bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel phenotype–genotype correlation with PEX6 gene in Saudi patients with Heimler syndrome
Authors: Almoallem Basamat 
Published: December 2022

AbstractPurpose: Peroxisome biogenesis disorders (PBDs; MIM# 601539) are heterogeneous disorders caused by defects in genes encoding proteins that are essential for peroxisomal matrix and membrane proteins. Heimler syndrome is one of PBDs that is caused by mutations in PEX1 and PEX6 genes. In this study, we aimed to fully characterize the clinical and molecular aspects of two Saudi probands who were diagnosed early as Usher syndrome.Methods: We set up a comprehensive clinical and molecular genetic workflow including detailed ophthalmological, audiological and systemic assessments followed by genome‐wide SNP microarrays analysis and targeted PEX6 gene screening by Sanger sequencing.Results: Clinically: both patients appeared dysmorphic with long faces, high forehead, short nose, small low set ears, and full lips. The ophthalmological assessment revealed advanced inherited retinal dysfunction represented by waxy pallor optic disc, attenuated vessels, RPE mottling with intraretinal bony spicules pigmentations and central foveal atrophic changes in both eyes. Both Indexes exhibited bilateral sensory neural hearing loss and amelogenesis imperfecta. Genetically: an autozygous block was identified on chromosome 6p21.1 encompassing PEX6 gene using SNP microarrays. Novel PEX6 (NM_000287.3) c.290 T > G (p.Val97Gly) was found by Sanger sequencing. The identified variant co‐segregated with the phenotype in both families and found to be “likely pathogenic” according to ACMG guidelines.Conclusions: Our study represents the first report of PEX6 associated Heimler syndrome in the middle east and considered to be the third in the literature so far. It highlights the importance of combining molecular diagnosis with the clinical findings to expand our knowledge of PEX6‐related PBDs phenotype and the allelic spectrum for this gene.
Corneal neovascularization associated with a novel PDGFRB gene variant: Implications for precision medicine treatment
Authors: Gladkauskas Titas , Bruland Ove , Safieh Leen , Deepak Edward , Rødahl Eyvind , Bredrup Cecilie 
Published: December 2022

AbstractPurpose: To identify the genetic cause of aggressive corneal neovascularization arising in otherwise healthy children in one family. Further, to study molecular consequences associated with the identified variant and implications for possible precision medicine treatment.Methods: Sanger sequencing of the candidate gene PDGFRB was performed in affected individuals. HeLa cells were transduced with wild type PDGFRB and the identified variant. Cells were treated with tyrosine kinase inhibitors (TKIs). ELISA and immunoblot analysis were used to detect phosphorylation of PDGFRβ and downstream signalling proteins.Results: A novel variant in PDGFRB was found in affected family members. HeLa cells transduced with this variant did not have increased baseline levels of phosphorylated PDGFRb. However, upon stimulation with ligand, excessive activation of PDGFRb was observed in these cells compared to cells transduced with the wild type variant. Inhibition with some TKIs in vitro successfully prevented upregulation of PDGFRβ and its downstream signalling.Conclusions: A novel substitution in PDGFRB was found in family members with isolated corneal neovascular overgrowth. Cells transduced with the variant showed increased phosphorylation upon ligand stimulation. While the examined TKIs had various effects in preventing such overactivation, this introduces the concept of precision medicine in preventing childhood blindness in these patients.
Tomographic prognostic factors for visual improvement after pars plana vitrectomy for epiretinal membrane
Authors: Nouri Slim , Amor Saloua Ben , Rekik Mouna , Ayedi Omar , Trigui Amira 
Published: December 2022

