DDX58 variant triggers IFN-ß-induced autophagy in trabecular meshwork and influences intraocular pressure.

Singleton-Merten syndrome (SMS) is a rare immunogenetic disorder affecting multiple systems, characterized by dental dysplasia, aortic calcification, glaucoma, skeletal abnormalities, and psoriasis. Glaucoma, a key feature of both classical and atypical SMS, remains poorly understood in terms of its molecular mechanism caused by DDX58 mutation. This study presented a novel DDX58 variant (c.1649A>C [p.Asp550Ala]) in a family with childhood glaucoma. Functional analysis showed that DDX58 variant caused an increase in IFN-stimulated gene expression and high IFN-ß-based type-I IFN. As the trabecular meshwork (TM) is responsible for controlling intraocular pressure (IOP), we examine the effect of IFN-ß on TM cells. Our study is the first to demonstrate that IFN-ß significantly reduced TM cell viability and function by activating autophagy. In addition, anterior chamber injection of IFN-ß remarkably increased IOP level in mice, which can be attenuated by treatments with autophagy inhibitor chloroquine. To uncover the specific mechanism underlying IFN-ß-induced autophagy in TM cells, we performed microarray analysis in IFN-ß-treated and DDX58 p.Asp550Ala TM cells. It showed that RSAD2 is necessary for IFN-ß-induced autophagy. Knockdown of RSAD2 by siRNA significantly decreased autophagy flux induced by IFN-ß. Our findings suggest that DDX58 mutation leads to the overproduction of IFN-ß, which elevates IOP by modulating autophagy through RSAD2 in TM cells.

Co-delivery of Brinzolamide and Timolol from Micelles-laden Contact Lenses: In vitro and In Vivo Evaluation.

PURPOSE: Traditional eye drops exhibit a modest bioavailability ranging from 1 to 5%, necessitating recurrent application. Thus, a contact lens-based drug delivery system presents substantial benefits. Nonetheless, pharmaceutical agents exhibiting poor solubility may compromise the quintessential characteristics of contact lenses and are, consequently, deemed unsuitable for incorporation. To address this issue, the present study has engineered a novel composite drug delivery system that amalgamates micellar technology with contact lenses, designed specifically for the efficacious conveyance of timolol and brinzolamide. METHODS: Utilizing mPEG-PCL as the micellar material, this study crafted mPEG-PCL micelles loaded with brinzolamide and timolol through the film hydration technique. The micelle-loaded contact lens was fabricated employing the casting method; a uniform mixture of HEMA and EGDMA with the mPEG-PCL micelles enshrouding brinzolamide and timolol was synthesized. Following the addition of a photoinitiator, 50 µL of the concoction was deposited into a contact lens mold. Subsequently, the assembly was subjected to polymerization under 365 nm ultraviolet light for 35 min, resulting in the formation of the micelle-loaded contact lenses. RESULTS: In the present article, we delineate the construction of a micelle-loaded contact lens designed for the administration of brinzolamide and timolol in the treatment of glaucoma. The study characterizes crucial properties of the micelle-loaded contact lenses, such as transmittance and ionic permeability. It was observed that these vital attributes meet the standard requirements for contact lenses. In vitro release studies revealed that timolol and brinzolamide could be gradually liberated over periods of up to 72 and 84 h, respectively. In vivo pharmacodynamic evaluation showed a significant reduction in intraocular pressure and a relative bioavailability of 10.84 times that of commercially available eye drops. In vivo pharmacokinetic evaluation, MRT was significantly increased, and the bioavailability of timolol and brinzolamide was 2.71 and 1.41 times that of eye drops, respectively. Safety assessments, including in vivo irritation, histopathological sections, and protein adsorption studies, were conducted as per established protocols, confirming that the experiments were in compliance with safety standards. IN CONCLUSION: The manuscript delineates the development of a safe and efficacious micelle-loaded contact lens drug delivery system, which presents a novel therapeutic alternative for the management of glaucoma.

Dendritic Oligoethylenimine Decorated Liposome with Augmented Corneal Retention and Permeation for Efficient Topical Delivery of Antiglaucoma Drugs.

