bluuebunny/crossref_metadata_2025_split huggingface dataset:
Involvement of the neurokinin 1 receptor pathway in aniridia associated keratopathy: Evidence from pre‐clinical models
Authors: Palombella Silvia , Fonteyne Philippe , Javidjam Seyedehdina , Suanno Giuseppe , Bartolomeo Nicolò , Tilaro Gianluca , Lagali Neil , Ferrari Giulio 
Published: January 2025

Aniridia is a rare ocular disorder characterized by the hypoplasia or absence of the iris associated with severe visual loss. Two‐thirds of cases are generated by mutations in the PAX6 gene and are frequently associated with severe aniridia‐associated keratopathy (AAK), which is characterized by pain, persistent epitheliopathy, corneal neovascularization and progressive loss of limbal stem cell function. The pathophysiology of AAK is still unclear; however, leukocyte infiltration and nerve degeneration have been reported. Substance P (SP) is a neuropeptide secreted by nerve fibers, immune and epithelial cells in the cornea and exerts its pro‐inflammatory functions by binding to neurokinin‐1 receptor (NK1R), promoting nerve activation, leukocyte chemotaxis and extravasation, thus contributing to the inflammatory response. In this context, the modulation of NK1R activation could be used as an innovative therapy to control inflammation and pain associated with AAK.Our main aim was to quantify the expression of NK1R and SP in the cornea of a PAX 6+/− mouse model of AAK compared to unaffected animals at different ages. This model express PAX6 gene in heterozygosis and is characterized by iris hypoplasia, abnormal lens morphology, cataracts, corneal opacification, and incomplete separation of lens from the cornea, typical features associated with AAK patients. Corneal samples were collected from mice at different ages, that is 1 month old, 2 months old, 4 months old, and 7 months old, and immunohistochemistry was performed on cross‐sections to quantify the expression of SP and NK1R. In the control samples, NK1R decreased over time albeit not significant. The expression level in the PAX6 +/− samples was comparable to controls at 1, 4, and 7 months old. However, the expression level of NK1R obtained from 2 months old mice was significantly higher compared not only to 1, 4 and 7 months old PAX6 +/− mice but also to all control groups (p < 0.001). The same trend was observed also for SP. Indeed, SP was significantly more expressed in the corneas of 2 months old mice compared to other time points and also to control groups (p < 0.01). These data confirm that the expression of SP goes together with the expression of NK1R during the development of healthy animals. Our data suggest that there may be a window of opportunity for the modulation of SP activity at 2 months of age. Future experiments will be performed in order to investigate the actual efficacy of NK1R blockade for the treatment of AAK.
Dalk – when and how
Authors: Goweida Mohamed 
Published: January 2025

Deep anterior lamellar keratoplasty (DALK) is a surgical procedure that involves replacing the anterior portion of the cornea with donor tissue while preserving the patient's endothelium. This technique has gained popularity in recent years as an alternative to traditional penetrating keratoplasty (PK) due to its potential advantages in terms of visual outcomes, graft survival and reduced risk of endothelial rejection.The decision to perform DALK in keratoconus is based on various factors, including the keratometric readings, corneal thickness, corneal clarity and RGP tolerability.Surgical technique plays a critical role in the success of DALK. Several approaches have been described to perform the DALKs; the big bubble technique is considered the most convenient for all surgeons. Other techniques were used according to the associated pathology.This presentation is a quick journey into DALK indications and various techniques used in eyes with keratoconus.
Choroidal neovascularization in best disease: A pediatric ophthalmology challenge
Authors: Bacci Giacomo 
Published: January 2025

Choroidal neovascularisation (CNV) is a rare but serious complication of Best disease. However, visualisation of the neovascular membrane is difficult on fluorescein angiography (FA) and indocyanine green angiography (ICGA) due to dye leakage from material accumulation. The authors' study reports a case series of paediatric Best's disease where optical coherence tomography angiography (OCT‐A) contributed to the diagnosis of CNV and prompt treatment.Three eyes of three patients with Best's disease were included. The mean age at diagnosis was 5.6 years (range 4‐7 years). OCT‐A showed the typical sea fan‐shaped neovascular membrane in three eyes, whereas in most cases conventional FA and ICGA imaging did not clearly show neovascularisation due to the masking effect of vitelliform material. OCT‐A appears to be a good alternative for diagnosing CNV in Best's disease, particularly in children, as it is a non‐invasive and rapid imaging technique that does not require the administration of dyes.The aim was to evaluate the effect of intravitreal injections on choroidal neovascularisation in patients with Best's disease using OCT and OCT‐A and to assess the increase in visual acuity after rehabilitation. During the talk, a literature data review on pathogenesis, evolution and future perspectives will be presented.
Genetic complexity of inherited retinal diseases in a large italian cohort
Authors: Karali Marianthi , Testa Francesco , Di Iorio Valentina , Torella Annalaura , Zeuli Roberta , Scarpato Margherita , Romano Francesca , Onore Maria Elena , Pizzo Mariateresa , Melillo Paolo , Brunetti‐Pierri Raffaella , Passerini Ilaria , Pelo Elisabetta , Cremers Frans P. M. , Esposito Gabriella , Nigro Vincenzo , Simonelli Francesca , Banfi Sandro 
Published: January 2025

