To establish a quality indicator that could be used in optimizing treatment for rhegmatogenous re... more To establish a quality indicator that could be used in optimizing treatment for rhegmatogenous retinal detachment (RRD). The Danish National Patient Registry was used to identify surgery conducted in Denmark for RRD in the period 01 January 2001-31 December 2009. Cases were identified by diagnosis and surgical codes. A total of 6522 cases were operated for a primary RRD in the study period, and 22% (1434 patients) were reoperated for a redetachment. A Cox regression analysis showed that the risk of redetachment was equal to or less than detachment on the fellow eye 1 year after primary surgery with techniques not using silicone oil. The same was true 1.5 years after surgery for techniques using silicone oil. Based on this, we established a quality indicator defining failure as the need for operation for redetachment within 1 year from initial surgery when using techniques without oil and after 1.5 years for techniques using oil. Also the lack of oil removal within 1 year from initial surgery should be noted as an operational failure. We applied the quality indicators on the cohort of 6522 RRDs and found that in Denmark the need for redetachment surgery has decreased over time and also that high-volume departments have better outcome compared to smaller ones. The risk of reoperation for redetachment after initial surgery fulfils the criteria for a good quality indicator and can be used in RRD surgery. This indicator could aid in optimizing the management of RRD patients to minimize morbidity.
Aims: To report a case of an unusual retinal vascular morphology in connection with a novel AIPL1... more Aims: To report a case of an unusual retinal vascular morphology in connection with a novel AIPL1 mutation in a patient with Leber’s congenital amaurosis (LCA).Methods: A patient with LCA and no light perception from birth had both eyes enucleated at the age of 22 years because of excruciating pain. Mutation analysis was performed on known LCA genes. The eyes
In nondiabetic subjects pulse pressure (PP) is an independent predictor of cardiovascular disease... more In nondiabetic subjects pulse pressure (PP) is an independent predictor of cardiovascular disease and microalbuminuria. Reduced circadian blood pressure (BP) variation is a potential risk factor for the development of diabetic complications. We investigated the association between retinopathy, nephropathy, macrovascular disease, PP, and diurnal BP variation in a group of type 2 diabetic patients. In 80 type 2 diabetic patients we performed 24-h ambulatory BP (AMBP) and fundus photographs. Urinary albumin excretion was evaluated by urinary albumin/creatinine ratio. Presence or absence of macrovascular disease was assessed by an independent physician. Forty-nine patients had no detectable retinal changes (grade 1), 13 had grade 2 retinopathy, and 18 had more advanced retinopathy (grades 3-6). Compared to patients without retinopathy (grade 1), patients with grades 2 and 3-6 had higher PP and blunted diurnal BP variation: night PP 55 +/- 10 mm Hg, 64 +/- 10 mm Hg, 61 +/- 15 mm Hg, P &l...
Hypoxia-induced relaxation of porcine retinal arterioles has been shown to be reduced during inhi... more Hypoxia-induced relaxation of porcine retinal arterioles has been shown to be reduced during inhibition of prostaglandin synthesis and nitric oxide synthase (NOS). The purpose of this study was to identity the specific prostaglandin receptor(s) and source(s) of NO mediating this effect. Porcine retinal arterioles with preserved perivascular retinal tissue were mounted in a myograph and were exposed to hypoxia in the presence of one of the following: the general NO synthase inhibitor L-NAME, the selective iNOS inhibitor 1400W, the selective nNOS inhibitor 7-nitroindazole, the general cyclooxygenase (COX) inhibitor ibuprofen or an antagonist to the FP- (AL 8810), DP- (BWA868C), EP1 - (SC-19220), EP2 - (PF-044189) or EP4 receptors (GW627368X). The experiments were repeated after removal of the perivascular retinal tissue. Hypoxia induced relaxation of retinal arterioles with preserved perivascular retinal tissue. This relaxation was significantly reduced in the presence of L-NAME, 1400W, ibuprofen and the EP4 receptor antagonist GW627368X. The simultaneous addition of L-NAME or 1400W in combination with ibuprofen, but not GW627368X, reduced hypoxia-induced vasorelaxation additively as compared to the effect of the compounds individually. Hypoxia-induced vasorelaxation of porcine retinal arterioles is mediated by inducible NOS and stimulation of EP4 receptors acting through separate pathways, but mechanisms unrelated to the studied prostaglandin receptors and NOS products are also involved.
