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An independent evaluation of the Age-Related Eye Disease Study (AREDS) cataract grading system.

PURPOSE: To assess intra- and interobserver reproducibility of the Age-Related Eye Disease Study (AREDS) system for grading lens opacities and to provide data on its capacity to reliably detect changes in lens status. METHODS: Independent and replicate grading of 40 sets of lens photographs (one slit-lamp and two retroillumination photographs) were performed by three experienced observers. Patients were participants in the Collaborative Italian-American Clinical Trial of Nutritional Supplements which is testing the effect of a mineral-multivitamin supplement on age-related cataract (CTNS). Scatterplots and intraclass correlation were used to assess measurement error. RESULTS: Analysis revealed good intra- and interobserver reproducibility of the system. Greatest intraobserver measurement error showed 100% of pairs within 10% areal difference for cortical cataract, 97.5% within 15% areal difference for posterior subcapsular cataract, and 100% within 1 density unit difference for nuclear opacity. Greatest interobserver measurement error showed 95% of pairs within 10% areal difference for cortical cataract, 97.5% within 15% areal difference for posterior subcapsular cataract, and 97.5% within 1.5 density unit difference for nuclear opacity. CONCLUSIONS: The AREDS lens opacities grading system appears to be sufficiently reliable to detect changes of at least 10% areal involvement for cortical, 15% areal involvement for posterior subcapsular, and 1.0 units for nuclear opacities. It therefore seems sufficiently sensitive to adequately monitor progression of lens opacities in a longitudinal study of patients with early cataract. Its applicability in a population with advanced or complex mixed opacities must await further testing.

Aging↗

A mutation in the connexin 50 (Cx50) gene is a candidate for the No2 mouse cataract.

PURPOSE: The No2 cataractous mouse mutant displays a bilateral, congenital, hereditary nuclear opacity of the ocular lens. The aim of this work was to identify and subsequently screen an optimal candidate gene for a mutation correlated and consistent with the observed phenotype. METHODS: The No2 cataract was mapped in relation to genes and microsatellite markers by crossing to the wild mouse strain Mus spretus and then backcrossing to the inbred strain C3H/ HeH. The Cx50 (MP70) protein coding region and flanking sequences were amplified from normal parental as well as heterozygous and homozygous mutant genomic DNAs. These PCR products were then sequenced directly. Sequence data was corroborated by restriction analysis of PCR products. RESULTS: Mapping of the No2 cataract placed it in the vicinity of Gja8, the gene encoding connexin 50 (MP70), a major component of lens fiber gap junctions. Amplification and subsequent sequencing of the Cx50 protein coding regions revealed a single A-->C transversion within codon 47. This sequence change resulted in the creation of an HhaI restriction endonuclease restriction site, allowing for corroboration of the sequence data via restriction analysis using this enzyme. The sequence alteration is also predicted to result in the nonconservative substitution of alanine (Ala) for the normally encoded aspartic acid (Asp) at this position within the polypeptide. CONCLUSIONS: The identified mutation in Gja8 is both correlated and consistent with the cataract observed in the No2 mouse mutant, making it an ideal candidate for the cataract. This study provides the first evidence that a mutation in a lens connexin can result in congenital hereditary cataract, highlighting the importance of lens connexins in maintaining lens transparency.

Animals↗

Nitric oxide participates in cataract development in selenite-treated rats.

