment for death and two were candidates for local therapy by exantheration.

Conclusions

The results obtained in our sample are concordant with those found in the literature, obtaining a median survival of 10 months after the diagnosis of choroidal metastases. Choroidal metastases are a rare entity and generally associated with poor survival. The most commonly identified primary origins are carcinomas of the lung and breast. In a significant percentage of cases, choroidal metastases are the initial presentation of an unknown systemic neoplasm.
Case report: persistent corneal epithelial defect after glaucoma device implantation for radiation glacoma
Authors: Shimizu Daisuke , Tawada Ayako , Yamamoto Shuichi
Published: December 2019

Purpose

We report a case with persistent epithelial defect after Barvert glaucoma implant for radiation glaucoma.

Methods and Results

62‐year‐old man had a total of 70 Gray radiation exposure for 2 months for left ethmoid sinus cancer In December 2015. In February 2016, the patient visited eye clinic for left eye pain. Only SPK was found and artificial tear drop was prescribed and followed‐up in the clinic. In January 2017, left intraocular pressure was elevated and angle neovascularization was found. Photocoagulation was started on diagnosis of radiation glaucoma. Although the treatment could not be completed due to progression of cataract, intraocular pressure had been within normal range under glaucoma drops treatment. He was referred to our hospital in August 2018 for the treatment of cataract surgery in his left eye. At the first visit, his left best corrected visual acuity was 0.01 and left Intraocular pressure was 20 mmHg. Mild Superficial punctate keratitis was found in his left eye but tear fluid meniscus was normal. We planned to add PC after cataract surgery at first. But in consideration of the possibility of deterioration of Neovasucular Glaucoma after surgery, we performed not only cataract surgery but also vitrectomy with Barvert glaucoma implantation and photocoagulation in September of the same year. Postoperative inflammation was transient, the intraocular pressure was good, and small corneal erosion was found immediately after the operation. However, after surgery, there was an extreme decrease in lacrimal secretion, and corneal erosions were enlarged, resulting in persistent epithelial defects. Treatment with a punctum plug, a therapeutic soft contact lens, eye drops etc. was poorly improved, and a corneal infiltration suspected of fungal keratitis was found during the course.

Conclusions

Implantation or vitreous surgery for radiation retinopathy or radiation glaucoma may cause persistent corneal epithelial defects. It is necessary to carefully check the preoperative evaluation of tears and corneal condition and to carry out minimally invasive treatment.
EYS606 for the Treatment of Non‐Infectious Uveitis
Authors: Hoogewoud Florence , Buggage Ronald , Behar‐Cohen Francine
Published: December 2019

Purpose

While effective for corticosteroid sparing, systemic anti‐tumor necrosis factor‐alpha (TNF) therapy is associated with potentially serious side effects. Intraocular anti‐TNF therapy offers the possibility to reduce systemic safety concerns, improve patient compliance and enhance efficacy. EYS606 is a novel non‐viral gene therapy that induces ciliary muscle cells to express a potent anti‐TNF fusion protein in the eye. Herein, we present the results from Part 1 of a first‐in‐human study investigating EYS606 in patients with NIU.

Methods

The EYS606‐CT1 study is an ongoing, 24 week, multicenter, open‐label, phase I/II study investigating the safety and tolerability EYS606 administered using a proprietary electrotransfection system. In Part 1, end stage NIU patients were assigned to treatment with one of three escalating EYS606 doses, while in Part 2, patients with less severe, active NIU will receive the maximally tolerated EYS606 dose. The primary outcome is the assessment of adverse events (AEs) after treatment administration.

Results

Nine patients (3 per cohort) with refractory posterior or panuveitis were enrolled and treated in Part 1 of the study. The majority AEs occurring within 4 weeks of EYS606 treatment were mild in severity, ocular in nature and related to the treatment administration procedure. No serious adverse events related to EYS606 were reported. Despite the advanced disease stage, clinically significant improvements from baseline were observed in 3 patients including >10 ETDRS letter gain in visual acuity in one and reductions in macular edema in two treated in the highest dose cohort.

