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Biomedical subjects

U Chakravarthy

Publications and source records attributed to U Chakravarthy.

At least 19 recordsLinked to original sources
PubMed2003

Molecular genetics of microvascular disease in diabetic retinopathy.

Diabetic retinopathy is a sight-threatening complication of the retinal microvasculature. While important environmental factors have been clearly identified as influencing its development, increasing evidence suggests that diabetic retinopathy has a genetic component. A variety of studies have explored associations between candidate genes and frequency and severity of retinopathy. Overall, this review has found that the majority of candidate genes studied exhibit weak or no association with retinopathy status, and where associations have been detected these results have not been replicated in multiple populations. This may reflect inaccurate case definition, small subject numbers and possibly inadequate markers for genetic studies.

Aldehyde Reductase↗
PubMed2003

Introduction of photodynamic therapy for the treatment of neovascular age-related macular degeneration: tracking a moving target.

OBJECTIVES: To identify changes in referral and treatment patterns of neovascular age-related macular degeneration with photodynamic therapy (PDT) within ophthalmology units in NHS hospitals and assess how beliefs about what would constitute a worthwhile level of clinical benefit had altered over a 12-month period. METHODS: Two questionnaire surveys (October 2000 and October 2001) to all clinical directors or lead consultants in UK NHS eye units. These sought data on which (if any) patients were referred or treated with PDT and the threshold of clinical benefit, in terms of numbers needed to treat, at which they would support the use of PDT. RESULTS: Response rates were 82% in the first survey and 79% in the second. The availability of PDT had significantly increased (P=0.0001). The proportion of units routinely providing PDT for patients with more than 50% classic subfoveal choroidal neovascularization (CNV) increased from 8 to 23%. Between the 2 surveys, there was a significant reduction in the threshold of effectiveness at which respondents would support the use of PDT (P=0.012). The proportion of respondents requiring further evidence before supporting the use of PDT decreased from 33 to 17% (P=0.009). There was a significant association between the threshold of support and the level of service provision for both surveys (P=0.01). CONCLUSIONS: Although substantial variations exist, availability of PDT has increased over the 12-month period. The differing thresholds at which introduction of PDT would be considered justifiable varied widely. PDT is being introduced into the NHS in a fragmented manner. In common with other new health technologies, factors other than the strength of evidence appear to be influencing beliefs about the effectiveness of PDT and its subsequent provision. While it is unlikely that such an action alone will lead to evidence-based practice, the variations in beliefs identified by this survey suggest that sufficient clinical uncertainty exists to support the need for further clinical trials.

Follow-Up Studies↗
PubMed2003

CNV subtype in first eyes predicts severity of ARM in fellow eyes.

AIM: To examine the relation between the type of choroidal neovascularisation (CNV) in the first eye and age related maculopathy (ARM) severity in the fellow eye. METHODS: Colour fundus photographs and fluorescein angiograms from 67 subjects with a clinical diagnosis of CNV in one eye were scrutinised. CNV was classified as wholly classic, predominantly classic, minimally classic, or occult based on the proportion of classic leakage within the lesion. ARM changes in the fellow eye were assigned a severity stage using the system described by the Rotterdam Eye Study. Logistic regression analysis was employed to examine the association between CNV subtype and ARM stage. RESULTS: Of subjects with classic or predominantly classic CNV in the first eye 78% exhibited least no or early ARM features in the fellow eye. By contrast, 85% of subjects with minimally classic or occult CNV in the first eye exhibited more advanced ARM features in the fellow eye. Kruskall-Wallis one way ANOVA by ranks showed that this was highly significant (p = 0.002). Logistic regression analysis showed that as the proportion of occult CNV increased in the first eye, fellow eyes of subjects in this category were more likely to have been assigned to a higher ARM stage (p = 0.019). The area occupied by the CNV in the first eye also influenced severity of ARM changes in the fellow eye. CONCLUSION: The type and extent of CNV in the first affected eye has a distinct relation to ARM severity in the fellow eye. Fellow eyes of subjects with minimally classic or occult CNV in the first affected eye show widespread ARM changes suggestive of retinal pigment epithelial dysfunction. These findings suggest that classic CNV may be focal disease while occult CNV is essentially a more widespread retinal pigment epithelial disorder.

Aged↗
PubMed2003

Identification of lesion components that influence visual function in age related macular degeneration.

