Radiotherapy for choroidal neovascularisation of age-related macular degeneration: a fresh perspective.
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Brachytherapy↗
Biomedical subjects
U Chakravarthy
Publications and source records attributed to U Chakravarthy.
Macular degeneration: do conventional measurements of impaired visual function equate with visual disability?
AIMS: To examine the relation between measures of vision and ability to perform daily living tasks in those visually impaired with macular degeneration. METHODS: A visual functioning index (daily living tasks dependent on vision: DLTV) was used to evaluate patients' perception of their ability to perform vision dependent tasks. Distance visual acuity, near visual acuity, reading speed, and contrast sensitivity were measured in all patients. In addition, a new measure of reading ability was derived, designated the reading index. This takes into account both the size of the text read and the time to read it and is equivalent to the reading speed in words per minute divided by text size in M. RESULTS: The reading index was found to show best associations with the majority of items within the DLTV. Stepwise regression identified the combination of reading index and distance visual acuity as having the best associations with DLTV items. The present study also demonstrated that specific levels of vision as measured by acuity, reading index, and contrast sensitivity corresponded with different perceived amounts of difficulty in the performance of daily living tasks. CONCLUSIONS: This study showed that reading index is valuable in predicting the ability to perform daily living tasks and therefore may be useful in the visual assessment of the visually impaired individual. In addition, this study identified specific levels of vision at which individuals reported different degrees of difficulty in performing daily living tasks.
Activities of Daily Living↗
Amblyopia: is visual loss permanent?
AIM: To ascertain whether recovery of visual function in amblyopic eyes is likely to occur when the fellow eye is lost as a result of age related macular degeneration. METHODS: The records of 465 patients with an established diagnosis of age related macular degeneration who had attended a specialist macular clinic between 1990 and 1998 were scrutinised. A full clinical examination and standardised refraction had been carried out in 189 of these cases on a minimum of two occasions. Cases were looked for where an improvement of one or more lines of either distance or near acuity was recorded in the eye unaffected by macular disease. In each one of these cases the improvement in visual acuity could not be attributed to treatment of other existing pathology. RESULTS: 12 such cases were detected. In nine of these the eye showing improvement of acuity had a history of amblyopia. The mean improvement in distance and near acuity in amblyopic eyes by 12 months was 3.3 and 1.9 lines logMAR respectively. The improvement in acuity generally occurred between 1 and 12 months from baseline and remained stable over the period of follow up. CONCLUSIONS: Older people with a history of amblyopia who develop visual loss in the previously normal eye can experience recovery of visual function in the amblyopic eye over a period of time. This recovery in visual function occurs in the wake of visual loss in the fellow eye and the improvement appears to be sustained.
Amblyopia↗
External beam radiotherapy in exudative age-related macular degeneration: a pooled analysis of phase I data.
In recent years external beam radiotherapy (EBRT) has been proposed as a treatment for the wet form of age-related macular degeneration (AMD) where choroidal neovascularization (CNV) is the hallmark. While the majority of pilot (Phase I) studies have reported encouraging results, a few have found no benefit, i.e. EBRT was not found to result in either improvement or stabilization of visual acuity of the treated eye. The natural history of visual loss in untreated CNV of AMD is highly variable. Loss of vision is influenced mainly by the presenting acuity, and size and composition of the lesion, and to a lesser extent by a variety of other factors. Thus the variable outcome reported by the small Phase I studies of EBRT published to date may simply reflect the variation in baseline factors. We therefore obtained information on 409 patients treated with EBRT from eight independent centres, which included details of visual acuity at baseline and at subsequent follow-up visits. Analysis of the data showed that 22.5% and 14.9% of EBRT-treated eyes developed moderate and severe loss of vision, respectively, during an average follow-up of 13 months. Initial visual acuity, which explained 20.5% of the variation in visual loss, was the most important baseline factor studied. Statistically significant differences in loss of vision were observed between centres, after considering the effects of case mix factors. Comparisons with historical data suggested that while moderate visual loss was similar to that of the natural history of the disease, the likelihood of suffering severe visual loss was halved. However, the benefit in terms of maintained/improved vision in the treated eye was modest.
Aged↗
Radiation therapy for age-related macular degeneration.
Neovascular age-related macular degeneration is the most common cause of severe irreversible blindness in the Western world in people older than age 50. Laser photocoagulation is the only proven treatment for this disease; however, fewer than 20% of patients are eligible for this treatment because the majority of choroidal neovascularization membranes are not visible by ophthalmoscopy or angiography. In addition, many patients elect not to undergo this treatment because laser treatment of subfoveal neovascular membranes results in immediate and permanent central visual loss. Several treatments are under investigation, including external-beam radiation therapy. There are multiple publications of early trials using radiation therapy, but to date there is only one randomized published study. This article reviews these trials and summarizes the status of radiation therapy as a treatment for macular degeneration.