AbstractPurpose: To evaluate postoperative changes and investigate tomographic prognostic factors of visual impairment after vitrectomy for epiretinal membrane (ERM).Methods: A retrospective observational study on patients who underwent pars plana vitrectomy for ERM by a single experimented surgeon. Best corrected visual acuity (BCVA) on the logMAR chart and optical coherence tomography (OCT) features were recorded before surgery and at the last visit. Tomographic parameters analysed were: central foveal thickness (CFT), foveal contour morphology, external limiting membrane (ELM), ellipsoid zone (EZ) and interdigitation zone (IZ) integrity, the presence of intraretinal fluid (IRF), subretinal fluid, disorganization of retinal inner layers (DRIL) and subfoveal deposits. Student's t‐test and Pearson's correlation coefficients were used for statistical analysis. p Values <0.05 were considered statistically significant.Results: Forty‐seven eyes of 43 patients were included. The mean age was 61.7 years (range 13–87). The ERM was idiopathic in 49% and secondary in 51%. The mean BCVA was 1.02 before and 0.5 after surgery and improved significantly (p < 0.001) with a mean gain of 5.2 lines. The postoperative BCVA correlated strongly with the preoperative one (R2 = 0,764, p < 0.001). Tomographic factors associated with worse final BCVA were higher baseline CFT (p = 0.004), abnormal foveal profile (p = 0.02), the presence of IRF (p < 0.001), DRIL (p = 0.01) and subfoveal deposits (p = 0.04). The disruption of ELM, EZ and IZ were as well associated with a poorer visual outcome (p < 0.001, p = 0.03 and p < 0.001 respectively).Conclusions: ERM surgery provides functional and anatomical improvement. Preoperative OCT is an essential tool to evaluate morphological retinal changes and identify prognostic factors for visual recovery.
Keratitis fugax hereditaria ‐ useful to consider when you have a child with non‐specific corneal findings and symptoms
Authors: Immonen Annamari , Majander Anna , Kawan Sabita , Backlund Michael , Vasara Kristiina , Lindahl Päivi , Kivelä Tero , Turunen Joni 
Published: December 2022

AbstractPurpose: To report clinical findings in children diagnosed with the autosomal dominant periodic corneal autoinflammation, keratitis fugax hereditaria (KFH, MIM 148200), and to highlight its geographical distribution.Methods: Patients were clinically examined in the Helsinki University Hospital between February 4, 2006, and December 31, 2021, and genetically verified to be carriers of the c.61G > C (rs200154873) variant in NLRP3 by Sanger sequencing. Variant allele frequencies were determined from Genome Aggregation Database (gnomAD) version 2.1.1.Results: The data consist of 10 children from 8 families; 6 boys and 4 girls. Age of onset varied from 3 to 14 (median, 8) years. Patients had typical KFH symptoms: eye pain, photophobia, conjunctival injection, and foreign body sensation. Five patients had corneal oval opacities, and 3 had a mild anterior chamber reaction. Seven were correctly diagnosed at the first visit based on family history. The remaining three children were diagnosed 1, 3, and 8 years after the first visit. Initial diagnoses were anterior uveitis, corneal erosion, and herpetic keratitis. Additionally, epithelial recurrent erosion dystrophy (ERED) or subepithelial mucinous corneal dystrophy (SMCD) had been suspected. Geographically, KFH concentrates to the bilingual Swedish‐speaking coastal areas of Finland. Allele frequencies are 0.014% in Finland, and 0.011% in Sweden, based on gnomAD.Conclusions: Scandinavian ophthalmologists should be aware of the possibility of KFH in case of suspected anterior uveitis, herpetic keratitis, or recurrent corneal erosion in children. Symptoms of paediatric KFH patients are equal to those in adults, but the typical corneal opacity still might recover between the attacks.
Evaluation of the neuroprotective effect of metformin in diabetic patients with glaucoma
Authors: Martucci Alessio , Carlucci Federico , Satriano Andrea , Cesareo Massimo , Russo Rossella , Nucci Carlo 
Published: December 2022

AbstractPurpose: Metformin, a biguanide used to treat diabetes, reduced neuroinflammation in vitro and in vivo and resulted neuroprotective in experimental Parkinson's disease. Metformin has also recently been shown to promote neurogenesis (1). The study aims to evaluate the putative neuroprotective effect of metformin in glaucomatous diabetic patients.Methods: For this retrospective pilot study, clinical notes of glaucomatous diabetic patients of the ophthalmological department of the University Hospital of Rome Tor Vergata were reviewed. Among all, 15 patients were compliant with the inclusion criteria. Patients were then divided into 2 sub‐groups: the Glaucoma group treated with metformin (n = 16 eyes) and the Glaucoma group treated with insulin (n = 14 eyes). Any glaucoma treatment was accepted with exception of brimonidine, citicoline, and coenzyme Q10. Patients must have performed in their clinical history two 24‐2 visual field examinations carried out 6 months apart.Results: Patients were homogeneous in terms of age (p = 0.09) and gender (p > 0.73). Metformin and Insulin groups were homogeneous in terms of Mean Deviation (MD) and Pattern Standard Deviation (PSD) at baseline (T0) (p = 0.70 and p = 0.73 respectively). After 6 months (T1) MD did not change significantly in the metformin group (p = 0.64). On the contrary, at T1 MD significantly worsened in the Insulin group (p = 0.01). No difference was found in terms of PSD in both groups. The visual field Index did not change in the Metformin group while significantly worsened in the Insulin group (p = 0.03).Conclusions: This study suggests for the first time a possible neuroprotective effect of metformin in glaucomatous diabetic patients. Patients under Metformin did not show a worsening of the visual field test in 6 months. Conversely, patients under Insulin worsened. Other prospective are required to confirm our results.Reference1. Rotermund C, Machetanz G, Fitzgerald JC. The Therapeutic Potential of Metformin in Neurodegenerative Diseases. Front Endocrinol (Lausanne). 2018; 9: 400. doi: 10.3389/fendo.2018.00400. PMID: 30072954; PMCID: PMC6060268.
Glaucoma and cardioprotective medication
Authors: Horwitz Anna , Klemp Marc , Andreasen Jens , Horwitz Henrik , Freiberg Josefine , Torp‐Pedersen Christian , Kolko Miriam 
Published: December 2022

