Microfluidic Fabricated Liposomes for Nutlin-3a Ocular Delivery as Potential Candidate for Proliferative Vitreoretinal Diseases Treatment.

Purpose: Proliferative vitreoretinal diseases (PVDs) represent a heterogeneous group of pathologies characterized by the presence of retinal proliferative membranes, in whose development retinal pigment epithelium (RPE) is deeply involved. As the only effective treatment for PVDs at present is surgery, we aimed to investigate the potential therapeutic activity of Nutlin-3a, a small non-genotoxic inhibitor of the MDM2/p53 interaction, on ARPE-19 cell line and on human RPE primary cells, as in vitro models of RPE and, more importantly, to formulate and evaluate Nutlin-3a loaded liposomes designed for ophthalmic administration. Methods: Liposomes were produced using an innovative approach by a microfluidic device under selection of different conditions. Liposome size distribution was evaluated by photon correlation spectroscopy and centrifugal field flow fractionation, while the liposome structure was studied by transmission electron microscopy and Fourier-transform infrared spectroscopy. The Nutlin-3a entrapment capacity was evaluated by ultrafiltration and HPLC. Nutlin-3a biological effectiveness as a solution or loaded in liposomes was evaluated by viability, proliferation, apoptosis and migration assays and by morphological analysis. Results: The microfluidic formulative study enabled the selection of liposomes composed of phosphatidylcholine (PC) 5.4 or 8.2 mg/mL and 10% ethanol, characterized by roundish vesicular structures with 150-250 nm mean diameters. Particularly, liposomes based on the lower PC concentration were characterized by higher stability. Nutlin-3a was effectively encapsulated in liposomes and was able to induce a significant reduction of viability and migration in RPE cell models. Conclusion: Our results lay the basis for a possible use of liposomes for the ocular delivery of Nutlin-3a.

The Hippo signalling pathway and its impact on eye diseases.

The Hippo signalling pathway, an evolutionarily conserved kinase cascade, has been shown to be crucial for cell fate determination, homeostasis and tissue regeneration. Recent experimental and clinical studies have demonstrated that the Hippo signalling pathway is involved in the pathophysiology of ocular diseases. This article provides the first systematic review of studies on the regulatory and functional roles of mammalian Hippo signalling systems in eye diseases. More comprehensive studies on this pathway are required for a better understanding of the pathophysiology of eye diseases and the development of effective therapies.

Intraocular pressure changes before and after a femtosecond laser procedure for cataract surgery.

This study aimed to evaluate the changes in intraocular pressure (IOP) before and after femtosecond laser capsulorhexis and lens fragmentation for cataract surgery. We measured the IOP before, immediately, 30 min, and 1 h after the laser procedure in 47 eyes of 47 patients who underwent the femtosecond laser procedure. The mean IOP was 17.51 ± 3.28 mmHg, 30.23 ± 6.70 mmHg, 17.96 ± 3.75 mmHg, and 21.77 ± 5.88 mmHg before, immediately after, 30 min after, and 1 h after the laser procedure, respectively. The mean IOP significantly increased immediately (adjusted P < 0.001) and 1 h (adjusted P = 0.001) after the laser procedure compared with the pre-laser IOP. The mean IOP at 30 min after the laser procedure was significantly lower than that immediately after the procedure (adjusted P < 0.001). However, the IOP 1 h after the laser procedure became higher than that 30 min after the laser procedure. Additionally, the IOP 1 h after the laser procedure was positively correlated with the baseline IOP and negatively correlated with the axial length. In conclusion, this study demonstrated that cataract surgery should be commenced within 30 min after the femtosecond laser procedure to ensure a safe cataract surgery that reduces the risk of increased intraocular pressure.

Can (Natural) deep eutectic systems increase the efficacy of ocular therapeutics?