Conclusions

These results suggest that EYS606 could be a safe and effective local treatment for NIU that avoids the safety concerns and inconveniences of systemic NIU therapies. Treatment of active NIU patients in Part 2 of study will further clarify the risks and benefits of sustained TNF inhibition in the eye.
In Vivo corneal confocal microscopy study of keratoendotheliitis fugax hereditaria caused by a pathogenic variant in the NLRP3 gene
Authors: Turunen Joni , Immonen Annamari , Järvinen Reetta‐Stiina , Kawan Sabita , Repo Pauliina , Korsbäck Anna , Jaakkola Aino , Majander Anna , Vesaluoma Minna , Kivelä Tero
Published: December 2019

Purpose

To elucidate by using in vivo corneal confocal microscopy (IVCM) the pathogenesis of keratoendotheliitis fugax hereditaria, an autosomal dominant cryopyrin‐associated periodic keratitis associated with a pathogenic variant in NLRP3, in its acute and chronic phase.

Methods

Cross‐sectional, hospital‐based study of 7 patients during an acute attack and 18 patients in the chronic phase. Corneal photography, IVCM and Sanger sequencing to confirm NLRP3 variant c.61C>G were performed.

Results

During the acute attack, the stroma was transiently infiltrated with hyperreflective small roundish bodies consistent with inflammatory cells. Other layers of the cornea were essentially normal. With multiple recurring attacks, a central corneal stromal opacity gradually develops. IVCM revealed that the opacities correspond to hyperreflective needle‐shaped structures in the extracellular matrix of the stroma.

Conclusions

Keratoendotheliitis fugax hereditaria mainly involves the middle layers of the corneal stroma, and is stromal keratitis rather than a true keratoendotheliitis. IVCM shows that inflammatory cells invade only the stroma during an acute attack. With repeated attacks, needle‐shaped hyperreflective extracellular matrix elements emerge and cause a persistent opacity. The disease will be excellent in vivo human model to study the activation of the NLRP3 inflammasome and the tissue specificity in cryopyrin‐associated periodic syndromes.
Towards improved siRNA delivery to the corneal epithelium: exploring cationic amphiphilic drugs as siRNA delivery enhancers
Authors: Wels Mike , Sauvage Félix , Raemdonck Koen , De Smedt Stefaan
Published: December 2019

Purpose

Corneal blindness is one of the most important causes of preventable blindness. With a shortage of donors people end up losing their vision. Alternatives to heal the cornea are clearly needed. Small interfering RNA (siRNA) has the ability to regulate intracellular protein concentration and shows potential to modulate corneal wound healing. However, to exert its function siRNA needs to reach the cytosol. Here we investigate a strategy to avoid lysosomal siRNA degradation.

Methods

Due to their capacity to permeabilize (lysosomal membranes, cationic amphiphilic drugs (CADs) can enhance the release of siRNA from lysosomes to the cytosol. By staining the lysosomes we were able to determine the effect of several CADs in primary bovine corneal epithelial cells (pBCECs) by flow cytometry and confocal microscopy. To correlate CAD‐induced lysosomal membrane permeabilization with improved siRNA delivery in pBCECs, we investigated the silencing efficiency of t siRNA when followed by a CAD treatment.

Results

Up to two‐fold increase of fluorescence signal was observed indicating swelling of existing lysosomes and/or an increase in the number of lysosomes inside pBCECs. Confocal imaging of stained pBCECs confirmed the increase in lysosomal size. Cytotoxicity tests (MTT assay) showed concentrations used to induce lysosomal swelling were not toxic (metabolic activity ≥80%).Treatment with siRNA with a subsequent treatment with CADs increased silencing efficiency suggesting an improved siRNA delivery.

Conclusions

We have shown the ability to induce lysosomal membrane permeabilization in primary bovine corneal epithelial cells with CADs. A subsequent administration of CADs after siRNA treatment increased its capacity of silencing indicating an enhanced release from the lysosomal compartment.
Substance P receptor antagonists fosaprepitant and spantide in an UVR‐B‐induced cataract mouse model
Authors: Wegener Alfred , Kronschläger Martin , Schönfeld Carl‐Ludwig , Holz Frank , Meyer Linda , Gross Janine
Published: December 2019

Purpose

To investigate the neurokinin receptor‐1 (NKR‐1) antagonists fosaprepitant and spantide in an UVR‐B‐induced cataract mouse model. To examine their effect on the expression of pro‐inflammatory cytokines and chemokines in ocular tissues of both eyes after unilateral UVR‐B exposure.

