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Background: The aim was to study the association of serum total calcium, ionic calcium, and magnesium with increases in macular thickness parameters and photoreceptor ellipsoid zone (EZ) disruption in diabetic macular edema (DME)., Methods: This study is a tertiary care center based observational cross-sectional study with sixty-six consecutive cases, divided into 3 groups of 22 cases each with no diabetic retinopathy (No DR), non-proliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy (PDR) and a control group of 22 healthy controls. Best corrected visual acuity (BCVA) was measured on logMAR scale. Central subfield thickness (CST), cube average thickness (CAT), and EZ disruption were assessed using spectral-domain optical coherence tomography (SD-OCT). Serum total calcium, ionic calcium, and magnesium were measured using standard protocol. Data was analyzed statistically., Results: Significant correlation was found between the increase in CST and the increase in serum total calcium and serum ionic calcium. Increase in CAT was significantly correlated with an increase in serum total calcium, serum ionic calcium, and a decrease in serum magnesium. Grades of EZ disruption and logMAR BCVA were also found to be significantly positively associated with serum total calcium and ionic calcium and negatively with serum magnesium., Conclusions: Increased levels of serum ionic calcium and decreased levels of serum magnesium are associated with an increase in macular thickness and EZ disruption in DME.

To evaluate the role of central subfield thickness (CST), cube average thickness (CAT), and cube volume (CV) as imaging biomarkers for severity of diabetic retinopathy within the ETDRS-based grades of retinopathy using spectral domain optical coherence tomography (SD-OCT). This study aims to evaluate the role of macular CST, CAT, and CV on SD-OCT as imaging biomarkers for severity of DR. One hundred ninety-four consecutive cases of type 2 diabetes mellitus were divided according to ETDRS classification: diabetes mellitus without retinopathy (No DR; n = 65), nonproliferative diabetic retinopathy (NPDR; n = 66), and proliferative diabetic retinopathy (PDR; n = 63). Sixty-three healthy controls were included. CST, CAT, and CV were analyzed using SD-OCT. Data were analyzed statistically. Analysis of variance revealed a significant increase in levels of CST, CAT, CV, and LogMAR visual acuity with the increase in severity of DR. Independent t-test revealed significant difference in CST, CAT, and CV between cases with DME and cases without DME. On multivariate linear regression analysis, increase in CST, CAT, and CV were found to indicate the increase in severity of DR. SD-OCT-based imaging biomarkers CST, CAT, and CV are effective tools for documenting the severity of diabetic retinopathy. These imaging biomarkers serve as significant indicators of severity of disease.

Purpose: To study the association of serum ionic calcium and glycated hemoglobin (HbA1c) with retinal photoreceptor ellipsoid zone (EZ) disruption in diabetic retinopathy (DR)., Methods: This is a tertiary care center-based observational cross-sectional study. Sixty-three consecutive cases, divided into 21 cases each with no diabetic retinopathy, non-proliferative diabetic retinopathy and proliferative diabetic retinopathy were included. Twenty-one healthy controls were also included. Ellipsoid zone disruption was assessed using spectral-domain optical coherence tomography. Serum ionic calcium and HbA1c were measured using standard protocol. Patient data from cases were divided into two groups according to their HbA1c levels: group 1 (HbA1c < 7, n = 26) and group 2 (HbA1c > 7, n = 37). Data were analyzed statistically., Results: Mean ionic calcium levels in group 1 and group 2 were 1.131 ± 0.073 mmol/dL and 1.170 ± 0.070 mmol/dL, respectively. In group 1, 11 out of 26 had EZ disruption (42.3%). Similarly, in group 2, 29 out of 37 had EZ disruption (78.4%). On logistic regression analysis, as compared to group 1, ellipsoid zone disruption was found to be positively associated with serum ionic calcium (p = 0.01) in group 2 cases., Conclusion: Increased levels of serum ionic calcium are associated with increased EZ disruption in patients with HbA1c > 7 in DR.