AbstractPurpose: To investigate the impact of cholesterol‐lowering medication, anticoagulants, and antihypertensive medication on the onset of glaucoma in Denmark from 1996 to 2018.Methods: We included all 2.5 million Danish individuals over 40 years of age. We used the National Danish Registry of Medicinal Products Statistics to identify all claimed prescriptions for glaucoma medication, cholesterol‐lowering medication, anticoagulants and antihypertensives. Glaucoma was defined as having three claimed prescriptions, being diagnosed in hospital or having undergone glaucoma surgery.Results: We first employed a cross‐sectional study design. We found that patients treated with cardioprotective medication have a significantly higher overall risk rate for glaucoma than those who do not take the medication after controlling for a range of factors. In particular, we found that cholesterol‐lowering medication (RR of 1.46, p < 0.0001), anticoagulants (RR of 1.36, p < 0.0001) and antihypertensive medication (RR of 1.35, p < 0.0001) all were significantly correlated with an increased risk of glaucoma. Furthermore, all three medications remain significantly correlated in a joint analysis, with the strongest association seen between glaucoma and cholesterol‐lowering medication. We then employed a panel data study design. We found that cholesterol‐lowering medication, anticoagulants, and antihypertensive medication are each significantly positively associated with glaucoma within 2‐ and 5‐year intervals. Finally, we employed a regression discontinuity study design. We confirmed a previous finding showing that antihypertensive medication has an apparent causal negative effect on the risk of developing glaucoma. Moreover, we found that prescription of cholesterol‐lowering and anti‐glaucomatous medication have similar causal effects.Conclusions: Overall, the present study indicates that cardioprotective medication may have a preventive effect on the development of glaucoma.
Therapeutic approach in non‐proliferative diabetic retinopathy using antioxidant supplementation
Authors: Campos‐Borges Helena Cristina , Pinazo‐Duran Maria Dolores , Andres‐Blasco Irene , Garcia‐Medina Jose Javier , Zanon‐Moreno Vicente , Gallego‐Martinez Alex , Salgado‐Borges Jose Manuel , Duarte Lilianne , Prudêncio Cristina 
Published: December 2022

AbstractPurpose: Overproduction of reactive oxygen species (ROS) leads to eye damage and causes effects of ROS signalling pathways. In this work, we evaluated oxidative stress (OS) biomarkers and the effects of a daily supplementation regimen containing antioxidants and essential fatty acids (A/ω3) in type 2 diabetic eyes (T2DM).Methods: This is a case–control study involving 480 participants, divided into 2 groups: (1) T2DM patients (n = 287) with (+)/without (−) non‐proliferative diabetic retinopathy (NPDR) and (2) controls (CG; n = 194)). Participants were randomly assigned to a daily pill of A/ω3. Patients were followed‐up for 38 months, allowing to outline patient characteristics, NPDR status, and classical and emerging blood parameters, including OS markers (candidate products and genes). Statistical analysis was performed using the SPSS 24.0 program.Results: Significantly higher levels of circulating pro‐oxidants (p = 0.001) and lower levels of antioxidants (p = 0.0001) were detected in patients with T2DM versus CG. Plasma malondialdehyde/thiobarbituric acid reactive species were significantly higher (MDA/TBARS; p = 0.006) and lower antioxidant load, based on the total antioxidant capacity of plasma (TAC; p = 0.042) and vitamins B12 (p = 0.05) and C (p = 020) levels were found inT2DM + NPDR versus T2DM‐NPDR. Overexpression of the matrix metalloproteinase‐9 (MMP‐9) gene was found in T2DM + NPDR versus T2DM‐NPDR and in GC (p = 0.021). It is important to note that the therapeutic regime with A/ω3 supplementation in all groups proved to be beneficial, particularly in the group of patients with diabetic retinopathy (DR).Conclusions: This study stresses the need for new strategies to increase the antioxidant load, as in the case of the A/ω3 supplementation regime, which can serve as a dietary prophylaxis and adjunctive intervention for better ophthalmic care in patients at risk of associated blindness to DR.
Evaluation of the effect of cigarette smoking on retina and choroid: An optical coherence tomography angiography study
Authors: Sassi Hela , Aoun Safa Ben , Fekih Khawla , Nouri Slim , Mzoughi Khadija , Cheour Monia 
Published: December 2022