The eye is one of the most complex organs in the human body, with a unique anatomy and physiology, being divided into anterior and posterior segments. Ocular diseases can occur in both segments, but different diseases affect different segments. Glaucoma and cataracts affect the anterior segment, while macular degeneration and diabetic retinopathy occur in the posterior segment. The easiest approach to treat ocular diseases, especially in the anterior segment, is through the administration of topical eye drops, but this route presents many constraints, namely precorneal dynamic and static ocular barriers. On the other hand, the delivery of drugs to the posterior segment of the eye is far more challenging and is mainly performed by the intravitreal route. However, it can lead to severe complications such as retinal detachment, endophthalmitis, increased intraocular pressure and haemorrhage. The design of new drug delivery systems for the anterior segment is very challenging, but targeting the posterior one is even more difficult and little progress has been made. In this review we will discuss various strategies including the incorporation of additives in the formulations, such as viscosity, permeability, and solubility enhancers, namely based on Deep eutectic systems (DES). Natural deep eutectic systems (NADES) have emerged to solve several problems encountered in pharmaceutical industry, regarding the pharmacokinetic and pharmacodynamic properties of drugs. NADES can contribute to the design of advanced technologies for ocular therapeutics, including hydrogels and nanomaterials. Here in, we revise some applications of (NA)DES in the development of new drug delivery systems that can be translated into the ophthalmology field.

No side effects on rabbit retina or vitreous microenvironment by nd:YAG laser vitreolysis.

BACKGROUND: To explore the safety of Neodymium:Yttrium-aluminum-garnet (Nd:YAG) laser vitreolysis based on the histological examination of the retina and the alteration of vitreous cytokines in the rabbits. METHODS: Nine male New Zealand rabbits underwent Nd:YAG laser vitreolysis of 10 mJ x 500 pulses in the left eyes, while the right eyes were used as controls. Intraocular pressure, color fundus photography, and ultrasound B scan were measured before, as well as 1 day, 4 weeks, and 12 weeks after Nd:YAG laser vitreolysis. Three rabbits were euthanized 1 day, 4 weeks, and 12 weeks after treatment, respectively. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and hematoxylin-eosin (H&E) staining were used to look for pathological changes in the retina. An enzyme-linked immunosorbent assay (ELISA) was utilized to detect the expression of vascular endothelial growth factor (VEGF) and some inflammatory cytokines, including interferon inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1) and interlenkin 6 (IL-6) in the vitreous humor. The ascorbic acid (AsA) and total reactive antioxidant potential (TRAP) in the vitreous humor were also measured. RESULTS: Following Nd:YAG laser vitreolysis, the levels of VEGF, IP-10, MCP-1, IL6, AsA, and TRAP in the vitreous humor did not change substantially (P > 0.05). There were no detectable pathological changes in the retinal tissues, and no apoptotic signal was found. CONCLUSIONS: Rabbits tolerate Nd:YAG laser vitreolysis without observable impact on retinal tissue or the microenvironment of the vitreous.

Susceptibility of optic nerve head in children with posture-related elevation of intraocular pressure.

BACKGROUND/AIMS: This work aimed to investigate changes in optic nerve head (ONH) morphometry based on Bruch membrane opening in children with extensive nocturnal intraocular pressure (IOP) elevations. METHODS: The course of Bruch membrane opening-based optic nerve head (ONH) morphometry was analysed in thirty-two patients younger than 18 years with evaluable SD-OCT examinations of the ONH and nocturnal posture-dependent IOP elevation above 25 mmHg. Longitudinal changes in neuroretinal rim tissue, as measured by Bruch Membrane opening minimum rim width (BMO-MRW) and peripapillary retinal nerve fiber layer (RNFL) thickness, were assessed. RESULTS: One year after the 24 h IOP measurement, global BMO-MRW (- 1.61 ± 16.8 µm, n.s.; p = 0.611) and RNFL (+ 0.64 ± 3.17 µm; n.s.; p = 0.292) measurements were not significantly different from the baseline. No significant BMO-MRW reduction (- 3.91 ± 24.3 µm; n.s. p = 0.458) or deviation in RNFL thickness (+ 1.10 ± 3.52 µm) was observed at the four-year follow-up. Absolute IOP values measured in the supine position did not correlate with changes in global BMO-MRW or RNFL thickness. CONCLUSION: Posture-dependent IOP elevations do not seem to influence retinal nerve fibre layer thickness or Bruch membrane opening-based morphometric data in childhood.

Hemoglobin levels are associated with retinal vascular caliber in a middle-aged birth cohort.

