Biomedical subjects
Publications and source records attributed to E M Kohner.
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AIMS/HYPOTHESIS: To determine whether microaneurysms, in the absence of other lesions, have a predictive role in the progression of diabetic retinopathy in Type II (non-insulin-dependent) diabetes mellitus. METHODS: Retinal photographs taken at diagnosis in patients participating in the United Kingdom Prospective Diabetes Study, and thereafter at 3 yearly intervals, were assessed using a modified Early Treatment of Diabetic Retinopathy grading system for lesions of diabetic retinopathy and end points of vitreous haemorrhage and photocoagulation. The number of microaneurysms in each eye was recorded. RESULTS: The changes between diagnosis and later photographs were analysed in 2424 patients at 6 years, 1236 at 9 years and 414 at 12 years. Of the 2424 patients studied in the 6 year cohort 1809 had either no retinopathy or microaneurysms only at entry. In these patients the presence of microaneurysms alone and also the number of microaneurysms had a high predictive value for worsening retinopathy at 3, 6, 9, and 12 years after entry into the study (e. g. at 6 years chi(2) for trend = 75 on 1 df, p < 0.001). The predictive value of the presence or absence of microaneurysms and their number at 3 years from diagnosis and subsequent worsening retinopathy was similar to that at entry. CONCLUSION/INTERPRETATION: Microaneurysms are important lesions of diabetic retinopathy and even one or two microaneurysms in an eye should not be regarded as unimportant.
There is now increasing evidence suggesting that non-enzymatic glycation (NEG) of proteins is involved in the pathogenesis of chronic diabetic complication. In this study we demonstrate that chronic exposure to high-glucose concentration leads to intracellular protein glycation in cultured bovine retinal capillary pericytes and endothelial cells. The level of intracellular protein glycation, as measured using a competitive enzyme-linked immunoabsorbant assay (ELISA), was found to increase in both pericytes and endothelial cells as function of time. As expected products of NEG were only detected when the Schiff base and the Amadori products were chemically reduced to glucitollysine by sodium borohydride. Despite the accumulation of early glycation products on cellular proteins there was no further rearrangement reaction into advanced glycation endproducts (AGEs), even after 12 days of incubation in high-glucose medium. Immunofluorescence microscopy demonstrated that the monoclonal antibody reacting with glucitollysine stains the cytoplasm of both pericytes and endothelial cells in a finely punctate pattern. Further studies using Western blot analysis suggested that a number of cellular proteins, including smooth muscle actin in pericytes, become rapidly glycated. The results from this in vitro study suggest that excessive accumulation of early products of non-enzymatic glycation in pericytes and endothelial cells may play an important role in the pathogenesis of diabetic retinopathy.
OBJECTIVES: To report on the prevalence of retinopathy in patients with newly diagnosed non-insulin-dependent diabetes mellitus (NIDDM) and to evaluate the relationship of retinopathy to clinical and biochemical variables. DESIGN: A multicenter, randomized, controlled clinical study of therapy in patients with NIDDM. SETTING AND PATIENTS: Patients were part of the United Kingdom Prospective Diabetes Study, a 23-center study of 2964 white patients who had both eyes photographed and assessed. OUTCOME MEASURES: The presence and severity of diabetic retinopathy were evaluated by sex, and the relationship of retinopathy to medical and biochemical parameters was assessed. RESULTS: Retinopathy, defined as microaneurysms or worse lesions in at least 1 eye, was present in 39% of men and 35% of women. Marked retinopathy with cotton wool spots or intraretinal microvascular abnormalities was present in 8% of men and 4% of women. The severity of retinopathy was related in both sexes to higher fasting plasma glucose levels, higher systolic and diastolic blood pressure, lower serum insulin levels, and reduced beta-cell function. In addition, in men, increased alcohol consumption was related to increased severity of retinopathy, while leaner women had more severe eye lesions. Visual acuity was normal in most patients, but in men there was a trend for those with more severe retinal lesions to have worse visual acuity. CONCLUSIONS: Diabetic retinopathy is common in patients with newly diagnosed NIDDM. Careful ophthalmic assessment at diagnosis is important.