Methods

Mice were injected intraperitoneally with NKR‐1 antagonists before and after unilateral UVR‐B exposure to a 5‐fold cataract threshold dose. The contralateral partner eye was completely shielded during the experiment. Control mice were similarly injected with saline only. Mice were categorized into latency period groups of 3 and 7 days following exposure. Subsequently, eyes were enucleated and ocular tissues were microsurgically dissected for NKR‐1 protein concentration by enzyme‐linked immunosorbent assay (ELISA). Cytokines and chemokines in ocular tissue samples were measured using a Multiplex Immunoassay.

Results

Pretreatment with fosaprepitant decreases NKR‐1 protein levels in mouse eyes after UVR‐B exposure to only one eye. NKR‐1 protein level was reduced in the exposed cornea, lens epithelium, iris/ciliary body, aqueous humor, retina and choroid as well as in the unexposed lens epithelium when compared with the saline treated mice. Spantide I treatment showed nearly the same NKR‐1 level in comparison to the saline group. Initiated fosaprepitant injection resulted in a significant reduction of Gro‐alpha/CXCL1 in the exposed cornea. No differences were measured between the treatment groups of other tested cytokines/chemokines in the mouse eye.

Conclusion

The UVR‐B induced expression of NKR‐1 in ocular tissues is decreased by fosaprepitant in the exposed as well as in the unexposed partner eye. A previously reported sympathizing NKR‐1 upregulation in the unexposed partner eye can be counteracted by fosaprepitant. Therefore, substance P and its receptor seem to be the signaling molecules involved in the contralateral reaction following unilateral UVR‐B exposure.
Ocular melanin binding of drugs: in vitro binding studies
Authors: Bahrpeyma Sina , Rimpelä Anna‐Kaisa , Hagström Marja , Urtti Arto
Published: December 2019

Certain drugs accumulate into pigmented tissues due to their binding to melanin, a macromolecule inside pigmented cells. Melanin can affect the drug’s pharmacokinetics by acting as a drug reservoir. Binding of drugs to the ocular melanin might enable ocular drug targeting, prolonged duration of action and retinal delivery after non‐invasive drug administration (eye drops, tablet). Interestingly, chloroquine levels are maintained in the pigmented retinal and choroidal cells for months after discontinuation of dosing. The aim of the experimental part was to study melanin binding of a set of compounds in vitro with isolated melanin from the retinal pigment epithelium (RPE) and choroid of porcine eyes. The in vitro binding with melanin was studied at three different pH (i.e. 5, 6, 7.4) since melanosomal pH is unknown but expected to be acidic, so these range of pH will help us to understand the effect of pH on binding affinity and capacity. The compounds chosen for the study; papaverine, levofloxacin, terazosin, pazopanib, are small molecules with diverse physicochemical properties (octanol/water partitioning coefficient (log P), pKa, acid/base status). The binding parameters (Bmax and Kd) estimated from Sips isotherm where the actual distribution of binding energies is most likely continuous and unimodal. Binding parameters were calculated based on experimental data and terazosin is the most potent melanin binder by having K value of 13.30 (K = Bmax/Kdn ). In addition, pH has quite large effect on binding for example binding affinity and capacity of levofloxacin at pH 5 is almost as three times as pH 7.4. This study demonstrates the importance of melanosomal pH on melanin binding of drugs and a useful step toward building a bottom‐up pharmacokinetic model for ocular drug delivery.
Across‐frequency interference in visual temporal gap detection revisited
Authors: Hirose Nobuyuki , Mori Shuji
Published: December 2019

Purpose

At EVER2017, we reported that visual detection of a temporal gap becomes difficult when spatial frequency separation is introduced between markers delimiting the gap. In that report, however, gap thresholds were measured separately, in different runs, for within‐frequency and across‐frequency gap detection. Therefore, our previous findings may be simply explained by the effect of spatial‐frequency specific adaptation on visible persistence. Here, we reassessed the across‐frequency interference in gap detection using a procedure uncontaminated by spatial‐frequency specific adaptation.

Methods

Gaussian‐windowed sinusoidal gratings were used for gap markers. Spatial frequencies of the leading and trailing markers were manipulated to be either 2 or 4 cpd. Gap thresholds were measured using a two‐interval, two‐alternative forced choice method with a two‐down/one‐up interleaved adaptive staircase procedure targeting 70.7% correct detection: Four staircases corresponding to the four combinations of marker frequencies were interleaved in a single run and randomly selected in each trial. Sixteen observers with normal vision completed two runs, and the mean of estimated thresholds between two runs for each condition were subject to analysis.