Aged↗
Endothelium-derived agents in pericyte function/dysfunction.
The major components of blood vessels are the vascular endothelium and its supporting smooth muscle. Significant strides have been made in the understanding of the cellular and molecular biology of these two cell types and in particular their interactions have been the subject of much interest and debate over the past two decades. The vascular endothelium is now known to profoundly influence the synthetic and motor functions of the underlying smooth muscle and participate in the pathogenesis of all the major vascular disorders. Similarly, the vascular smooth muscle has important effects on the overlying endothelium, and any disruption in the cellular physiology of either cell type can result in dysfunction with important effects on blood flow and vascular permeability The majority of this accumulated knowledge relates to the vascular cells of the macrocirculation. Pericytes are the supporting cells of the microvasculature and a body of evidence is now available to show that similar regulatory mechanisms and vessel-wall cross-talk exists between these cells and the microvascular endothelium. Nowhere are these interactions more important than in the retinal microcirculation where autoregulation is vital for the maintenance of smooth and uninterrrupted blood flow. This review focuses on the interactions between retinal microvascular endothelial cells and their associated pericytes and examines the role of the endothelial cell and the pericyte in the pathogenesis of disease.
Animals↗
Dinucleotide repeat polymorphisms in EDN1 and NOS3 are not associated with severe diabetic retinopathy in type 1 or type 2 diabetes.
PURPOSE: Endothelin-1, and constitutive endothelial nitric oxide synthase, have been implicated in the pathogenesis of diabetic retinopathy. We therefore screened polymorphisms within the genes encoding these two vasoactive agents in a sample of individuals with 15 years of diabetes and no retinopathy (ETDRS level 10 or better) and those with severe retinopathy (ETDRS level 50 or worse). METHODS: PCR primers for highly polymorphic sites within the EDN1 and NOS3 genes were used to genotype individuals with type 1 or type 2 diabetes with severe or no retinopathy. Allele frequencies were compared between groups using chi-squared analysis and adjusting for multiple comparisons. RESULTS: No significant differences were observed in allele frequencies for these two markers between the patients who had retinopathy and the patients who did not. CONCLUSION: Polymorphic variability in the EDN1 and NOS3 genes does not appear to have a major impact on determining susceptibility or resistance to diabetic retinopathy.
Adult↗
Plasma levels of endothelin-1 in diabetic retinopathy in pregnancy.
PURPOSE: Raised circulating levels of the potent vasoconstrictor endothelin-1 (ET-1) have been demonstrated in diabetes and pregnancy-induced hypertension. Pregnant women with diabetic retinopathy are known to be at a higher risk of developing pregnancy-induced hypertension than those without retinopathy. To examine the association between ET-1, pregnancy, diabetes and diabetic retinopathy, circulating ET-1 levels were measured in each trimester in a cohort of women with and without diabetes during pregnancy. METHODS: A cohort of women with diabetes (n = 13) and normal controls (n = 8) were followed throughout pregnancy. Detailed clinical and fundoscopic examinations were carried out according to ETDRS protocols. Plasma ET-1 levels were measured in each trimester using a sensitive radioimmunoassay. Those with diabetes were further divided into those with retinopathy (n = 7) and those without (n = 6). RESULTS: Plasma levels of ET-1 increased progressively during normal pregnancy and peaked in the third trimester. Women with diabetes had significantly higher levels of plasma ET-1 (14.0 vs 4.6 pg/ml in the first trimester, 14.0 vs 4.8 pg/ml in the second trimester and 15.8 vs 7.2 pg/ml in the third trimester) compared with those without diabetes. These were no significant differences in plasma ET-1 levels between women with diabetes who had pre-existing diabetic retinopathy and those without. CONCLUSION: This study has shown that ET-1 levels rise during normal pregnancy, and are higher in women with diabetes, which may reflect pre-existing endothelial damage. Although no association could be demonstrated between diabetic retinopathy and serum ET-1 levels, this may reflect the small sample size in this study.
Adult↗
Genotyping and functional analysis of a polymorphic (CCTTT)(n) repeat of NOS2A in diabetic retinopathy.