The topically administered glaucoma medications usually encounter serious precorneal drug loss and low corneal penetration, leading to a low bioavailability. In addition, due to the complexity of glaucoma etiology, a single medication is often insufficient. In this work, we report a novel dendritic oligoethylenimine decorated liposome for codelivery of two antiglaucoma drugs, latanoprost and timolol. The liposome showed a uniform nanoscopic particle size, positive surface charge, and excellent dual-drug loading capacity. A prolonged precorneal retention is observed by using this liposomal delivery system. This liposomal delivery system presents increased cellular uptake and tight junctions opening capacity, contributing respectively to the transcellular and paracellular permeation, thereby enhancing the trans-corneal transportation. Following topical administration of one eye drop in brown Norway rats, the dual-drug-loaded liposome formulation resulted in a sustained and effective intraocular pressure reduction as long as 5 days, without inducing ocular inflammation, discomfort, and tissue damage.

[Continuous Optimisation of Experimental Models - an Example from Glaucoma Research]. / Die kontinuierliche Optimierung von experimentellen Modellen ­ Darstellung an einem Beispiel aus der Glaukomforschung.

BACKGROUND: There is a great demand for suitable models to test novel surgical and therapeutic approaches in glaucoma therapy. To address this need and to provide further alternatives to in vivo animal models, we aimed at modifying an established in vitro porcine eye perfusion model. METHODS: Two weaknesses of the previously established porcine anterior segment model include media leakage during perfusion and setup disintegration due to mechanical instability. To overcome these, we slightly modified the previously used custom-made perfusion dishes and incorporated new components into the model setup. To prevent fluid leakage, we secured the anterior segments more firmly to the perfusion trays using a compression ring, steel screws, and nuts. Customised mounts were used to stabilise the perfusion dish and pressure transducer as a single unit. The mounts were made of polylactide (PLA) and printed using a 3D printer. RESULTS: The use of steel screws and nuts allowed tighter clamping of the anterior segments and prevented medium leakage. Our PLA custom mounts stabilised the entire assembly and facilitated handling during experiments and improved comparability between tested eyes. They also prevented accidental detachment of the pressure transducers, which resulted in more stable pressure curves. Our PLA mounts tolerated incubation temperatures of up to 37 °C and disinfection with enzymatic detergents and 70% ethanol without showing signs of deformation or degradation after four months of regular usage. CONCLUSION: Modifications introduced to an established in vitro perfusion model improved its efficacy and reproducibility. Our adjusted model is an example of how many models can be optimised through critical analysis, thereby saving resources and providing reliable results in the long run.

New suture probe canaloplasty combined with suprachoroidal collagen implantation.

PURPOSE: To present the modified surgery technique of new suture probe canaloplasty with a specially prepared monofilament 4.0 polypropylene suture combined with suprachoroidal drainage (ScD) and collagen sheet implantation for non-penetrating glaucoma surgery. METHODS: Prospective study with a twelve months follow-up. A standard 4/0 polypropylene suture (ProleneTM by Ethicon; thickness: approximately 250 m) is cut and shaped with an ophthalmic knife (MANI® Crescent Knife, Mani Inc 8-3 Kiyohara Industrial Park, Utsunomiya, Tochigi 321-3231, Japan) to create a blunt end without sharp or compressed edges. This improves suture probe canaloplasty by providing a more stable and smoother probing device. Schlemm's canal is prepared using the standard technique of canaloplasty with suprachoroidal drainage. Then, instead of using the canaloplasty microcatheter or the previously published 6/0 double-helix suture, Schlemm's canal is probed with the blunt ending of the 4/0 Prolene suture. After successful 360-degree probing, a doubled 10/0 polypropylene tension suture is threaded through the tip of the 4/0 suture. The 4/0 suture is then pulled back and the 10/0 tension sutures are tied at both ends to tension Schlemm's canal. A special collagen sheet (Ologen®) is placed in suprachoroidal space, and the scleral flap is firmly sewed. RESULTS: 115 eyes were included in this prospective study. In 113 cases the Schlemm's canal could completely be probed with the suture probe and canaloplasty with ScD and collagen sheet implantation succeeded. In two cases the intervention was transformed to 360-degree suture trabeculotomy due to an intraoperative cheese-wiring. Twelve months after successful new suture probe canaloplasty with ScD and Collagen Implantation the IOP had decreased by 37.1% (from 21.6 ± 6.0 mmHg with 3.3 different IOP lowering eye drops to 13.5 ± 3.5 mmHg with 1.0 eye drops). 16 Patients did not achieve sufficient IOP levels and underwent 360-degree suture trabeculotomy during the follow-up. One patient had to be treated with further glaucoma surgery to achieve a sufficient IOP level. Complications were hyphema, postoperative IOP elevation and transient hypotony. No serious or sight-threatening complications occurred. CONCLUSION: New suture probe canaloplasty with ScD and collagen sheet implantation yields the opportunity to conduct a cost-effective canaloplasty easier and less complicated than with the previously described method with the twisted 6/0 suture. The safety profile and IOP lowering effect is comparable. In cases where complete probing fails, there is still the opportunity to switch to suture trabeculotomy over the majorly probed part of Schlemm's canal. The pressure lowering effect of the deep sclerectomy with ScD and suprachoroidal collagen sheet implant seems to have an additional impact on the sufficient pressure lowering procedure.

