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Mitochondrial Haplogroups Modify the Effect of Diabetes Duration and HbA1c on Proliferative Diabetic Retinopathy Risk in Patients With Type 2 Diabetes.
Mitchell SL, Neininger AC, Bruce CN, Chocron IM, Bregman JA, Estopinal CB, Muhammad A, Umfress AC, Jarrell KL, Warden C, Harlow PA, Wellons M, Samuels DC, Brantley MA
(2017) Invest Ophthalmol Vis Sci 58: 6481-6488
MeSH Terms: Aged, Blood Glucose, Case-Control Studies, DNA, Mitochondrial, Diabetes Mellitus, Type 2, Diabetic Retinopathy, European Continental Ancestry Group, Female, Glycated Hemoglobin A, Haplotypes, Humans, Male, Mitochondria, Polymorphism, Single Nucleotide, Risk Factors, United States
Show Abstract · Added March 21, 2018
Purpose - We previously demonstrated an association between European mitochondrial haplogroups and proliferative diabetic retinopathy (PDR). The purpose of this study was to determine how the relationship between these haplogroups and both diabetes duration and hyperglycemia, two major risk factors for diabetic retinopathy (DR), affect PDR prevalence.
Methods - Our population consisted of patients with type 2 diabetes with (n = 377) and without (n = 480) DR. A Kruskal-Wallis test was used to compare diabetes duration and hemoglobin A1c (HbA1c) among mitochondrial haplogroups. Logistic regressions were performed to investigate diabetes duration and HbA1c as risk factors for PDR in the context of European mitochondrial haplogroups.
Results - Neither diabetes duration nor HbA1c differed among mitochondrial haplogroups. Among DR patients from haplogroup H, longer diabetes duration and increasing HbA1c were significant risk factors for PDR (P = 0.0001 and P = 0.011, respectively). Neither diabetes duration nor HbA1c was a significant risk factor for PDR in DR patients from haplogroup UK.
Conclusions - European mitochondrial haplogroups modify the effects of diabetes duration and HbA1c on PDR risk in patients with type 2 diabetes. In our patient population, longer diabetes duration and higher HbA1c increased PDR risk in patients from haplogroup H, but did not affect PDR risk in patients from haplogroup UK. This relationship has not been previously demonstrated and may explain, in part, why some patients with nonproliferative DR develop PDR and others do not, despite similar diabetes duration and glycemic control.
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16 MeSH Terms
Mitochondrial Haplogroups Affect Severity But Not Prevalence of Diabetic Retinopathy.
Bregman JA, Herren DJ, Estopinal CB, Chocron IM, Harlow PA, Warden C, Brantley MA, Samuels DC
(2017) Invest Ophthalmol Vis Sci 58: 1346-1351
MeSH Terms: Aged, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Diabetic Retinopathy, European Continental Ancestry Group, Female, Glycated Hemoglobin A, Haplotypes, Humans, Logistic Models, Male, Middle Aged, Mitochondria, Prevalence, Risk Factors, Severity of Illness Index, United Kingdom
Show Abstract · Added March 21, 2018
Purpose - We previously reported European mitochondrial haplogroup H to be a risk factor for and haplogroup UK to be protective against proliferative diabetic retinopathy (PDR) among Caucasian patients with diabetic retinopathy (DR). The purpose of this study was to determine whether these haplogroups are also associated with the risk of having DR among Caucasian patients with diabetes.
Methods - Deidentified medical records for 637 Caucasian patients with diabetes (223 with DR) were obtained from BioVU, Vanderbilt University's electronic, deidentified DNA databank. An additional 197 Caucasian patients with diabetes (98 with DR) were enrolled from the Vanderbilt Eye Institute (VEI). We tested for an association between European mitochondrial haplogroups and DR status.
