Early Retinal Changes Research Articles

Colour vision losses in diabetes in the absence of proliferative retinopathy

AbstractPurpose There are over 30 published studies evaluating colour vision in diabetes. The evidence is, however, not consistent – the predictive accuracy of the studies does not support the use of colour vision as a screening test for diabetic retinopathy (Health Technol Assess, 13 (60), 2009). The CAD colour vision test (Expert Rev.Ophthalmol. 6(4):409‐420, 2011) addresses some of the major flaws in clinical colour testing. This poster reports the application of the CAD test to 214 diabetic patients.Methods A consecutive series of diabetics attending a diabetes center in Abu Dhabi were invited to participate in the study. Inclusion criteria were a best corrected visual acuity of 6/18 or better, no more than moderate non‐proliferative retinopathy or moderate maculopathy and no co‐existing glaucoma. Patients had a full eye examination (including colour photography and macular OCT), a full assessment of their diabetes and the CAD colour test.Results Age‐corrected binocular colour threshold limits were employed to screen for normal colour vision. Abnormal colour vision was noted in 80% of Arab and 67% of non Arabs. This did not correlate with duration of diabetes, age, HBA1C, body mass index, visual acuity or central retinal thickness.Conclusion Colour vision is abnormal in the large majority of the study population. The severity of colour vision loss is not correlated with age or gender of the patients, duration or severity of diabetes, current diabetic control, or central macular thickness. These findings suggest the existence of early retinal changes in diabetes that affect specifically colour vision and occur independently of factors such as those causing macula edema.

Structure/Function Studies and the Effects of Memantine in Monkeys with Experimental Glaucoma

Purpose. The scanning laser polarimetry with variable corneal compensation (GDx VCC) methodology was established and verified in monkeys with experimental glaucoma (ExpG). Terminal GDx parameters were correlated with axon counts and electrophysiologic measures. The effects of memantine on these parameters were investigated. Methods. ExpG was induced in monkeys and intraocular pressure monitored weekly. Some monkeys received memantine in their diet before and after ExpG induction (1-10 months). GDx VCC scans, stereophotographs, and multifocal visual evoked potential (mfVEP) data were collected at baseline and every 6 to 8 weeks until euthanasia. Optic nerves were prepared for axon counting and other morphologic analysis. Results. There was no difference in IOP elevation exposure between memantine-treated and no-memantine-treated monkeys. The percentage of the optic nerve area composed of connective tissue septa was significantly greater in ExpG eyes than in Fellow eyes. There was a strong positive correlation between axon counts and terminal GDx parameter measures. Animals not receiving memantine exhibited significantly lower mfVEP amplitudes in ExpG eyes compared with the ipsilateral baseline or the final value in the Fellow eye. ExpG eyes from memantine-treated animals had higher overall mean amplitudes that were not significantly different relative to the ipsilateral baseline and final amplitudes in the Fellow eye. Conclusions. The authors' studies confirm that GDx VCC can be utilized in monkey ExpG studies to detect early retinal structural changes and that these changes are highly correlated with optic nerve axon counts. These structural changes may or may not lead to central functional changes as shown by the mfVEP in response to investigational therapies.

Early Retinal Arteriolar Changes and Peripheral Neuropathy in Diabetes

OBJECTIVETo examine the association between early retinal arteriolar abnormalities and diabetic peripheral neuropathy (DPN).RESEARCH DESIGN AND METHODSData from 608 people (aged 40–80 years) with diabetes from the population-based Singapore Malay Eye Study were analyzed. Participants underwent binocular two-field digital retinal photography and quantitative sensory testing. DPN was defined as an abnormal response to a monofilament or neurothesiometer test. Quantitative changes of retinal vascular caliber and arteriolar bifurcation geometry were measured using a computer-based program. Qualitative retinal signs of retinopathy and retinal arteriolar wall signs were graded by standardized methods.RESULTSDPN was present in 155 people (25.5%). After adjusting for age, sex, diabetes duration, HbA1c, cardiovascular risk factors, antihypertensive medication use, and peripheral arterial disease, people with suboptimal arteriolar caliber (odds ratio 1.94 [95% CI 1.22–3.10]), larger arteriolar branching coefficient (1.58 [1.03–2.42]), diabetic retinopathy (1.82 [1.20–2.75]), and focal arteriolar narrowing (2.92 [1.48–5.76]) were more likely to have DPN. Participants with a greater number of retinal microvascular signs were more likely to have DPN than those without retinal changes (6.11 [2.11–17.71] for two or more signs and 3.47 [1.18–10.21] for one sign compared with none).CONCLUSIONSIndividuals with diabetes with early retinal arteriolar abnormalities are more likely to have DPN, independent of hyperglycemia and major vascular risk factors. These data support the hypothesis that early microvascular dysfunction, evident in the retina, is an independent risk factor for DPN.