The effect of angiotensin-converting enzyme (ACE) inhibitors on the diabetic retinal circulation has not been studied previously. The aim of this study was to evaluate the effect of ACE inhibition and beta-blockade on retinal blood flow (RBF) in a group of 45 hypertensive diabetic subjects using a randomized double-blind trial over a period of 12 months. Laser Doppler velocimetry and computed image analysis were used to measure RBF. The changes in blood pressure over 12 months were comparable (perindopril [PE]: systolic [SBP] 152.1 +/- 3.3 and diastolic [DBP] 97.2 +/- 1.7 mm Hg to SBP 136.8 +/- 3.4 and DBP 85.8 +/- 2.1; atenolol: SBP 158.9 +/- 5.1 and DBP 97.5 +/- 1.6 mm Hg to SBP 137.9 +/- 3.4 and DBP 85.1 +/- 1.6; P = .607, mean +/- SEM). RBF decreased from 17.19 +/- 2.21 microL x min(-1) to 14.18 +/- 1.50 microL x min(-1) in the PE group (n = 15, P = .208) while it increased with atenolol from 15.80 +/- 1.24 microL x min(-1) to 16.99 +/- 1.18 microL x min(-1) (n = 17, P = .399). The comparison of percentage changes in RBF (PE -7.16% +/- 11.49%; atenolol, +15.31% +/- 9.51%) reached statistical significance (P < .05). There was an increase in RBF in 33.3% of subjects receiving PE and in 70.6% of those receiving atenolol. Similar trends were found for retinal conductance. There were no significant changes in the parameters of retinal vascular permeability. Albuminuria decreased to a greater degree with PE, but did not reach significance (PE, 112.1 +/- 39.5 mg/24 h to 88.6 +/- 30.5 mg/24 h; atenolol, 87.3 +/- 51.7 mg/24 h to 82.1 +/- 47.7 mg/24 h). This suggests that ACE inhibition therapy may promote a hemodynamic milieu in the hypertensive diabetic retinal circulation that serves to protect against the progression of diabetic retinopathy, whereas beta-blockade has the opposite effect.
OBJECTIVE: The authors studied the changes in retinal blood flow (RBF) and oxygen reactivity in a major temporal vein in patients with central retinal vein occlusion (CRVO). PARTICIPANTS: Eleven patients with nonischemic CRVO approximately 7 weeks from onset of disease. INTERVENTION: Laser Doppler velocimetric measurement of RBF and vessel reactivity to inhaling 60% oxygen. Measurements were performed at baseline and 3 months. RESULTS: Flow velocity in the affected eye had increased significantly by 3 months, from 1.6 +/- 0.4 cm/second to 2.0 +/- 0.4 cm/second (P = 0.02). Retinal blood flow, however, remained unchanged (13.7 +/- 5.8 microl/minute versus 15.0 +/- 6.5 microl/minute). The two comparable RBF values, despite differing velocity values, suggest that the relatively normal baseline value was achieved through higher intravascular pressure at baseline (Bernoulli's principle). This is supported by the fact that oxygen reactivity had improved from 2.1% +/- 3.6% at baseline to 3.8% +/- 3.1% (P = 0.001) at 3 months, which suggests an improved ability to respond to hyperoxia from reduced intravascular pressure. CONCLUSION: Intravascular pressure in CRVO appears to continue to decrease during the first 5 months after the onset of CRVO, indicating continuing reduction in the degree of outflow obstruction during this time.