Accumulating evidence shows that the severity and rapidity of onset of diabetic retinopathy are influenced by genetic factors. Expression of the nitric oxide synthases is altered in the retinal vasculature in the early stages of diabetic retinopathy. We analyzed the allele distribution of a polymorphic pentanucleotide repeat within the 5' upstream promoter region of the NOS2A gene in samples of diabetic patients. In diabetic patients from Northern Ireland, the 14-repeat allele of the NOS2A marker was significantly associated with the absence of diabetic retinopathy. Carriers of this repeat had 0.21-fold the relative risk of developing diabetic retinopathy than noncarriers of this allele. They also had significantly fewer renal and cardiovascular complications. The ability of differing numbers of (CCTTT)(n) pentanucleotide repeats to induce transcription of the NOS2A gene was analyzed using a luciferase reporter gene assay in transfected colonic carcinoma cells. Interleukin 1beta (IL-1beta) induction was most effective in constructs carrying the 14-repeat allele. When cells were incubated in 25 mM glucose to mimic the diabetic state, IL-1beta induction was inhibited in all cases, but to a significantly lesser extent with the 14-repeat allele. These unique properties of the 14-repeat allele may confer selective advantages in diabetic individuals, which may delay or prevent microvascular complications of diabetes.
Adult↗
A vision specific functional index for use in patients with age related macular degeneration.
AIM: To develop and evaluate a new vision specific functional index for use in individuals with age related macular degeneration (AMD). METHODS: Following consultation with patients with AMD and healthcare professionals, a questionnaire entitled the Daily Living Tasks Dependent on Vision (DLTV) was constructed. It was administered by interview to three separate groups of individuals aged 50 years or older: people with AMD, people with cataract, and people with no visual disability. The relations between DLTV, distance visual acuity, and disorder were examined using Pearson's product moment correlation coefficients, stepwise regression, and principal component analysis. RESULTS: There was a positive correlation between DLTV items and distance visual acuity in the better eye. Principal component analysis showed that the DLTV has a major single dimension within it. This first principal component accounted for 59% of the variation and correlated well with distance visual acuity in the better eye. Other components were found, one of which correlated with the difference in vision in the two eyes and one which featured in the differentiation of AMD subjects from individuals with cataracts. CONCLUSIONS: The DLTV provided information on visual impairment in patients over and above that obtained from a measure of visual acuity. It also showed that patients with AMD experience greater difficulty with daily living tasks for any given level of acuity than do patients with cataract.
Activities of Daily Living↗
Comet assay of UV-induced DNA damage in retinal pigment epithelial cells.
PURPOSE: The molecular mechanisms mediating photic injury to the retinal pigment epithelial (RPE) cell are not clearly understood. This study examined qualitative and quantitative aspects of DNA damage caused by broadband UVA and UVB radiation in RPE cells. METHODS: Cultured bovine RPE cells were exposed to doses of between 0 and 0.9 J/cm2 UVA or 0 and 0.09 J/cm2 UVB, as either a suspension or as an attached monolayer. The damage to DNA resulting in single-strand breaks was assessed by means of the comet assay in which the damaged DNA migrates out of the nucleus forming a tail, and this was quantified using image analysis. Two measurements were taken: the mean percentage of tail DNA, which reflects the overall level of DNA damage in the group of cells, and the Olive tail moment, which represents the extent of migration and thus the pattern of DNA damage in individual cells. Cells were processed by the comet assay immediately after UV exposure in acute experiments. To study the occurrence of DNA repair, RPE cells were first exposed to UVB and then incubated at 37 degrees C for either 1 or 24 hours before processing for the comet assay. RESULTS: UVA- and UVB-exposed cells showed a mean percentage of tail DNA that was significantly greater than in unexposed cells. Olive tail moment was higher in cells exposed to larger doses of UVB. This parameter also showed a bimodal distribution when assessed 24 hours after exposure to UVB indicating the presence of two distinct subpopulations of cells with small and large tail moments. Cells with very large tail moments were not seen with doses below 0.045 J/cm2. CONCLUSIONS: Relatively low doses of UVA and UVB induce the formation of DNA strand breaks in cultured RPE. The tail moment profiles for cells incubated for 24 hours after UVB irradiation are consistent with the occurrence of DNA repair in most cells exposed to low doses and apoptosis in a subpopulation of the cells exposed to high doses.
Animals↗
Radiotherapy and the treatment of age-related macular degeneration. External beam radiation therapy is effective in the treatment of age-related macular degeneration.
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Choroidal Neovascularization↗
External beam radiation therapy for CNV.
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Choroidal Neovascularization↗
Questionnaire-based survey on the importance of quality of life measures in ophthalmic practice.
