Obstructive sleep apnoea is associated with sight threatening retinopathy and predicts the developement of preproliferative and proliferative retinopathy in patients with type 2 diabetes:a longitudinal analysis

troduct I on . An observational longitudinal study. P ur P ose . Assess the relationship between obstructive sleep apnoea (OSA) and DR cross-sectionally and longitudinally. M ethods . Adults with Type 2 diabetes mellitus (T2DM), who were re - cruited from a hospital-based diabetes clinic in the UK. Patients with pre-existing OSA, end-stage renal disease and non-diabetic retinopa - thy were excluded. OSA (apnoea hypopnea index ≥ 5 events/hour) was assessed by a single overnight home-based cardio-respiratory study (Alice PDX, Philips Respironics, USA). DR was assessed us - ing retinal images between 2007 and 2012. Sight threatening diabetic retinopathy (STDR) was defined as presence of pre-proliferative or proliferative DR, maculopathy or photocoagulation. Advanced DR was defined as pre-proliferative or proliferative DR. r esults . 199 patients were included (57.3% (n=114) men, 47.7% (n=95) White Europeans). STDR and OSA prevalence were 38.7% (n=77) and 62.8% respectively. A t b A sel I ne . STR prevalence was higher in patients with OSA (OSA+) compared to those without OSA (OSA-) [48.8% n=61 vs. 21.6% n=16, p<0.001]. After adjustment for confounders, OSA remained independently associated with STR (OR 3.7, 95% CI 1.6-8.9, p=0.006), maculopathy (OR 4.5, 95% CI 1.8-11.4, p=0.002) and advanced DR (OR 3.9, 95% CI 1.02-15.3, p=0.047). Mild and moderate to severe OSA were independently associated with STR and maculopathy and only moderate to severe OSA was associated with advanced DR following adjustment for con - founders. l ong I tud I n A lly . Over the follow-up period of (4.4±1 years), more OSA+ patients progressed from no or background DR to advanced DR (15.3% (n=17) vs. 3% (n=2), p=0.01). OSA was an independent pre - dictor of advanced DR development after adjustment for confounders (OR 6.6, 95% CI 1.2-35.1, p=0.03). OSA did not predict the develop - ment of maculopathy. c onclus I ons . OSA is independently associated with STR and predicts the development of preproliferative and proliferative DR. Intervention - al studies are needed to assess the impact of OSA treatment on DR.

Obstructive sleep apnoea predicts the development of preproliferative and proliferative retinopathy in patients with type 2 diabetes:a longitudinal analysis

Background and aims: Diabetic Retinopathy (DR) is a leading cause of blindness. OSA is associated with increased oxidative and nitrosative stress and endothelial dysfunction in patients with type 2 diabetes (T2DM). Hence, it is plausible that OSA can promote the development and progression of DR. Materials and methods: An observational longitudinal study in adults with T2DM. Patients with pre-existing OSA, end-stage renal disease and non-diabetic retinopathy were excluded. OSA (apnoea hypopnea index ≥ 5 events/hour) was assessed by a single overnight home-based cardio-respiratory monitoring (Alice PDX, etc.). DR was assesses using retinal images between 2007 and 2012. Sight threatening retinopathy (STR) was defined as pre-proliferative or proliferative DR, maculopathy or photocoagulation. Advanced DR was defined as pre-proliferative or proliferative DR. Results: 199 patients were included (57.3% men, 47.7% White Europeans). STR and OSA prevalence were 38.7 % and 62.8% respectively. STR preva-lence was higher in patients with OSA (OSA+) compared to those with-out (OSA-) [48.8% vs. 21.6%, p <0.001]. After adjustment for confounders, OSA remained independently associated with STR (OR 3.7, 95%CI 1.6-8.9, p=0.006, maculopathy (OR 4.5, 1.8-11.4, p=0.002) and advanced DR (OR 3.9, 1.02-15.3, p=0.047). Over 4.4±1 years, more OSA+ patients progressed from no or background DR to advanced DR (15.3% vs. 3%, p=0.01). OSA was an independent predictor of advanced DR development after adjustment (OR 6.6, 95%CI 1.2-35.1, p=0.03). OSA did not predict the development of maculopathy. Patients received continuous positive airway pressure treatment were less likely to develop advanced DR. Conclusion: OSA is independently associated with STR and predicts the development of preproliferative and proliferative DR. Interventional studies are needed to assess the impact of OSA treatment on DR.Supported by: NIHR (UK) and The UK Novo Nordisk Research Foundation.