Introduction: Inherited retinal diseases (IRDs) are the leading cause of vision loss in the working‐age population and represent one of the most genetically heterogeneous, rare Mendelian diseases. This heterogeneity mirrors a spectrum of clinical phenotypes which vary in terms of cell/tissue involvement, disease onset, severity, and progression.Aim: To determine the genetic basis of IRD pathogenesis in a large Italian cohort (n = 2790) followed at a single referral center.Methods: We performed a retrospective epidemiological study by reviewing the clinical records and genetic data of the IRD patients followed at the Eye Clinic of the University of Campania ‘Luigi Vanvitelli’ (Naples, Italy). Almost 70% of cases were analysed by Next Generation Sequencing approaches using panels of known retinopathy genes, clinical exome or whole exome sequencing. A third of the molecular diagnoses were performed by candidate gene sequencing, APEX‐based genotyping microarrays and single molecule Molecular Inversion Probes.Results: We provided conclusive molecular diagnosis for 2036 patients (from 1683 unrelated families). The overall diagnostic success rate was 73%. We identified a total of 1327 causative sequence variations in 127 genes, including 348 novel variants, and 866 potentially actionable genotypes for therapeutic approaches. ABCA4 was the most frequently mutated gene (n = 535; 26.3% of solved cases), followed by USH2A (n = 228; 11.2%) and RPGR (n = 102; 5%). About 60% of RPGR variants were detected in ORF15, a mutational hotspot refractory to NGS analyses. The other 124 genes had a lower contribution to IRD pathogenesis (e.g. CHM 3.5%, RHO 3.5%; MYO7A 3.4%; CRB1 2.7%; RPE65 2%, RP1 1.8%; GUCY2D 1.7%). Seventy‐eight genes were mutated in five patients or less. Mitochondrial DNA variants were responsible for 2.1% of cases. The combined genetic and clinical assessment uncovered novel genotype‐phenotype associations and phenotypic expansions.Conclusions: We report on the largest cohort of molecularly characterised IRD patients from Italy to date. Our findings confirm the complex genetic etiology of IRDs and reveal the high prevalence of ABCA4 and USH2A mutations. The results suggest that mutations in RPGR‐ORF15 likely account for a significant fraction of male IRD patients who remain undiagnosed after a first tier NGS analysis. This study also uncovers novel genetic associations with a spectrum of clinical phenotypes and identifies numerous cases potentially eligible for clinical trials and, ultimately, for molecular therapies.Keywords: Inherited retinal diseases, genetic epidemiology, retinitis pigmentosa, Stargardt disease, Leber Congenital Amaurosis
Panretinal photocoagulation for the treatment of proliferative diabetic retinopathy
Authors: Karakosta Christina , Chatziralli Irini , Kabanarou Stamatina A. 
Published: January 2025

After the completion of DRS study in 1979, Panretinal Photocoagulation (PRP) became the gold standard for the treatment of proliferative diabetic retinopathy.Light from the laser is absorbed by the retinal pigment epithelium (RPE), and the underlying choroid and it is converted to thermal energy. Those thermal burns denature tissue protein, causing local retinal cell death, coagulative necrosis and eventually scarring. In that respect, laser photocoagulation leads to diminished oxygen demands of the areas of capillary non perfusion, and reduced expression of vasoactive factors such as vascular endothelial growth factor (VEGF) and protein kinase C (PKC) in the retina. As a result, adequate oxygen and nutrients are diverted towards the non‐ischemic retinal areas.As documented by the DRS study, after a 5‐year follow‐up period, the rates of severe visual loss were diminished by at least 50% in all eyes treated with PRP in comparison with untreated control eyes. The greatest beneficial effect was shown for treated eyes with high risk PDR characteristics (any NVD with extent greater than or equal to one‐fourth disc area without vitreous or preretinal hemorrhage, any NVD with vitreous or preretinal hemorrhage,any NVE with extent greater than or equal to one‐half disc area, with vitreous or preretinal hemorrhage). Harmful effects of PRP includes peripheral visual field loss, decrease in visual acuity, nyctalopia etc. Treatment of non‐high risk PDR cases, could also be proposed under certain circumstances such as in patients with difficulty to attend regular appointments, advanced diabetic disease in the fellow eye etc.Although anti‐VEGF agents have been approved for the treatment of PDR, PRP remains an effective therapeutic option and the choice of treatment could be made on an individualized basis. However, in high risk PDR patients with co‐existing maculopathy the addition of anti‐VEGF injections to PRP treatment is advisable.
Visual evoked potential
Authors: Neveu Magella 
Published: January 2025

