Involvement of plasmalogens in post-natal retinal vascular development

Objective: Proper development of retinal blood vessels is essential to ensure sufficient oxygen and nutrient supplies to the retina. It was shown that polyunsaturated fatty acids (PUFAs) could modulate factors involved in tissue vascularization. A congenital deficiency in ether-phospholipids, also termed "plasmalogens'', was shown to lead to abnormal ocular vascularization. Because plasmalogens are considered to be reservoirs of PUFAs, we wished to improve our understanding of the mechanisms by which plasmalogens regulate retinal vascular development and whether the release of PUFAs by calcium-independent phospholipase A2 (iPLA2) could be involved. [br/]Methods and Results: By characterizing the cellular and molecular steps of retinal vascular development in a mouse model of plasmalogen deficiency, we demonstrated that plasmalogens modulate angiogenic processes during the early phases of retinal vascularization. They influence glial activity and primary astrocyte template formation, endothelial cell proliferation and retinal vessel outgrowth, and impact the expression of the genes involved in angiogenesis in the retina. These early defects led to a disorganized and dysfunctional retinal vascular network at adult age. By comparing these data to those obtained on a mouse model of retinal iPLA2 inhibition, we suggest that these processes may be mediated by PUFAs released from plasmalogens and further signalling through the angiopoietin/tie pathways. [br/]Conclusions: These data suggest that plasmalogens play a crucial role in retinal vascularization processes

A combined analysis of five observational studies evaluating the efficacy and tolerability of bimatoprost/timolol fixed combination in patients with primary open-angle glaucoma or ocular hypertension

OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of a fixed combination of bimatoprost 0.03% and timolol (BTFC) in a clinical setting, in a large sample of patients with primary open-angle glaucoma or ocular hypertension and insufficient intraocular pressure (IOP) lowering on prior therapy. METHODS: Patient data were combined (n = 5556) from five multicenter, observational, non-controlled, open-label studies throughout Europe. Patients were identified from 830 sites in Austria, France, Germany, The Netherlands, and Switzerland. Assessments were made at baseline, 6 weeks (in Austrian, German and Swiss centers), and 12 weeks in all centers. RESULTS: BTFC lowered mean IOP from baseline by 5.4 mmHg over the 12-week duration of the studies (P < 0.0001). At study entry, 92.9% of patients were receiving another ocular hypotensive medication. In patients with no previous treatment (n = 311), BTFC reduced IOP by -9.1 mmHg, corresponding to a reduction from baseline of 36.4% (P < 0.0001). In patients receiving prior therapy of a prostaglandin analog, a beta-blocker, or a fixed combination, BTFC reduced IOP by a further 24.5%, 25.9%, and 21.4%, respectively. The majority of patients (90.3%) reported no adverse events. The most common adverse events were conjunctival hyperemia (3.2%) and eye irritation (2.8%). BTFC was rated as "good" or "very good" by 92.5% of physicians and 88.0% of patients. Most patients (96.3%) were equally or more compliant with BTFC than with their previous treatment. CONCLUSION: In routine clinical practice, BTFC achieved consistent IOP lowering in both previously treated and untreated patients with primary open-angle glaucoma or ocular hypertension. BTFC was associated with significant IOP reductions, good tolerability, and good compliance

DNAJB6b-enriched small extracellular vesicles decrease polyglutamine aggregation in in vitro and in vivo models of Huntington disease

Huntington disease (HD) is a devastating neurodegenerative disorder characterized by aggregation of huntingtin (HTT) protein containing expanded polyglutamine (polyQ) tracts. DNAJB6, a member of the DNAJ chaperone family, was reported to efficiently inhibit polyQ aggregation in vitro, in cell models, and in vivo in flies, xenopus, and mice. For the delivery of exogenous DNAJB6 to the brain, the DNAJB6 needs to be protected against (enzymatic) degradation and show good penetration into brain tissue. Here, we tested the potential of small extracellular vesicles (sEVs) derived from neural stem cells (NSCs) for delivery of DNAJB6 as anti-amyloidogenic cargo. Administration of sEVs isolated from DNAJB6-overexpressing cells to cells expressing expanded polyQ tracts suppressed HTT aggregation. Furthermore, intrathecal injection of DNAJB6-enriched sEVs into R6/2 transgenic HD mice significantly reduced mutant HTT aggregation in the brain. Taken together, our data suggest that sEV-mediated molecular chaperone delivery may hold potential to delay disease onset in HD