Eriodictyol prevents early retinal and plasma abnormalities in streptozotocin-induced diabetic rats

Diabetic retinopathy is a complex disease that has potential involvement of inflammatory and oxidative stress-related pathways in its pathogenesis. We hypothesized that eriodictyol, one of the most abundant dietary flavonoids, could be effective against diabetic retinopathy, which involves significant oxidative stress and inflammation. The aim of the present study was to investigate the effects of eriodictyol in early retinal and plasma changes of streptozotocin-induced diabetic rats. The effect of eriodictyol treatment (0.1, 1, 10mg/kg daily for 10 days) was evaluated by TNF-α, ICAM-1, VEGF, and eNOS protein levels measurement in the retina, plasma lipid peroxidation, and blood–retinal barrier (BRB) integrity. Increased amounts of cytokines, adhesion molecule, and nitric oxide synthase were observed in retina from diabetic rats. Eriodictyol treatment significantly lowered retinal TNF-α, ICAM-1, VEGF, and eNOS in a dose-dependent manner. Further, treatment with eriodictyol significantly suppressed diabetes-related lipid peroxidation, as well as the BRB breakdown. These data demonstrated that eriodictyol attenuates the degree of retinal inflammation and plasma lipid peroxidation preserving the BRB in early diabetic rats.

The pathogenesis of early retinal changes of diabetic retinopathy

Recent successful trials of antibodies to vascular endothelial growth factor (VEGF) in diabetic retinopathy implicate this cytokine as a major cause of diabetic retinopathy (DR) and diabetic macular oedema (DME). The mechanisms which cause VEGF to be over-expressed to cause the vasculopathy are not entirely clear. This review explores the earliest changes to the retina in DR and the factors that predispose or prevent DR, including sleep apnoea, receptor degenerations laser treatment and VEGF polymorphism. The review also presents the evidence that retinal hypoxia, existing in the earliest stages, causes DR. This hypoxia is much increased by dark adaptation, indicating a new and possibly superior therapy.

Luminance-modulated adaptation in the global flash mfERG: a preliminary study of early retinal functional changes in high-risk glaucoma patients

To investigate the association of the luminance-modulation global flash multifocal electroretinogram (mfERG) and other clinical assessments of vision in subsets of subjects at high risk of developing glaucomatous damage. Eighteen subjects (28 eyes) with asymmetric glaucoma and ocular hypertension were measured in this longitudinal study of visual field, OCT, and multifocal electroretinogram (mfERG). Five ophthalmic examinations were scheduled, once every 12months over a 4-year period. The mfERG was assessed using a luminance-modulated global flash stimulation paradigm. The adaptive index which we have reported previously was calculated. There was a significant thinning of the peripapillary retinal nerve fiber layer over the course of the study for eyes with ocular hypertension, or for fellow eyes with asymmetric glaucoma which initially had an abnormal adaptive index; such eyes showed a thinning rate of -3.59 and -3.69μm/year, respectively. However, no significant thinning was found for eyes which initially had a normal adaptive index. Two subjects were shown to have glaucomatous damage, confirmed by abnormal thinning of the retinal nerve fiber layer and visual field loss respectively at the last visit. However, these patients had shown an abnormal adaptive index in the mfERG measurement at the first visit. The adaptive index calculated from the measurement of luminance-modulated global flash mfERG is useful for predicting progression of signs related to glaucoma, especially in high-risk groups. The abnormal adaptive index reflects the change in fast-adaptive mechanisms in the retina and indicates the risk of developing glaucoma.