Distribution of TGFBI variants in patients with early onset glaucoma.

Purpose: To describe a novel association of TGFBI variants with congenital glaucoma in a family with GAPO (growth retardation, alopecia, pseudoanodontia, and progressive optic atrophy) syndrome, as well as among other unrelated cases of juvenile onset open-angle glaucoma (JOAG) and primary congenital glaucoma (PCG). Methods: This study of one family of GAPO with congenital glaucoma and three unrelated patients with JOAG analyzed a common link to glaucoma pathogenesis. Three girls with GAPO syndrome born to consanguineous parents in a multi-generation consanguineous family were identified. Two of the girls had congenital glaucoma in both eyes, while the elder sibling (a 10-year-old female) had features of GAPO syndrome without glaucoma. Results: A genetic evaluation using whole exome sequencing revealed a novel homozygous ANTXR1 mutation in all three affected siblings with GAPO. No other mutations were detected in the genes associated with glaucoma. A rare missense variant in the TGFBI gene was shared in the two siblings with congenital glaucoma and GAPO syndrome. We found three other unrelated patients with JOAG and one patient with primary congenital glaucoma with no known glaucoma causing gene mutations, but having four different missense variants in the TGFBI gene. One of these patients with JOAG had familial granular corneal dystrophy. Molecular dynamic simulations of TGFBI and 3-D structural models of three of its variants showed significant alterations that could influence TGFBI protein function. Conclusions: The possibility that variations in the TGFBI gene could have a possible role in the pathogenesis of congenital and juvenile onset open-angle glaucomas needs further evaluation.

Chromosome 6p25 deletion syndrome: A case report and review of ophthalmic features.

The 6p25 deletion syndrome is a rare genetic disorder characterized by a wide spectrum of congenital anomalies. Ophthalmic abnormalities appear to be highly associated with the syndrome, although this relationship has not been well characterized to date. We conducted a systematic literature review to highlight the ocular features in patients with this deletion syndrome and describe a 7-month-old female who has a 6.07 MB 6p25.1p25.3 deletion and a 4.25 MB 17q25.3 duplication. Our patient presented with multiple congenital anomalies, including macrocephaly, frontal bossing, low set ears, tent-shaped mouth, saddle nose, flat midface, and hearing impairment. Her ophthalmic features included proptosis, down-slanting palpebral fissures, hypertelorism, nystagmus, bilateral posterior embryotoxon, and decentered and abnormally shaped pupils. A systematic review of the published cases with sufficient clinical eye descriptions included 63 cases with a confirmed 6p25 deletion. The most common eye findings observed were posterior embryotoxon, iris hypoplasia, corectopia, cornea opacity, and glaucoma.

Familial Paget's disease of bone with ocular manifestations and a novel TNFRSF11A duplication variant (72dup27).