PURPOSE: To assess the awareness of the existence of quality of life (QOL) instruments and their perceived relative merit in the management of various eye conditions among ophthalmologists in the United Kingdom. METHODS: A self-administered questionnaire was circulated among various grades of ophthalmologists attending a major UK ophthalmology conference. The respondents were asked to rank from a list in order of importance various tests of visual function in different ophthalmic conditions. RESULTS: Distance and near visual acuity were consistently rated high with mean ranks lower than 4.0. Contrast sensitivity and reading speed were consistently rated as low in importance with mean ranks ranging from 4 to 5.8. QOL instruments were deemed to be of some importance in the management of cataract and to a lesser extent in the management of age-related macular degeneration. Only 2 respondents of 36 could name either a generic or a vision-specific QOL instrument. CONCLUSION: UK ophthalmologists appear to be unfamiliar with QOL measures, despite the fact that in health economics they have become the standard means of assessing the results of health care interventions and of prioritizing funding. Notwithstanding the evolution of a variety of tests for the assessment of visual function, ophthalmologists still rely primarily on distance and, to a lesser extent, near visual acuity to plan their patient management. It is important to identify those tests of visual function that correlate best with the patient's ability to function in the seeing world, and to develop appropriate QOL instruments for use in ophthalmic disorders.
Attitude of Health Personnel↗
Constitutive nitric oxide synthase expression in retinal vascular endothelial cells is suppressed by high glucose and advanced glycation end products.
It has been suggested that increased production of nitric oxide (NO), a potent endothelium-derived vasodilator, may be responsible for increased blood flow in the retinal and renal vascular beds in early diabetes. However, NO-mediated vasodilation has been reported as impaired in diabetes, and there is evidence that the synthesis and release of NO by the vascular endothelium may be flawed in this condition. We examined the effect of high ambient glucose and exposure to exogenous glycated proteins on NO synthesis in cultured retinal microvascular endothelial cells (RMECs), using a polarographic sensor to measure released NO gas. Nitrite (the stable end product of the reaction between NO and molecular oxygen) was measured in tissue culture supernatants. The expression of vascular endothelial constitutive nitric oxide synthase (eNOS), which is responsible for NO synthesis in endothelial cells, was studied by Western blot analysis and Northern hybridization experiments. A dose-dependent reduction of NO synthesis by RMECs occurred 5 days after exposure to 15 and 25 mmol/l glucose, and concomitantly we found that accumulation of nitrite in culture supernatants of high-glucose exposed cells was also reduced. Coincubation of endothelial cells with inhibitors of protein kinase C (PKC) increased the accumulation of nitrite but did not restore it to the levels obtained when cells were cultured in 5 mmol/l glucose. The expression of eNOS by RMECs was markedly reduced by 5 days of exposure to 25 mmol/l glucose and glycated albumin. This study implicates the PKC pathway, which is known to be upregulated on exposure to high ambient glucose concentrations, as a possible factor in the inhibition of eNOS expression in RMECs. This study also suggests that glycated proteins may be involved in the pathogenesis of vascular endothelial dysfunction by modulating the nitric oxide synthase (NOS)/NO pathway in retinal vascular endothelial cells.
Animals↗
Radiation therapy for exudative age-related macular degeneration.
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Choroidal Neovascularization↗
Clinicopathological correlations provide new insights into the pathogenesis of age-related macular degeneration.
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Bruch Membrane↗
Sperm nitric oxide and motility: the effects of nitric oxide synthase stimulation and inhibition.
Nitric oxide (NO) is synthesized from L-arginine by a family of enzymes known as the nitric oxide synthases (NOS). We have recently shown a NOS similar to constitutive brain NOS (bNOS) and endothelial NOS (ecNOS) to be present in spermatozoa. The aim of this study is to investigate NO production by human spermatozoa and the effects of stimulation and inhibition of NOS. This was carried out using the Iso-NO, an isolated NO meter and sensor, which provides rapid, accurate and direct measurements of NO. Semen samples with normozoospermic and asthenozoospermic profiles were prepared using a direct swim-up technique. Basal concentrations of NO and stimulated NO production were measured after exposure to the calcium ionophore (A23187; 0.01-10 microM) a potent activator of constitutive NOS. NO production in human spermatozoa was significantly increased by the addition of A23187 30 seconds after stimulation. Furthermore, this response was greatly diminished by pre-incubating the samples with competitive inhibitors of L-arginine, the substrate for NOS, before treatment with calcium ionophore. In the presence of N(G)-nitro-L-arginine methyl ester (L-NAME), N(G)-nitro-L-arginine (L-NA) or N(G)-methyl-L-arginine (L-NMMA; all at 10 microM), NO production was inhibited with a rank order of potency L-NAME > L-NMMA > L-NA which is in accordance with the inhibition of an endothelial type of constitutive NOS.
Calcimycin↗