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Glaucoma is the leading cause of blindness worldwide. However, its surgical treatment, in particular via trabeculectomy, can be complicated by fibrosis. In current clinical practice, application of the drug, Mitomycin C, prevents or delays fibrosis, but can lead to additional side effects, such as bleb leakage and hypotony. Previous in silico drug screening and in vitro testing has identified the known antibiotic, josamycin, as a possible alternative antifibrotic medication with potentially fewer side effects. However, a suitable ocular delivery mechanism for the hydrophobic drug to the surgical site does not yet exist. Therefore, the focus of this paper is the development of an implantable drug delivery system for sustained delivery of josamycin after glaucoma surgery based on crosslinked γ-cyclodextrin. γ-Cyclodextrin is a commonly used solubilizer which was shown to complex with josamycin, drastically increasing the drug’s solubility in aqueous solutions. A simple γ-cyclodextrin crosslinking method produced biocompatible hydrogels well-suited for implantation. The crosslinked γ − cyclodextrin retained the ability to form complexes with josamycin, resulting in a 4-fold higher drug loading efficiency when compared to linear dextran hydrogels, and prolonged drug release over 4 days.

Glaucoma treatment options as well as its etiology are far from understood. Gene expression (transcriptomics) data of the anterior segment of the eye can help by elucidating the molecular-mechanistic underpinnings, and we present an up-to-date description and discussion of what gene expression data are publicly available, and for which purposes these can be used. We feature the few resources covering all segments of the eye, and we then specifically focus on the anterior segment, and provide an extensive list of the Gene Expression Omnibus data that may be useful. We also feature single-cell data of relevance, particularly three datasets from tissues of relevance to aqueous humor outflow. We describe how the data have been used by researchers, by following up resource citations and data re-analyses. We discuss datasets and analyses pertaining to fibrosis following glaucoma surgery, and to glaucoma resulting from the use of steroids. We conclude by pointing out the current lack and underutilization of ocular gene expression data, and how the state of the art is expected to improve in the future.

One major complication after fistulating glaucoma surgeries are fibroblast-mediated scarring processes and their specific prevention is key in the development of novel pharmaceutical concepts. Within this study a possible antifibrotic potential of kitasamycin (KM) in a transforming growth factor (TGF)-β1-mediated fibroblast model was evaluated in vitro. Primary ocular fibroblasts were isolated, cultivated and a dose–response test including determination of the half maximal effective concentration (EC50) for KM was conducted. Transformation of fibroblasts into myofibroblasts was induced by TGF-β1and immunofluorescence (IF), and Western blot (WB) analyses were performed with fibroblasts and myofibroblasts. IF analyses were carried out using antibodies against α-smooth muscle actin (α-SMA) and fibronectin, and protein detection of intracellular and extracellular proteins was performed by WB. Using the dose–response test, the viability, cytotoxicity and EC50 of KM after 24 and 48 h were determined. Fibroblasts exposed to various KM concentrations showed no increase in α-SMA and extracellular matrix expression. In TGF-ß1-stimulated myofibroblasts, KM inhibited the expression of α-SMA and fibronectin in a concentration-dependent manner. These findings demonstrate that KM could impair the transformation of fibroblasts into myofibroblasts and the expression of proteins involved in fibrotic processes, representing a potential agent for specific fibrosis prevention in future therapeutic concepts.

In remitting–relapsing multiple sclerosis (RR-MS), relapses are driven by autoreactive immune cells that enter the brain and spinal cord and damage myelin sheaths of axons in white and grey matter, whereas during remissions myelin is repaired by activated oligodendroglial cells. Disease-modifying therapies (DMTs) may either retard/attenuate myelin damage or promote/enhance/speed up myelin repair. Almost all currently approved DMTs inhibit myelin damage and are considerably toxic. Enhancement of myelin repair is considered an unmet medical need of MS patients. Citicoline, known for many years as a nootropic and neuroprotective drug and recently pronounced food supplement, has been found to be significantly efficacious in two complementary rodent models of MS, experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced myelin toxicity. Moreover, citicoline treatment improves visual evoked potentials (VEPs) in glaucoma patients, which is relevant because VEP monitoring is frequently used as an indicator of remyelination in MS. Although over-the-counter availability of citicoline may impede its formal translation to the clinic of MS, evaluation of its efficacy for supporting remyelination in this disease is strongly indicated.