Results

Gap thresholds for across‐frequency markers (2‐4 and 4‐2 conditions) were significantly higher than those for within‐frequency markers (2‐2 and 4‐4 conditions). For within‐frequency gap detection, gap thresholds were significantly higher for 4 cpd than for 2 cpd markers, which was consistent with the well‐known decreased temporal resolution with increasing spatial frequency.

Conclusion

We confirmed our previous findings that temporal gaps bounded by different frequency markers are more difficult to detect than those bounded by identical frequency markers. We propose that perceptual discontinuity signaling the frequency separation interferes with gap representation and longer gaps are required for correct gap detection.
The role of magnetic resonance imaging in diagnosis of uveal melanoma
Authors: Serras‐Pereira Rita , Morais Teresa , Vieira Luísa , Batalha Carlos , Ramalho Joana , Duarte Ana , Magriço Ana
Published: December 2019

Purpose

To evaluate the potential role of Magnetic Resonance Imaging (MRI) in the diagnosis of uveal melanoma.

Methods

Retrospective case series involving a total of 10 patients, 9 with uveal melanoma and 1 with a suspicious melanocytic lesion, diagnosed by A‐mode and B‐mode ultrasound (US) scan. 6 of the 10 patients simultaneously performed MRI for diagnostic purposes. The results of both modalities were compared with respect to lesion dimensions, extra‐scleral extension and presence of retinal detachment (RD).

Results

In this case series, 4 patients were diagnosed with uveal melanoma based exclusively on echographic findings and 6 patients underwent both US and MRI for diagnostic purposes. The MRI excluded the diagnosis of uveal melanoma in one patient with suspected US imaging. In the remaining 5 patients that underwent both modalities, we did not identify significant differences in lesion dimensions. Extra‐scleral extension was not identified in this subgroup by US, and MRI findings corroborated these results. With respect to RD, it was identified in 2 of these 6 subjects by US but MRI failed to identify a discrete RD in one of the subjects.

Conclusions

The present case series focused on the differences between US and MRI in the diagnosis of uveal melanoma in order to assess the potential role of MRI in such cases. We did not find any difference in diagnostic accuracy, lesion dimensions and detection of extra‐scleral extension between the two modalities, except for one patient with a suspected lesion on US that was excluded with MRI. US, however, was found to be more sensitive than MRI in the diagnosis of RD, detecting a small RD not identified by MRI. The authors identify as main limitation the small number of subjects included in the case study. Further studies involving a greater number of patients are necessary to precisely determine the role of MRI in diagnosis of uveal melanoma.
The Role of TGF‐□1 on RHO GTPase, GSK3, JNK, MMP‐2, ‐Catenin and ‐SMA expression in myofibroblast cell culture orbital soket contracture
Authors: Dewi Debby Shintiya
Published: December 2019

Purpose

To study the role of TGF‐□1 on the expression of RHO GTPase, GSK3, JNK, MMP‐2, □‐catenin and □‐SMA in the myofibroblast cell culture of orbital socket contracture.

Methods

This research is an experimental research with invitro model of the myofibroblast cell culture of orbital socket contracture. □‐Sma expression examine with immunohistochemistry and confocal microscopy. Examination of the RHO GTPase, GSK3, JNK, MMP‐2, and □‐catenin expression using ELISA KIT, while the morphology of fibroblasts or myofibroblasts was examined by 100× magnification with an inverted Olympus IX 71 microscope and 400× magnification with CLSM FV1000

Results

Increased dose of TGF‐□1 in passages 3 decreased the expression of a‐SMA and no morphological changes in myofibroblast cells. The morphology of myofibroblasts cells can not turn back into fibroblasts. Increased doses of TGF‐□1 increase JNK expression, slightly increase RHO GTPase expression, decrease GSK3 and a‐SMA expression, and doesn’t change MMP‐2 and □‐cathenine expression.

Conclusions

TGF‐□1 increase JNK expression and slightly RHO GTPase, but decrease the expression GSK3 and a‐SMA, and has no effect on MMP‐2 and □‐cathenine expression in Myofibroblast Cell Culture Orbital Soket Contracture.
The development of inflammatory eye diseases in patients with endocrine ophthalmopathy after the removal of restrictive strabismus
Authors: Gladysheva Galina
Published: December 2019

Research objective

Is to show the ways of prevention of corneal complications that patients with endocrine ophthalmopathy (EOP) may have after restrictive strabismus removal.