INTRODUCTION: Paget's disease of bone (PDB) is a skeletal disorder characterized by disorganized bone remodeling due to abnormal osteoclasts. Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) gene encodes the receptor activator of nuclear factor kappa B (RANK), which has a critical role in osteoclast function. There are five types of rare PDB and related osteolytic disorders due to TNFRSF11A tandem duplication variants so far, including familial expansile osteolysis (84dup18), expansile skeletal hyperphosphatasia (84dup15), early-onset familial PDB (77dup27), juvenile PDB (87dup15), and panostotic expansile bone disease (90dup12). MATERIALS AND METHODS: We reviewed a Japanese family with PDB, and performed whole-genome sequencing to identify a causative variant. RESULTS: This family had bone symptoms, hyperphosphatasia, hearing loss, tooth loss, and ocular manifestations such as angioid streaks or early-onset glaucoma. We identified a novel duplication variant of TNFRSF11A (72dup27). Angioid streaks were recognized in Juvenile Paget's disease due to loss-of-function variants in the gene TNFRSF11B, and thought to be specific for this disease. However, the novel recognition of angioid streaks in our family raised the possibility of occurrence even in bone disorders due to TNFRSF11A duplication variants and the association of RANKL-RANK signal pathway as the pathogenesis. Glaucoma has conversely not been reported in any case of Paget's disease. It is not certain whether glaucoma is coincidental or specific for PDB with 72dup27. CONCLUSION: Our new findings might suggest a broad spectrum of phenotypes in bone disorders with TNFRSF11A duplication variants.

An update on ophthalmological perspectives in oculodermal melanocytosis (Nevus of Ota).

PURPOSE: To provide a review of the literature on oculodermal melanocytosis (ODM) with a focus on the diagnostic and therapeutic implications of multimodal imaging techniques in the management of ophthalmic complications. METHODS: The authors carried out a literature search on PubMed, Medline, and Scopus of English language articles published on ODM through August 2021. This review presents traditional and novel diagnostic methods in the diagnosis and follow-up of patients with particular emphasis on addressing the role of imaging in the management of the ophthalmic complications of the condition towards improving current practice patterns. RESULTS: ODM is a rare, prevalently unilateral, congenital condition that presents with brown or blue/gray flat asymptomatic lesions of the skin, mucosae, episclera/sclera, and uvea localized within the territory of distribution of the ophthalmic and mandibular branches of the trigeminal nerve. Glaucoma and predisposition to uveal melanoma are the main ophthalmic complications. Diagnosis and management are through comprehensive opthalmological examination and traditional imaging methods such as ultrasonography and fluorescein/indocyanine green angiography as pigmentation of the fundus can conceal subtle retinal and choroidal alterations. Anterior segment optical coherence tomography and ultrasound biomicroscopy are used to evaluate the anterior segment and the ciliary body in the presence of glaucoma or melanoma of the anterior uveal tract. Fundus autofluorescence and retinal pigment epithelium (RPE) alterations are of aid in the differential diagnosis between choroidal nevi and melanoma. Enhanced depth imaging spectral domain optical coherence tomography offers outstanding in vivo evaluation of the dimensions and details of tumors or nevi and surrounding choroidal tissues and small choroidal melanomas may show distortions of the retinal and sub-retinal profile, presence of intra and sub-retinal fluid, abnormalities of the RPE, and compression of the choriocapillaris. CONCLUSIONS: Novel multimodal imaging techniques are significant in the diagnosis and management of the ophthalmic complications of ODM. Fundus autofluorescence and enhanced depth spectral domain optical coherence tomography have adjunctive value in the detection of early-stage melanoma and differential diagnosis between nevi and melanoma. Awareness of current and emerging imaging techniques can propagate improved standardized definition and assessment of the complications of ODM.

Direct Exchange of PerfluoroCarbon Liquid for Silicone Oil: A Surgical Technique to Control Pressure and Avoid Retinal Slippage.

BACKGROUND/PURPOSE: Perfluorocarbon heavy liquid (PFCL) is used in vitreoretinal surgery to flatten the unsupported detached retina before insertion of silicone oil in cases of giant retinal tear or relaxing retinectomy. Direct exchange of PFCL for silicone oil is recommended to reduce retinal slippage when compared with fluid-air exchange, but it is commonly regarded as a difficult procedure. We describe our technique for direct PFCL-silicone oil exchange using a 20-gauge drainage cannula, reliably avoiding the complications of retinal slippage and high intraoperative intraocular pressure. METHODS: We present a consecutive case series of patients undergoing PFCL-oil exchange and explain, using Poiseuille's equation for laminar fluid flow through a cannula, the rationale for using a 20-gauge drainage cannula rather than smaller gauges to avoid high intraocular pressure. RESULTS: Twenty-six patients underwent PFCL-oil exchange from February 1, 2019, to September 30, 2019. There was no intraoperative retinal slippage or pressure-related complications. Postoperatively 20 patients underwent oil removal. Six suffered retinal redetachment, and 14 remained attached. The vision postoil removal ranged from 6/6 to hand movements. CONCLUSION: We are confident that the PFCL-oil exchange technique described here is reliable and safe. The use of a 20-gauge drainage cannula is recommended regardless of vitrectomy gauge.