Scandinavian Journal of Clinical & Laboratory Investigation, 2007
Plasma levels of osteoprotegerin (OPG) are elevated in subjects with diabetes as well as in non-d... more Plasma levels of osteoprotegerin (OPG) are elevated in subjects with diabetes as well as in non-diabetic subjects with cardiovascular disease. In previous studies a positive correlation was found between plasma levels of OPG and markers of glycaemic control in diabetic subjects. The aim of the present study was to examine the effect of acute hyperglycaemia on plasma levels of OPG in non-diabetic subjects. Nine healthy, lean, male subjects were examined in a randomized, blinded, cross-over study design during hyperglycaemic (plasma glucose = 15 mmol/L, study H) as well as during euglycaemic (plasma glucose = 5 mmol/L, study E) conditions. Blood samples were collected at baseline and at t=240 min. Plasma OPG decreased slightly during study H (1.26+/-0.39 versus 1.19+/-0.35 ng/mL, p<0.05), whereas the level did not change significantly during study E (1.40+/-0.46 ng/mL versus 1.57+/-0.50 ng/mL, NS). The decrease in plasma OPG during hyperglycaemia did not correlate with the change in plasma glucose but correlated significantly with changes in serum insulin (r=-0.70, p=0.038). Acute hyperglycaemia does not seem to increase plasma levels of OPG in non-diabetic subjects, whereas hyperinsulinaemia may suppress plasma levels of OPG. This finding indicates that the elevated plasma levels of OPG observed in diabetic subjects with poor metabolic control cannot be ascribed to hyperglycaemia per se.
Proceedings of the National Academy of Sciences, 2000
Familial Danish dementia (FDD), also known as heredopathia ophthalmo-oto-encephalica, is an autos... more Familial Danish dementia (FDD), also known as heredopathia ophthalmo-oto-encephalica, is an autosomal dominant disorder characterized by cataracts, deafness, progressive ataxia, and dementia. Neuropathological findings include severe widespread cerebral amyloid angiopathy, hippocampal plaques, and neurofibrillary tangles, similar to Alzheimer's disease. N-terminal sequence analysis of isolated leptomeningeal amyloid fibrils revealed homology to ABri, the peptide originated by a point mutation at the stop codon of gene BRI in familial British dementia. Molecular genetic analysis of the BRI gene in the Danish kindred showed a different defect, namely the presence of a 10-nt duplication (795-796insTTTAATTTGT) between codons 265 and 266, one codon before the normal stop codon 267. The decamer duplication mutation produces a frame-shift in the BRI sequence generating a larger-than-normal precursor protein, of which the amyloid subunit (designated ADan) comprises the last 34 C-terminal amino acids. This de novo-created amyloidogenic peptide, associated with a genetic defect in the Danish kindred, stresses the importance of amyloid formation as a causative factor in neurodegeneration and dementia.
ABSTRACT Familial Danish dementia, formally known as heredopathia ophthalmo-oto-encephalica, was ... more ABSTRACT Familial Danish dementia, formally known as heredopathia ophthalmo-oto-encephalica, was described in the early 1970s as a dominantly inherited disorder originating in the Djursland peninsula, north-east of the city of Aarhus, Denmark. The clinical presentation of the disease is cataracts and the other ocular systems in early adult life, followed by hearing impairment around the age of 30. Neurological symptoms and dementia start after the age 40. Most patients die in their fifth or sixth decade of life.
Journal of the American Society of Hypertension, 2007
Reduced diurnal blood pressure (BP) variation (&a... more Reduced diurnal blood pressure (BP) variation ("non-dipping") is associated with both micro- and macrovascular complications in patients with type 2 diabetes. The relation between endothelial perturbation and diurnal BP variation in diabetic subjects has not previously been studied. Seventy-six subjects, stratified to 4 gender-, age-, and duration-matched groups of 19 subjects each, were studied (group A: non-diabetic subjects; group B to D, type 2 diabetic subjects; group B: no retinopathy; group C: minimal background retinopathy; group D: diabetic maculopathy). All subjects underwent a 24-hour ambulatory BP monitoring. von Willebrand factor (vWF), fibrinogen, E-selectin, and intercellular adhesion molecule-1 were measured in plasma. Systolic night/day BP ratio increased gradually in groups A to D: 85.2 +/- 5%, 85.7 +/- 7%, 88.5 +/- 6%, and 90.5 +/- 7%, respectively, P < .05. Among diabetic patients, non-dippers had significantly higher plasma levels of vWF and fibrinogen than dippers (median/interquartile range 1.7/1.4 to 2.1 vs. 1.2/0.9 to 1.5 U/mL, P < .01 and 3.6/3.6 to 3.7 vs. 2.9/2.5 to 3.6 g/L, P = .01). Non-dipping is associated with elevated plasma levels of proteins related to endothelial cell activation as well as with retinopathy in subjects with type 2 diabetes. This finding suggests a possible mechanism linking non-dipping with microvascular complications in these subjects.