Vascular and neural structures of the retina can be visualized non-invasively and used to predict ocular and systemic pathologies. We set out to evaluate the association of hemoglobin (Hb) levels within the national reference interval with retinal vascular caliber, optical coherence tomography (OCT) and visual field (VF) parameters in the Northern Finland 1966 Birth Cohort (n = 2319, 42.1% male, average age 47 years). The studied parameters were evaluated in Hb quintiles and multivariable linear regression models. The lowest Hb quintile of both sexes presented the narrowest central retinal vein equivalent (CRVE) and the healthiest cardiometabolic profile compared to the other Hb quintiles. In the regression models, CRVE associated positively with Hb levels in both sexes, (Bmales = 0.068 [0.001; 0.135], Bfemales = 0.087 [0.033; 0.140]), after being adjusted for key cardiometabolic and inflammatory parameters, smoking status, and fellow vessel caliber. No statistically significant associations of Hb levels with central retinal artery equivalent, OCT or VF parameters were detected. In conclusion, Hb levels were positively and specifically associated with CRVE, indicating that Hb levels are an independent factor affecting CRVE and the effect is in parallel with established risk factors for cardiometabolic diseases.

Painful Eyes in Neurology Clinic: A Guide for Neurologists.

Eye pain is a common complaint among patients presenting to the neurology clinic. It can be related to neurologic diseases, but it can also be a localized eye condition. Such disorders can be misleading, as their benign appearance might mask more grave underlying conditions, potentially leading to misdiagnoses or delayed treatment. Clinicians should be aware of the specific neurologic or systemic disorders (eg, demyelinating diseases or vascular abnormalities) that might first manifest as eye pain. Formal ophthalmic consultation is recommended for patients presenting with eye pain as the predominant complaint especially when red flags for more serious pathology are present.

Association of Long-Term Exposure to Ambient Air Pollution With the Risk of Acute Primary Angle Closure.

Purpose: The purpose of this study was to investigate the association between long-term exposure to ambient air pollutants and the risk of acute primary angle closure (APAC). Methods: Two hundred eighty-one (281) patients with APAC and 730 age- and sex-matched controls hospitalized between January 2017 and December 2019 were enrolled in this retrospective case-control study. Residential exposure to ambient air pollutants, including fine particulate matter (PM2.5), inhalable particulate (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), and ozone were estimated by satellite-models or ground measurement. Multivariate regression analyses explored the association between annual air pollutants exposure and the risk of APAC. Results: Of the 1011 participants (31.1% were male subjects), the average age was 64.0 years. Long-term exposure to PM2.5, PM10, and SO2 were significantly associated with an increased risk of APAC. The adjusted odds ratios (aORs) for each interquartile range (IQR) increment of PM2.5, PM10, and SO2 were 1.28 (95% confidence interval [CI] = 1.06-1.57), 1.26 (95% CI = 1.06-1.50), and 1.30 (95% CI = 1.04-1.62) separately, after controlling for confounders. Robust associations were observed for a longer lag 2-year exposure. Conclusions: Long-term exposure to PM2.5, PM10, and SO2 was associated with an increased risk of APAC in a Chinese population. Our findings provide epidemiological implications on the adverse effects of air pollution on ocular diseases. Translational Relevance: Long-term exposure to ambient air pollutants increased the risk of APAC.

Encephalocraniocutaneous Lipomatosis: A Case Report.