Recanalization of Xen45 gel stent implant occlusion using 10 - 0 nylon suture in refractory glaucoma: a case report.

BACKGROUND: Xen Gel Stent implant is a new minimally invasive surgical treatment for glaucoma that has been proven effectiveness and safety profile. However, it may also lead to some complications. Xen Gel Stent occlusion is a relatively rare complication reported less frequently and has limited treatment experience. In our case report, we proposed a novel surgical treatment using a 10 - 0 nylon suture to successfully recanalize the occluded Xen45 Gel Stent. CASE PRESENTATION: A 16-year-old female patient had bilateral juvenile glaucoma for the past 5 years. Her right eye had undergone three glaucoma surgeries but failed. At a presentation to our hospital, the right eye's intraocular pressure (IOP) was 30 mmHg despite applying four different active principles. Xen45 Gel Stent implant was chosen for treatment, but six days after implantation, the IOP rose to 40 mmHg as a result of an anterior chamber tip occlusion of the Xen45 Gel Stent. Nd: YAG laser shockwave therapy was attempted but failed. The patient eventually had to return to the operating room for a revision procedure. The Xen45 Gel Stent was recanalized from the ab externo by making an L-shaped conjunctival incision at the fornix base and threading a 10 - 0 nylon suture through it. The IOP was successfully controlled in the 11-month follow-up without medication. CONCLUSION: If postoperative occlusion arises after Xen45 Gel Stent implantation, surgery using 10 - 0 nylon suture to recanalize Xen45 Gel Stent should be considered as a relatively safe, effective that does not require removal of Xen45 Gel Stent.

Clinical outcomes of the PAUL® glaucoma implant: One-year results.

BACKGROUND: To report one-year outcomes from a single-centre cohort undergoing PAUL® Glaucoma Implant (PGI) surgery. METHODS: Retrospective review of patients undergoing PGI surgery at the University Eye Hospital Bonn, Germany, from April 2021 to September 2021. RESULTS: Forty-five eyes of 41 patients were included. Qualified and complete success rates (95% CI) were 95.6% (88.9%-100%) and 73.3% (60%-86.7%) for Criterion A (IOP ≤ 21 mmHg), 84.4% (73.3%-93.3%) and 74.4% (51.1%-80.0%) for Criterion B (IOP ≤ 18 mmHg), 62.2% (48.9%-75.6%) and 46.7% (31.2%-62.2%) for Criterion C (IOP ≤ 15 mmHg) and 26.7% (13.3%-40.0%) and 22.2% (11.1%-33.3%) for Criterion D (IOP ≤ 12 mmHg), respectively. Mean IOP decreased from 26.1 mmHg (7-48 mmHg) to 12.0 mmHg (3-24 mmHg) (reduction of 48.83%) after 12 months with a reduction of IOP-lowering agents from 0.5 (0-3). One eye (2.2%) needed an injection of viscoelastic due to significant hypotony with AC shallowing, and four eyes (8.9%) developed choroidal detachments due to hypotony which resolved without further interventions after 6 weeks. Three patients (6.7%) developed tube exposure which required conjunctival revision with an additional pericardial patch graft. An intraluminal prolene stent was removed in 19 eyes (42.2%) after a mean time period of 8.4 months (2-12 m). Mean IOP before the removal was 21.9 mmHg (12-38 mmHg) and decreased to 11.3 mmHg (6-16 mmHg). CONCLUSIONS: PGI surgery is an effective procedure for reducing IOP and pressure-lowering therapy. An intraluminal prolene stent impedes hypotony in the early postoperative phase and enables further IOP lowering without additional interventions during the postoperative course.

Biodegradable Polymer-Based Drug-Delivery Systems for Ocular Diseases.