PURPOSE: The role of nitric oxide in the development of selenite-induced cataracts in rats was examined using nitric oxide synthase (NOS) inhibitors. METHODS: Subcutaneous injection of sodium selenite was used to induce cataracts in rats, with or without pretreatment with NOS inhibitors. The anterior eye segment analysis system (EAS-1000, Nidek) was used to measure lens opacity. The glutathione content of the lenses was determined by an HPLC method and the Ca2+ content by atomic absorption spectrometry. Nitrite, a stable metabolite of nitric oxide, was determined fluorometrically. NADPH-diaphorase activity staining and Western blot analysis were used to determine NOS levels. RESULTS: Administration of the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), inhibited lens opacification in selenite-treated rats. NG-nitro-d-arginine methyl ester, an inactive enantiomer of l-NAME, had no effect. Aminoguanidine, another NOS inhibitor, also inhibited the development of cataracts in a dose-dependent manner. On the other hand, L-arginine, a substrate of NOS, accelerated the development of cataracts. Although the opacification of the lenses was apparent approximately 3 days after selenite injection, the nitrite level was increased within one day. In addition, NOS was induced in the eye within one day of selenite injection. CONCLUSIONS: The present study demonstrated that NOS inhibitors prevented the development of cataracts in selenite-treated rats. The results also suggest that nitric oxide had an important role in the development of selenite-induced cataracts.

Animals↗

Comparison of Lp82- and m-calpain-mediated proteolysis during cataractogenesis in Shumiya cataract rat (SCR).

PURPOSE: It is well known that m-calpain, a ubiquitous calpain, is involved in cataract formation in rodent lens. Involvement of Lp82, a lens-specific calpain, in the cataract formation is also suggested. However, the exact relationship between Lp82-mediated proteolysis and lens opacification has not yet been established. We therefore compared Lp82- and m-calpain-mediated proteolyses of alphaA-crystallin during cataractogenesis to clarify whether Lp82 is involved in cataract formation. METHODS: In order to analyze the Lp82- and m-calpain-mediated proteolyses, we developed antibodies exclusively specific to the proteolytic products of alphaA-crystallin produced by Lp82 and m-calpain actions, respectively. The proteolytic profiles of alphaA-crystallin by Lp82 and m-calpain during cataractogenesis in SCR lenses were analyzed by Western blotting and immunohistochemical staining. RESULTS: While m-calpain-mediated proteolysis was detected predominantly in cataractous lenses, Lp82-mediated proteolysis was detected not only in cataractous but in normal lenses. The m-calpain-mediated proteolysis was observed in restricted areas developing and destined to develop opacification, i.e., the nuclear and perinuclear regions of lens. On the other hand, Lp82-mediated proteolysis was observed not only in the same regions but also in the cortical region where opacity does not develop. Unlike m-calpain-mediated proteolysis, Lp82-mediated proteolysis was not inhibited by the oral administration of aminoguanidine (AG), which acts to prevent lens opacification. CONCLUSIONS: From these results, it is shown that there is no direct contribution of Lp82-mediated proteolysis to cataract formation in SCR. Rather, Lp82 may function in fiber cell development and/or fiber cell remodeling during lens maturation under physiological conditions, since Lp82-mediated proteolysis occurs in the cortical region of normal lens.

Aging↗

Cataract: relationship between nutrition and oxidation.

Opacification of the lens, or cataract, is causally related to the precipitation of proteins or other constituents upon aging. Proteins in the lens are unusually long lived and are subject to extensive damage, including (photo)oxidation. Accumulation of damaged proteins also appears to be due in part to attenuated activity of some proteolytic pathways, which in younger tissue may serve to identify and remove such moieties. The damaged proteins accumulate, aggregate, and precipitate. Compared with other health problems, surgery to remove cataract and related visits to physicians consume the largest proportion of the Medicare budget, i.e., $3.2 billion annually in the United States. The situation is exacerbated in many parts of the world where there is a dearth of ophthalmologists to perform the required number of procedures. Historically efforts to delay cataract assumed a low profile in ophthalmologic research. Recent data, however, indicate that consuming elevated levels of antioxidants such as ascorbate, carotenoids, and tocopherol is associated with delayed development of various forms of cataract. The same beneficial relationship to vision pertains to plasma antioxidant status and to fruit and vegetable intake. Thus, it seems that assuring optimal antioxidant intake can extend lens function. It has been estimated that in the United States over half of the cataract extractions and associated costs would be obviated if cataract could be delayed by 10 years. The data reviewed indicate that optimizing nutrition will help achieve that objective.

Aged↗

Age-related cataract in a randomized trial of beta-carotene in women.