Methods

A patient with an acute keratouveuitis, a purulent helcoma of the left eye against the background of EOP of both eyes after left eye restrictive strabismus removal was examined. The patient underwent biomicroscopic examination with staining solution of fluorescein, beta scanning, anterior segment optical coherence tomography and anti‐inflammatory, antibacterial, keratoprotective treatment was prescribed. There was done bacteriological conjunctival test. Design of the research – case series.

Results

An important point of intraoperative case management in patients with EOP was to prevent corneal complications. It was related to the duration of surgical intervention, risk of damage to the corneal epithelium during its contact with expander as a result of significant vertical eye rotations during the surgery. We use more frequent irrigation of cornea with normal saline solution or instillation of viskoelastics as keratoprotectors. After surgery, the patient does not have the ability to close the eyelids. It also increases the risk of corneal damage. The cause may be the contact of the cornea with a sterile gauze bandage applied and its non‐moisturizing due to the lack of blinking. In addition, the preoperative hypotropia created protection of the cornea by its contact with the conjunctiva of the lower eyelid. The eye level achieved after the surgery deprives the patient of this “protection”. Therefore there wasn’t applied a gauze bandage but a perforated convex plastic occluder. The cornea is irrigated with keratoprotectors till the ability to close eyelids is reached.

Conclusions

Suggested intraoperative and postoperative strategies to manage cases in patients with EOP are the most effective. As long as they allow to reduce all possible corneal complications.
Papillorenal syndrome with secondary serous retinal detachment: family history can help the diagnosis
Authors: Roulez Francoise
Published: December 2019

Introduction

Cavitary congenital optic discs anomalies include optic disc coloboma, optic disc pit, morning glory syndrome and papillorenal syndrome. Optic disc aspect and retinal complications are often very similar

Method

Case report of a young boy with bilateral congenital malformation of the optic disc and secondary exsudative maculopathy.

Results

Optic disc morphology and slow spontaneous resolution of the serous retinal detachment is illustrated. Family history and father examination oriented towards the diagnosis of papillorenal syndrome.

Conclusion

Characteristic optic disc features of the syndrome is described. Patients with multiple cilioretinal vessels should be evaluated to identify the sometimes serious renal abnormalities in papillorenal syndrome. Early diagnosis is important, because prophylactic systemic antihypertensive treatment can limit renal morbidity.
Oxidative stress induces mitochondrial dysfunction and autophagy in ARPE‐19 cells
Authors: Blasiak Janusz , Barszczewska Gabriela , Gralewska Patrycja , Kaarniranta Kai
Published: December 2019

Purpose

Oxidative stress plays an important role in the pathogenesis of age‐related macular degeneration (AMD), but the exact mechanism of the influence of the stress is not completely clear. The stress can affect both neural retina and retinal pigment epithelium (RPE) cells The purpose of our study was to evaluate changes in some mitochondrial properties and autophagy in the response of RPE cells to oxidative stress.

Methods

Retinal pigment epithelium ARPE‐19 cells were challenged with 200 mM H2O2 for 2 h. Mitochondrial ROS (mtROS) were assessed by the MitoSOX probe, mitochondrial membrane potential (MMP) with JC‐1, the activity of the complex I of the mitochondrial respiratory chain with MitoCheck. To assess autophagy cells were transfected with the pBABE‐puro mCherry‐EGFP‐LC3B plasmid and autophagic flux was evaluated with confocal fluorescent microscopy; expression of the LC3‐I and LC3‐II proteins were quantified by immunoblotting.

Results

Hydrogen peroxide induced an increase in mtROS and decrease in MMP in ARPE‐19 cells as well as it inhibited the activity of the complex I. Furthermore, an increase in the LC3‐II/LC3‐I ratio and an increased number of autophagolysosomes was observed in ARPE‐19 cells challenged with hydrogen peroxide.

Conclusion

Oxidative stress induces detrimental changes in mitochondria of RPE cells that can respond to these changes by increased autophagy, confirming that mitochondrial homeostasis and autophagy may be important in AMD pathogenesis.

This work was supported by National Science Centre, Poland grant number 2017/27/B/NZ3/00872.