Myopia-Related Optic Disc and Retinal Changes in Adolescent Children from Singapore

To examine early myopia-related optic disc and retinal changes in a Singapore Chinese adolescent sample without confounding ocular or systemic disease. Population-based cross-sectional study. Children aged 12 to 16 years at a follow-up visit for Singapore Cohort Study of Risk Factors for Myopia. Detailed eye examinations, including cycloplegic autorefraction and contact biometry, were performed. Retinal photographs were acquired using nonmydriatic retinal photography among children who attended follow-up examinations in 2006, and were graded for myopia-related optic disc signs and macular changes by a single experienced grader. Optic nerve head parameters were measured adjusting for camera and ocular magnification with appropriate formulae. Optic disc changes (tilt, beta peripapillary atrophy [β-PPA], and optic nerve parameters) and macular changes (staphyloma, lacquer cracks, Fuchs' spot, and chorioretinal atrophy). Retinal photography data were available for 1227 children (median age, 14 years; range 12-16). Tilted optic discs were found in 454 subjects (37%), and were associated with myopic spherical equivalent refractions (-3.6 diopters [D] vs -1.3 D; P<0.0001), higher cylindrical error (0.9 vs 0.7 D; P = 0.0001) and longer axial length (24.93 vs 23.96 mm; P<0.0001). The pattern of distribution of the axes of the tilted discs and corneal curvature were similar (P = 0.4). All linear optic nerve parameters, except vertical disc diameter (P = 0.15), were significantly smaller in eyes with than without tilted discs (P <0.001) after adjusting for confounders. Apart from 20 cases, all eyes with tilted optic discs had associated β-PPA. We identified only 1 case each (0.1% prevalence) of staphyloma and lacquer cracks in this sample. In this Asian adolescent population, tilted optic discs were highly prevalent, in contrast with the lower prevalence reported in Caucasian populations. Eyes with tilted discs tended to have smaller optic cups with smaller cup-to-disc ratios, and were associated with myopic refraction, higher astigmatism, and longer axial length. There were similar patterns of distribution between the axis of disc tilt and the axis of corneal curvature, which could have embryologic origins. In contrast with optic disc changes, myopic macular changes were rare in this age group, suggesting that these changes may develop later in life. The authors have no proprietary or commercial interest in any of the materials discussed in this article.

The relationship of body fatness indices and retinal vascular caliber in children

To examine the association between body fatness indices and retinal vascular calibre in Singapore Chinese children. We recruited 136 Singapore Chinese children aged 6-16 years from the STARS (The Strabismus, Amblyopia and Refractive Error Study in Singaporean Chinese Preschoolers) Family study in 2008-2010. Anthropometric measurements including weight, height and triceps skinfold (TSF) and right eye retinal photographs were performed. TSF was measured with Holtain-Tanner calliper on the back of the arm and midway between the point of the acromoion and olecranon process while the arm was hanging relaxed. TSF and BMI threshold (cut-off points for overweight and obesity) were defined as 85th and above of age- and gender-specific TSF and BMI standard charts which were based on American representative survey data. The mean retinal arteriolar and venular calibres were 155.78 ? 15.02 ?m and 219.66 ? 21.88 ?m, respectively in the STARS Family study. Each standard deviation (SD) increase in TSF (4.49 mm) and BMI (3.52 kg/m(2)) was associated with a 2.94 ?m (p = 0.012) and a 3.40 ?m (p = 0.005) widening in retinal venular calibre, respectively. Compared with children with TSF and BMI below threshold, children with TSF and BMI above threshold had a 10.21 ?m (p = 0.001) and a 9.33 ?m (p = 0.021) increase in retinal venular calibre, respectively. Greater TSF and BMI are associated with wider retinal venular calibre in healthy children aged 6 years and above. These findings suggest a possible effect of abnormal body fatness indices on early retinal vascular changes that reflect microvasculature in children.