AIMS: To assess the efficacy of isovolaemic haemodilution therapy (IHT) in the treatment of patients with branch retinal vein occlusion (BRVO). METHODS: Patients presenting with BRVO between 1 July 1991 and 31 August 1993 were eligible for inclusion and randomised into treatment and control groups. Patients randomised to receive IHT were treated for 6 weeks with venesection and volume replacement using hydroxyethylstarch, a plasma expander. The target haematocrit was 35%. Follow up was for 1 year. RESULTS: The baseline visual acuity of the two groups was similar at 0.74 and 0.75 logMAR units (Snellen 6/36), for the IHT and control groups, respectively. At 6 weeks, visual acuity in the IHT group had improved by 0.20 logMAR units (2 lines on the Bailey-Lovie chart) (p = 0.0001). Vision was unchanged in the control group. At 1 year, the IHT group exhibited an improvement of 0.43 logMAR units. By comparison, the improvement in the control group at 1 year was significantly less at 0.17 logMAR units (p = 0.03). The final visual acuity in the IHT and control groups was 0.30 (Snellen 6/12) and 0.60 (Snellen 6/24) logMAR units, respectively. CONCLUSIONS: The results support the theory that IHT has a positive effect on the visual outcome in patients with BRVO.
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The toxic effects of advanced glycation end products (AGEs) on bovine retinal capillary pericytes (BRP) and endothelial cells (BREC) were studied. AGE-modified bovine serum albumin (AGE-BSA) was toxic to BRP. At a concentration of 500 micrograms/ml it reduced the BRP number to 48 +/- 3% (p < 0.05) of untreated controls, as determined by cell counting with haemocytometer. AGE-BSA was also toxic to bovine aortic endothelial cells (BAEC) reducing cell number to 84 +/- 3.1% of untreated controls. Under similar conditions, low concentrations (62.5 micrograms/ml) of AGE-BSA were mitogenic to BREC increasing the cell proliferation to 156 +/- 11% (p < 0.05) above that of untreated controls. At a higher dose of 500 micrograms/ml AGE-BSA decreased the proliferation of BREC to 85 +/- 6% of untreated controls. Immunoblot analysis demonstrated that BRP and BREC express the p60 AGE-receptor. Retinal capillary bed from the human also stained positively for the p60 AGE-receptor. Addition of 0.25 micrograms/ml of p60 AGE-receptor antibody was able to block the effects of AGE-BSA on BRP and BREC. The level of binding of [125I]-labelled AGE-BSA to the cell surface was small but significant among the three cell types. There was also an increase in the internalized pool of radioligand in BRP and BREC but this was very much lower than in BAEC. In all the cell types the internalized pool of [125I]-labelled AGE-BSA was much larger than the amount associated with the cell surface. Degradation products were not detected in the media over the 24-h incubation of the cells with [125I]AGE-BSA. The binding of [125I]-labelled AGE-BSA to the cell surface was prevented by the addition of p60 AGE-receptor. These results suggest that the interaction of AGE-modified proteins with the membrane-bound AGE-receptor may play an important role in the pathogenesis of diabetic retinopathy.
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Autoregulation of blood flow in response to changes in perfusion pressure is known to occur in a number of tissues including the human retina. Defective autoregulation may play a part in the pathophysiology of several retinal diseases. Laser Doppler velocimetry has been used to study retinal blood flow. Technically superior measurements are obtained from veins by this method but arterial measurements might provide additional information. The response of the normal human retina to an acute elevation of systemic blood pressure induced by isometric exercise was investigated in nine normal volunteers using laser Doppler velocimetry and computer-assisted image analysis. Measurements were taken from retinal veins and arteries. Autoregulation was demonstrated by an 8.4% rise in flow in response to a 34% rise in perfusion pressure (P = 0.0007) using data derived from veins and a 4.8% rise in flow in response to a 33% rise in perfusion pressure (P = 0.01) using data derived from arteries. Arteries constricted by 3.4% (P = 0.002) and veins dilated by 1.6% (P = 0.02). Red cell velocity rose in veins by 5.0% (P = 0.008) and in arteries by 12.2% (P = 0.02). The variability in velocity change derived from veins (SD 3.4%) was lower than that from arteries (SD 12.1%). A similar pattern of flow change was found in both sets of data. This makes venous measurements more useful for obtaining statistically reliable results from these techniques.