Primary open-angle glaucoma: association with cholesterol 24S-hydroxylase (CYP46A1) gene polymorphism and plasma 24-hydroxycholesterol levels

Purpose. Genetics has made significant contributions to the study of glaucoma over the past few decades. Cholesterol-24S-hydroxylase (CYP46A1) is a cholesterol-metabolizing enzyme that is especially expressed in retinal ganglion cells. CYP46A1 and its metabolic product, 24S-hydroxycholesterol, have been linked to neurodegeneration. A single-nucleotide polymorphism (SNP) in the CYP46A1 gene, designated as rs754203 and associated with Alzheimer disease, was evaluated as a genetic risk factor for primary open-angle glaucoma (POAG), as well as plasma 24S-hydroxycholesterol levels. Methods. The frequency of the CYP46*C and CYP46*T alleles was analyzed in 150 patients with POAG and 118 control subjects. Plasma 24S-hydroxycholesterol levels were quantified. Sex, age, alleles, and genotype frequencies between patients with POAG and control subjects were compared by using the {chi}2 and Student's t-tests. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression to assess the relative association between disease and age, sex, and genotypes. Results. The frequency of the TT genotype was significantly higher in patients with POAG than in control subjects (61.3% versus 48.3%, respectively, OR = 1.26; 95% CI = 1.006–1.574, P < 0.05). Plasma 24S-hydroxycholesterol levels did not differ between control subjects and patients with POAG. The ratio of estimated brain weight to liver volume as an estimate of the capacity of the human body to synthesize and metabolize 24S-hydroxycholesterol was found to correlate to plasma 24S-hydroxycholesterol in control subjects and patients with POAG. Conclusions. The rs754203 SNP in CYP46A1 was associated with a risk for POAG. This polymorphism was not associated with changes in plasma 24S-hydroxycholesterol, highlighting that despite its retinal origin, 24S-hydroxycholesterol cannot be used as a biomarker for POAG

International vision requirements for driver licensing and disability pensions: using a milestone approach in characterization of progressive eye disease

OBJECTIVE: Low vision that causes forfeiture of driver's licenses and collection of disability pension benefits can lead to negative psychosocial and economic consequences. The purpose of this study was to review the requirements for holding a driver's license and rules for obtaining a disability pension due to low vision. Results highlight the possibility of using a milestone approach to describe progressive eye disease. METHODS: Government and research reports, websites, and journal articles were evaluated to review rules and requirements in Germany, Spain, Italy, France, the UK, and the US. RESULTS: Visual acuity limits are present in all driver's license regulations. In most countries, the visual acuity limit is 0.5. Visual field limits are included in some driver's license regulations. In Europe, binocular visual field requirements typically follow the European Union standard of ≥120°. In the US, the visual field requirements are typically between 110° and 140°. Some countries distinguish between being partially sighted and blind in the definition of legal blindness, and in others there is only one limit. CONCLUSIONS: Loss of driving privileges could be used as a milestone to monitor progressive eye disease. Forfeiture could be standardized as a best-corrected visual acuity of <0.5 or visual field of <120°, which is consistent in most countries. However, requirements to receive disability pensions were too variable to standardize as milestones in progressive eye disease. Implementation of the World Health Organization criteria for low vision and blindness would help to establish better comparability between countries

Erythrocyte phospholipid and polyunsaturated fatty acid composition in diabetic retinopathy