Disturbances in retinal perfusion due to impaired regulation of vascular tone are believed to be ... more Disturbances in retinal perfusion due to impaired regulation of vascular tone are believed to be involved in the pathogenesis of several vision-threatening retinal diseases. Two recent studies have shown that the glutamate receptor agonist, N-methyl-D-aspartic acid (NMDA), and adenosine induce relaxation of isolated porcine retinal arterioles in vitro. However, it remains to be elucidated whether the relaxing action of the two substances are coupled. Porcine retinal arterioles with preserved perivascular retinal tissue were mounted in a myograph for isometric tone measurements. Changes in tone were induced by increasing concentrations of NMDA in the presence of blockers of adenosine receptors and ATP hydrolysis and by increasing concentrations of adenosine in the presence of the NMDA receptor blocker DL-APV (DL-amino-5-phosphonovaleric acid). The experiments were repeated after the perivascular tissue had been removed. NMDA produced a relaxing effect on retinal vessels with preserved perivascular retinal tissue (P < 0.001) which disappeared after removal of the tissue. Blocking of the NMDA and adenosine receptors and hydrolysis of adenosine triphosphate (ATP) significantly reduced the vasorelaxing effect of NMDA in the presence of perivascular retinal tissue (P < 0.05 for all three comparisons). Adenosine produced a concentration-dependent relaxation that was not significantly affected by blocking the NMDA receptor with DL-APV (P = 0.088). The findings suggest that the vasorelaxing effect of NMDA on porcine retinal arterioles in vitro is mediated by hydrolysis of ATP to adenosine in the perivascular retinal tissue.
Endothelial dysfunction and impaired vasodilation may be involved in the pathogenesis of retinal ... more Endothelial dysfunction and impaired vasodilation may be involved in the pathogenesis of retinal vascular diseases. In the present study, the mechanisms underlying bradykinin vasodilation were examined and whether calcium-activated potassium channels of small (SK(Ca)) and intermediate (IK(Ca)) conductance are involved in regulation of endothelium-dependent vasodilation in retinal arterioles was investigated. Porcine retinal arterioles (diameter approximately 112 microm, N = 119) were mounted in microvascular myographs for isometric tension recordings. The arterioles were contracted with the thromboxane analogue, U46619, and concentration-response curves were constructed for bradykinin and a novel opener of SK(Ca) and IK(Ca) channels, NS309. In U46619-contracted arterioles, bradykinin and NS309 induced concentration-dependent relaxations. In vessels without endothelium, bradykinin relaxation was abolished and NS309 relaxation was attenuated. Inhibition of NO synthase with asymmetric dimethylarginine and/or cyclooxygenase with indomethacin markedly reduced bradykinin and NS309 relaxation. NO synthase and cyclooxygenase inhibition together with oxyhemoglobin abolished bradykinin relaxation and attenuated NS309 relaxation. Blocking of SK(Ca) and IK(Ca) channels with apamin plus charybdotoxin or blocking of SK(Ca) channels alone in the absence and the presence of indomethacin markedly reduced bradykinin and NS309 relaxation, whereas blocking of IK(Ca) channels had no significant effect. In vessels without endothelium, blocking of SK(Ca) channels alone had no effect on sodium nitroprusside-induced relaxation. In porcine retinal arterioles, NO and prostaglandins mediate endothelium-dependent relaxation to bradykinin and NS309. Moreover, these findings suggest that SK(Ca) channels contribute to NO-mediated relaxation induced by bradykinin and NS309 and, hence, may play an important role in retinal arterial endothelial function.
Investigative Ophthalmology & Visual Science, 2007
Inhibition of carbonic anhydrase in the eye is an important treatment modality for reducing the i... more Inhibition of carbonic anhydrase in the eye is an important treatment modality for reducing the intraocular pressure in glaucoma. However, evidence suggests that carbonic anhydrase inhibition also exerts a relaxing effect on the vessels in the optic nerve, and it has been suggested that this vasorelaxing effect is a result of an interplay between the perivascular tissue and constituents in the retinal vascular wall. However, the exact nature of this interplay is unknown. Isolated porcine retinal arterioles and arterioles with preserved perivascular retinal tissue were mounted in a myograph. After precontraction with the prostaglandin analogue U46619, the vasorelaxing effect of the carbonic anhydrase inhibitors methyl bromopyruvate, ethyl bromopyruvate, acetazolamide, and dorzolamide were studied. All the examined carbonic anhydrase inhibitors induced a significant relaxation of retinal arterioles. There was no significant difference between the effect of the different carbonic anhydrase inhibitors in the presence of perivascular retinal tissue. However, in the isolated retinal arterioles the vasodilating effect of dorzolamide was significantly lower, and the vasodilating effect of acetazolamide almost disappeared. A further elucidation of the mechanisms of action of carbonic anhydrase-induced dilation of retinal arterioles may contribute to a better understanding of the regulation of retinal blood flow. The perivascular retinal tissue may play a significant role in diameter control of retinal arterioles.