Medical management of diabetic retinopathy:fenofibrate and ACCORD eye studies

The approach of all ophthalmologists, diabetologists and general practitioners seeing patients with diabetic retinopathy should be that good control of blood glucose, blood pressure and plasma lipids are all essential components of modern medical management. The more recent data on the use of fenofibrate in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye studies is reviewed. In FIELD, fenofibrate (200 mg/day) reduced the requirements for laser therapy and prevented disease progression in patients with pre-existing diabetic retinopathy. In ACCORD Eye, fenofibrate (160 mg daily) with simvastatin resulted in a 40% reduction in the odds of retinopathy progressing over 4 years, compared with simvastatin alone. This occurred with an increase in HDL-cholesterol and a decrease in the serum triglyceride level in the fenofibrate group, as compared with the placebo group, and was independent of glycaemic control. We believe fenofibrate is effective in preventing progression of established diabetic retinopathy in type 2 diabetes and should be considered for patients with pre-proliferative diabetic retinopathy and/or diabetic maculopathy, particularly in those with macular oedema requiring laser. © 2011 Macmillan Publishers Limited All rights reserved.

Diagnosis of retinopathy in children younger than 12 years of age:implications for the diabetic eye screening guidelines in the UK

Aim: To assess whether the current starting age of 12 is suitable for diabetic retinopathy (DR) screening and whether diabetes duration should be taken into account when deciding at what age to start screening patients. Materials and methods: A retrospective analysis of 143 patients aged 12 years or younger who attended diabetic eye screening for the first time in the Birmingham, Solihull and Black Country Diabetic Eye Screening Programme was performed. Results: The mean age of the patients was 10.7 (7-12) years with 73 out of 143 aged below 12 years and 70 were 12 years of age. 98% had type 1 diabetes and mean diabetes duration was 5 (1 month-11 years) years. For those younger than 12 years, 7/73 (9.6%) had background DR (BDR), of these mean diabetes duration was 7 years (6-8). The youngest patient to present with DR was aged 8 years. In those aged 12 years, 5/70 (7.1%) had BDR; of these mean diabetes duration was 8 years (6-11). No patient developed DR before 6 years duration in either group. Conclusions: The results show that no patient younger than the age of 12 had sight-threatening DR (STDR), but BDR was identified. Based on the current mission statement of the Diabetic Eye Screening Programme to identify STDR, 12 years of age is confirmed as the right age to start screening, but if it is important to diabetic management to identify first development of DR, then screening should begin after 6 years of diabetes diagnosis.

Modelling the cost-effectiveness of adopting risk stratified approaches to extended screening intervals in the national diabetic retinopathy screening programme in Scotland

Funding sources: The study was funded by a research grant from the Chief Scientist’s Office of the Scottish Government Health and Social Care Directorates (CZH/4/971). The funder played no role in study design, data collection, data analysis, manuscript preparation and/or publication decisions. The views expressed herein are those of the authors and do not necessarily reflect those of the funder.

Natural history of retinopathy in children and young people with type 1 diabetes

Purpose: To describe the prevalence and natural history of retinopathy in a cohort of children and young people with type 1 diabetes attending a tertiary hospital diabetes clinic. Methods: We analysed retinopathy screening data from 2008 to 2010 on all eligible children using the 'Twinkle' diabetes database and the regional retinal screening database. Results: A total of 88% (149/169) of eligible children were screened in 2008, median age 14 years, 52% male. The prevalence of retinopathy was 19.5% (30/149). All children had background retinopathy grade R1. There was significant difference in median (range) duration of diabetes, 7.7 years (0.6–13.7) vs 5 years (0.2–12.5) (P<0.001) and median (range) HbA1C, 9.1% (7.2–14) vs 8.6% (5.6–13.1) (P=0.02), between the groups with and without retinopathy. At 2- years follow-up, 12/30 (40%) had unchanged retinopathy grade R1, 10/30 (33.3%) showed resolution of changes (R0), 1/30 progressed to maculopathy, and 7/30 had no follow-up data. Median (range) HbA1C in 2008 and 2010 for the groups with stable vs resolved changes was similar, 9.1% (7.2–14.0) and 9.2% (7–14.0) vs 9.5% (7.8–14.0) and 9.2% (8.7–14.0). Of the 119 without retinopathy in 2008, 27 (22.5%) had developed retinopathy within 2 years, including 1 with pre-proliferative retinopathy and 1 with maculopathy. There was no significant difference in HbA1c between those who progressed to retinopathy (8.7% (7.1–13.1)) (8.7% (7.1–13.1)), and those who did not (8.6% (6.3–12.2)). Conclusions: Prevalence of background retinopathy in our cohort was comparable to the previously published reports, with higher HbA1c and longer duration of diabetes being significant risk factors. On short-term follow-up, Grade 1 retinopathy is likely to resolve in a third of patients and remain unchanged in just over a third.