Ocular drug delivery is a challenging field due to the unique anatomical and physiological barriers of the eye. Biodegradable polymers have emerged as promising tools for efficient and controlled drug delivery in ocular diseases. This review provides an overview of biodegradable polymer-based drug-delivery systems for ocular diseases with emphasis on the potential for biodegradable polymers to overcome the limitations of conventional methods, allowing for sustained drug release, improved bioavailability, and targeted therapy. Natural and synthetic polymers are both discussed, highlighting their biodegradability and biocompatibility. Various formulation strategies, such as nanoparticles, hydrogels, and microemulsions, among others, are investigated, detailing preparation methods, drug encapsulation, and clinical applications. The focus is on anterior and posterior segment drug delivery, covering glaucoma, corneal disorders, ocular inflammation, retinal diseases, age-related macular degeneration, and diabetic retinopathy. Safety considerations, such as biocompatibility evaluations, in vivo toxicity studies, and clinical safety, are addressed. Future perspectives encompass advancements, regulatory considerations, and clinical translation challenges. In conclusion, biodegradable polymers offer potential for efficient and targeted ocular drug delivery, improving therapeutic outcomes while reducing side effects. Further research is needed to optimize formulation strategies and address regulatory requirements for successful clinical implementation.

Liposomal Encapsulation of Citicoline for Ocular Drug Delivery.

Glaucoma represents a group of neurodegenerative diseases characterized by optic nerve damage and the slowly progressive death of retinal ganglion cells. Glaucoma is considered the second leading cause of irreversible blindness worldwide. Pharmaceutical treatment of glaucoma is critical because of the properties of the ocular barrier that limit the penetration of drugs, resulting in lower systemic bioavailability. This behavior causes the need of frequent drug administration, which leads to deposition of concentrated solutions on the eye, causing toxic effects and cellular damage to the eye. To overcome these drawbacks, novel drug-delivery systems, such as liposomes, can play an important role in improving the therapeutic efficacy of antiglaucomatous drugs. In this work, liposomes were synthesized to improve various aspects, such as ocular barrier penetration, bioavailability, sustained release of the drug, targeting of the tissue, and reduction in intraocular pressure. Citicoline (CDP-choline; cytidine 5'-diphosphocholine) is an important intermediate in the biosynthesis of cell membrane phospholipids, with neuroprotective and neuroenhancement properties, and it was used in the treatment on retinal function and neural conduction in the visual pathways of glaucoma patients. In this study, citicoline was loaded into the 1,2-dioleoyl-sn-glycerol-3-phosphocholine and cholesterol liposomal carrier to enhance its therapeutic effect. The citicoline encapsulation efficiency, drug release, and size analysis of the different liposome systems were investigated using dynamic light scattering, nuclear magnetic resonance, infrared spectroscopy, and ToF-SIMS experiments.

Peptide-Modified Gemini Surfactants as Delivery System Building Blocks with Dual Functionalities for Glaucoma Treatment: Gene Carriers and Amyloid-Beta (Aß) Self-Aggregation Inhibitors.

Retinal ganglion cell (RGC) neurodegeneration in glaucoma has potential links with amyloid-ß (Aß) deposition. Targeting the Aß pathway was shown to reduce RGC apoptosis and protect RGCs from degeneration. We report exploratory studies on the amyloid Aß40 aggregation inhibition properties of four cell adhesion peptide (CAP)-gemini surfactants that are intended as building blocks for gene carrier nanoparticles for glaucoma treatment. The CAP-gemini surfactants (18-7N(p1-4)-18) were evaluated as potential Aß40 peptide aggregation inhibitors by a fluorescence kinetic assay and for their binding interactions with Aß40 dimers by molecular docking studies. In vitro Aß40 peptide aggregation inhibition studies showed that the 18-7N(p3)-18 and 18-7N(p1)-18 ligands inhibit Aß40 peptide aggregation and prevent the formation of higher order structures. CDOCKER energies and CDOCKER interaction energies demonstrated that the CAP-gemini surfactants formed more stable complexes in the Aß40 dimer assembly and underwent both polar and nonpolar interactions compared to CAP peptides alone. Also, 18-7N(p3)-18 showed a significantly lower CDOCKER energy compared to that of the unmodified gemini surfactant 18-7NH-18 (p < 0.0001) and 18-7N(p4)-18 (p < 0.001), 18-7N(p1)-18, and 18-7N(p2)-18. Similarly, 18-7N(p3)-18 showed a significantly lower CDOCKER interaction energy compared to that of 18-7NH-18, 18-7N(p4)-18 (p < 0.0001), and 18-7N(p2)-18 (p < 0.001), while 18-7N(p3)-18 and 18-7N(p1)-18 showed similar CDOCKER interaction energies. These studies suggest that a combination of both hydrophobic and electrostatic interactions contributes to the anti-Aß40 aggregation activity of CAP-gemini surfactants. CAP-gemini surfactants showed 10-fold better Aß40 peptide aggregation inhibition compared to previously reported values and could provide a new opportunity for glaucoma treatment as dual-functional gene carriers.