To study the diameter response of retinal arterioles as a function of the arteriolar diameter. Te... more To study the diameter response of retinal arterioles as a function of the arteriolar diameter. Ten healthy young volunteers aged 22 to 33 years were subjected to diameter measurement of four successive segments of a retinal arteriole with a retinal vessel analyzer (RVA). At each of the segments, the diameter response during an increase in the systemic blood pressure (mean arterial pressure [MAP]) induced by isometric exercise was compared to the diameter of the arterioles during rest. The isometric exercise induced a significant contraction of the studied vessel segments averaging 2.5% +/- 0.4% (P < 0.0001, n = 40). There was a significant negative correlation between the baseline diameter of the studied vessel segments and the diameter response induced by isometric exercise (P = 0.02). The blood pressure-induced diameter response of retinal arterioles increased with decreasing diameter of the vessels. The results indicate that the distal retinal arterioles play a major role in the regulation of retinal blood flow.
Graefe's Archive for Clinical and Experimental Ophthalmology, 1989
The influence of perimetric stimulus size on the detection of small scotomata was examined, and t... more The influence of perimetric stimulus size on the detection of small scotomata was examined, and the blind spot was used as a paradigm of a small scotoma. A customized point pattern for perimetry was created on a Humphrey field analyzer. The point pattern had a density of 1.4 degrees and was arranged in a grid in the area of the blind spot. Four normal persons were tested with full-threshold strategy in the points of this grid using Goldmann stimulus sizes ranging from I to V. The delimitation of the blind spot was found to depend strongly on stimulus size. For small stimulus sizes, the blind spot could be delimited as an absolute scotoma with almost sharp borders. However, with larger spot sizes a relative scotoma zone gradually developed, extending centrally from the borders of the blind spot. The central absolute scotoma component of the blind spot totally disappeared for the largest stimulus sizes. We could establish that some of these larger stimuli would be projected totally within the optic nerve head, if perfect imaging through the refractive media of the eye, was assumed. We interpret our findings to be a result of light scattering in the refractive media of the eye, causing a blur to appear around the image of the light stimulus at the retinal plane. We conclude that perimetric resolution power is highly dependent on stimulus size. The smallest stimulus size possible should be used when dense stimulus patterns are used for perimetric detection of small scotomata.
Graefe's Archive for Clinical and Experimental Ophthalmology, 2011
Diabetic retinopathy is assumed to be due to impaired retinal autoregulation, involving both pres... more Diabetic retinopathy is assumed to be due to impaired retinal autoregulation, involving both pressure autoregulation and metabolic autoregulation. The disease displays regional differences, with signs of hyperperfusion in the macular area and capillary occlusion with retinal ischemia in the peripheral retinal areas. It can be hypothesized that these regional differences in the occurrence of retinopathy lesions may reflect differences in the capacity of retinal arterioles to autoregulate the diameter of retinal arterioles. Seventeen normal persons and two matched groups of patients with respectively diabetic maculopathy and proliferative diabetic retinopathy were examined. The diameter change of a macular and a peripheral retinal arteriole during an increase in the arterial blood pressure induced by isometric exercise, during an increase in retinal metabolism induced by flicker stimulation, and during both stimulus paradigms simultaneously were studied using the dynamic vessel analyzer (DVA). During isometric exercise, the diameter response was reduced in both macular and peripheral retinal arterioles in the two groups of patients with diabetes mellitus. During flicker stimulation, the diameter response was significantly reduced in patients with proliferative diabetic retinopathy, but there was no significant difference between the responses of macular and peripheral arterioles. During simultaneous isometric exercise and flicker stimulation, there was no difference between the diameter response of macular arterioles in the three groups, whereas the diameter response of macular arterioles was significantly lower in normal persons and significantly higher in persons with proliferative diabetic retinopathy as compared to peripheral arterioles. Regional differences in the disturbances of the diameter response to increased blood pressure may contribute to the regional differences in the distribution of diabetic retinopathy lesions. In the central retinal areas, the diameter response to increased blood pressure and retinal metabolism interacted in a way that may potentially protect this area from ischaemia, whereas this protective mechanism was absent in the peripheral retinal arterioles. An elucidation of the mechanisms underlying diameter regulation to increased blood pressure and retinal metabolism, and the interaction between these two mechanisms, may help in understanding the pathophysiology of diabetic retinopathy.