PURPOSE: To examine the development of age-related cataract in a trial of beta-carotene supplementation in women. METHODS: The Women's Health Study is a randomized, double-masked, placebo-controlled trial originally designed to test the balance of benefits and risks of beta-carotene (50 mg on alternate days), vitamin E, and aspirin in the primary prevention of cancer and cardiovascular disease among 39,876 female health professionals aged 45 years or older. The beta-carotene component of the trial was terminated early after a median treatment duration of 2.1 years. Main outcome measures were visually-significant cataract and cataract extraction, based on self-report confirmed by medical record review. RESULTS: There were 129 cataracts in the beta-carotene group and 133 in the placebo group (relative risk [RR] = 0.95, 95% CI 0.75-1.21). For cataract extraction, there were 94 cases in the beta-carotene group and 89 cases in the placebo group (RR = 1.04, 95% CI 0.78-1.39). Subgroup analyses suggested a possible beneficial effect of beta-carotene in smokers. CONCLUSIONS: These randomized trial data from a large population of apparently healthy female health professionals indicate that two years of beta-carotene treatment has no large beneficial or harmful effect on the development of cataract during the treatment period.

Aged↗

Economic cost of cataract surgery procedures in an established eye care centre in Southern India.

PURPOSE: To estimate the direct and indirect costs of three cataract surgery procedures: extracapsular cataract extraction with intra-ocular lens implantation (ECCE-IOL), phacoemulsification (PHACO) and manual small incision cataract surgery (MSICS) using economic costing principles in a well-established eye care programme (Aravind Eye Hospital) in Tamil Nadu, South India during 2000-01. Previous literature suggests that PHACO and MSICS have similar effectiveness. METHODS: The average unit cost for each surgical procedure was calculated from the societal perspective using economic costing methods. Total annual provider's direct costs for each input to surgery were calculated and apportioned appropriately to different cataract surgery techniques using a 'micro-costing approach'. The patient's direct and indirect costs for each procedure were calculated by interviewing staff and patients and by using assumptions about prices for relevant cost items such as transportation, food, medicine, spectacles and economic productivity loss. RESULTS: Average provider's direct costs were highest for PHACO procedures (25.55 US dollars) compared to MSICS (17.03 US dollars) and ECCE-IOL (16.25 US dollars). The difference can be attributed to the cost of equipment and materials. Average direct and indirect patient costs were highest for ECCE-IOL (19.85 US dollars), while the costs for PHACO and MSICS were identical (12.37 US dollars). ECCE-IOL had the highest total costs and MSICS had the lowest total costs from the societal perspective. CONCLUSIONS: Our results suggest that MSICS may have a lower societal cost than other options. Government and NGO hospitals providing cataract surgeries should invest in regular cost analyses, reviews of the literature on effectiveness, and formal cost-effectiveness analyses in order to plan economically efficient interventions. Considering the small incremental cost for providers (less than 1 US dollar), improved outcomes, and lower patient costs, we also believe that MSICS is an important technique to use in efforts to eliminate cataract blindness in India and this result may be generalised to other developing countries.

Cataract Extraction↗

Estrogen protects lenses against cataract induced by transforming growth factor-beta (TGFbeta).

Cataract, already a major cause of visual impairment and blindness, is likely to become an increasing problem as the world population ages. In a previous study, we showed that transforming growth factor-beta (TGFP) induces rat lenses in culture to develop opacities and other changes that have many features of human subcapsular cataracts. Here we show that estrogen protects against cataract. Lenses from female rats are more resistant to TGFbeta-induced cataract than those from males. Furthermore, lenses from ovariectomized females show increased sensitivity to the damaging effects of TGFbeta and estrogen replacement in vivo, or exposure to estrogen in vitro, restores resistance. Sex-dependent and estrogen-related differences in susceptibility to cataract formation, consistent with a protective role for estrogen, have been noted in some epidemiological studies. The present study in the rat indicates that estrogen provides protection against cataract by countering the damaging effects of TGFbeP. It also adds to an increasing body of evidence that hormone replacement therapy protects postmenopausal women against various diseases.