Early histological alteration of the retina following photocoagulation treatment in diabetic retinopathy as measured by spectral-domain optical coherence tomography

Dear Editor, We read with great interest the article by Kang et al. [1]. The study provides insight into the early retinal changes following laser photocoagulation treatment in diabetic retinopathy. As ophthalmopathologists, however, we are concerned about the terminology used by the authors. Spectral-domain optical coherence tomography (SD-OCT) is — unquestionably — a fantastic diagnostic tool that enables ophthalmologists to detect delicate retinal structures and to follow structural changes in retinal diseases at exactly the same localization over time. However, a SD-OCT does not provide a histological section of the retina. Histology (compound of the Greek words: tissue, and λογία doctrine, theory, science) is the study of the microscopic anatomy of tissue and other structures. Modern pathology comprises different techniques for tissue processing, and different stains are available to highlight certain structures. In contrast, SD-OCT records the reflectivity of retinal tissue layers and generates high resolution images of — amongst others — retinal structures, and thus information that correlates in part with histological findings. But not all SDOCT findings can be unequivocally transferred to anatomical structures, as many still-ongoing discussions about the interpretation in various retinal diseases and their possible histopathological correlations show. Therefore, we suggest reserving the terms “histology” and “histological” for the microscopic investigation, and avoiding terms like “in vivo histology” for SD-OCT examination in order to prevent confusion. Instead, the term “in vivo visualization of the retinal microstructure” could be employed.

Effects of Topical Nipradilol on Early Diabetic Retinopathy in SDT Rats

We tested the effect of topical nipradilol, an antiglaucoma drug with α- and β-blocker and nitric oxide (NO) donor activities, on the early retinal changes using electron microscopy in Spontaneously Diabetic Torii (SDT) rats. In seven young male SDT rats (17 to 18 weeks old), nipradilol solution was instilled in the right eyes and nipradilol-free base solution in the left eyes three times daily for 3 months. All rats were sacrificed and both eyes were enucleated for electron microscopy at the end of the experiments. All rats had blood glucose levels exceeding 350 mg/dl within 2 weeks after the beginning of the experiment (mean final blood glucose level, 558±100.2 mg/dl). In untreated eyes of young SDT rats, the overall pathological features were almost comparable to those in older SDT rats, although the pinocytotic vesicles and free ribosomes were not as remarkable in the latter. In contrast, in nipradilol-treated eyes of SDT rats, although the basement membrane was thickened, microvilli were seen, and a larger number of electron-dense mitochondria were in the wide cytoplasm. Lipofuscin-like electron-dense granules and lamellated myelin figures also were identified. Nipradilol reduced the early morphologic changes in the endothelial cells, which reflects the metabolically active state of diabetic retinopathy in SDT rats through its action as a NO donor.

Modulation of retinal blood flow by kinin B 1 receptor in Streptozotocin-diabetic rats

The vasoactive kinin B 1 receptor (B 1R) is overexpressed in the retina of diabetic rats in response to hyperglycemia and oxidative stress. The aim of the present study was to determine whether B 1R could contribute to the early retinal blood flow changes occurring in diabetes. Male Wistar rats were rendered diabetic with a single i.p. injection of Streptozotocin (STZ) and studied 4 days or 6 weeks after diabetes induction. The presence of B 1R in the retina was confirmed by Western blot. The impact of oral administration of the B 1R selective antagonist SSR240612 (10 mg/kg) was measured on alteration of retinal perfusion in awake diabetic rats by quantitative autoradiography. Data showed that B 1R was upregulated in the STZ-diabetic retina at 4 days and 6 weeks. Retinal blood flow was not altered in 4-day diabetic rats compared with age-matched controls but was significantly decreased following SSR240612 treatment. In 6-week diabetic rats, retinal blood flow was markedly reduced compared to control rats and SSR240612 did not further decrease the blood flow. These results suggest that B 1R is upregulated in STZ-diabetic retina and has a protective compensatory role on retinal microcirculation at 4 days but not at 6 weeks following diabetes induction.

Retinal functional changes measured by frequency-doubling technology in patients treated with hydroxychloroquine