To establish a quality indicator that could be used in optimizing treatment for rhegmatogenous re... more To establish a quality indicator that could be used in optimizing treatment for rhegmatogenous retinal detachment (RRD). The Danish National Patient Registry was used to identify surgery conducted in Denmark for RRD in the period 01 January 2001-31 December 2009. Cases were identified by diagnosis and surgical codes. A total of 6522 cases were operated for a primary RRD in the study period, and 22% (1434 patients) were reoperated for a redetachment. A Cox regression analysis showed that the risk of redetachment was equal to or less than detachment on the fellow eye 1 year after primary surgery with techniques not using silicone oil. The same was true 1.5 years after surgery for techniques using silicone oil. Based on this, we established a quality indicator defining failure as the need for operation for redetachment within 1 year from initial surgery when using techniques without oil and after 1.5 years for techniques using oil. Also the lack of oil removal within 1 year from initial surgery should be noted as an operational failure. We applied the quality indicators on the cohort of 6522 RRDs and found that in Denmark the need for redetachment surgery has decreased over time and also that high-volume departments have better outcome compared to smaller ones. The risk of reoperation for redetachment after initial surgery fulfils the criteria for a good quality indicator and can be used in RRD surgery. This indicator could aid in optimizing the management of RRD patients to minimize morbidity.
Aims: To report a case of an unusual retinal vascular morphology in connection with a novel AIPL1... more Aims: To report a case of an unusual retinal vascular morphology in connection with a novel AIPL1 mutation in a patient with Leber’s congenital amaurosis (LCA).Methods: A patient with LCA and no light perception from birth had both eyes enucleated at the age of 22 years because of excruciating pain. Mutation analysis was performed on known LCA genes. The eyes
In nondiabetic subjects pulse pressure (PP) is an independent predictor of cardiovascular disease... more In nondiabetic subjects pulse pressure (PP) is an independent predictor of cardiovascular disease and microalbuminuria. Reduced circadian blood pressure (BP) variation is a potential risk factor for the development of diabetic complications. We investigated the association between retinopathy, nephropathy, macrovascular disease, PP, and diurnal BP variation in a group of type 2 diabetic patients. In 80 type 2 diabetic patients we performed 24-h ambulatory BP (AMBP) and fundus photographs. Urinary albumin excretion was evaluated by urinary albumin/creatinine ratio. Presence or absence of macrovascular disease was assessed by an independent physician. Forty-nine patients had no detectable retinal changes (grade 1), 13 had grade 2 retinopathy, and 18 had more advanced retinopathy (grades 3-6). Compared to patients without retinopathy (grade 1), patients with grades 2 and 3-6 had higher PP and blunted diurnal BP variation: night PP 55 +/- 10 mm Hg, 64 +/- 10 mm Hg, 61 +/- 15 mm Hg, P &l...
Hypoxia-induced relaxation of porcine retinal arterioles has been shown to be reduced during inhi... more Hypoxia-induced relaxation of porcine retinal arterioles has been shown to be reduced during inhibition of prostaglandin synthesis and nitric oxide synthase (NOS). The purpose of this study was to identity the specific prostaglandin receptor(s) and source(s) of NO mediating this effect. Porcine retinal arterioles with preserved perivascular retinal tissue were mounted in a myograph and were exposed to hypoxia in the presence of one of the following: the general NO synthase inhibitor L-NAME, the selective iNOS inhibitor 1400W, the selective nNOS inhibitor 7-nitroindazole, the general cyclooxygenase (COX) inhibitor ibuprofen or an antagonist to the FP- (AL 8810), DP- (BWA868C), EP1 - (SC-19220), EP2 - (PF-044189) or EP4 receptors (GW627368X). The experiments were repeated after removal of the perivascular retinal tissue. Hypoxia induced relaxation of retinal arterioles with preserved perivascular retinal tissue. This relaxation was significantly reduced in the presence of L-NAME, 1400W, ibuprofen and the EP4 receptor antagonist GW627368X. The simultaneous addition of L-NAME or 1400W in combination with ibuprofen, but not GW627368X, reduced hypoxia-induced vasorelaxation additively as compared to the effect of the compounds individually. Hypoxia-induced vasorelaxation of porcine retinal arterioles is mediated by inducible NOS and stimulation of EP4 receptors acting through separate pathways, but mechanisms unrelated to the studied prostaglandin receptors and NOS products are also involved.