The visual evoked potential (VEP) is a measure of time locked visual cortical activity, measured at the scalp, to a controlled stimulus that enables objective assessment of the integrity of the retino‐cortical visual pathway. VEP waveform characteristics and morphology are dependant upon signal generators, in response to pattern or flash, achromatic or chromatic stimuli, and positioning of the active recording electrodes over the visual area of interest (e.g. V1 or MT).In clinical electrophysiology, the VEP is recorded according to the ISCEV (International Society of Clinical Electrophysiology of Vision) standards using pattern reversal, pattern onset‐offset or flash stimulation. The clinical uses of the VEP include assessment of optic nerve dysfunction consequent upon demyelination, ischaemia, or nutritional deficiency; genetically determined optic neuropathy such as Autosomal Dominant Optic Atrophy (DOA), Leber Hereditary Optic Neuropathy, and intracranial misrouting of the retino‐cortical projection, as associated with albinism.Although the VEP is used clinically primarily to assess optic nerve, chiasmal and cortical function, any disturbance in the visual pathway may result in an abnormal VEP, such as eye closure, optical degradation and retinal dysfunction. In addition, the clinical presentation in optic nerve disease and macular/retinal is often similar. Clinical features common in both include visual acuity loss, a pale disc, colour vision defect and less commonly, a RAPD. These factors must be taken into consideration when interpreting the VEP, therefore recording of the pattern ERG, multifocal ERG (mfERG) and/or ERG in conjunction with the VEP enables more accurate assessment of visual pathway function and the distinction between optic nerve disease and retinal disease.
Visual acuity outcomes by sex in a historical population of patients with leber hereditary optic neuropathy from case record survey‐2 (CRS‐2)
Authors: Votruba Marcela , Leroy Bart , Yu‐Wai‐Man Patrick , Van Everdingen Judith , Krawczynski Maciej , Lamperti Costanza , Carelli Valerio , Llòria Xavier , Klopstock Thomas 
Published: January 2025

Aims/Purpose: Leber hereditary optic neuropathy (LHON) is a rare mitochondrial disorder resulting in severe bilateral vision loss. Age at symptom onset and estrogen levels are thought to influence disease progression. The Case Record Survey‐2 (CRS‐2; NCT02796274) was conducted to establish the natural history of LHON in idebenone‐naïve patients. Here, we report 12‐month clinical outcomes by sex and age at symptom onset.Methods: Retrospective clinical data were extracted from case records of LHON patients. Eligibility: aged ≥12y, m.11778G>A, m.3460G>A, or m.14484T>C mitochondrial DNA mutation, symptom onset after 1999, ≥2 visual acuity (VA) assessments within 5y of symptom onset. Patients were subset by sex and age at symptom onset. Spontaneous clinically relevant benefit (sCRB), recovery (sCRR), stabilisation (sCRS), and worsening (sCRW) at 12 ± 3 months from baseline (first VA assessment after symptom onset) were calculated in subacute/dynamic eyes (≤1y since symptom onset) as previously described1.Results: Overall, male and female eyes had similar rates of sCRB (male: 21.0% [17/81]; female: 20.0% [3/15]) and sCRW (male: 65.1% [41/63]; female: 69.2% [9/13]); however male eyes had a lower rate of sCRR (male: 11.1% [9/81]; female: 20.0% [3/15]) and a higher rate of sCRS (male: 32.4% [11/34]; female: 0.0% [0/8]). In females, there were no eyes aged <15y at symptom onset. Eyes aged 15–50y at onset had a higher rate of sCRR (15–50y: 33.3% [3/9] vs >50y: 0.0% [0/6]) and a lower rate of sCRW (15–50y: 50.0% [4/8] vs >50y: 100.0% [5/5]) compared to eyes aged >50y. In males, eyes aged 15–50y at onset had the lowest rate of sCRR (<15y: 19.0% [4/21]; 15–50y: 6.0% [3/50]; >50y: 20.0% [2/10]) and the highest rate of sCRW (<15y: 47.4% [9/19]; 15–50y: 77.1% [27/35]; >50y: 55.6% [5/9]) compared to eyes aged <15y and >50y.Conclusions: The clinical course of LHON may differ based on sex and age at symptom onset.References: 1. Yu‐Wai‐Man P, et al. Cell Reports Medicine 2024;5:101437.
Comparative efficacy of receptor tyrosine kinase inhibitors in a mouse model of alkali burn‐induced corneal neovascularization
Authors: Gladkauskas Titas , Rundgren Ida , Cristea Ileana , Rødahl Eyvind , Bredrup Cecilie 
Published: January 2025