Glaucoma is a frequent ocular disease that may lead to blindness. Primary open-angle glaucoma (POAG) and ocular hypertension (OHT) are common diseases with increased intraocular pressure (IOP), which are mainly responsible for these disorders. Their pathogenesis is widely unknown. We screened the sera of patients with POAG and OHT for the prevalence of autoantibodies (AAb) against G protein-coupled receptors (GPCRs) in comparison to controls. Employing frequency modulation of spontaneously contracting neonatal rat cardiomyocytes in vitro, agonistic GPCR AAb were to be detected in roughly 75% of the patients with POAG and OHT, however, not in controls. Using inhibitory peptides the AAb’ target was identified as β2 adrenergic receptor (β2AR). The AAb interact with the second extracellular loop of β2AR. The peptides 181–187 and 186–192 were identified as binding sites of the AAb within the extracellular loop II. The binding of the AAb to β2ARs was verified by surface-plasmon-resonance analysis. The isotype of the AAb was (immunoglobulin) IgG3. In an additional pilot principal-of-proof study, including four patients with POAG, the removal of the AAb against the β2AR and other immunoglobulins G by immunoadsorption resulted in a transient reduction of IOP. These findings might indicate a possible role of agonistic AAb directed against β2ARs in the dynamics of aqueous humor and might support a contribution of adaptive autoimmunity in the etiopathogenesis of POAG and OHT.

Purpose. To compare phacocanaloplasty (PC) and phaco-non-penetrating deep sclerectomy (PDS). Methods. 75 patients with uncontrolled glaucoma and cataract were randomized for PC (37 eyes) or PDS (38 eyes). Intraocular pressure (IOP) and number of medications (meds) were prospectively evaluated. Follow-up examinations were performed on days 1 and 7 and after 1, 3, 6, 12, 18, and 24 months. Surgical success was calculated. Complications and postoperative interventions were noted. Quality of life (QoL) was analyzed. Results. Preoperatively, mean IOP and meds were comparable (P>0.05). After 24 months, IOP significantly decreased in PC from 19.4 ± 5.9 mmHg (2.6 ± 0.9 meds) to 13.8 ± 3.3 mmHg (0.5 ± 0.9 meds) and in PDS from 19.7 ± 5.4 mmHg (2.9 ± 0.9 meds) to 15.1 ± 2.9 mmHg (1.1 ± 1.2 meds). Statistically lower IOP was observed in PC in the 6th month and persisted until 24 months (P0.05). The most frequent complication in PC was transient hyphema (46%), in PDS bleb fibrosis (24%). PC patients during postoperative period required only goniopuncture (22% of subjects), whereas PDS patients required, in order to maintain subconjuctival outflow, subconjunctival 5-fluorouracil injections in 95% of cases (median = 3), suture lysis (34%), needling (24%), and goniopuncture (37%). NEI VFQ-25 mean composite score for PC was 78.04 ± 24.36 points and for PDS 74.29 ± 24.45 (P=0.136). α Cronbach’s correlation coefficient was 0.913. Conclusions. PC leads to a more effective decrease in IOP than PDS in midterm observation with similar safety profiles. PDS patients required a vast number of additional procedures in contrast to PC patients, but this fact did not influence QoL.

Purpose. Different IOL materials, particularly blue-light filtering materials, have different spectral transmittance characteristics. The color stimuli, which influence retinal receptors objectively, have consequently implications for color perception. We report on the quantitative determination of IOL-specific transmittance characteristics and present a method visualizing the resultant changes in color stimulus. Methods. A setup was realized to quantify IOL-absorption in a range of 390–780 nm. To visualize the influence of the different spectral transmittance characteristics an algorithm was developed, which converts RGB-pixel values of images into spectra, which performs the corresponding transmittance correction, reconverts to RGB, and reconstructs the image. IOLs of hydrophobic acrylate and hydrophilic acrylate with a hydrophobic surface in each case with/without blue-light filter were examined. Results. Assessment of the reference images verifies the suitability of the pipeline. Evaluation of the transmittance spectra reveals differences of material- and manufacturer-specifics, which are capable of inducing considerable changes in color perception, particularly in the blue color range and mixed colors involving blue. Conclusions. The developed technique provides an approach for determining IOL-specific transmittance behavior and subsequently its influence on the retinal color stimulus. Problems of altered color perception are occasionally reported after cataract surgery and these become obvious with the visualization procedure developed here.