Background: Long chain polyunsaturated fatty acids (LCPUFAs) including docosahexaenoic acid and arachidonic acid are suspected to play a key role in the pathogenesis of diabetes. LCPUFAs are known to be preferentially concentrated in specific phospholipids termed as plasmalogens. This study was aimed to highlight potential changes in the metabolism of phospholipids, and particularly plasmalogens, and LCPUFAs at various stages of diabetic retinopathy in humans. Methodology and Principal Findings: We performed lipidomic analyses on red blood cell membranes from controls and mainly type 2 diabetes mellitus patients with or without retinopathy. The fatty acid composition of erythrocytes was determined by gas chromatography and the phospholipid structure was determined by liquid chromatography equipped with an electrospray ionisation source and coupled with a tandem mass spectrometer (LC-ESI-MS/MS). A significant decrease in levels of docosahexaenoic acid and arachidonic acid in erythrocytes of diabetic patients with or without retinopathy was observed. The origin of this decrease was a loss of phosphatidyl-ethanolamine phospholipids esterified with these LCPUFAs. In diabetic patients without retinopathy, this change was balanced by an increase in the levels of several phosphatidyl-choline species. No influence of diabetes nor of diabetic retinopathy was observed on the concentrations of plasmalogen-type phospholipids. Conclusions and Significance: Diabetes and diabetic retinopathy were associated with a reduction of erythrocyte LCPUFAs in phosphatidyl-ethanolamines. The increase of the amounts of phosphatidyl-choline species in erythrocytes of diabetic patients without diabetic retinopathy might be a compensatory mechanism for the loss of LC-PUFA-rich phosphatidyl-ethanolamines

Retinal Vessel Phenotype In Patients With Primary Open-Angle Glaucoma

International audiencePURPOSE: To characterize the phenotype of retinal vessels using central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), tortuosity and fractal dimension (FD) in primary open-angle glaucoma (POAG) subjects. METHODS: This prospective case-control multicentre study included 61 POAG subjects and 61 controls matched for age, systemic hypertension and body mass index. Fundus images of the right eye were acquired using a non-mydriatic camera. Central retinal artery equivalent (CRAE), CRVE, arteriole-to-venule ratio, FD and tortuosity of the vascular network were measured using VAMPIRE software (Vessel Assessment and Measurement Platform for Images of the Retina). Primary open-angle glaucoma (POAG) patients underwent 24.2 sita-standard visual field and peri-papillary optical coherence tomography (OCT) examinations. Data were expressed as median and interquartile range (75-25th percentiles). RESULTS: The control group was comparable to the POAG group for sex ratio, refraction and intraocular pressure. The mean CRAE and the mean CRVE were significantly lower in the POAG group than in the control group [150.5 (137.9; 157.1) mum versus 161.3 (154.0; 168.4) mum and 204.8 (190.1; 218.1) mum versus 233.5 (222.3; 246.9) mum, respectively; p < 0.001] and for fractal parameters as well. No significant difference was found for tortuosity between the two groups. There was a significant correlation between CRAE and retinal nerve fibre layer (RNFL) thickness (r = 0.27; p = 0.03). VAMPIRE parameters were not correlated with visual field indices. CONCLUSION: Primary open-angle glaucoma (POAG) was associated with a narrowing of arterial and venous retinal vessels, a higher arteriole-to-venule ratio and lower values of FD. The relationship between CRAE and RNFL thickness needs further investigation

Nutrition in ophthalmology – Clinical application to age-related macular degeneration

« Let food be your medicine. » This contribution from Hippocrates is still timely addressed, especially in the field of ophthalmology. Observational epidemiology reports close associations between food habits and the risk or prevention of several ocular pathologies such as cataract or Age-related Macular Degeneration (AMD). Anti-oxidant vitamins, minerals and lipids are the nutrients that have been the most widely studied. Interventional epidemiology and experimental works partially corroborated these findings. Unexpectedly, the benefit of long chain omega 3 polyunsaturated fatty acids in the prevention of late AMD was not firmly established in Age-Related Eye Disease Study 2 (AREDS2). Nevertheless, one should not omit to refer to well established data in this field. Still, further works are needed and warranted, especially for better delineating the role of, not only nutrients but also dietary habits, and gene-nutrients interactions.« Que ton aliment soit ta seule médecine ». Cette citation d'Hippocrate est d'actualité aujourd'hui, plus encore qu'hier et particulièrement en ophtalmologie. L'épidémiologie observationnelle rapporte des associations solides entre alimentation et risque ou prévention de certaines pathologies oculaires, comme la cataracte ou la Dégénérescence Maculaire Liée à l'Âge (DMLA). Vitamines anti-oxydantes, minéraux et lipides sont les nutriments qui ont été les plus étudiés. L'épidémiologie interventionnelle et la recherche expérimentale ont permis de corroborer un certain nombre de ces observations. De façon plus inattendue, le bénéfice d'une supplémentation en acides gras oméga 3 à longue chaîne dans la prévention de l'évolution de la DMLA vers ses formes avancées n'a pas été retrouvé dans l'étude AREDS2 (Age-Related Eye Disease Study 2). Sans vouer aux gémonies plusieurs décennies de travaux dans ce domaine, les problématiques de la nutrition en ophtalmologie sont encore porteuses de découvertes et d'espoirs, en particulier lorsque l'on considère le cadre plus large de l'alimentation et des relations gènes-nutriments