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The temporal retina is larger than the nasal retina and contains the metabolically active fovea. The variation in the distribution of blood between the temporal and nasal retinal circulations was investigated in 15 healthy volunteers, and the autoregulatory capacity of the temporal and nasal circulations was quantitated using 60% oxygen in the inspired air. Retinal blood flow was determined from red cell velocity using laser Doppler velocimetry and retinal vessel diameter from retinal photographs using a digital image analysis system. Volume flow was lower in the nasal than the temporal circulation by 52.49% (p < 0.001). This is a consequence of both significantly smaller vessels (20.4%, p < 0.001) and slower blood velocity in the nasal circulation (24.64%, p = 0.003) compared with the temporal vessels. After breathing 60% oxygen for 10 minutes, there was significant vasoconstriction (temporal, 10.42 +/- 1.24%, p < 0.001; nasal, 7.66 +/- 1.48%, p < 0.001), slower red cell velocity (temporal, 27.10 +/- 3.92%, p < 0.001; nasal, 27.36 +/- 5.51%, p < 0.001) and a significant reduction in the volumetric flow rate (temporal, 41.16 +/- 3.64%, p < 0.001; nasal, 37.99 +/- 5.07%, p < 0.001). The reduction in the haemodynamic parameters was comparable in the temporal and nasal circulations, indicating similar autoregulatory capacity. Retinal vascular conductance was calculated from volume flow and retinal perfusion pressure. It was 53% larger in the temporal than the nasal circulations. This provides an index of the metabolic needs of the different regions of the retina.
BACKGROUND: Vascular endothelial growth factor (VEGF) has been shown to play a major role in intraocular neovascularisation in ischaemic retinal diseases. Subretinal neovascularisation is an important cause of central visual loss, but little is known about the role of this growth factor in its pathogenesis. The aim of this study was to investigate the possible role of VEGF in the development of subretinal neovascularisation. METHODS: Undiluted vitreous samples were obtained from patients undergoing vitrectomy for removal of non-age-related subfoveal neovascular membranes (SFNM). For comparison vitreous from patients undergoing vitrectomy for idiopathic full thickness macular holes (FTMH) and proliferative diabetic retinopathy (PDR) was used. Indirect enzyme linked immunosorbent assay (ELISA), with an antibody directed against the conserved N-terminal region of human VEGF165, was used to determine vitreous levels of VEGF. The growth factor was also localised in the vitreous of patients with SFNM by western blot analysis. RESULTS: The mean (SE) VEGF concentration in the vitreous of patients with SFNM was 27.78 (2.22) ng/ml (n = 8), FTMH was 16.62 (0.9) ng/ml (n = 18), and PDR was 37.77 (3.28) ng/ml (n = 16). The differences between the PDR group and SFNM group versus the FTMH group were both significant (p = 0.0001 and p = 0.0015) as analysed by the Wilcoxon rank sum test). CONCLUSIONS: Vitreous levels of VEGF are significantly elevated in eyes with non-age-related subretinal neovascularisation compared with eyes with FTMH but not as elevated as in PDR. This suggests that VEGF is involved in subretinal angiogenesis.
PURPOSE: Detection and precise quantification of changes in retinal vessel diameter by image analysis techniques is important in a number of fields of research. The retinal vessels have been shown to exhibit pulse related changes in diameter. These may need to be taken into account when studying diameter changes due to other causes. This study examined the effect of using multiple fundus photographs with and without electrocardiographic synchronisation on the size and statistical significance of changes in mean retinal vessel diameter. METHODS: Twelve fundus photographs spaced throughout the cardiac cycle by electrocardiographic synchronisation were taken in 10 normal volunteers: (a) at rest, (b) during isometric exercise, and (c) during oxygen inhalation. Vessel diameters were measured using a computer assisted image analysis system. Subsequently smaller sample sizes, with and without electrocardiograph synchronisation were modeled from the available data. RESULTS: With a group of ten subjects six or more electrocardiograph synchronised photographs enable reliable detection of small diameter changes (1.4%) induced by isometric exercises while other methods either failed to detect change or were unreliable at doing so. With six subjects twelve synchronised photographs were required to reliably detect a change of the same magnitude. Larger diameter changes (5.4%) were detected by any method including a single unsynchronised photograph. CONCLUSIONS: Multiple frame electrocardiograph synchronized fundus photography permits more accurate detection of small changes in retinal vessel diameter.