Animals↗

A juvenile-onset, progressive cataract locus on chromosome 3q21-q22 is associated with a missense mutation in the beaded filament structural protein-2.

Juvenile-onset cataracts are distinguished from congenital cataracts by the initial clarity of the lens at birth and the gradual development of lens opacity in the second and third decades of life. Genomewide linkage analysis in a multigenerational pedigree, segregating for autosomal dominant juvenile-onset cataracts, identified a locus in chromosome region 3q21.2-q22.3. Because of the proximity of the gene coding for lens beaded filament structural protein-2 (BFSP2) to this locus, we screened for mutations in the coding sequence of BFSP2. We observed a unique C-->T transition, one that was not observed in 200 normal chromosomes. We predicted that this led to a nonconservative R287W substitution in exon 4 that cosegregated with cataracts. This mutation alters an evolutionarily conserved arginine residue in the central rod domain of the intermediate filament. On consideration of the proposed function of BFSP2 in the lens cytoskeleton, it is likely that this alteration is the cause of cataracts in the members of the family we studied. This is the first example of a mutation in a noncrystallin structural gene that leads to a juvenile-onset, progressive cataract.

Adolescent↗

Naphthoquinone cataract in mice: mitochondrial change and protection by superoxide dismutase.

An injection of 1,2-naphthoquinone (NQ) into the anterior chamber of mouse eye produces anterior cortical cataract. It was previously shown by histology that mitochondria in lens epithelial cells are the target of ocular drug toxicity. In this work we investigated NQ-induced cataract by closely examining morphological changes of mitochondria and other cellular organelles in the lens epithelium. Mitochondria exhibited marked swelling in 2 hrs after NQ injection but restored the normal condensed configuration at 4.5 hrs. The nuclear chromatin showed condensation at 2 hrs and returned to the normal appearance at 4.5 hrs. This was unexpected because the lens at 4.5 hrs was cataractous due to vacuole formation in fiber cell layers. The result indicates that, although lens epithelial mitochondria are the target of NQ toxicity, cataract begins to develop before mitochondria and other subcellular organelles become totally dysfunctional. At 1 week after NQ injection, most mitochondria disintegrated and the fragmented chromatin appeared to leak out through the ruptured nuclear membrane. SOD injected with NQ significantly delayed the onset of cataract and protected lens epithelial cells. A second SOD injection further delayed cataract development.

Animals↗

The evaluation of therapeutic efficacy of hachimi-jio-gan (traditional Chinese medicine) to mouse hereditary cataract.

This study was of a series of the evaluation of Hachimi-Jio-Gan (Rehmannia Eight Formula, pa-wei-ti-huang-wan or Bawei dihuang wan) to the various cataracts. In this study, the drug was evaluated for its therapeutic efficacy to mouse hereditary cataract from the delay effect of cataract appearance age and the suppression rates of variation of some biochemical parameters. The dose of 200 mg of Hachimi-Jio-Gan/day/100 g of mouse body weight significantly delayed the cataract appearance age by 4 days as compared to that of non-treated group. We estimated that the delay effect of 4 days in mouse may be corresponded to 13.9 years, when it was converted into the case of human. This drug also suppressed variation of sodium and potassium ions level in the lens with cataractogenesis. Furthermore, the drug dramatically reactivated the sodium-potassium ATPase activity damaged with the cataract formation, and also had a slight action of reducing agent. From these facts, we presumed that the drug may have a prophylactic efficacy to the cataract caused by the inhibition of sodium-potassium ATPase activity and also the oxidation of lens protein.

Administration, Oral↗

Glucocorticoid-induced cataract of developing chick embryo as a screening model for anticataract agents.