ABSTRACT: Encephalocraniocutaneous lipomatosis (ECCL) is a rare congenital syndrome and subclassification of oculoectodermal syndrome. Encephalocraniocutaneous lipomatosis may be associated with postzygotic mutations. However, absence of an identifiable mutation does not preclude a diagnosis of ECCL. Encephalocraniocutaneous lipomatosis commonly causes skin, eye, and central nervous system anomalies. Diagnosis can be made through genetic sequencing or standardized clinical criteria. One clinically apparent major criterion for the diagnosis of ECCL is nevus psiloliparus (NP), a fatty nevus with overlying nonscarring alopecia. In this case, a 50-day-old female infant with uncomplicated birth history presented to dermatology clinic for evaluation of 2 superficial cranial masses that had been present since birth without regression or evolution. One of the masses was located within the hairline and demonstrated overlying nonscarring alopecia, suspicious of NP. Because of concern for ECCL, brain magnetic resonance imaging was ordered and revealed 2 intracranial lipomas. Genetic testing was inconclusive. Excision of the masses was performed at the request of the parents for cosmetic purposes. Histologic evaluation of the surgical specimens confirmed the diagnosis of NP and ECCL. A suspected NP should raise concern for ECCL and prompt further evaluation for systemic involvement. In particular, patients with suspected ECCL should be screened for ocular and CNS involvement. Early identification and diagnosis are important for prognostication because patients with ECCL are at increased risk of developing neoplasms of the head and neck and may require more frequent screening examinations.

The effect of polyethylene cover intervention on ocular surface disorder of intensive care unit patients: a systematic review and meta-analysis.

BACKGROUND: Polyethylene covers have been proven to be effective in protecting the eyes in patients with decreased or disappeared blink reflexes, but their advantages compared to other conventional methods are still unclear. This systematic review and meta-analysis study aimed to elucidate the impact of polyethylene covers in the prevention of ocular surface disease (OSD) in patients admitted to the intensive care unit (ICU). METHODS: We searched the Scopus, PubMed, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) databases to identify randomized controlled trial studies. This study followed the PRISMA guidelines and used the Cochrane Collaboration tool to assess the risk of bias. RESULTS: The findings were expressed as risk ratio (RR) with 95% confidence intervals. The incidence of OSD in the polyethylene cover group was lower than that in the eye drops group (RR = 0.27; 95% CI (0.07, 1.09), P = 0.07) and adhesive tape group (RR = 0.11, 95%CI (0.04, 0.31), P < 0:0001) but the polyethylene cover group showed no significant difference compared to the eye gel group (RR = 0.79, 95%CI (0.18, 3.51), P = 0.76) and the eye ointment group (RR = 0.85; 95% CI (0.36, 1.99), P = 0.71). CONCLUSION: This study showed that polyethylene covers, eye gels, and eye ointments had an equal effect on preventing OSD in ICU patients, and eye drops and adhesive tapes were relatively less effective. However, other intervention methods had not been compared due to the small number of articles. Hence, further studies should assess the available methods to choose the best practical method.

Ophthalmic manifestations of nasopharyngeal carcinoma (NPC): A systematic review of reported cases with and without prior history of nasopharyngeal carcinoma.

PURPOSE: We aimed to study reported cases of nasopharyngeal carcinoma presenting with ophthalmic manifestations with and without a prior diagnosis of nasopharyngeal carcinoma. METHODS: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A literature search was conducted using the MEDLINE database in PubMed and Google Scholar. We included patients with a previous diagnosis of nasopharyngeal carcinoma in Group I and those without a prior diagnosis of nasopharyngeal carcinoma in Group II. Data included demographics, clinical presentation, history of nasopharyngeal carcinoma, treatment, histopathological description, World Health Organization classification, and outcome. RESULTS: Fifty-eight patients (26 in Group I and 32 in Group II) were included. The male-to-female ratio was 3:1. The mean age of the patients (53.3 ± 11.7 years and 54.8 ± 16.2 years, respectively) and gender did not differ significantly between the two groups. The most common ocular presentations were diplopia and proptosis in the first group (each in 34.6%), whereas visual disturbance was most common in the second group (46.9%). Treatment options and World Health Organization grading were comparable. The outcome in 38 patients (after a comparable follow-up period) was significantly better in group II (p=0.003). There was no statistically significant difference in the outcome of 23 patients in correlation with World Health Organization grades II versus III irrespective of group (p=0.094). CONCLUSIONS: The demographics of patients with nasopharyngeal carcinoma presenting with ophthalmic manifestations were similar between the two study groups, with a wide age range and male predominance. Patients presenting initially to ophthalmologists with no history of nasopharyngeal carcinoma have a more favorable outcome. World Health Organization grading may have less value as a prognostic indicator.

Options for Topical Treatment of Oxidative Eye Diseases with a Special Focus on Retinopathies.