Results - The percentage of diabetes patients with DR did not differ across the haplogroups (P = 0.32). The percentage of patients with nonproliferative DR (NPDR; P = 0.0084) and with PDR (P = 0.027) significantly differed across the haplogroups. In logistic regressions adjusting for sex, age, diabetes type, duration of diabetes, and hemoglobin A1c, neither haplogroup H nor haplogroup UK had a significant effect on DR compared with diabetic controls. Haplogroup UK was a significant risk factor (OR = 1.72 [1.13-2.59], P = 0.010) for NPDR compared with diabetic controls in the unadjusted analysis, but not in the adjusted analysis (OR = 1.29 [0.79-2.10], P = 0.20).
Conclusions - Mitochondrial haplogroups H and UK were associated with severity, but not presence, of DR. These data argue that the effect of these haplogroups is related to ischemia and neovascularization, the defining features of PDR.
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17 MeSH Terms
RNA-Seq reveals a role for NFAT-signaling in human retinal microvascular endothelial cells treated with TNFα.
Savage SR, Bretz CA, Penn JS
(2015) PLoS One 10: e0116941
MeSH Terms: Diabetic Retinopathy, Endothelial Cells, Humans, Microvessels, Molecular Targeted Therapy, NFATC Transcription Factors, Retina, Sequence Analysis, RNA, Signal Transduction, Transcriptome, Tumor Necrosis Factor-alpha
Show Abstract · Added February 19, 2015
TNFα has been identified as playing an important role in pathologic complications associated with diabetic retinopathy and retinal inflammation, such as retinal leukostasis. However, the transcriptional effects of TNFα on retinal microvascular endothelial cells and the different signaling pathways involved are not yet fully understood. In the present study, RNA-seq was used to profile the transcriptome of human retinal microvascular endothelial cells (HRMEC) treated for 4 hours with TNFα in the presence or absence of the NFAT-specific inhibitor INCA-6, in order to gain insight into the specific effects of TNFα on RMEC and identify any involvement of NFAT signaling. Differential expression analysis revealed that TNFα treatment significantly upregulated the expression of 579 genes when compared to vehicle-treated controls, and subsequent pathway analysis revealed a TNFα-induced enrichment of transcripts associated with cytokine-cytokine receptor interactions, cell adhesion molecules, and leukocyte transendothelial migration. Differential expression analysis comparing TNFα-treated cells to those co-treated with INCA-6 revealed 10 genes whose expression was significantly reduced by the NFAT inhibitor, including those encoding the proteins VCAM1 and CX3CL1 and cytokines CXCL10 and CXCL11. This study identifies the transcriptional effects of TNFα on HRMEC, highlighting its involvement in multiple pathways that contribute to retinal leukostasis, and identifying a previously unknown role for NFAT-signaling downstream of TNFα.
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11 MeSH Terms
Development of an MRI biomarker sensitive to tetrameric visual arrestin 1 and its reduction via light-evoked translocation in vivo.
Berkowitz BA, Gorgis J, Patel A, Baameur F, Gurevich VV, Craft CM, Kefalov VJ, Roberts R
(2015) FASEB J 29: 554-64
MeSH Terms: Animals, Arrestins, Biomarkers, Body Weight, Colloids, Diabetes Mellitus, Experimental, Diabetic Retinopathy, Ferric Compounds, Immunohistochemistry, Light, Light Signal Transduction, Magnetic Resonance Imaging, Male, Manganese, Mice, Mice, Inbred C57BL, Nanoparticles, Protein Transport, Retina, Retinal Rod Photoreceptor Cells, Rod Cell Outer Segment, Signal Transduction, beta-Arrestin 1, beta-Arrestins
Show Abstract · Added February 12, 2015
Rod tetrameric arrestin 1 (tet-ARR1), stored in the outer nuclear layer/inner segments in the dark, modulates photoreceptor synaptic activity; light exposure stimulates a reduction via translocation to the outer segments for terminating G-protein coupled phototransduction signaling. Here, we test the hypothesis that intraretinal spin-lattice relaxation rate in the rotating frame (1/T1ρ), an endogenous MRI contrast mechanism, has high potential for evaluating rod tet-ARR1 and its reduction via translocation. Dark- and light-exposed mice (null for the ARR1 gene, overexpressing ARR1, diabetic, or wild type with or without treatment with Mn2+, a calcium channel probe) were studied using 1/T1ρ MRI. Immunohistochemistry and single-cell recordings of the retinas were also performed. In wild-type mice with or without treatment with Mn2+, 1/T1ρ of avascular outer retina (64% to 72% depth) was significantly (P < 0.05) greater in the dark than in the light; a significant (P < 0.05) but opposite pattern was noted in the inner retina (<50% depth). Light-evoked outer retina Δ1/T1ρ was absent in ARR1-null mice and supernormal in overexpressing mice. In diabetic mice, the outer retinal Δ1/T1ρ pattern suggested normal dark-to-light tet-ARR1 translocation and chromophore content, conclusions confirmed ex vivo. Light-stimulated Δ1/T1ρ in inner retina was linked to changes in blood volume. Our data support 1/T1ρ MRI for noninvasively assessing rod tet-ARR1 and its reduction via protein translocation, which can be combined with other metrics of retinal function in vivo.