Purpose: To study the correlation between disorganization of inner retinal layer (DRIL) and macular thickness parameters, ellipsoid zone (EZ) disruption and retinal nerve fiber layer (RNFL) thickness on spectral domain optical coherence tomography (SD-OCT) in diabetic retinopathy (DR), for the first time., Methods: A tertiary care center-based cross-sectional study was undertaken. One hundred and four consecutive study subjects of type 2 diabetes mellitus were included: diabetes mellitus with no retinopathy (No DR) (n = 26); non-proliferative DR (NPDR) (n = 26); proliferative DR (PDR) (n = 26) and healthy controls (n = 26). Best Corrected Visual Acuity (BCVA) was measured on the logarithm of the minimum angle of resolution (logMAR) scale. Clinician-friendly, SD-OCT based, grading systems were created for DRIL and EZ disruption, within the macular cube. DRIL was graded as: grade 0, DRIL absent; and grade 1, DRIL present. EZ disruption was graded as; Grade 0: Intact EZ; Grade 1: Focal disruption and Grade 2: Global disruption. Every study subject underwent RNFL thickness analysis., Results: DRIL was significantly associated with increase in severity of DR.Pearson correlation analysis showed significant positive correlation between DRIL and CST CAT and grades of EZ disruption . However, a significant negative correlation was found between DRIL and RNFL thickness ., Conclusion: Presence of DRIL correlates with severity of DR, EZ disruption and RNFL thinning., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The aim of this work was to study the association of serum ionized calcium with retinal photoreceptor apoptosis on spectral domain optical coherence tomography (SD-OCT) in diabetic retinopathy (DR)., Methods: Sixty consecutive cases with Type 2 diabetes mellitus were categorized into three groups: no diabetic retinopathy; non-proliferative DR; proliferative DR. The eye with more severe form of the disease was considered. Twenty healthy controls were also included. Best corrected visual acuity (BCVA) was measured on logMAR scale. Retinal photoreceptor apoptosis was defined as disruption of retinal photoreceptor ellipsoid zone (EZ). Ellipsoid zone disruption was assessed using SD-OCT. Serum levels of total and ionized calcium were measured using standard protocol., Results: EZ disruption was found to be positively associated with serum total calcium and ionized calcium. Also, EZ disruption was found to be positively associated with logMAR BCVA., Conclusion: Increased serum ionized calcium induces retinal photoreceptor apoptosis resulting in increased EZ disruption in DR., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Retinopathy is the leading cause of blindness and visual disability in working-aged people. The pathogenesis of retinopathy is an actual and still open query. Alterations contributing to oxidative and nitrosative stress, including elevated nitric oxide and superoxide production, changes in the expression of different isoforms of nitric oxide synthase or endogenous antioxidant system, have been implicated in the mechanisms how this ocular disease develops. In addition, it was documented that renin-angiotensin system has been implicated in the progression of retinopathy. Based on comprehensive preclinical and clinical researches in this area, the role of above-mentioned factors in the pathogenesis of diabetic retinopathy, hypertensive retinopathy and ischaemic proliferative retinopathy is reviewed in this study. Moreover, the genetic susceptibility factors involved in the development of the retinopathy and possible strategies that utilize antioxidants as additive therapy are also highlighted here., (© 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: Diabetic retinopathy is a serious sight-threatening complication which is manifested by excessive angiogenesis in diabetic patients., Aim: We hypothesize that cultured Rhesus monkey retinal endothelial cells (RhRECs) respond to high glucose with a change in cell proliferation and vascular endothelial growth factor (VEGF) secretion., Materials and Methods: In our study, 20 000 cells per well were treated without glucose or with 5.5 mM, 18.5 mM and 30 mM glucose for 24 hours. Viable cells were counted using trypan blue dye exclusion method. VEGF concentrations were measured in cell media by ELISA method., Results: The number of viable cells incubated with 5.5 mM glucose increased significantly by 53.7% after 24 hours. In comparison, the number of viable cells decreased by 2.8% at 18.5 mM of glucose and by 20.4% at 30 mM of glucose after 24 hours of incubation. In contrast to this effect of glucose on the number of viable cells, a significant increase in VEGF levels (pg/mL) in the cell media with a glucose concentration of 0 mM compared to 5.5 mM of glucose was found. VEGF secretion in cell medium with 18.5 and 30 mM of glucose increased non-significantly in comparison with euglycemic levels., Conclusion: Our results show that viability of retinal endothelial cells and VEGF release are highly responsive to changes in glucose concentration. Such glucose-induced changes in retinal endothelial cells may negatively impact the integrity of the microvasculature in the diabetic retina leading to angiogenesis and microaneursym.