Prevalence and implications of the presence of intraocular silicone oil droplets in patients treated with intravitreal injections of anti-VEGF.

BACKGROUND: To determine the percentage of patients who have silicone droplets in the vitreous after treatment with different anti-Vascular Endothelial Growth Factor (anti-VEGF) intravitreal injections (IVI) and how symptomatic they are. METHODS: One hundred fifty-two eyes of 140 patients who had at least received an IVI were recruited for this study. Data collection included the number and type of IVI (aflibercept, ranibizumab and bevacizumab) and the follow-up time. A complete ophthalmologic examination was carried out and patients were classified in four groups according to the amount of silicone droplets found in dilated fundoscopy (nonexistent, scarce, moderate and abundant). Measurement of intraocular pressure (IOP) was also carried out. An interview was conducted to report the presence and intensity of the symptomatology. RESULTS: Silicone oil droplets were reported in 109 eyes (71.7%). A positive correlation was found between the number of IVIs received and the quantity of droplets found, especially when aflibercept was used. Posterior vitreous detachment (PVD) was present in 65.8% of the patients, showing a positive correlation with the number of bubbles. Regarding the symptomatology, 60 eyes (39.5%) had floaters and the disturbance was reported to be 4 out of 10. The group with a moderate amount of silicone droplets had the highest percentage of floaters (60%). No statistical differences in the IOP were found between groups, although the group with abundant droplets had a higher mean IOP. CONCLUSION: A high prevalence of silicone droplets in vitreous of patients who undergo IVI treatment was found. It appears to have little impact on symptomatology and rise of IOP.

Spanlastics nanovesicular ocular insert as a novel ocular delivery of travoprost: optimization using Box-Behnken design and in vivo evaluation.

Currently, travoprost is a synthetic prostaglandin F2α analogue used in the treatment of glaucoma, it is delivered by eye drop solution. Due to its very low bioavailability and patient non-compliance, the objective of the current study was to enhance its bioavailability, and prolong its release Spanlastic nano-vesicles gels were designed and optimized using Box-Behnken design. The optimized spanlastic nano-vesicles gel exhibited the lowest particle size (PS), polydispersity index (PDI) and the highest zeta potential (ZP), encapsulation efficiency (EE) and mucoadhesive strength was fabricated into spanlastic nano-vesicles ocular insert by solvent casting. In vivo studies showed enhanced bioavailability of travoprost spanlastic nano-vesicles gel and ocular insert compared to the marketed eye drops (travoswix®), as proven by their higher Cmax and AUC0-∞, in addition to being nonirritant to ocular surfaces. However, spanlastic nano-vesicles ocular insert showed more prolonged effect than spanlastic nano-vesicles gel. According to our study, it can be suggested that travoprost spanlastic nano-vesicles ocular insert is a novel ocular delivery system for glaucoma treatment.

Results and clinical aspects of primary endonasal endoscopic dacryocystorhinostomy with silicone tube.