Antimalarial drugs such as chloroquine (CQ) and hydroxychloroquine (HCQ) are mainly used in the treatment of rheumatologic diseases, and their use may be associated with irreversible retinal toxicity. Previous studies indicate early paracentral visual field loss (Humphrey 10-2) in patients taking HCQ". These paracentral defects appear before changes in other clinical parameters as visual acuity and fundoscopy. The mechanism of CQ toxicity remains unclear. It was reported that toxic doses of CQ administered for as long as 4.5 years to Rhesus monkeys caused an initial dramatic effect on ganglion cells, followed later by photoreceptors and RPE degeneration. The purpose of this study is to explore early retinal functional changes measured by frequency-doubling technology (FDT) in patients treated with hydroxychloroquine (HCQ). Forty-eight eyes of 48 subjects treated with hydroxychloroquine (HCQ), with no signs of retinal toxicity, and 36 eyes of 36 age and sex-matched healthy subjects were enrolled in this cross-sectional, prospective, observational, case control study. Functional testing included frequency-doubling Humphrey-matrix perimetry (FDP), white-on-white Humphrey visual field perimetry (HFA), using the 24-2 and 10-2 threshold programs, multifocal electroretinogram (mfERG, Veris 4.9) and low contrast sensitivity (CS) measurement. FDP mean deviation (MD) was found to be significantly reduced in HCQ-treated patients compared to controls both in the 24-2 (-1.38 ± 2.41 dB vs 0.21 ± 1.83 dB, p < 0.01) and in the 10-2 program (-0.97 ± 2.88 dB vs 0.15 ± 1.72 dB, p < 0.01). FDP pattern standard deviation (PSD) was found to be significantly worse in HCQ-treated patients compared to controls both in the 24-2 (2.70 ± 0.65 dB vs 2.41 ± 0.31 dB, p < 0.01 and in the 10-2 program (2.86 ± 0.48 dB vs 2.48 ± 0.39 dB, p < 0.01). HFA PSD and CS was also significantly reduced in HCQ patients, while response amplitude densities (RAD) were similar between patients and controls. A statistically significant difference in the ratio of the 5°-10° RAD and the 0°-2.5° RAD (0.31 ± 0.08 vs 0.36 ± 0.07 respectively, p < 0.05) was found between groups. Frequency doubling perimetry could be useful to detect early retinal impairment in patients treated with hydroxychloroquine.

Hyperviscosity syndrome associated with systemic plasmacytosis

Systemic plasmacytosis is characterized by plasma cell proliferation in multiple organs including skin, and by polyclonal hypergammaglobulinaemia. Hyperviscosity-related retinopathy has never been described with this condition, to our knowledge. We report a case of systemic plasmacytosis in a 49-year-old Japanese woman, who presented with fever, multiple erythematous plaques, hypergammaglobulinaemia, renal failure and bilateral retinal haemorrhage. Reduction of immunoglobulin with oral steroid reversed the retinopathy related to hyperviscosity syndrome. When marked hypergammaglobulinaemia is found in a patient with systemic plasmacytosis, funduscopic examination should be performed to reveal early asymptomatic retinal changes, because the retinopathy is treatable by control of the underlying disease.

Cytotoxic role of methylglyoxal in rat retinal pericytes: Involvement of a nuclear factor-kappaB and inducible nitric oxide synthase pathway

Methylglyoxal (MGO), a cytotoxic metabolite, is produced from glycolysis. Elevated levels of MGO are observed in a number of diabetic complications, including retinopathy, nephropathy and cardiomyopathy. Loss of retinal pericyte, a hallmark of early diabetic retinal changes, leads to the development of formation of microaneurysms, retinal hemorrhages and neovasculization. Herein, we evaluated the cytotoxic role of MGO in retinal pericytes and further investigated the signaling pathway leading to cell death. Rat primary retinal pericytes were exposed to 400 μM MGO for 6 h. Retinal vessels were prepared from intravitreally MGO-injected rat eyes. We demonstrated apoptosis, nuclear factor-kappaB (NF-κB) activation and inducible nitric oxide synthase (iNOS) induction in cultured pericytes treated with MGO and MGO-injected retinal vessels. In MGO-treated pericytes, TUNEL-positive nuclei were markedly increased, and NF-κB was translocalized into the nuclei of pericytes, which paralleled the expression of iNOS. The treatment of pyrrolidine dithiocarbamate (an NF-κB inhibitor) or l-N6-(1-iminoethyl)-lysine (an iNOS inhibitor) prevented apoptosis of MGO-treated pericytes. In addition, in intravitreally MGO-injected rat eyes, TUNEL and caspase-3-positive pericytes were significantly increased, and activated NF-κB and iNOS were highly expressed. These results suggest that the increased expression of NF-κB and iNOS caused by MGO is involved in rat retinal pericyte apoptosis.