In order to develop an effective screening model for anticataract agents, we examined the age dependence of cataract induction by glucocorticoid in developing chick embryos. Hydrocortisone sodium succinate (0.25 mumol) was administered to chick embryos on day 15 (15-day-old) and cataract formation was examined 48 hr later. Administration earlier than on day 13 or later than on day 15 was a little or ineffective. These results indicate that the formation of glucocorticoid-induced cataract in developing chick embryos depends on developing stages. The embryos treated with hydrocortisone sodium succinate on day 15 decreased GSH amount in the lens, approximately 50% of the control in 48hr. However, the embryos treated at other ages, in which cataract was not induced, showed little or no decrease of GSH. The cataract formation in chick embryos appeared to depend on structure of steroid and was due to biological activities of glucocorticoids. Since cataract is easily produced in a reproducible manner with high incidence by glucocorticoid, our chick embryo model will be a valuable model system for screening anticataract agents.

Animals↗

Nutritional status in persons with and without senile cataract: blood vitamin and mineral levels.

As part of an exploratory study of nutrition and senile cataract relationships between biochemical markers of nutritional status and senile cataract were examined in 112 subjects aged 40-70 y. Seventy-seven subjects had a cataract in at least one lens. Blood levels were determined for total carotenoids, vitamin A, vitamin D, vitamin E, vitamin C, riboflavin, thiamin, vitamin B-6, zinc, copper, selenium, and magnesium. Subjects were grouped into quintiles for each nutrient. Logistic regression was used to estimate the odds ratios (ORs) for cataract among subjects in the highest quintile and the middle three quintiles relative to subjects in the lowest quintile. ORs were adjusted for age, sex, race, and presence of diabetes. Results suggest that risk of cortical cataract was reduced for subjects in the highest quintile of vitamin D and total carotenoids and that persons with cataract may have lower levels of vitamin C and higher levels of vitamin B-6 and Se.

Adult↗

Epidemiologic evidence of a role for the antioxidant vitamins and carotenoids in cataract prevention.

The relationship between antioxidant nutrient status and senile cataract was examined in 77 subjects with cataracts and 35 control subjects with clear lenses. Subjects with low (below the 20th percentile) and moderate (20th-80th percentiles) plasma nutrient and nutrient intake levels of vitamin C, vitamin E, and carotenoids were compared with subjects with high levels (above the 80th percentile). The odds ratio (OR) of cortical (CX) cataract among subjects with low plasma carotenoid levels was 7.2 (P less than 0.05) and the OR of posterior subcapsular (PSC) cataract for persons with low plasma vitamin C was 11.3 (P less than 0.10). Low vitamin C intake was associated with an increased risk of CX (OR = 3.7, P less than 0.10) and PSC (OR = 11.0, P less than 0.05) cataract. Subjects who consumed fewer than 3.5 servings of fruit or vegetables per day had an increased risk of both CX (OR = 5.0, P less than 0.05) and PSC cataract (OR = 12.9, P less than 0.01).

Adult↗

Case-control study of indoor cooking smoke exposure and cataract in Nepal and India.

BACKGROUND: The prevalence of cataract is higher in developing countries, and in both developed and developing countries more females than males are blind from cataracts. Three epidemiological studies have associated indoor cooking with solid fuels (e.g. wood or dung) and cataract or blindness. However, associations in these studies may have been caused by unmeasured confounding. METHODS: A hospital-based case-control study was conducted on the Nepal-India border. Cases (n = 206) were women patients, aged 35-75 years with confirmed cataracts. Controls (n = 203), frequency matched by age, were patients attending the refractive error clinic at the same hospital. A standardized questionnaire was administered to all participants. Logistic regression analysis involved adjustment for age, literacy, residential area, ventilation, type of lighting, incense use, and working outside. RESULTS: Compared with using a clean-burning-fuel stove (biogas, LPG, or kerosene), the adjusted odds ratio (OR) for using a flued solid-fuel stove was 1.23 [95% confidence interval (CI) 0.44-3.42], whereas use of an unflued solid-fuel stove had an OR of 1.90 (95% CI 1.00-3.61). Lack of kitchen ventilation was an independent risk factor for cataract (OR 1.96; 95% CI 1.25-3.07). CONCLUSION: This study provides confirmatory evidence that use of solid fuel in unflued indoor stoves is associated with increased risk of cataract in women who do the cooking. The association is not likely to be due to bias, including confounding, and strengthens the findings of three previous studies. Replacing unflued stoves with flued stoves would greatly reduce this risk, although cooking with cleaner-burning fuels would be the best option.