AbstractPurpose: To study the effect of active cigarette smoking on retinal and choroidal micro‐vascularization using Swept Source Optical Coherence Tomography Angiography (SS‐OCT A).Methods: This is a cross‐sectional, observational, comparative study carried out at the Ophthalmology department of Habib Thameur University Hospital of Tunis. Twelve eyes of “healthy” smokers, 10 eyes of former smokers (less than 3 years after quitting smoking) and 6 eyes of healthy non‐smokers controls were included. SS‐OCT A 3 × 3 mm angiograms were exported and analysed with image J, Fiji Software. Perimeter of avascular central zone (ACZ), superficial retinal plexus density (SRPD), deep retinal plexus density (DRPC) and choriocapillaris capillary vessel density (CVD) were calculated and analysed. Comparative Kruskal Wallis and Spearman tests were performed using 21.0 SPSS.Results: Volunteers with a smoking history had an average of 13.75 ± 10.26 pack‐years. The mean smoking period was 3.2 ± 5.13 years and mean smoking cessation period was 1.28 ± 0.85 years. Mean ACZ, SRPD, DRPD and CVD were respectively 2.62 ± 0.52 mm, 13.20 ± 2.10%, 17.14 ± 1.17% and 51.05 ± 0.85%. There was no significant difference between the three groups for the measurements of ACZ, SRPD, DRPD and CVD (p = 0.57, p = 0.97, p = 0.53 and p = 0.07; respectively). However, there was a significant positive correlation between the smoking cessation period and the DRPD (p = 0.003, r = 0.865).Conclusions: Despite the known effects of nicotine and other chemical substances in cigarettes on peripheral vascular structures, no significant difference in quantitative analysis of retinal and choroidal networks could be found. Deep retinal plexus density seems to increase after long smoking cessation periods.
Pigment epithelium and choroid changes in pachychoroid pigment epitheliopathy: A descriptive study
Authors: Abid Yosra , Sassi Hela , Chaabouni Karim , Ouederni Meriem , Maamouri Rim , Cheour Monia 
Published: December 2022

AbstractPurpose: To describe characteristic elementary lesions of retinal pigment epithelium and choroidal vascular parameters determined by swept source optical coherence tomography (SS‐OCT) and OCT‐angiography (OCT‐A) in eyes with pachychoroid pigment epitheliopathy.Methods: Twenty‐seven patients with retinal pigment epithelium (RPE) abnormalities associated to pachychoroid features, with no history or findings indicative of subretinal fluid or soft drusen were evaluated. All eyes underwent comprehensive ophthalmic examination, fundus photography, SS‐OCT and OCT‐A. After binarization of B‐scan images with ImageJ Software, the choroidal vascularity index (CVI), the choroidal vascularity proportion (CVP) and flow voids area were calculated.Results: A total of 27 eyes of 23 patients, 19 of whom were male (70.37%), with a mean age of 59.11 ± 12.76 years were enrolled in this study. We detected six different types of RPE lesions: focal disruption in ellipsoid and interdigitation zones in 18 eyes (66.66%), RPE elevation with microbreak appearance in 12 eyes (44.44%), RPE thickening in 10 eyes (37.03%), small pigment epithelium detachment in seven eyes (25.92%), RPE spike in five eyes (18.51%) and outer nuclear layer thinning in five eyes (18.51%). The subfoveal choroidal thickness (SFCT) was 399, 78 ± 88, 13 μm. The mean inner choroidal thickness was 87.18 ± 36.67 μm. The CVI was 65.28 ± 3.35%. The CVP was 59.10 ± 0.58% in the choriocapillaris and 59.69 ± 1.42% in the Haller layer. The total choriocapillaris flow void area was 39.87 ± 1.21%.Conclusions: SS‐OCT and OCT‐A are valuable diagnostic tools to characterize pigment epithelium and choroidal changes in PPE eyes.
Synchrotron‐based FTIR microspectroscopy of human primary retinal pigmented epithelial cells as a model for age‐related macular degeneration
Authors: Josifovska Natasha , Andjelic Sofija , Lumi Xhevat , Ducic Tanja , Petrovski Goran 
Published: December 2022