Optical Coherence Tomography for Complete Management of Patients with Diabetic Retinopathy

Diabetic retinopathy is a major complication of patients with diabetes mellitus and can lead to a decrease in vision. The precise mechanisms leading to the development of diabetic retinopathy and the progressive decrease of vision are still undetermined. Recent studies have shown that not only vascular but also neuronal abnormalities are associated with the pathogenesis of diabetic retinopathy. Because neuronal cell death leads to an irreversible decrease in visual function, early changes in the morphology and physiology of the neural retinas of diabetic patients are important. The alterations of the morphology of the retina can be obtained by high-resolution B-scan optical coherence tomography (OCT). The thickness of the macular area and retinal nerve fiber layer can be measured reliably and accurately by the installed software of OCT instruments. The high-resolution images can be used to evaluate diabetic macular edema and optic nerve damage quantitatively in patients with diabetic retinopathy. This review describes how the OCT measurements can be used to manage patients with diabetic retinopathy. We also present the early retinal changes involved in the pathogenesis of diabetic retinopathy.

OCT is not useful for detection of minimal diabetic retinopathy in type 1 diabetes

Optical coherence tomography (OCT) has been proven useful in measuring retinal thickness (RT) in patients with diabetes, although with discordant results in different studies. We examined RT in patients with type 1 diabetes (T1D) with or without minimal diabetic retinopathy (MDR) to test whether OCT is able to identify early retinal changes and potential correlations with metabolic parameters. RT of 102 patients with T1D (53 females, 49 males, aged 27.03 +/- 7.4 years) and of 42 healthy controls was examined, with analysis of nine different sectors (fovea, four pericentral and four peripheral sectors). According to the results of basal fundus photography, patients were divided into two groups, without MDR (48 cases) and with MDR (54 cases). Patients with proliferative DR or macular edema were excluded. No difference was found between patients with or without MDR and the control group for all OCT parameters investigated. Mean HbA1c of the last 5 years (P < 0.001), microalbuminuria (P = 0.002), total (P = 0.046) and LDL cholesterol (P = 0.007) and triglyceride (P < 0.001) levels were higher in patients with MDR, along with higher prevalence of hypertension (P = 0.013), younger age at diagnosis (P = 0.018) and longer diabetes duration (P < 0.001) with regard to the patients without MDR and controls, although no significant correlation between these parameters and RT was found. Our study suggests that MDR without macular edema in patients with T1D cannot be detected with OCT. Therefore, the conventional diagnostic methods are mandatory to detect early DR.

Evidence of Early Retinal Microvascular Changes in Patients With Type 2 Diabetes and Depression

To examine retinal vascular caliber, an indicator of early microvascular disease and depression in patients with Type 2 diabetes. We conducted a clinic-based study, comparing participants with Type 2 diabetes with major depression (n = 43), without depression (n = 49), and healthy controls without diabetes or depression (n = 54). Retinal vascular caliber was measured from digital photographs. Depression status was determined, using standardized clinical assessment. After adjusting for age and gender, participants with diabetes and depression had larger arteriolar and venular calibers (147.7 microm for arteriolar and 215.7 microm for venular calibers) than participants with diabetes but without depression (143.3 microm and 213.9 microm) and healthy controls (135.8 microm and 202.5 microm, p for trend = .002 for arteriolar and p = .02 for venular caliber). In multivariate models adjusting for duration of diabetes, systolic blood pressure, cigarette smoking, serum glucose, Cerebrovascular Risk Factor Scale, Cumulative Illness Rating Scale, and retinopathy levels, this relationship remained significant for retinal arterioles (p = .02) but not for retinal venules (p = .10). These data show that patients with Type 2 diabetes with major depression have wider retinal arterioles, supporting the concept that depression is associated with early microvascular changes in Type 2 diabetes.