AIMS: To explore the relation between lesion composition as assessed by fundus photography and fluorescein angiography with clinical measures of vision in eyes of patients with age related macular degeneration (AMD). METHODS: A standardised visual function assessment along with colour stereo pair fundus photography was carried out in both eyes of 58 subjects with a confirmed clinical diagnosis of AMD. The size, location, and composition of the macular lesion (blood, exudate, subretinal fluid, pigment, membrane, atrophy, and fibrosis) were measured on the colour photographs using computer assisted image analysis. Of the 58 subjects, 44 also had concurrent fluorescein angiography. Classic and occult choroidal neovascularisation (CNV), blood, blocked fluorescence, fibrosis, geographic atrophy, and the total area of abnormal fluorescence were measured. Multiple linear regression was used to examine the relation between clinical measures of vision and the location and extent of lesion components identified by both colour and fluorescein image capture. RESULTS: The composition of the macular lesion strongly influenced visual function, with atrophy (p=0.001) and fibrosis (p=0.002) accounting for most of the variation. When the location of the lesion with respect to the fovea was examined, fibrosis within the fovea significantly influenced all clinical measures of vision (p=0.008). The regression model selected the total area of abnormal fluorescence and a composite parameter (a semiquantitative measure of the following characteristics: atrophy, exudates, blood, and fibrosis ) from colour photography (r(2) =0.52) as the variables that explained most of the variation in clinical measures of vision. CONCLUSIONS: The composition and extent of the macular lesion strongly influences visual function in eyes with AMD. Both colour photography and angiography yielded information, which together explained considerably more of the variation in the clinical measures of vision than either on its own.

Aged↗
PubMed2002

Visual outcomes in the subfoveal radiotherapy study: a randomized controlled trial of teletherapy for age-related macular degeneration.

OBJECTIVE: To determine whether teletherapy with 6-mV photons can reduce visual loss in patients with subfoveal choroidal neovascularization in age-related macular degeneration. DESIGN: A multicenter, single-masked, randomized controlled trial of 12 Gy of external beam radiation therapy delivered to the macula of an affected eye vs observation only. SETTING: Three United Kingdom-based hospital units. PARTICIPANTS: Patients with age-related macular degeneration, aged 60 years and older, who had subfoveal choroidal neovascularization and a visual acuity of 20/200 (logMAR 1.0) or better. METHODS: Two hundred three patients were randomly assigned to radiotherapy or observation. Treatment was undertaken at designated radiotherapy centers, and patients assigned to the treatment group received a total dosage of 12 Gy of 6-mV photons in 6 fractions. Follow-up was scheduled at 3, 6, 12, and 24 months. After excluding protocol violators, the data from 199 patients were analyzed. MAIN OUTCOME MEASURES: The primary outcome measure was mean loss of distance visual acuity in the study eye at 12 and 24 months. Other outcome variables analyzed were near visual acuity and contrast sensitivity. The proportions of patients losing 3 or more or 6 or more lines of distance and near acuity and 0.3 or more or 0.6 or more log units of contrast sensitivity at each follow-up were also analyzed. RESULTS: At all time points, mean distance visual acuity was better in the radiotherapy-treated group than in the control group, but the differences did not reach statistical significance. At 24 months, analysis of the proportions of patients with loss of 3 or more (moderate) (P =.08) or 6 or more (severe) (P =.29) lines of distance vision showed that fewer treated patients had severe losses, but there was no statistically significant difference between groups. For near visual acuity, although there was no evidence of treatment benefit at 12 and 24 months, a significant difference in favor of treatment was present at 6 months (P =.048). When analyzed by the proportions of patients losing 3 lines of contrast sensitivity, there was a significant difference in favor of treatment at 24 months (P =.02). No adverse retinal effects were observed during the study, but transient disturbance of the precorneal tear film was noted in treated patients. CONCLUSION: The results of the present trial do not support the routine clinical use of external beam radiation therapy in subjects with subfoveal choroidal neovascularization in age-related macular degeneration.

Aged↗
PubMed2002

A new health technology: where is the consensus on a clinically worthwhile benefit?

AIM: New therapies are often introduced into the NHS prior to full evaluation, leading to inequities in provision. Uncertainty exists regarding the value of photodynamic therapy in the treatment of neovascular age-related macular degeneration. We ascertained the availability of this treatment and the information used to inform clinical policy. METHODS: A postal survey of all clinical directors/lead consultants in the UK sought data on which (if any) patients were referred or treated with PDT by their unit, the sources of evidence informing clinical policy and the threshold of clinical benefit at which respondents would support the use of PDT. RESULTS: 123/152 questionnaires were returned. 42% of units make some provision for PDT on the NHS, including routine provision by 9%. 14.5% of units offer the option of care in the private sector, whilst 26.5% treated or referred no patients. The threshold at which respondents considered introduction of PDT would be justifiable varied widely. Respondents cited local literature review, advice from clinicians, guidance from the Royal College and information from the pharmaceutical industry as most influential in determining current policy. However, the National Institute for Clinical Excellence (NICE) and the Cochrane Library were anticipated as playing a greater role in shaping future practice. CONCLUSIONS: Substantial variation exists in the availability of PDT. Advocates of PDT may interpret our data as an indication of the NHS failing to provide an effective therapy equitably, whilst others may deduce that patients are receiving an under-evaluated treatment in routine clinical practice. The differing thresholds at which clinicians believe treatment would be justified may further exacerbate variations and the priority given to PDT.

Attitude of Health Personnel↗
PubMed2001

Binding characteristics of ET receptors in retinal pericytes and effects of high glucose incubation.