Aims/Purpose: This study evaluates the efficacy of topical dasatinib and axitinib for treating experimentally induced corneal neovascularization (CNV) in a mouse alkali burn model, comparing these treatments to established therapies like dexamethasone and bevacizumab. The study aims to determine which treatment provides superior efficacy in inhibiting CNV in this model.Methods: Thirty‐six C57BL/6;129Sv mice underwent a standardized alkali burn to induce CNV in both eyes using a paper disc soaked in 1M NaOH. The mice were randomly assigned to one of six treatment groups: saline (0.9% sodium chloride), DMSO (5%), dexamethasone (0.1%), bevacizumab (0.5%), dasatinib (0.5%), or axitinib (0.5%). Treatments were applied topically three times daily. CNV assessments, including corneal neovascularization area (CNA), vessel length index (VLI), and limbus vasculature thickness, were conducted post‐mortem using corneal flat‐mounts stained with CD31 antibody for immunohistochemistry.Results: Dexamethasone proved the most effective in inhibiting alkali burn‐induced CNA (p < 0.0001), with bevacizumab showing comparable efficacy (p < 0.001). Axitinib also effectively reduced CNA (p < 0.001) and VLI (p < 0.01). In contrast, dasatinib did not significantly reduce CNA (p = 0.74) or VLI (p = 0.98).Conclusions: While dexamethasone was most effective, both bevacizumab and axitinib successfully reduced CNA, with axitinib additionally decreasing VLI. Axitinib has a broad‐spectrum inhibition of vascular endothelial growth factor receptors 1, 2, and 3 (VEGFR1, VEGFR2, VEGFR3), and platelet‐derived growth factor receptor β (PDGFRβ). This may offer superior benefits compared to narrower‐spectrum TKIs like dasatinib, which primarily target PDGFRβ and fibroblast growth factor receptor (FGFR). The results highlight the effectiveness of targeting the VEGF‐VEGFR pathway for managing corneal neovascularization, presenting a viable option for patients who are sensitive to steroids.
Efficacy and tolerability of a new riboflavin‐based dye compared to double staining with fluorescein and lissamine green in the evaluation of corneal‐conjunctival epithelial defects: preliminary data
Authors: Troisi Mario , Caruso Ciro , Troisi Salvatore , Bellucci Carlo , Costagliola Ciro 
Published: January 2025

Aims/Purpose: To evaluate the diagnostic sensitivity and tolerability of a new 0.5% riboflavin vital dye (Remark®, Servimed Ind. SpA, Rome, IT), on corneal and conjunctival epithelial defects, compared to standard stains (fluorescein and lissamine green).Methods: 56 eyes of 28 patients (15M, 13F; mean age 51.3 ± 9) with bilateral ocular surface epithelial defects were evaluated. In one eye of each patient selected randomly, after the application in the conjunctival fornix of Lissamine Green Ophthalmic strip (GreenGloTM, Stag Medical, Raleigh, NC) moistened with an eye drop of fluorescein 0.5% solution (Fluorofta®, Fidia Farmaceutici S.p.A., Abano Terme, IT), SLE was carried out using cobalt blue filter to evaluate corneal staining and white filter for the conjunctiva. Grading was assessed according to NEI score. After 30 minutes and washing with 5 drops of saline instilled every 10 minutes, a similar evaluation was carried out with cobalt blue light and yellow filter in the eyepiece after instillation of Remark® (Group A). The same evaluation was performed in the fellow eyes by reversing the sequence of dyes (Group B). A symptom score questionnaire was obtained for each group.Results: The average corneal NEI score was 3.32 (Gr. A) and 3.12 (Gr. B) for double staining, 3.38 (Gr. A) and 3.22 (Gr. B) for Remark®; average conjunctival score was 5.12 (Gr. A) / 4.88 (Gr. B) for double staining and 5.04 (Gr. A) / 4.76 (Gr.B) for Remark®. The differences between the two staining methods were not statistically significant in both groups (p>0.05). In no case an intolerance to the products used has been recorded.Conclusions: The new riboflavin‐based dye was effective in detecting both corneal and conjunctival defects, without statistically significant differences compared to double staining, and with a good tolerability. The study highlights the potential of this new dye overcoming the limit of the need of 2 different dyes, reducing costs and evaluation time.
Therapeutic potential of targeting BMP/ALK pathway in pathological retinal neovascularization
Authors: AL‐Shabrawey Mohamed , Ghishan Maria , Koneru Nandini , Sharma Sonali , Moustafa Mohamed 
Published: January 2025