Scandinavian Journal of Clinical & Laboratory Investigation, 2007
Plasma levels of osteoprotegerin (OPG) are elevated in subjects with diabetes as well as in non-d... more Plasma levels of osteoprotegerin (OPG) are elevated in subjects with diabetes as well as in non-diabetic subjects with cardiovascular disease. In previous studies a positive correlation was found between plasma levels of OPG and markers of glycaemic control in diabetic subjects. The aim of the present study was to examine the effect of acute hyperglycaemia on plasma levels of OPG in non-diabetic subjects. Nine healthy, lean, male subjects were examined in a randomized, blinded, cross-over study design during hyperglycaemic (plasma glucose = 15 mmol/L, study H) as well as during euglycaemic (plasma glucose = 5 mmol/L, study E) conditions. Blood samples were collected at baseline and at t=240 min. Plasma OPG decreased slightly during study H (1.26+/-0.39 versus 1.19+/-0.35 ng/mL, p<0.05), whereas the level did not change significantly during study E (1.40+/-0.46 ng/mL versus 1.57+/-0.50 ng/mL, NS). The decrease in plasma OPG during hyperglycaemia did not correlate with the change in plasma glucose but correlated significantly with changes in serum insulin (r=-0.70, p=0.038). Acute hyperglycaemia does not seem to increase plasma levels of OPG in non-diabetic subjects, whereas hyperinsulinaemia may suppress plasma levels of OPG. This finding indicates that the elevated plasma levels of OPG observed in diabetic subjects with poor metabolic control cannot be ascribed to hyperglycaemia per se.
Proceedings of the National Academy of Sciences, 2000
Familial Danish dementia (FDD), also known as heredopathia ophthalmo-oto-encephalica, is an autos... more Familial Danish dementia (FDD), also known as heredopathia ophthalmo-oto-encephalica, is an autosomal dominant disorder characterized by cataracts, deafness, progressive ataxia, and dementia. Neuropathological findings include severe widespread cerebral amyloid angiopathy, hippocampal plaques, and neurofibrillary tangles, similar to Alzheimer's disease. N-terminal sequence analysis of isolated leptomeningeal amyloid fibrils revealed homology to ABri, the peptide originated by a point mutation at the stop codon of gene BRI in familial British dementia. Molecular genetic analysis of the BRI gene in the Danish kindred showed a different defect, namely the presence of a 10-nt duplication (795-796insTTTAATTTGT) between codons 265 and 266, one codon before the normal stop codon 267. The decamer duplication mutation produces a frame-shift in the BRI sequence generating a larger-than-normal precursor protein, of which the amyloid subunit (designated ADan) comprises the last 34 C-terminal amino acids. This de novo-created amyloidogenic peptide, associated with a genetic defect in the Danish kindred, stresses the importance of amyloid formation as a causative factor in neurodegeneration and dementia.
ABSTRACT Familial Danish dementia, formally known as heredopathia ophthalmo-oto-encephalica, was ... more ABSTRACT Familial Danish dementia, formally known as heredopathia ophthalmo-oto-encephalica, was described in the early 1970s as a dominantly inherited disorder originating in the Djursland peninsula, north-east of the city of Aarhus, Denmark. The clinical presentation of the disease is cataracts and the other ocular systems in early adult life, followed by hearing impairment around the age of 30. Neurological symptoms and dementia start after the age 40. Most patients die in their fifth or sixth decade of life.
Journal of the American Society of Hypertension, 2007
Reduced diurnal blood pressure (BP) variation (&a... more Reduced diurnal blood pressure (BP) variation ("non-dipping") is associated with both micro- and macrovascular complications in patients with type 2 diabetes. The relation between endothelial perturbation and diurnal BP variation in diabetic subjects has not previously been studied. Seventy-six subjects, stratified to 4 gender-, age-, and duration-matched groups of 19 subjects each, were studied (group A: non-diabetic subjects; group B to D, type 2 diabetic subjects; group B: no retinopathy; group C: minimal background retinopathy; group D: diabetic maculopathy). All subjects underwent a 24-hour ambulatory BP monitoring. von Willebrand factor (vWF), fibrinogen, E-selectin, and intercellular adhesion molecule-1 were measured in plasma. Systolic night/day BP ratio increased gradually in groups A to D: 85.2 +/- 5%, 85.7 +/- 7%, 88.5 +/- 6%, and 90.5 +/- 7%, respectively, P < .05. Among diabetic patients, non-dippers had significantly higher plasma levels of vWF and fibrinogen than dippers (median/interquartile range 1.7/1.4 to 2.1 vs. 1.2/0.9 to 1.5 U/mL, P < .01 and 3.6/3.6 to 3.7 vs. 2.9/2.5 to 3.6 g/L, P = .01). Non-dipping is associated with elevated plasma levels of proteins related to endothelial cell activation as well as with retinopathy in subjects with type 2 diabetes. This finding suggests a possible mechanism linking non-dipping with microvascular complications in these subjects.