We present the methodology for 45 degrees retinal photography and detail the development, application and validation of a new system of 45 degrees field grading standards for the assessment of diabetic retinopathy. The systems were developed for the EURODIAB IDDM Complications Study, part of a European Community funded Concerted Action Programme into the epidemiology and prevention of diabetes (EURODIAB). Assessment of diabetic retinopathy was carried out centrally by a trained reader of colour retinal photographs using the newly-developed system. The system proved to be acceptably accurate, repeatable repeatable and relatively simple to apply. It compared well with the recognised 'gold standard' 7-field 30 degrees stereo photography (assessed using a modified Airlie House classification scheme), against which the new system was validated in a series of 48 eyes. Selection was as a stratified random sample based on clinical retinopathy status: 5, no retinopathy; 25, non-proliferative retinopathy; 16, proliferative or photocoagulated; plus 2, eyes with potentially confounding lesions (vein occlusion). Simple presence of retinal lesions was correctly detected by both systems in 43 of the 48 eyes, giving 100% agreement on detection. Both systems correctly identified the two known cases of confounding vein occlusion. In eyes with diabetic retinopathy (n = 41), when severity was expressed in three groups: mild background, moderate/severe background and proliferative/photocoagulated, at least one grader (out of five) using the new system matched the verified results in 38 out of 31 (93%) eyes and three or more graders matched in 31 (76%) eyes.(ABSTRACT TRUNCATED AT 250 WORDS)
Since the retinal vessels have no sympathetic innervation, blood flow in response to raised blood pressure is dependent on autoregulation. To determine the effect of hypertension on retinal haemodynamics and the autoregulatory capacity of the retinal circulation under conditions of normoglycaemia and hyperglycaemia, retinal blood flow was measured before and after raising the systemic blood pressure in ten normal control subjects, ten diabetic subjects with blood glucose < 10 mmol l-1 and ten diabetic subjects with blood glucose > 15 mmol l-1. A controlled rise in systemic blood pressure was achieved using an intravenous infusion of tyramine. Retinal volume flow was determined from red cell velocity using laser Doppler velocimetry and from retinal vessel diameter measurements using digital image analysis of fundus photographs. With a 40% increase in mean arterial blood pressure (MAP), there was a significant increase in retinal blood flow of 32.9 +/- 7.1% in non-diabetic controls. In diabetics at the low blood glucose level, the increase in retinal blood flow was significant at 30% increase in MAP (23.6 +/- 8.7%, P = 0.032) and at 40% increase (49.9 +/- 12.03%, P = 0.004). Diabetics with high blood glucose failed to autoregulate at any of the increased levels of MAP (15% increase, 27.0 +/- 11.1%; 30% increase, 66.9 +/- 19.8%; and 40% increase, 101.9 +/- 21.4%; P < 0.022). The coefficients of autoregulation showed that in non-diabetic controls, retinal vascular autoregulation broke down with increases in MAP of between 30 and 40%. In diabetic subjects, it broke down between 15 and 30% in normoglycaemia and at less than 15% in hyperglycaemia. This study demonstrates an impairment in retinal vascular autoregulation in response to raised systemic blood pressure in diabetic subjects, more so at an elevated blood glucose level, thus providing a mechanism for the detrimental effect of hypertension on diabetic retinopathy.