Antioxidants, usually administered orally through the systemic route, are known to counteract the harmful effects of oxidative stress on retinal cells. The formulation of these antioxidants as eye drops might offer a new option in the treatment of oxidative retinopathies. In this review, we will focus on the use of some of the most potent antioxidants in treating retinal neuropathies. Melatonin, known for its neuroprotective qualities, may mitigate oxidative damage in the retina. N-acetyl-cysteine (NAC), a precursor to glutathione, enhances the endogenous antioxidant defense system, potentially reducing retinal oxidative stress. Idebenone, a synthetic analogue of coenzyme Q10, and edaravone, a free radical scavenger, contribute to cellular protection against oxidative injury. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, possesses anti-inflammatory and antioxidant effects that could be beneficial in cases of retinopathy. Formulating these antioxidants as eye drops presents a localized and targeted delivery method, ensuring effective concentrations reach the retina. This approach might minimize systemic side effects and enhance therapeutic efficacy. In this paper, we also introduce a relatively new strategy: the alkylation of two antioxidants, namely, edaravone and EGCG, to improve their insertion into the lipid bilayer of liposomes or even directly into cellular membranes, facilitating their crossing of epithelial barriers and targeting the posterior segment of the eye. The synergistic action of these antioxidants may offer a multifaceted defense against oxidative damage, holding potential for the treatment and management of oxidative retinopathies. Further research and clinical trials will be necessary to validate the safety and efficacy of these formulations, but the prospect of antioxidant-based eye drops represents a promising avenue for future ocular therapies.

A case of IgG4-related ophthalmic disease after SARS-CoV-2 vaccination: case report and literature review.

Coronavirus disease 19 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is affecting the world with a surge in cases. A variety of autoimmune diseases occur after SARS-CoV-2 infection or vaccination, of which IgG4-related disease (IgG4-RD) is an important type. IgG4-RD can involve multiple organs of the body. The ocular manifestation of IgG4-RD is called IgG4-related ophthalmic disease (IgG4-ROD). We herein report a patient diagnosed with IgG4-ROD. The patient developed ptosis and vision loss after SARS-CoV-2 vaccination, and the symptoms worsened after SARS-CoV-2 infection. After excluding other diseases like myasthenia gravis and Eaton-Lambert syndrome that may cause ptosis, the diagnosis of IgG4-ROD was confirmed by pathological examination. We discussed the predisposing factors, diagnosis and treatment of this patient to provide a more empirical and theoretical basis for clinical diagnosis and treatment. We conducted a literature review of previously reported cases of IgG4-RD following SARS-CoV-2 infection or vaccination. We retrieved a total of 9 cases, of which 5 developed symptoms after vaccination and 4 after infection. Demographic and clinical characteristics were summarized. In conclusion, our case represents the first case of proven IgG4-ROD after COVID-19 vaccination. We believe that IgG4-ROD and SARS-CoV-2 infection or vaccination are closely related, and the immune system disorder caused by SARS-CoV-2 infection or vaccination may be a key factor in the pathogenesis of IgG4-RD. But for now, there is no direct evidence that there is a causal relationship between SARS-CoV-2 infection or vaccination and IgG4-ROD, which still needs more research and exploration to confirm.

Congenital solitary osseous choristoma of the left lateral canthus: a case report.

BACKGROUND: An ocular osseous choristoma is a growth of mature, compact bone in the ocular or periocular soft tissue, and it is the rarest form of ocular choristoma, accounting for only 1.7% of all epibulbar choristomas. CASE PRESENTATION: Herein we present the case of a 20-month-old girl who was referred to the oculoplasty clinic with a progressively growing mass in the left lateral canthus. It had been present since birth without ocular involvement. Upon examination the mass was firm with a smooth surface, measured 9 × 6 × 3 mm, and exhibited no episcleral attachment or ocular involvement. An excisional biopsy was performed, and the histopathological findings were consistent with osseous choristoma of the left lateral canthus. CONCLUSIONS: This report highlights the importance of considering osseous choristoma in the differential diagnosis of eyelid lesions, particularly those that have been present since birth. It also emphasizes the need for further studies investigating associations between osseous choristomas and ocular canthi.