Disturbances in retinal perfusion due to impaired regulation of vascular tone are believed to be ... more Disturbances in retinal perfusion due to impaired regulation of vascular tone are believed to be involved in the pathogenesis of several vision-threatening retinal diseases. Two recent studies have shown that the glutamate receptor agonist, N-methyl-D-aspartic acid (NMDA), and adenosine induce relaxation of isolated porcine retinal arterioles in vitro. However, it remains to be elucidated whether the relaxing action of the two substances are coupled. Porcine retinal arterioles with preserved perivascular retinal tissue were mounted in a myograph for isometric tone measurements. Changes in tone were induced by increasing concentrations of NMDA in the presence of blockers of adenosine receptors and ATP hydrolysis and by increasing concentrations of adenosine in the presence of the NMDA receptor blocker DL-APV (DL-amino-5-phosphonovaleric acid). The experiments were repeated after the perivascular tissue had been removed. NMDA produced a relaxing effect on retinal vessels with preserved perivascular retinal tissue (P < 0.001) which disappeared after removal of the tissue. Blocking of the NMDA and adenosine receptors and hydrolysis of adenosine triphosphate (ATP) significantly reduced the vasorelaxing effect of NMDA in the presence of perivascular retinal tissue (P < 0.05 for all three comparisons). Adenosine produced a concentration-dependent relaxation that was not significantly affected by blocking the NMDA receptor with DL-APV (P = 0.088). The findings suggest that the vasorelaxing effect of NMDA on porcine retinal arterioles in vitro is mediated by hydrolysis of ATP to adenosine in the perivascular retinal tissue.
Endothelial dysfunction and impaired vasodilation may be involved in the pathogenesis of retinal ... more Endothelial dysfunction and impaired vasodilation may be involved in the pathogenesis of retinal vascular diseases. In the present study, the mechanisms underlying bradykinin vasodilation were examined and whether calcium-activated potassium channels of small (SK(Ca)) and intermediate (IK(Ca)) conductance are involved in regulation of endothelium-dependent vasodilation in retinal arterioles was investigated. Porcine retinal arterioles (diameter approximately 112 microm, N = 119) were mounted in microvascular myographs for isometric tension recordings. The arterioles were contracted with the thromboxane analogue, U46619, and concentration-response curves were constructed for bradykinin and a novel opener of SK(Ca) and IK(Ca) channels, NS309. In U46619-contracted arterioles, bradykinin and NS309 induced concentration-dependent relaxations. In vessels without endothelium, bradykinin relaxation was abolished and NS309 relaxation was attenuated. Inhibition of NO synthase with asymmetric dimethylarginine and/or cyclooxygenase with indomethacin markedly reduced bradykinin and NS309 relaxation. NO synthase and cyclooxygenase inhibition together with oxyhemoglobin abolished bradykinin relaxation and attenuated NS309 relaxation. Blocking of SK(Ca) and IK(Ca) channels with apamin plus charybdotoxin or blocking of SK(Ca) channels alone in the absence and the presence of indomethacin markedly reduced bradykinin and NS309 relaxation, whereas blocking of IK(Ca) channels had no significant effect. In vessels without endothelium, blocking of SK(Ca) channels alone had no effect on sodium nitroprusside-induced relaxation. In porcine retinal arterioles, NO and prostaglandins mediate endothelium-dependent relaxation to bradykinin and NS309. Moreover, these findings suggest that SK(Ca) channels contribute to NO-mediated relaxation induced by bradykinin and NS309 and, hence, may play an important role in retinal arterial endothelial function.
Investigative Ophthalmology & Visual Science, 2007
Inhibition of carbonic anhydrase in the eye is an important treatment modality for reducing the i... more Inhibition of carbonic anhydrase in the eye is an important treatment modality for reducing the intraocular pressure in glaucoma. However, evidence suggests that carbonic anhydrase inhibition also exerts a relaxing effect on the vessels in the optic nerve, and it has been suggested that this vasorelaxing effect is a result of an interplay between the perivascular tissue and constituents in the retinal vascular wall. However, the exact nature of this interplay is unknown. Isolated porcine retinal arterioles and arterioles with preserved perivascular retinal tissue were mounted in a myograph. After precontraction with the prostaglandin analogue U46619, the vasorelaxing effect of the carbonic anhydrase inhibitors methyl bromopyruvate, ethyl bromopyruvate, acetazolamide, and dorzolamide were studied. All the examined carbonic anhydrase inhibitors induced a significant relaxation of retinal arterioles. There was no significant difference between the effect of the different carbonic anhydrase inhibitors in the presence of perivascular retinal tissue. However, in the isolated retinal arterioles the vasodilating effect of dorzolamide was significantly lower, and the vasodilating effect of acetazolamide almost disappeared. A further elucidation of the mechanisms of action of carbonic anhydrase-induced dilation of retinal arterioles may contribute to a better understanding of the regulation of retinal blood flow. The perivascular retinal tissue may play a significant role in diameter control of retinal arterioles.