PURPOSE: Autoregulation and control of blood flow within the retina is dependent on vascular endothelial release of vasoconstrictors and dilators. The effector cells are the pericytes and vascular smooth muscle cells of the retinal microvascular bed. Many studies show that the responses of these effector cells are affected by diabetes or artificially elevated glucose. In particular, the contractile response of pericytes to endothelin-1 (ET-1) is markedly reduced. ET-1 and related isopeptides exert their effects by binding and activating specific cell surface receptors (ETRs). Pericytes express two subtypes of ETRs, ET(A) and ET(B). The purpose of this study was to assess the dynamics of [(125)I]ET-1 binding to ET(A) and ET(B) receptors when cultured in normal and high glucose concentrations. METHODS: Bovine retinal pericytes (BRP) were exposed to normal (5 mM) or high glucose (25 mM) concentrations for up to 14 days. Displacement of binding and competitive inhibition of binding was carried out in perictye membranes. mRNA expression for ETR subtypes was examined using northern blotting. The expression of G protein alpha subunits (Galpha(s) and Galpha( q)) was detected by western blotting. RESULTS: Highly specific binding of [125I]ET-1 was seen with BRP membranes. In competition assays, ET-3 was found to displace [125I]ET-1 binding to BRP membranes in a biphasic manner, indicating the presence of two classes of binding sites. The presence of both ETR subtypes was supported by competition experiments with selective ligands. The expression of Galpha(s) and Galpha(q) subunits decreased in pericytes incubated with 25 mM glucose. Conclusions. No significant differences in binding parameters were evident after culture in high glucose concentrations. However northern blot analysis which confirmed the presence of ET(B) receptor mRNA did identify an increase in the expression of this receptor.

Animals↗
PubMed2001

Improvements in measures of vision and self-reported visual function after cataract extraction in patients with late-stage age-related maculopathy.

PURPOSE: A recent study indicated that patients with cataracts and early age-related maculopathy may benefit from cataract extraction. To ascertain whether cataract extraction in the presence of concurrent advanced age-related maculopathy was also associated with a clear benefit, we studied visual function and self-reported visual functioning in a cohort of 12 patients pre- and post-phakoemulsification. METHODS. All 12 patients had a diagnosis of advanced age-related maculopathy in the eye scheduled for cataract surgery. Preoperative assessment included refraction and recording of best corrected distance and near acuity and contrast sensitivity in both eyes. The Daily Living Tasks Dependent on Vision questionnaire was administered. After phakoemulsification and intraocular lens implantation, all patients were reviewed and assessed. RESULTS: After surgery, improvement in acuity was recorded in nine operated eyes, whereas acuity remained unchanged in three eyes. Improvement in contrast sensitivity in the operated eye occurred in 10 patients, but in two patients contrast was reduced postoperatively. In terms of self-reported visual functioning, improvement in the ability to undertake many daily living tasks dependent on vision was recorded after cataract surgery. CONCLUSIONS: Significant improvements in specific areas of self-reported visual functioning and measures of vision were recorded after cataract surgery. During the follow-up period, none of the operated eyes suffered a fall in visual acuity. There was also no evidence of worsening of the pre-existing macular lesion as judged by clinical examination and fundus photography.

Aged↗
PubMed2001

Relation between macular morphology and visual function in patients with choroidal neovascularisation of age related macular degeneration.

AIM: To examine the relation between three measures of visual function (distance acuity, near acuity, and contrast sensitivity) and specific fluorescein angiographic characteristics of the macular lesion in patients with subfoveal choroidal neovascularisation (CNV) due to age related macular degeneration (AMD). METHODS: Visual evaluation and digital fundus fluorescein angiography were performed in 93 patients with subfoveal CNV. Standard morphometric techniques were used on two frames from the angiographic series closest to 30 seconds and 60 seconds respectively, to ascertain total lesion size (defined as the entire area of abnormal fluorescence), the size of the classic component, and the distance from the fovea to the closest point of healthy retina. Correlations were sought using Pearson's correlation coefficients. Stepwise regression was used to minimise multiple colinearity. RESULTS: When the study eye was the better eye of a patient's pair of eyes, the strongest correlation was between the size of the classic component and contrast sensitivity (r= 0.48, p <0.001) and was highly significant. When the study eye was the worse eye, significant correlations were observed between total lesion size and all three measures of visual function. The strongest correlation was observed between overall lesion size and contrast sensitivity (r = 0.52, p <0.001). CONCLUSIONS: This study has shown that the status of the study eye (that is, better or worse eye of a pair of eyes) influences the impact of macular pathology in AMD on visual function. The distance of the fovea from healthy retina was found to be an important factor in predicting visual function.

Aged↗
PubMed2000

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↗
PubMed2000

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↗
PubMed2000

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↗
PubMed1999

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↗
PubMed1999

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↗
PubMed1999

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↗
PubMed1999

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↗
PubMed1999

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↗