Scaffold proteins contain multiple protein–protein interaction modules that physically assemble functionally related proteins into larger complexes. ZIPs [PKC (protein kinase C) ζ-interacting proteins] link the enzymatic activity of the atypical PKC isoforms PKCλ/ι or PKCζ to target proteins and are associated with neurodegenerative disorders. In the rat, alternative splicing generates three ZIP variants. Previously, we identified the ZIP3 transcript, containing 13 C-terminal amino acids encoded by intron 4, in the rat CNS (central nervous system). In the present study, we identified intronic polyadenylation signals in rat and human ZIP genes [known as SQSTM1 (sequestosome-1) in humans] and detected the corresponding ZIP3-like transcripts. In addition, we generated ZIP3-specific immune sera and observed expression of the protein in the brain and retina of the adult rat. In the retina, ZIP3 is present in nuclear layers where it co-localizes with PKCζ. An immune serum recognizing all three ZIP isoforms labelled the same cells as the newly generated ZIP3-specific antibodies and, in addition, stained both synaptic layers of the retina. There, ZIPs are localized in axon terminals of rod bipolar cells that also contain ZIP-interacting PKCζ and GABAC (γ-aminobutyric acid type C) receptors. In summary, we detected ZIP3-like transcripts in rat- and human-derived samples and describe the expression of ZIP3 in the rat CNS. [ABSTRACT FROM AUTHOR]

Abstract  The photopic negative response of the flash-electroretinogram driven by the middle- and long-wavelength cones has been shown to be reduced in non-human primates with experimental glaucoma and in human patients with glaucoma. The photopic negative response for the blue-sensitive response has been studied using a blue-green silent-substitution-technique on a red background. The aim of this study was to re-evaluate the value of the photopic negative response of the blue-sensitive pathway in glaucoma using a conventional flash-electroretinogram. In 37 eyes of 37 controls (age: 53 ± 13.6 years) and 37 eyes of 37 patients with open-angle glaucoma of different perimetric visual field defects (age: 58.3 ± 10 years; MD: 11.7 ± 6.7 dB) of the Erlangen glaucoma registry Ganzfeld flash-electroretinograms (LKC, UTAS 3000) were recorded using blue Xenon-flashes of increasing photopic luminance (0.013, 0.018, 0.030, and 0.052 cd s/m2; 440 nm) on a bright yellow background (238 cd/m2; 550 nm) after 2 min of light adaptation. Amplitudes and implicit times of the photopic negative response and of L&M-cone- and S-cone-driven b-waves were compared between glaucomas and controls for all flash energies (unpaired t-test). The amplitudes of the photopic negative response were significantly reduced in glaucoma patients for all flash energies (P 2) and S-cone-driven b-wave (0.030 and 0.052 cd s/m2) were significantly prolonged in glaucoma patients (P  [ABSTRACT FROM AUTHOR]

Abstract   Background Laser injuries to the eyes occasionally occur in occupational accidents or during free-time activities. The aim of this study was to compare clinical and functional findings. Methods We describe a 34-year-old male complaining about reduced visual acuity after an accidental laser injury. We correlate changes in the multifocal ERG with visual field defects due to focal laser application 1.5 years after the trauma. Results A small central retinal scarring resulting in a perimetric defect and a focal reduction of amplitude in the multifocal ERG have been observed in an area closely corresponding to the area where the scarring and the field losses occurred. Conclusion Structural and perimetric damage as a consequence of laser injury can be associated with focal change in multifocal ERG. [ABSTRACT FROM AUTHOR]