AbstractPurpose: To investigate the characteristics of untreated and treated human retinal pigmented epithelial cells (hRPEs) as an ex vivo model for age‐related macular degeneration (AMD) using high resolution synchrotron radiation‐based Fourier Transform Infrared (FTIR) microspectroscopy and multivariate analysis.Methods: hRPEs obtained from cadavers were treated by autophagy ‐inducer rapamycin (Rap), and ‐inhibitor bafilomycin A1 (Baf), as well as hydrogen peroxide (H2O2) to induce oxidative stress, in an ex vivo model for studying AMD. FTIR measurements were performed at the MIRAS beamline of the ALBA Synchrotron, Barcelona, Spain.Results: The FTIR spectra consisted of several bands arising from the vibration of different groups belonging to proteins, lipids and nucleic acids, indicating the rich biochemical composition of the hRPEs. In the protein region, the amide I band of the treated groups (Rap, Baf, H2O2) was different from the control untreated group, indicating an overall protein disordering under such treatments. In the DNA region, two spectral areas appeared to be modified upon treatment, indicating different modifications of the DNA conformational changes or rearrangements attributed to the distortions of the DNA double helix in the presence of Rap, Baf or H2O2. The same treatments could also induce several modifications in the lipid spectral region, which can affect a wide range of biological processes. The H2O2 treated group showed higher prevalence for the lipid peroxidation, a process generated by the effect of several reactive oxygen species.Conclusions: The present study shows that high resolution FTIR can be used to evaluate the complete bio−/macro‐molecular spectra of hRPEs such as proteins, lipids and nucleic acids, which can be used as an ex vivo model for AMD, thus giving possibilities for developing and testing new treatment modalities.
The phase 3 REFLECT trial: Efficacy and safety of bilateral gene therapy for Leber hereditary optic neuropathy (LHON)
Authors: Yu‐Wai‐Man Patrick , Newman Nancy , Subramanian Prem , Moster Mark , Wang An‐Guor , Donahue Sean , Leroy Bart , Carelli Valerio , Biousse Valérie , Vignal‐Clermont Catherine , Sadun Alfredo , Sergott Robert , Fernández Gema Rebolleda , Chwalisz Bart , Banik Rudrani , Cox Eric , Roux Michel , Taiel Magali , Sahel José‐Alain 
Published: December 2022

AbstractPurpose: To evaluate the efficacy and safety of a bilateral injection of lenadogene nolparvovec in patients with Leber Hereditary Optic Neuropathy (LHON) carrying the m.11778G > A mutation.Methods: REFLECT is a randomized, placebo‐controlled, phase 3 study that included 98 patients with vision loss ≤1 year at enrolment. Patients received a single intravitreal injection of lenadogene nolparvovec (9E10 viral genomes per eye) in their first‐affected eye. The second‐affected eye was randomized to a second injection of gene therapy or placebo.Results: A total of 48 patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in best‐corrected visual acuity (BCVA) of the second‐affected eyes was not statistically different between the two arms (primary endpoint). Two years after injection, a statistically significant improvement in BCVA was reported from baseline in treated eyes. Mean BCVA showed an absolute difference between the arms of +6 ETDRS letters in favour of bilaterally treated patients. The improvement from nadir was +20 and +17 letters for the first‐ and second‐affected eyes treated bilaterally, and +19 and +14 letters for first‐ and second‐affected eyes treated unilaterally (all p < 0.0001). Clinically meaningful improvement from nadir ≥ +15 letters was found in the majority of bilaterally and unilaterally treated patients (73% and 66%, respectively). The main ocular adverse event related to gene therapy was intraocular inflammation, which was mostly mild and responsive to conventional treatment. Overall, the safety profile was favourable and comparable in patients treated unilaterally and bilaterally.Conclusions: The 2‐year data confirm the results observed 1.5 years after treatment: bilaterally treated patients have better improvement of BCVA than unilaterally treated patients with a favourable safety profile. Placebo eyes showed a contralateral therapeutic effect as previously observed in the RESCUE and REVERSE trials.