Aims/Purpose: Pathological retinal neovascularization (PRNV) in ischemic retinopathies presents a significant clinical challenge. This study investigates the role of bone morphogenetic protein (BMP) signaling via ALK receptors in PRNV, with a focus on epigenetic modifications.Methods: The oxygen‐induced retinopathy (OIR) mouse model was utilized to investigate BMP signaling. Experimental groups included OIR mice treated with Noggin (a BMP inhibitor) or vehicle via ip from postnatal day 12‐16. Additional groups included a combined ALK2 and ALK3 endothelial conditional knockout mice (ALK2/3eKO), subjected to OIR. Capillary degeneration and neovascularization were assessed at postnatal day 17 in flat‐mount retinas using isolectin‐B4 staining. Immunostaining of retinal sections evaluated BMP2, BMP4, and ALK3 localization. In vitro experiments involved human retinal endothelial cells (HRECs) treated with BMP2 (50 ng/ml) or exposed to hypoxia (1% O2) for 48 hours. The impact of BMP2 on vascular endothelial growth factor (VEGF) was assessed through ELISA. MicroRNA (miRNA) expression was analyzed using the GeneChip miRNA 3.0 array. DNA methylation of HRECs was quantified using a colorimetric kit.Results: Immunostaining revealed an upregulation of BMP2, BMP4, and ALK3 expression in retinal vessels. Noggin‐treated and ALK2/3eKO OIR mice exhibited a significant reduction in capillary dropout and neovascularization (p < 0.01). BMP2 treatment of HRECs elevated VEGF production. MiRNA array analysis indicated significant alterations by BMP2 (4%) and hypoxia (5%), including miRNAs linked to VEGF signaling and angiogenesis. Specifically, BMP2 downregulated miR‐4521, miR‐769‐3p, miR‐23b‐5p, miR‐3195, and miR‐6781‐5p, while upregulating miR‐126‐3p, miR‐921, miR‐7515, miR‐29c, and miR‐20b‐5p. Interestingly, BMP2 and hypoxia induced similar effects on certain miRNAs, such as miR‐769‐3p, miR‐23b, and miR‐20b. The DNA methylation assay demonstrated a statistically significant reduction induced by BMP2.Conclusions: BMP/ALK signaling plays a potential role in the pathogenesis of PRNV, possibly mediated through epigenetic modifications. Thereby, targeting BMP/ALK signaling holds a promise to mitigate PRNV in ischemic retinopathies
Orbital abscesses in children: An update on microbiology trends and antibiotic selection
Authors: Kawar Luai , Kubba Haytham 
Published: January 2025

Aims/Purpose: Orbital abscesses are a common cause of morbidity in children. This study aims to provide an update on the microbiology, sensitivity rates and antibiotic prescribing patterns for orbital abscesses at Scotland's largest paediatric tertiary centre. This is essential for empirical antibiotic choices given the rapidly growing rates of resistance among commonly encountered isolates.Methods: A retrospective case note review of all patients admitted to the Royal Hospital for Children (RHC) in Glasgow between April 2019 and 2022 with an orbital abscess that underwent incision and drainage. Exclusion criteria included patients with underlying anatomic eye abnormalities and/or immunodeficiency.Results: Seventeen orbital abscesses were identified. Streptococcus pyogenes was the commonest micro‐organism (47 per cent), followed by Streptococcus intermedius (24 per cent). One abscess grew Fusobacterium necrophorum complicated by a subdural empyema and Lemierre's syndrome. Most organisms were widely sensitive; there was a single episode of penicillin resistance in an abscess caused by S. aureus. The most common initial antibiotic regimen was a combination of flucloxacillin and cefotaxime. In approximately half of the identified cases, the antibiotics were changed to a regimen containing clindamycin.Conclusions: Gram positive cocci remain the most common organisms isolated in orbital abscesses, with a relative increase in the Streptococcus anginosus group. Resistance among orbital abscesses remains low. Empirical use IV cefotaxime and flucloxacillin is recommended. Additional anaerobic cover (eg, metronidazole, clindamycin) should only be added if there is no clinical improvement after 24‐36 hours.