Survival or death: a dual role of autophagy in stress-induced pericyte loss in diabetic retinopathy

Aims/hypothesis
Intra-retinal extravasation and modification of LDL have been implicated in diabetic retinopathy: autophagy may mediate these effects.
Methods
Immunohistochemistry was used to detect autophagy marker LC3B in human and murine diabetic and non-diabetic retinas. Cultured human retinal capillary pericytes (HRCPs) were treated with in vitro-modified heavily-oxidised glycated LDL (HOG-LDL) vs native LDL (N-LDL) with or without autophagy modulators: green fluorescent protein–LC3 transfection; small interfering RNAs against Beclin-1, c-Jun NH(2)-terminal kinase (JNK) and C/EBP-homologous protein (CHOP); autophagy inhibitor 3-MA (5 mmol/l) and/or caspase inhibitor Z-VAD-fmk (100 μmol/l). Autophagy, cell viability, oxidative stress, endoplasmic reticulum stress, JNK activation, apoptosis and CHOP expression were assessed by western blots, CCK-8 assay and TUNEL assay. Finally, HOG-LDL vs N-LDL were injected intravitreally to STZ-induced diabetic vs control rats (yielding 50 and 200 mg protein/l intravitreal concentration) and, after 7 days, retinas were analysed for ER stress, autophagy and apoptosis.
Results
Intra-retinal autophagy (LC3B staining) was increased in diabetic vs non-diabetic humans and mice. In HRCPs, 50 mg/l HOG-LDL elicited autophagy without altering cell viability, and inhibition of autophagy decreased survival. At 100–200 mg/l, HOG-LDL caused significant cell death, and inhibition of either autophagy or apoptosis improved survival. Further, 25–200 mg/l HOG-LDL dose-dependently induced oxidative and ER stress. JNK activation was implicated in autophagy but not in apoptosis. In diabetic rat retina, 50 mg/l intravitreal HOG-LDL elicited autophagy and ER stress but not apoptosis; 200 mg/l elicited greater ER stress and apoptosis.
Conclusions
Autophagy has a dual role in diabetic retinopathy: under mild stress (50 mg/l HOG-LDL) it is protective; under more severe stress (200 mg/l HOG-LDL) it promotes cell death.

Twins prematurity--the influence of prenatal surveillance

OBJECTIVE: To evaluate the influence of the local prenatal surveillance of twin pregnancies in the obstetrical results. METHODS: A prospective cohort study of multiple pregnancies delivered over a period of 16 years in a tertiary centre was conducted. In this study 861 twin pregnancies were included. They were compared for obstetric complications, gestational age at delivery, mode of delivery and birthweight, according to the place of the surveillance. RESULTS: Of the 861 cases examined, the following obstetric complications were significantly different: metrorrhagia (p = 0.039), infections (p < 0.001), HELLP (p = 0.007), PROMPT (p < 0.001) and fetal death (p = 0.024). The mode of delivery was similar but occurred mostly ≤32 weeks (p < 0.001), the birthweight was mostly <2000 g and occurred more NICU admission (p < 0.001) when surveillance was outside the MPC-MDM. CONCLUSION: Our results demonstrate the crucial importance of prenatal surveillance be carried in a differentiated referral centers with specific/strict protocols or the urgent implementation of same protocols in all other places of surveillance, since this straight surveillance greatly reduces the occurrence of prenatal complications, mainly PROMPT, PTD.