Adult↗

Vitamin C is associated with reduced risk of cataract in a Mediterranean population.

Cataract is an important visual problem of older people and a substantial health care cost in many countries. Most studies investigating risk factors for cataract have been conducted in the United States, and there is less information on the possible role of dietary factors in European populations. We conducted a case-control study to investigate the association of antioxidant vitamins (vitamin C, vitamin E, vitamin A, beta-carotene, alpha-carotene, beta-cryptoxanthin, lycopene, zeaxanthin and lutein) and minerals (zinc and selenium) and risk of cataract in a Mediterranean population. Cases with cataract (343) and 334 age/sex frequency-matched controls aged 55 to 74 y were selected from an ophthalmic outreach clinic in Valencia, Spain. Participants were interviewed about their diet using a Food Frequency Questionnaire, and other information on potential confounders, such as smoking, alcohol, and education. Blood samples were analyzed by a colorimetric method for vitamin C and by reversed-phase HLPC for other blood antioxidants. Blood levels of vitamin C above 49 micromol/L were associated with a 64% reduced odds for cataract (P < 0.0001). Dietary intake of vitamins C, E and selenium were marginally associated with decreased odds (P = 0.09, P = 0.09, P = 0.07, respectively), whereas moderately high levels of blood lycopene (>0.30 micromol/L) were associated with a 46% increased odds of cataract (P = 0.04). Our results strengthen the evidence for a protective role for vitamin C on the aging lens as this effect was seen in a population characterized by high vitamin C intakes.

Aged↗

Associations among cataract prevalence, sunlight hours, and altitude in the Himalayas.

The relationship between cataract prevalence, altitude, and sunlight hours was investigated in a large national probability sample survey of 105 sites in the Himalayan kingdom of Nepal, December 1980 through April 1981. Cataract of senile or unknown etiology was diagnosed by ophthalmologists in 873 of 30,565 full-time life-long residents of survey sites. Simultaneously, the altitude of sites was measured using a standard mountain altimeter. Seasonally adjusted average daily duration of sunlight exposure for each site was calculated by a method which took into account latitude and obstructions along the skyline. Age- and sex-standardized cataract prevalence was 2.7 times higher in sites at an altitude of 185 meters or less than in sites over 1000 meters. Cataract prevalence was negatively correlated with altitude (r = -0.533, p less than 0.0001). However, a positive correlation between cataract prevalence and sunlight was observed (r = 0.563, p less than 0.0001). Sites with an average of 12 hours of sunlight exposure had 3.8 times as much cataract as sites with an average of only seven hours of exposure. Sunlight was blocked from reaching certain high altitude sites by tall neighboring mountains.

Adolescent↗

Would eliminating differences in physician practice style reduce geographic variations in cataract surgery rates?

This study uses Medicare physician-claims data to examine patient and physician contributions to variations in cataract surgery rates across U.S. metropolitan areas. Utilization is modelled as having two phases: the decision to seek an ophthalmologist's care, which is made by patients, and the decision to perform surgery on patients who seek care, which is partially controlled by ophthalmologists. Under this model, the effect of physician practice style on cataract surgery rates occurs through the influence of practice style on the second phase of utilization. Variation in patient care-seeking behavior contributed to the variation in the rate of cataract surgery. Moreover, multivariate regression analyses found that cataract surgery rates were influenced by economic and sociodemographic variables in predictable ways. Using the regression results, a "purged" cataract surgery rate that was free of any possible influence of physician practice style was calculated. Variation in the purged surgery rate was only slightly lower than variation in the observed surgery rate, suggesting that eliminating practice style as a factor in physician decision making (e.g., through practice guidelines) would reduce variations in cataract surgery rates by only a small amount.

Cataract Extraction↗