Aim: To study the association of serum levels of anti-myeloperoxidase (MPO) antibody with retinal photoreceptor ellipsoid zone (EZ) disruption in diabetic retinopathy., Methods: Consecutive patients with type 2 DM [diabetes mellitus with no retinopathy (NODR; n=20); non-proliferative diabetic retinopathy (NPDR; n=18); proliferative diabetic retinopathy (PDR; n=16)] and healthy controls (n=20) between the ages of 40 and 65years were included. Disruption of EZ was graded by spectral domain optical coherence tomography as no disruption of EZ and disrupted EZ. The serum levels of anti-MPO antibody was analyzed using standard protocol. Association between the variables was evaluated using multiple regression analysis., Results: A significant difference was found between the serum levels of anti-MPO antibody in various study groups (p<0.001). A positive association was found between EZ disruption and levels of anti-MPO antibody [adjusted odd's ratio (AOR)=1.079, CI 1.010-1.124, p=0.04]. A significant positive correlation was found between logMAR visual acuity and grade of disruption (AOR=1.008, CI 1.006-5.688, p=0.04)., Conclusions: An increased serum anti-MPO antibody levels is associated with retinal photoreceptor EZ disruption and decreased visual acuity in diabetic retinopathy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the role of serum urea and creatinine as surrogate markers for disruption of retinal photoreceptor external limiting membrane (ELM) and inner segment ellipsoid zone (EZ) in Type 2 diabetic retinopathy (DR) using spectral-domain optical coherence tomography, for the first time., Methods: One hundred and seventeen consecutive cases of Type 2 diabetes mellitus (diabetes without retinopathy [No DR; n = 39], nonproliferative diabetic retinopathy [NPDR; n = 39], proliferative diabetic retinopathy [PDR; n = 39]) and 40 healthy control subjects were included. Serum levels of urea and creatinine were assessed using standard protocol. Spectral-domain optical coherence tomography was used to grade the disruption of ELM and EZ as follows: Grade 0, no disruption of ELM and EZ; Grade 1, ELM disrupted, EZ intact; Grade 2, ELM and EZ disrupted. Data were analyzed statistically., Results: Increase in serum levels of urea (F = 22.93) and creatinine (F = 15.82) and increased grades of disruption of ELM and EZ (γ = 116.3) were observed with increased severity of DR (P < 0.001). Increase in serum levels of urea (F = 10.45) and creatinine (F = 6.89) was observed with increased grades of disruption of ELM and EZ (P = 0.001)., Conclusion: Serum levels of urea and creatinine are surrogate markers for disruption of retinal photoreceptor ELM and EZ on spectral-domain optical coherence tomography in DR.