Self-reported dual sensory impairment and related factors: a European population-based cross-sectional survey

International audienceBackground Data on population-based self-reported dual vision and hearing impairment are sparse in Europe. We aimed to investigate self-reported dual sensory impairment (DSI) in European population. Methods A standardised questionnaire was used to collect medical and socio-economic data among individuals aged 15 years or more in 29 European countries. Individuals living in collective households or in institutions were excluded from the survey. Results Among 296 677 individuals, the survey included 153 866 respondents aged 50 years old or more. The crude prevalence of DSI was of 7.54% (7.36–7.72). Among individuals aged 60 or more, 9.23% of men and 10.94% of women had DSI. Eastern and southern countries had a higher prevalence of DSI. Multivariable analyses showed that social isolation and poor self-rated health status were associated with DSI with ORs of 2.01 (1.77–2.29) and 2.33 (2.15–2.52), while higher income was associated with lower risk of DSI (OR of 0.83 (0.78–0.89). Considering country-level socioeconomic factors, Human Development Index explained almost 38% of the variance of age-adjusted prevalence of DSI. Conclusion There are important differences in terms of prevalence of DSI in Europe, depending on socioeconomic and medical factors. Prevention of DSI does represent an important challenge for maintaining quality of life in elderly population

A new HPLC-ESI-MS/MS method to characterize and quantify phosphatidyl-choline with VLC-PUFA: Application to human retina

Purpose: Mutations in the ELOVL4 gene have been found in Stargardt-like macular dystrophy or STD3. Previous studies have shown that ELOVL4 is involved in the biosynthesis of very long chain polyunsaturated fatty acids (VLC-PUFA). The aim of this work was to develop a HPLC-ESI-MS/MS method of characterization and quantification of dipolyunsaturated phosphatidyl-choline (PC) molecular species containing VLC-PUFA and to apply it on retinas from human donors. Methods: Eyeballs were collected from calf as well as from nine human donors (body donation to Science). The neural retina was dissected from the RPE/choroid. Following lipid extraction, phosphorus content of total phospholipids was determined.Using a triple quadrupole MS instrument, PC molecular species were structurally characterized by collision-induced dissociation in the negative mode with a method based on normal-HPLC-ESIMS/MS. PC molecular species were then quantified using precursor ion scanning of m/z 184amu in the positive mode. Results: The characterization of PC species was done on bovine retinas. Among them, 28 were dipolyunsaturated PC species containing one VLC-PUFA (C24 to C36) with three to six double bonds. VLC-PUFA were always in the sn-1 position whilst PUFA at the sn-2 position was exclusively docosahexaenoic acid (DHA, C22:6.n-3). Most of these VLC-PUFA-containing dipolyunsaturated PC were detected and quantified in human retinas. The main represented compounds were those having VLC-PUFA of 32 carbon atoms (C32:3, C32:4, C32:5 and C32:6) and 34 carbon atoms (C34:3, C34:4, C34:5 and C34:6). Dipolyunsaturated PC with 36:5 and 36:6 were detected in lower quantities. Conclusions: This new HPLC-ESI-MS/MS method is sensitive and specific enough to structurally characterize and quantify all molecular species of PC, including those esterified with VLC-PUFA. This technique is valuable for a precise characterization of PC containingVLC-PUFA in retina and may be useful for better understanding their implication in the pathogenesis of STD3