© FASEB.
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24 MeSH Terms
Mitochondrial haplogroups are associated with severity of diabetic retinopathy.
Estopinal CB, Chocron IM, Parks MB, Wade EA, Roberson RM, Burgess LG, Brantley MA, Samuels DC
(2014) Invest Ophthalmol Vis Sci 55: 5589-95
MeSH Terms: Adult, Aged, Case-Control Studies, Cohort Studies, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Diabetic Retinopathy, Female, Genotype, Glycated Hemoglobin A, Haplotypes, Humans, Male, Middle Aged, Mitochondria, Odds Ratio
Show Abstract · Added February 12, 2015
PURPOSE - To determine if specific mitochondrial haplogroups associate with nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR).
METHODS - Deidentified medical records for Caucasian patients with diabetic retinopathy (DR; 153 NPDR and 138 PDR) were obtained from BioVU, Vanderbilt University's electronic, deidentified DNA databank. An independent cohort of Caucasian patients with DR (44 NPDR and 57 PDR) from the Vanderbilt Eye Institute (VEI) was used for validation. We tested for an association between mitochondrial haplogroups and PDR among patients with DR.
RESULTS - In the BioVU cohort, PDR frequency among Caucasian DR patients differed significantly by mitochondrial haplogroup (P = 0.027). Replication in the VEI cohort confirmed this association (P = 0.0064). In the combined cohort, patients from the common haplogroup H were more likely to have PDR (odds ratio [OR] = 2.0 [95% confidence interval (CI) = 1.3-3.0], P = 0.0012), while patients from haplogroup Uk were less likely to have PDR (OR = 0.5 [95% CI = 0.3-0.8], P = 0.0049). In logistic regression analyses, the addition of diabetes duration, hemoglobin A1c (HgbA1c) levels, and hypertension had no effect on the associations of haplogroups H and Uk with PDR.
CONCLUSIONS - In this study, DR patients from mitochondrial haplogroup H were more likely to have PDR, while DR patients from haplogroup Uk were less likely to have PDR. The association was independent of the major clinical variables affecting PDR. The mitochondrial haplogroups were as strong a risk factor for PDR as were elevated HgbA1c levels.
Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
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16 MeSH Terms
Automated detection of microaneurysms using scale-adapted blob analysis and semi-supervised learning.
Adal KM, Sidibé D, Ali S, Chaum E, Karnowski TP, Mériaudeau F
(2014) Comput Methods Programs Biomed 114: 1-10
MeSH Terms: Aneurysm, Automation, Diabetic Retinopathy, Fundus Oculi, Humans, Learning
Show Abstract · Added June 11, 2018
Despite several attempts, automated detection of microaneurysm (MA) from digital fundus images still remains to be an open issue. This is due to the subtle nature of MAs against the surrounding tissues. In this paper, the microaneurysm detection problem is modeled as finding interest regions or blobs from an image and an automatic local-scale selection technique is presented. Several scale-adapted region descriptors are introduced to characterize these blob regions. A semi-supervised based learning approach, which requires few manually annotated learning examples, is also proposed to train a classifier which can detect true MAs. The developed system is built using only few manually labeled and a large number of unlabeled retinal color fundus images. The performance of the overall system is evaluated on Retinopathy Online Challenge (ROC) competition database. A competition performance measure (CPM) of 0.364 shows the competitiveness of the proposed system against state-of-the art techniques as well as the applicability of the proposed features to analyze fundus images.
Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
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MeSH Terms
Retina image analysis and ocular telehealth: the Oak Ridge National Laboratory-Hamilton Eye Institute case study.
Karnowski TP, Giancardo L, Li Y, Tobin KW, Chaum E
(2013) Conf Proc IEEE Eng Med Biol Soc 2013: 7140-3
MeSH Terms: Academies and Institutes, Algorithms, Automation, Databases, Factual, Diabetic Retinopathy, Eye Diseases, Humans, Optic Nerve, Retina, Telemedicine
Show Abstract · Added June 11, 2018
Automated retina image analysis has reached a high level of maturity in recent years, and thus the question of how validation is performed in these systems is beginning to grow in importance. One application of retina image analysis is in telemedicine, where an automated system could enable the automated detection of diabetic retinopathy and other eye diseases as a low-cost method for broad-based screening. In this work, we discuss our experiences in developing a telemedical network for retina image analysis, including our progression from a manual diagnosis network to a more fully automated one. We pay special attention to how validations of our algorithm steps are performed, both using data from the telemedicine network and other public databases.
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Statistical atlas based exudate segmentation.
Ali S, Sidibé D, Adal KM, Giancardo L, Chaum E, Karnowski TP, Mériaudeau F
(2013) Comput Med Imaging Graph 37: 358-68
MeSH Terms: Anatomic Landmarks, Atlases as Topic, Diabetic Retinopathy, Exudates and Transudates, Humans, Macular Edema, Models, Statistical, United States
Show Abstract · Added June 11, 2018
Diabetic macular edema (DME) is characterized by hard exudates. In this article, we propose a novel statistical atlas based method for segmentation of such exudates. Any test fundus image is first warped on the atlas co-ordinate and then a distance map is obtained with the mean atlas image. This leaves behind the candidate lesions. Post-processing schemes are introduced for final segmentation of the exudate. Experiments with the publicly available HEI-MED data-set shows good performance of the method. A lesion localization fraction of 82.5% at 35% of non-lesion localization fraction on the FROC curve is obtained. The method is also compared to few most recent reference methods.
Copyright © 2013 Elsevier Ltd. All rights reserved.
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MeSH Terms
Telemedicine and retinal imaging for improving diabetic retinopathy evaluation.
Garg S, Jani PD, Kshirsagar AV, King B, Chaum E
(2012) Arch Intern Med 172: 1677-8
MeSH Terms: Diabetic Retinopathy, Female, Humans, Male, Middle Aged, Retina, Telemedicine
Added June 11, 2018
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MeSH Terms
Genetics and diabetic retinopathy.
Schwartz SG, Brantley MA, Flynn HW
(2013) Curr Diabetes Rev 9: 86-92
MeSH Terms: Blindness, Diabetic Retinopathy, Disease Progression, Eye Proteins, Female, Genetic Predisposition to Disease, Glycation End Products, Advanced, Humans, Insulin-Like Growth Factor I, Male, Nerve Growth Factors, Protein Kinase C, Risk Factors, Serpins, Vascular Endothelial Growth Factor A
Show Abstract · Added February 23, 2017
There are many reasons to suspect a genetic influence on the development and progression of diabetic retinopathy, including substantial variability in disease severity among patients with similar risk factors. Linkage studies have suggested associations with chromosomes 1, 3, 12 and others. The most studied individual genes are those encoding vascular endothelial growth factor, aldose reductase, and the receptor for advanced glycation end products, all of which have shown statistically significant associations in multiple series from various parts of the world. At this time, no definite genetic associations with diabetic retinopathy have been consistently reported. This may be due to small sample sizes, differences in study design, underlying genetic differences between study populations, or other factors. As we continue to collect data, these relationships may become more clear.
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15 MeSH Terms