Purpose: To evaluate the association of serum levels of N(ε)- Carboxy methyl lysine (N(ε)-CML), an advanced glycation end product with topographic alterations in retinal pigment epithelium (RPE) in diabetic retinopathy on spectral domain optical coherence tomography (SD-OCT)., Method: Consecutive cases of type 2 diabetes mellitus with no retinopathy (n=20); non-proliferative diabetic retinopathy (n=20); proliferative diabetic retinopathy (n=20) and healthy controls (n=20) between the ages of 40 and 65years were included. RPE alterations were graded on segmentation map of SD-OCT: grade 0, No RPE alterations; grade 1, RPE alterations in up to two quadrants and grade 2, RPE alterations in more than two quadrants. Serum level of N(ε)-CML and glycated hemoglobin (HbA1c) was analyzed using the standard protocol. Statistical analysis was done., Results: Significant increase in N(ε)-CML was observed with increased severity of diabetic retinopathy (F=34.1; p<0.0001). Fisher exact test revealed significant increase in grades of RPE alterations with increased severity of diabetic retinopathy (p<0.001). Univariate ordinal regression analysis was done to calculate the risk of progression in grades of RPE alteration with individual changes in variables like duration of diabetes (odds ratio=1.37; p=0.001), HbA1c (odds ratio=1.37; p=0.002) and Nε-CML (odds ratio=1.37; p<0.0001). Multivariate ordinal regression analysis for predicting progression in grades of RPE alteration revealed Nε-CML to be an independent predictor of increase in grades of RPE alteration (adjusted odds ratio=1.07; p<0.01) when duration of diabetes and HbA1c were held constant., Conclusion: Increase in serum levels of N(ε)- Carboxy methyl lysine is significantly associated with topographic alterations in RPE. Grades of RPE alteration increase significantly with increased severity of diabetic retinopathy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aim: To study the correlation between serum antimyeloperoxidase (MPO) antibody levels with severity of diabetic retinopathy (DR)., Methods: Study subjects included 60 consecutive cases of type 2 diabetes mellitus (DM): no diabetic retinopathy (NODR, n=20); nonproliferative DR (NPDR, n=20); proliferative DR (PDR, n=20) and 20 healthy controls. Best corrected visual acuity (BCVA) was measured on logMAR scale. Serum anti-MPO antibody levels were evaluated using ELISA IgG kit. Serum urea and creatinine was measured using standard protocol. Data were analysed statistically., Results: Mean serum anti-MPO antibody (RU/ml) was 16.94 ± 4.85 in controls, 17.66 ± 4.78 in NODR, 21.51 ± 5.27 in NPDR and 37.27 ± 11.92 in PDR groups. On ANOVA, significant difference in visual acuity was found among the study groups (F=73.46, p<0.001). Serum anti-MPO antibody was correlated significantly with decrease in visual acuity (F=48.40, p<0.001), increase in serum urea (F=128.13, p<0.001) and creatinine (F=77.10, p<0.001)., Conclusion: Increase in serum anti-MPO antibody levels correlate with increased severity of DR. Serum anti-MPO antibody may be a noteworthy biochemical marker for progression of retinopathy from nonproliferative to proliferative stage., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To correlate serum levels of N-epsilon-carboxy methyl lysine (N(ε)-CML) with severity of retinopathy, in vivo macular edema and disruption of external limiting membrane (ELM) and photoreceptor ellipsoid zone in type 2 diabetes mellitus (DM)., Methods: Consecutive cases of type 2 DM [diabetes mellitus with no retinopathy (No DR) (n=20); non- proliferative diabetic retinopathy (NPDR) with diabetic macular edema (n=20); proliferative diabetic retinopathy with diabetic macular edema (PDR) (n=20)] and healthy controls (n=20) between the ages of 40 and 65 years were included (power of study=93.8%). In vivo histology of retinal layers was assessed using spectral domain optical coherence tomography. Every study subject underwent macular thickness analysis using the macular cube 512×128 feature. Disruption of ELM and photoreceptor ellipsoid zone was graded: grade 0, no disruption of ELM and ellipsoid zone; grade 1, ELM disrupted and ellipsoid zone intact; grade 2, both ELM and ellipsoid zone disrupted. Data were statistically analyzed., Results: The mean levels of N(ε)-CML were 31.34±21.23 ng/ml, 73.88±35.01 ng/ml, 91.21±66.65 ng/ml, and 132.08±84.07 ng/ml in control, No DR, NPDR and PDR respectively. N(ε)-CML level was significantly different between the study groups (control, No DR, NPDR and PDR) (p<0.001). Mean logMAR visual acuity decreased with increased levels of N(ε)-CML (p<0.001). The association of N(Ɛ)CML with the grades of disruption was found to be statistically significant (F value=18.48, p<0.001). Univariate analysis was done with N(Ɛ)-CML as a dependent variable. The values of N(Ɛ)-CML were normalized (log10) and were subjected to univariate analysis with fasting blood glucose level, glycosylated hemoglobin, central subfield macular thickness and cube average thickness among the diseased groups (NPDR and PDR) that act as confounders. It was found that none of the variables had significant effect on N(Ɛ)-CML (fasting blood glucose p=0.12, HBA1c p=0.65, central subfield macular thickness p=0.13, cube average thickness p=0.19). N(Ɛ)-CML tends to be a significant and important predictor of grade of ELM and ellipsoid zone disruption in diabetic retinopathy., Conclusions: Increased N(ε)-CML levels are associated with increased severity of diabetic retinopathy, macular edema and structural changes in macula that is ELM and ellipsoid zone disruption, which serves as a prognosticator of visual outcome., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Oxidative stress plays an important role in the pathogenesis of diabetes and its complications. The aim of this study was to examine the possible association between seven single nucleotide polymorphisms (SNPs) of the Trx2/TXNIP and TrxR2 genes encoding proteins involved in the thioredoxin antioxidant defence system and the risk of diabetic retinopthy (DR)., Design: Cross-sectional case-control study., Participants: A total of 802 Slovenian patients with Type 2 diabetes mellitus; 277 patients with DR and 525 with no DR were enrolled., Methods: Patients genotypes of the SNPs; including rs8140110, rs7211, rs7212, rs4755, rs1548357, rs4485648 and rs5748469 were determined by the competitive allele specific PCR method., Main Outcome Measures: Each genotype of examined SNPs was regressed in a logistic model, assuming the co-dominant, dominant and the recessive models of inheritance with covariates of duration of diabetes, HbA1c, insulin therapy, total cholesterol and LDL cholesterol levels., Results: In the present study, for the first time we identified an association between the rs4485648 polymorphism of the TrxR2 gene and DR in Caucasians with Type 2 DM. The estimated ORs of adjusted logistic regression models were found to be as follows: 4.4 for CT heterozygotes, 4.3 for TT homozygotes (co-dominant genetic model) and 4.4 for CT+TT genotypes (dominant genetic model)., Conclusions: In our case-control study we were not able to demonstrate any association between rs8140110, rs7211, rs7212, rs4755, rs1548357, and rs5748469 and DR, however, our findings provide evidence that the rs4485648 polymorphism of the TrxR2 gene might exert an independent effect on the development of DR., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to examine the role of the rs6060566 polymorphism of the reactive oxygen species modulator 1 (Romo-1) gene in the development of diabetic retinopathy (DR) in Caucasians with type 2 diabetes (T2DM). Moreover, another aim was to investigate the effect of Romo-1 genotypes on Romo-1 expression in fibrovascular membranes from patients with proliferative DR., Methods: A total of 806 subjects with T2DM were enrolled in cross-sectional case-control study: 278 patients with DR and 528 subjects without clinical signs of DR. Genetical analysis was performed in 806 subjects with T2DM. Moreover, immunohistochemical analysis of 40 fibrovascular membranes of patients with proliferative DR was performed. The number of positive (labelled) cells per area - numerical areal density of the Romo-1-positive cells (the number of positive cells/mm(2) ) - was calculated., Results: A significantly higher frequency of the CC genotype of the rs6060566 polymorphism of the Romo-1 gene was found in subjects with T2DM with DR compared to those without DR (odds ratio=3.3, 95% confidence interval=1.1-8.8; p = 