Exogenous SOD Mimetic Tempol Ameliorates the Early Retinal Changes Reestablishing the Redox Status in Diabetic Hypertensive Rats

The purpose of this study was to investigate the efficacy of tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), a superoxide dismutase mimetic, in preventing early retinal molecular changes in a model that combines hypertension and diabetes. Four-week-old spontaneously hypertensive rats (SHR) were rendered diabetic by streptozotocin. Diabetic SHR rats (DM-SHR) were randomized to receive or not receive tempol treatment. After 20 days of induction of diabetes, the rats were euthanatized, and their retinas were collected. The early molecular markers of diabetic retinopathy (DR), glial fibrillary acidic protein, and fibronectin were evaluated by Western blot assays and showed an increase in DM-SHR compared with the SHR group. The oxidative balance, evaluated by superoxide production and nitric oxide end product levels estimated by a nitric oxide analyzer, and the counterpart antioxidative defense revealed an accentuated imbalance in DM-SHR compared with the SHR group. As a result, the product peroxynitrite, which was detected by immunohistochemistry for nitrotyrosine, was higher in the DM-SHR group. The retinal poly-ADP-ribose (PAR)-modified proteins, which reflect the activation of PAR polymerase (PARP), and the inducible nitric oxide synthase (iNOS) expressions were found to have increased in this group. Treatment with tempol reestablished the oxidative parameters and decreased the PAR-modified proteins, thus preventing extracellular matrix accumulation and glial reaction. The administration of tempol prevented oxidative damage, decreased iNOS levels, and ameliorated the activation of PARP in the retinas of diabetic hypertensive rats. Consequently, the early molecular markers of DR, such as glial reaction (glial fibrillary acidic protein [GFAP]) and extracellular matrix accumulation (fibronectin), were prevented in tempol-treated rats.

Diabetic retinopathy ‐ Apoptosis and BRB breakdown prevention in early diabetic retinopathy

Abstract Purpose Diabetic retinopathy (DR) is complex multifactorial neurovascular degenerative complication of systemic disease with evidence of inflammation/oxidative stress induced by hyperglycemia leading to early retinal cell apoptosis and BRB breakdown confirmed in STZ diabetic rats. Erythropoietin (EPO,40.3kDa) multifuctional protein approved drug for anemia has confirmed antiapoptotic effects in retinal cell cultures, various models of stress: ischaemia, reperfusion,glaucoma,diabetes: rats, mice, rabbits. It is upregulated in the retina in prolipherative DR. We studied EPO serum levels in diabetics with and without retinopathy comparing to non diabetic controls. Methods In 60 type 2 diabetics, 26 with and 34 without retinopathy of both sexes and age of 64.24 ± 11.64 years EPO serum was determined (mIu/ml) by ELISA and compared to 44 non diabetics, age and sex matched controls. Student t test was used. Results EPO serum levels were high in retinopathy patients 15±11.14 vs 9.47±6.57 in controls p=0.043. Intermediary levels in diabetics without retinopathy 10.84±6.11. Conclusion High EPO serum expression in diabetic retinopathy supports endogenous overproduction by Hif‐1?, as protective mechanism of BRB breakdown and vascular/neuronal cell apoptosis demonstrated in STZ diabetic rats. Intravitreal EPO prevented all early diabetic retinal changes by activation of Erk 1/2 pathway. Antioxidant/inflamatory related molecules earlier studied, TMR, Haptoglobin, ACP, MHR and EpOx give additional support to this hypothesis. These proteins are related to EPO and ACE activity. EPO besides retinopathy preventive is angiogenic with viscosity effects. EPO derivative carbamylated forms which do not raise hematocrit have been developed.

Retinal changes and cardiac remodelling in systemic hypertension

The clinical value of left ventricular hypertrophy (LVH), a cardinal manifestation of hypertensive organ damage, in predicting cardiovascular (CV) events, independently of blood pressure (BP) and other accompanying risk factors, has been widely documented and its role in CV stratification indisputability recognized. Although the examination of the fundus oculi provides a unique opportunity to evaluate retinal microvascular abnormalities, which may mirror systemic arteriolar damage due to high BP, no consistent evidence exists, on the prognostic value of mild degrees of retinopathy, encompassing the vast majority of uncomplicated hypertensive subjects. Personal and literature data indicate that: (1) there is a tight association between advanced retinopathy and LVH suggesting the existence of a parallel involvement of retinal tree and cardiac damage in severe untreated or poorly controlled hypertension; (2) in contrast, a firm conclusion about the relationship between early or nonspecific retinal changes (narrowing or arteriovenous crossing) and cardiac damage is not allowed by the majority of the studies; (3) future investigations, based on computer-assisted methods, are further required to document the relation between initial retinal changes with organ damage and more importantly to test their predictive value for clinical outcomes.