‘Teaching corner’: Management of Diabetic Retinopathy

Sub-Saharan Africa faces an epidemic of diabetes. Visual loss from diabetic retinopathy (DR) is both preventable and treatable. This article reviews the epidemiology and clinical features of DR and current evidencebased interventions in three areas: primary prevention of retinopathy by optimum medical management, early detection of pre-symptomatic disease and management of established retinopathy to prevent or mitigate visual loss. There are significant challenges to DR care in resource poor environments. Appropriate provision of effective interventions by health services can reduce social and economic costs associated with patient care.

Prevalence of diabetic retinopathy in type II diabetic patients in a health facility in Karachi, Pakistan

Purpose: To study the prevalence of diabetic retinopathy in known diabetic patients attending the diabetes outpatient department (OPD) of Sind Government Hospital (SGH), New Karachi Township (NKT), Pakistan. Methods: A cross-sectional observational study was carried out at the diabetic OPD of SGH, NKT over the period of 17 months from March 2013 to August 2014. The selected patients were interviewed based on a questionnaire; laboratory investigations were performed and examination of the eye was conducted by a specialist ophthalmologist. One hundred and fifty four (154) subjects out of 305 patients contacted fully completed the study. Stratification of the data on gender basis was done, after which one-way ANOVA, χ2 test of correlation, binary logistic regression and relative risk analyses were carried out using SPSS-20. Results: It was found that 66 % men of normal weight (χ2 = 4.667, p < 0.05) and 60.7 % overweight women (χ2 = 5.143, p < 0.05) were more likely to present with diabetic retinopathy (DR). Prevalence of DR in this target population was 42.86 % (N = 66). Background DR (56 %) and maculopathy (23 %) were more prevalent than advanced conditions of the disease. There was no gender-based preponderance for the presentation of DR (χ2 = 0.663; p > 0.05), nor was this seen in different ethnic groups. Conclusion: DR is prevalent in the target population and, therefore, emphasis should be on the education of the local population of New Karachi Township on how to attain euglycemic state with regular medication, diet and exercise to avoid development and progress of DR.

Management and outcome of cholesterol embolus identified in a diabetic retinopathy screening program

Purpose. We examined the incidence, management, and outcomes of patients known to be at high cardiovascular risk, and to assess whether specialist referral to an ophthalmic medical clinic is worthwhile. Methods. Patients in the East Birmingham area with cholesterolembolus who were identified on digital diabetic retinopathy screening over a 3-year period were referred to a specialist ophthalmic medicine clinic within Heart of England NHS Trust for management and investigation. Results. A total of 33 patients were referred for clinical management.(male:female = 22:11, mean age 72 years). A total of 28 patients were known to be receiving medication: 14 anti hypertensive therapy(42%), 19 aspirin (59%), and 21 statin (64%). A total of 18 patients had known cardiovascular disease, 10 of whom had received carotid stenting or coronary artery bypass surgery. Ten patients diagnosed with embolus required and consented to carotid Doppler studies. Six patients were confirmed with significant carotid stenosis and 2 (6%)of these patients required carotid endarterectomy surgery. Overall, 4patients died, a mortality rate of 12% over 3 years. Conclusions. Annual diabetic retinopathy screening provide sopportunistic identification of asymptomatic cholesterol emboli and provides an opportunity for review of medical management in the high-risk patient group with appropriate identification and referral for carotid stenosis surgery. A total of 11 patients were identified with sub optimal cardiovascular risk management: e.g., statin use.

Advancing Bag-of-visual-words Representations For Lesion Classification In Retinal Images.