0.024). Moreover, the Romo-1 C allele was found to effect Romo-1 expression in fibrovascular membranes of patients with proliferative DR., Conclusions: The rs6060566 polymorphism of the Romo-1 gene was found to be an independent risk factor for DR in Caucasians with T2DM. Moreover, the rs6060566 is most probably functional and its effect might be mediated through the increased expression of Romo-1 in the retina., (© 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: The aim of the study was to determine plasma nitric oxide (NO) and lipid peroxide (LPO) levels in diabetic retinopathy and its association with severity of disease., Design: Prospective observational study., Participants: A total of 60 consecutive cases and 20 healthy controls were included., Methods: Severity of retinopathy was graded according to early treatment diabetic retinopathy study (ETDRS) classification. Photoreceptor inner segment ellipsoid band (ISel) disruption and retinal pigment epithelium (RPE) alteration were graded using spectral domain optical coherence tomography. Data were statistically analyzed., Main Outcome Measures: Plasma thiobarbituric acid reactive substances, NO assay and reduced glutathione (GSH) were measured using standard protocol., Results: Increased severity of diabetic retinopathy was significantly associated with increase in plasma levels of LPO (P < 0.05), NO (P < 0.001) and decrease in plasma levels of GSH (P < 0.0001), ISel disruption (P < 0.001) and RPE topographic alteration (P < 0.01)., Conclusion: Increased plasma NO levels are associated with increased severity of diabetic retinopathy. For the first time, it has been demonstrated that increased plasma LPO, NO and decreased GSH levels are associated with in vivo structural changes in inner segment ellipsoid and RPE., (© 2015 Royal Australian and New Zealand College of Ophthalmologists.)

Correlation of increased levels of serum urea and creatinine with retinal nerve fibre layer (RNFL) thinning on spectral domain optical coherence tomography (SD-OCT) was studied in diabetic retinopathy (DR). Sixty consecutive cases and 20 healthy controls were included. Cases were divided into three groups: without DR, non-proliferative DR with macular oedema and proliferative DR with oedema. Serum urea and creatinine were measured using a standard protocol. Average (RNFL) was measured using SD-OCT. Increased severity of DR was associated with decrease in levels of serum urea and serum creatinine levels. RNFL thinning correlated positively with increase in serum urea and creatinine levels.

Purpose: To study the correlation of serum vitamin D levels with quantitative (central subfield thickness [CST], cube average thickness [CAT]), cross-sectional (disorganisation of retinal inner layer [DRIL] and ellipsoid zone [EZ]) and topographic parameters (retinal pigment epithelium [RPE]) on spectral domain optical coherence tomography (SD-OCT) in diabetic retinopathy (DR), for the first time. Methods: Eighty-eight consecutive cases of type 2 diabetes mellitus with no retinopathy (No DR; n = 22); non-proliferative DR (NPDR; n = 22); proliferative DR (PDR; n = 22) and healthy controls (n = 22) were included, after sample size calculation. On SD-OCT, physician-friendly grading systems were created for DRIL, EZ disruption and RPE alterations. Serum vitamin D was analysed using a standard protocol. Statistical analysis was done using Pearson correlation, Student's t-test, ANOVA, Newman–Keuls test, chi-square test and univariate ordinal logistic regression analysis. Results: Mean serum vitamin D levels (ng/ml) were: No DR = 23.36 ± 2.00, NPDR = 17.88 ± 1.86, PDR = 14.07 ± 1.21, and controls = 25.11 ± 1.59. Low vitamin D levels correlated significantly with severity of retinopathy, VA (r = 0.50), CST (r = 0.36), CAT (r = 0.41), DRIL (r = 0.35), EZ disruption (r = 0.40) and RPE alterations (r = 0.37), respectively (p < 0.01). Significantly low vitamin D levels were observed in subjects with DRIL present versus DRIL absent; EZ disruption, focal versus global versus intact; RPE alterations, focal versus global versus none, respectively (p < 0.05). Conclusions: Low serum vitamin D levels correlate with the presence of DRIL, EZ disruption and RPE alterations and increased severity of DR. [ABSTRACT FROM AUTHOR]