OBJECTIVE: Endonasal endoscopic dacryocystorhinostomy (DCR) is a common treatment for saccal and post-saccal stenosis of the lacrimal pathway or chronic dacryocystitis (DC). The main symptom is chronic epiphora (tearing) and dacryocystitis (infection). The objective of this study is to assess the short-term surgical result of this treatment based on possible prognostic factors; such as gender, age, the pathogen spectrum and the histopathological result as well as the influence of these parameters on hospital stay. METHODS: It is a retrospective analysis, which includes 197 cases in 177 patients, who received an endonasal endoscopic DCR with a silicone tube between January 2009 and December 2016, as primary procedure. The follow-up was carried out 3 months after the surgery, with the silicone tube being removed as part of the last examination including a flushing of the tear ducts with saline. This procedure is part of determining to measure the short-term success of the intervention. The definition of success of the surgery is an absence of epiphora or an acute infection of the nasolacrimal duct system, as well as an absent reflux in case of flushing the tear duct. RESULTS: The success rate was 86.3% (N = 170). Higher incidence was seen in females (N = 146; 74.1%) and patients with a mean age of 65.4 (± 17.2). The presence of pathogens as well as the histopathological result do not have an impact on the short-term surgical success. Patients diagnosed with rheumatic diseases appear to have a worse prognosis with relation to procedure success. Also, the length of hospital stay was related to possible prognostic factors. Type II diabetes and glaucoma had a significant influence on a longer hospital stay. CONCLUSION: The endonasal endoscopic DCR is a surgical procedure with high success rate. Patients with rheumatic diseases should be aware of increased failure rates. Patients with glaucoma and Type II diabetes might need a more intense aftercare.

Drug-Loaded Polymeric Micelles Based on Smart Biocompatible Graft Copolymers with Potential Applications for the Treatment of Glaucoma.

Glaucoma is the second leading cause of blindness in the world. Despite the fact that many treatments are currently available for eye diseases, the key issue that arises is the administration of drugs for long periods of time and the increased risk of inflammation, but also the high cost of eye surgery. Consequently, numerous daily administrations are required, which reduce patient compliance, and even in these conditions, the treatment of eye disease is too ineffective. Micellar polymers are core-shell nanoparticles formed by the self-assembly of block or graft copolymers in selective solvents. In the present study, polymeric micelles (PMs) were obtained by dialysis from smart biocompatible poly(ε-caprolactone)-poly(N-vinylcaprolactam-co-N-vinylpyrrolidone) [PCL-g-P(NVCL-co-NVP)] graft copolymers. Two copolymers with different molar masses were studied, and a good correlation was noted between the micellar sizes and the total degree of polymerisation (DPn) of the copolymers. The micelles formed by Cop A [PCL120-g-P(NVCL507-co-NVP128)], with the lowest total DPn, have a Z-average value of 39 nm, whereas the micellar sizes for Cop B [PCL120-g-P(NVCL1253-co-NVP139)] are around 47 nm. These PMs were further used for the encapsulation of two drugs with applications for the treatment of eye diseases. After the encapsulation of Dorzolamide, a slight increase in micellar sizes was noted, whereas the encapsulation of Indomethacin led to a decrease in these sizes. Using dynamic light scattering, it was proved that both free and drug-loaded PMs are stable for 30 days of storage at 4 °C. Moreover, in vitro biological tests demonstrated that the obtained PMs are both haemo- and cytocompatible and thus can be used for further in vivo tests. The designed micellar system proved its ability to release the encapsulated drugs in vitro, and the results obtained were validated by in vivo tests carried out on experimental animals, which proved its high effectiveness in reducing intraocular pressure.

Silicone Oil-Induced Glaucomatous Neurodegeneration in Rhesus Macaques.

Previously, we developed a simple procedure of intracameral injection of silicone oil (SO) into mouse eyes and established the mouse SOHU (SO-induced ocular hypertension under-detected) glaucoma model with reversible intraocular pressure (IOP) elevation and significant glaucomatous neurodegeneration. Because the anatomy of the non-human primate (NHP) visual system closely resembles that of humans, it is the most likely to predict human responses to diseases and therapies. Here we tried to replicate the mouse SOHU glaucoma model in rhesus macaque monkeys. All six animals that we tested showed significant retinal ganglion cell (RGC) death, optic nerve (ON) degeneration, and visual functional deficits at both 3 and 6 months. In contrast to the mouse SOHU model, however, IOP changed dynamically in these animals, probably due to individual differences in ciliary body tolerance capability. Further optimization of this model is needed to achieve consistent IOP elevation without permanent damage of the ciliary body. The current form of the NHP SOHU model recapitulates the severe degeneration of acute human glaucoma, and is therefore suitable for assessing experimental therapies for neuroprotection and regeneration, and therefore for translating relevant findings into novel and effective treatments for patients with glaucoma and other neurodegenerations.