Purpose: Multifocal pattern reversal stimulation can be used to detect inner retinal dysfunction. Commonly, the stimulus is generated on a monitor using m-sequence technique. We describe a pattern reversal ERG evoked by LED arrays using cyclic summation (CS). Methods: One eye of eight healthy subjects was examined with an arrangement of 13 LED arrays. Each array consisted of 100 LEDs separated by thin walls. One of the fields was placed centrally, three fields each were placed above, below, left and right of the central field. CS technique at a temporal frequency of 16 reversals per second (RPS) was used for stimulation. Viewing distance was 30 cm, check size was 0.58 cyc/deg. Luminance of the bright fields was 340 cd/m2.Results: Fourier analysis was performed. Centrally, the amplitude of the 2nd harmonic wave was highest (0.87 μV). In the first paracentral fields, amplitudes were 0.28 μV (nasally), 0.21 μV (superior, inferior and temporally). In the second paracentral fields, amplitudes were 0.11 μV (nasally), 0.09 μV (superior), 0.13 μV (inferior) and 0.15 μV (temporally). With exception of the temporal field (0.1 μV), in the outermost fields no reproducible ERG response could be recorded. Conclusion: Peripheral ERG responses to a pattern reversal stimulus can be recorded with LED stimulation using CS technique up to an eccentricity of 30°. Responses are highest centrally and decrease with increasing distance to the centre. [ABSTRACT FROM AUTHOR]

Purpose: Pattern stimulation is widely used to detect inner retinal dysfunction. In this work we describe a pattern stimulation technique with LEDs and compare the results with conventional methods. Methods: PERG and VEP were derived from three normal subjects. Three different techniques were used to generate a checkerboard pattern reversal stimulus: a 70 Hz monitor, a Maxwellian-view system equipped with a Xenon-arc lamp and a mechanical mirror system, and a LED array (Roland Consult) consisting of 100 white LEDs. Two kinds of luminance (125 and 340 cd/m2) and four temporal frequencies (4, 8, 12 and 24 reversals per second) were studied on three healthy subjects. Additionally, a luminance tuning experiment (30, 60, 90, 125 and 340 cd/m2) was performed on one subject. Results: Comparison of different stimulation techniques shows reproducible responses of PERG and VEP with all three methods. The LED array leads to slightly smaller amplitudes than both other techniques, which we ascribe to the design of the LED field. No difference of peak times or phases was noticed between different stimulation techniques. A luminance dependency of PERG and VEP is noticeable using stimulation with LED: with decreasing luminance we measured increasing peak times of PERG and VEP and decreasing amplitude of PERG. Conclusion: We conclude that central retinal stimulation with checkerboard pattern reversal is possible with LED. It gives comparable results to monitor and Maxwellian-view system. [ABSTRACT FROM AUTHOR]

Abstract Background. Large-scale screening in glaucoma diagnosis is expensive and time consuming. Sequential classification strategies can provide an effective combination of time-efficiency and diagnostic accuracy for glaucoma screening. Methods. In a cross-sectional clinical study, a sequential diagnostic strategy, based on several psychophysical and electrophysiological tests, was evaluated on measurements from 595 eyes from 310 patients with primary open-angle glaucoma, and 419 eyes from 213 control subjects (age range 18-70 years in each group). Patients and controls successively underwent up to five psychophysical and electrophysiological diagnostic tests. Optic disc morphometry was taken as gold standard. Adapting group sequential techniques, sensitivity and specificity for the whole diagnostic program were controlled, allotting overall error rates of 10%. The criteria for the diagnostic process were developed in a learning sample (677 eyes) and verified in a validation sample (337 eyes). Results. In the validation sample, 62.0% of the examined eyes could be classified, using a sequential 15-min two-step program. An overall 13.6% ''gain'' of saved time, compared to non-sequential discriminant analysis, was achieved without loss of diagnostic accuracy. A sequential 45-min five-step program classified 68.8% of the whole sample before morphometry, saving approximately 39% of examination time, compared to taking the complete discriminant score. Conclusion. Especially in screening, where the use of time-consuming and complicated diagnostic procedures is restricted, the implementation of testing programs based on group sequential strategies might be a promising means of saving personnel resources and reducing inconvenience for patients. [ABSTRACT FROM AUTHOR]