To study the diameter response of retinal arterioles as a function of the arteriolar diameter. Te... more To study the diameter response of retinal arterioles as a function of the arteriolar diameter. Ten healthy young volunteers aged 22 to 33 years were subjected to diameter measurement of four successive segments of a retinal arteriole with a retinal vessel analyzer (RVA). At each of the segments, the diameter response during an increase in the systemic blood pressure (mean arterial pressure [MAP]) induced by isometric exercise was compared to the diameter of the arterioles during rest. The isometric exercise induced a significant contraction of the studied vessel segments averaging 2.5% +/- 0.4% (P < 0.0001, n = 40). There was a significant negative correlation between the baseline diameter of the studied vessel segments and the diameter response induced by isometric exercise (P = 0.02). The blood pressure-induced diameter response of retinal arterioles increased with decreasing diameter of the vessels. The results indicate that the distal retinal arterioles play a major role in the regulation of retinal blood flow.
Graefe's Archive for Clinical and Experimental Ophthalmology, 1989
The influence of perimetric stimulus size on the detection of small scotomata was examined, and t... more The influence of perimetric stimulus size on the detection of small scotomata was examined, and the blind spot was used as a paradigm of a small scotoma. A customized point pattern for perimetry was created on a Humphrey field analyzer. The point pattern had a density of 1.4 degrees and was arranged in a grid in the area of the blind spot. Four normal persons were tested with full-threshold strategy in the points of this grid using Goldmann stimulus sizes ranging from I to V. The delimitation of the blind spot was found to depend strongly on stimulus size. For small stimulus sizes, the blind spot could be delimited as an absolute scotoma with almost sharp borders. However, with larger spot sizes a relative scotoma zone gradually developed, extending centrally from the borders of the blind spot. The central absolute scotoma component of the blind spot totally disappeared for the largest stimulus sizes. We could establish that some of these larger stimuli would be projected totally within the optic nerve head, if perfect imaging through the refractive media of the eye, was assumed. We interpret our findings to be a result of light scattering in the refractive media of the eye, causing a blur to appear around the image of the light stimulus at the retinal plane. We conclude that perimetric resolution power is highly dependent on stimulus size. The smallest stimulus size possible should be used when dense stimulus patterns are used for perimetric detection of small scotomata.
Graefe's Archive for Clinical and Experimental Ophthalmology, 2011
Diabetic retinopathy is assumed to be due to impaired retinal autoregulation, involving both pres... more Diabetic retinopathy is assumed to be due to impaired retinal autoregulation, involving both pressure autoregulation and metabolic autoregulation. The disease displays regional differences, with signs of hyperperfusion in the macular area and capillary occlusion with retinal ischemia in the peripheral retinal areas. It can be hypothesized that these regional differences in the occurrence of retinopathy lesions may reflect differences in the capacity of retinal arterioles to autoregulate the diameter of retinal arterioles. Seventeen normal persons and two matched groups of patients with respectively diabetic maculopathy and proliferative diabetic retinopathy were examined. The diameter change of a macular and a peripheral retinal arteriole during an increase in the arterial blood pressure induced by isometric exercise, during an increase in retinal metabolism induced by flicker stimulation, and during both stimulus paradigms simultaneously were studied using the dynamic vessel analyzer (DVA). During isometric exercise, the diameter response was reduced in both macular and peripheral retinal arterioles in the two groups of patients with diabetes mellitus. During flicker stimulation, the diameter response was significantly reduced in patients with proliferative diabetic retinopathy, but there was no significant difference between the responses of macular and peripheral arterioles. During simultaneous isometric exercise and flicker stimulation, there was no difference between the diameter response of macular arterioles in the three groups, whereas the diameter response of macular arterioles was significantly lower in normal persons and significantly higher in persons with proliferative diabetic retinopathy as compared to peripheral arterioles. Regional differences in the disturbances of the diameter response to increased blood pressure may contribute to the regional differences in the distribution of diabetic retinopathy lesions. In the central retinal areas, the diameter response to increased blood pressure and retinal metabolism interacted in a way that may potentially protect this area from ischaemia, whereas this protective mechanism was absent in the peripheral retinal arterioles. An elucidation of the mechanisms underlying diameter regulation to increased blood pressure and retinal metabolism, and the interaction between these two mechanisms, may help in understanding the pathophysiology of diabetic retinopathy.
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