Diabetic Retinopathy (DR) is a complication of diabetes that can lead to blindness if not readily discovered. Automated screening algorithms have the potential to improve identification of patients who need further medical attention. However, the identification of lesions must be accurate to be useful for clinical application. The bag-of-visual-words (BoVW) algorithm employs a maximum-margin classifier in a flexible framework that is able to detect the most common DR-related lesions such as microaneurysms, cotton-wool spots and hard exudates. BoVW allows to bypass the need for pre- and post-processing of the retinographic images, as well as the need of specific ad hoc techniques for identification of each type of lesion. An extensive evaluation of the BoVW model, using three large retinograph datasets (DR1, DR2 and Messidor) with different resolution and collected by different healthcare personnel, was performed. The results demonstrate that the BoVW classification approach can identify different lesions within an image without having to utilize different algorithms for each lesion reducing processing time and providing a more flexible diagnostic system. Our BoVW scheme is based on sparse low-level feature detection with a Speeded-Up Robust Features (SURF) local descriptor, and mid-level features based on semi-soft coding with max pooling. The best BoVW representation for retinal image classification was an area under the receiver operating characteristic curve (AUC-ROC) of 97.8% (exudates) and 93.5% (red lesions), applying a cross-dataset validation protocol. To assess the accuracy for detecting cases that require referral within one year, the sparse extraction technique associated with semi-soft coding and max pooling obtained an AUC of 94.2 ± 2.0%, outperforming current methods. Those results indicate that, for retinal image classification tasks in clinical practice, BoVW is equal and, in some instances, surpasses results obtained using dense detection (widely believed to be the best choice in many vision problems) for the low-level descriptors.

Endocytosis Of Tight Junctions Caveolin Nitrosylation Dependent Is Improved By Cocoa Via Opioid Receptor On Rpe Cells In Diabetic Conditions.

Retinal pigment epithelium cells, along with tight junction (TJ) proteins, constitute the outer blood retinal barrier (BRB). Contradictory findings suggest a role for the outer BRB in the pathogenesis of diabetic retinopathy (DR). The aim of this study was to investigate whether the mechanisms involved in these alterations are sensitive to nitrosative stress, and if cocoa or epicatechin (EC) protects from this damage under diabetic (DM) milieu conditions. Cells of a human RPE line (ARPE-19) were exposed to high-glucose (HG) conditions for 24 hours in the presence or absence of cocoa powder containing 0.5% or 60.5% polyphenol (low-polyphenol cocoa [LPC] and high-polyphenol cocoa [HPC], respectively). Exposure to HG decreased claudin-1 and occludin TJ expressions and increased extracellular matrix accumulation (ECM), whereas levels of TNF-α and inducible nitric oxide synthase (iNOS) were upregulated, accompanied by increased nitric oxide levels. This nitrosative stress resulted in S-nitrosylation of caveolin-1 (CAV-1), which in turn increased CAV-1 traffic and its interactions with claudin-1 and occludin. This cascade was inhibited by treatment with HPC or EC through δ-opioid receptor (DOR) binding and stimulation, thereby decreasing TNF-α-induced iNOS upregulation and CAV-1 endocytosis. The TJ functions were restored, leading to prevention of paracellular permeability, restoration of resistance of the ARPE-19 monolayer, and decreased ECM accumulation. The detrimental effects on TJs in ARPE-19 cells exposed to DM milieu occur through a CAV-1 S-nitrosylation-dependent endocytosis mechanism. High-polyphenol cocoa or EC exerts protective effects through DOR stimulation.

Increased Circulating Pedf And Low Sicam-1 Are Associated With Sickle Cell Retinopathy.

Sickle cell retinopathy (SCR) develops in up to 30% of sickle cell disease patients (SCD) during the second decade of life. Treatment for this affection remains palliative, so studies on its pathophysiology may contribute to the future development of novel therapies. SCR is more frequently observed in hemoglobin SC disease and derives from vaso-occlusion in the microvasculature of the retina leading to neovascularization and, eventually, to blindness. Circulating inflammatory cytokines, angiogenic factors, and their interaction may contribute to the pathophysiology of this complication. Angiopoietin (Ang)-1, Ang-2, soluble vascular cell adhesion molecule-1, intercellular adhesion molecule (ICAM)-1, E-selectin, P-selectin, IL1-β, TNF-α, pigment epithelium derived factor (PEDF) and vascular endothelial growth factor plasmatic levels were determined in 37 SCD patients with retinopathy, 34 without retinopathy, and healthy controls. We observed that sICAM-1 is significantly decreased, whereas PEDF is elevated in HbSC patients with retinopathy (P=0.012 and P=0.031, respectively). Ang-1, Ang-2 and IL1-β levels were elevated in SCD patients (P=0.001, P<0.001 and P=0.001, respectively), compared to controls, and HbSS patients presented higher levels of Ang-2 compared to HbSC (P<0.001). Our study supports the possible influence of sICAM-1 and PEDF on the pathophysiology of retinal neovascularization in SCD patients.