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Purpose: To conduct an epidemiological survey of cataracts and examine the characteristics of lens opacities in Chinese Singaporeans. The results are then compared with those from two similar surveys previously done in Japan in Noto Area, Honshu, and Amami, Kyushu, respectively., Subjects and Methods: 468 subjects of > or = 50 years of age, who responded to the invitation to participate, were examined. Examination principally included photo-documentation of the anterior and posterior segments of both eyes. Evaluation and grading of lens opacities were done using graphical analysis of Scheimpflug and retro-illumination images. Inter-group comparisons were based on statistical analysis of cataract prevalence and distribution., Results: The prevalence of clear lenses decreased with aging with no significant difference between males and females--a finding common to Singapore and the two Japanese study groups. The prevalence of cataracts (or lens opacities of Grade II and above) in 60-79 year-old Singapore subjects was significantly higher than Noto and Amami subjects in the same age group. Further, cortical opacity was the main type in Singapore subjects in their 50s and which was significantly higher than Noto subjects of the same age group. In all age groups, the distribution and prevalence of both nuclear and subcapsular types in the Singapore group were higher than the two Japanese study groups., Conclusions: Cataracts in Chinese Singaporeans are characterized by a high prevalence of nuclear opacities which was generally seen in tropics and sub-tropics. Our study also suggested the involvement of solar-UV in cortical cataracts as well as that of additional risk factors, such as environmental temperature and race, in nuclear and subcapsular cataract formation.

Cataract epidemiological surveys applying objective judgement through lens images in the climatically different places of Noto and Amami, Japan, Singapore and Reykjavik, Iceland yielded several significant results about the influence of solar UV. 1) The percentage of transparent and of lens opacification was significantly higher in the Reykjavik subjects than in the Singaporeans. 2) The percentages including early changes were higher in Amami and Singapore than in Noto and Reykjavik. 3) Progressed lens opacification was highest in Singapore. While the main type of lens opacification was cortical in Noto and Reykjavik, that of Singapore was nuclear. 4) A significant correlation between cortical opacification and the history of time spent outdoors was noticed. The UV risk for formation and/or progression of cortical opacification should be acceptable from the epidemiological standpoint.

Movement of water in the lens, specifically water diffusion, was examined with diffusion imaging and H217O-enhanced proton imaging. Diffusion imaging showed restricted water self-diffusion in the cortex which was not concurrent with the change in proton density; nevertheless it was dependent on the gradient direction and might be related to lens fiber/protein organization. The difference in water diffusion patterns between control and galactosemic cataract was subtle but distinguishable. On the other hand, intracameral H217O injection allowed visualization of water movement across the lens. In galactosemic cataracts, water diffused from the anterior cortex towards posterior cortex and into the vitreous. This pattern was not seen in the normal lens.

We here report the analysis of single rabbit lenses under high-glucose stress using four-dimensional 13C nuclear magnetic resonance (NMR) spectroscopy (three spatial and one chemical-shift). We have produced spatial maps of lenticular metabolites (glucose, sorbitol, and lactate) with submillimeter in-plane resolution. The production of sorbitol and its inhibition are also presented. This is the first study to report regional tissue metabolism. We expect further improvements in spatial resolution and acquisition times that will enable localized kinetic studies in intact tissues.

Experimental diabetic and galactosemic animal models are widely used to study diabetes-induced complications. Galactose feeding can rapidly produce cataract, retinopathy and nephropathy; it is therefore favored over the diabetic model. Although the common feature for both models is the activation of aldose reductase, there are substantial differences between the two--not only does the rate of cataract progression differ but the metabolic patterns are far more complex than for polyol production alone. We here present the result of a comparison between diabetic and galactosemic lenses and show the differences in phosphorus and aldose metabolism, cell integrity and osmotic environment.

Immediately after cataract extraction, lenses from diabetic and nondiabetic patients were collected, classified, and assayed or incubated in high-glucose medium. The distribution of cataract types within the diabetic and nondiabetic groups was almost identical. The aldose reductase (AR) inhibitor AY22,284 (Alrestatin) was as effective in blocking sorbitol formation in diabetic as in nondiabetic lenses. While there was no difference in the level of intralenticular glucose, the diabetic lens produced significantly more sorbitol than did the nondiabetic lens. Also, the activity of polyol dehydrogenase (PD) was much lower in the diabetic population. The diabetic lenses swelled slightly more (P <.2) than nondiabetic lenses in high glucose media, and AY22,284 was effective in reducing the swelling of diabetic lenses in 35.5 mM glucose medium. While these results are preliminary, they suggest that diabetes, in some way, may confer on the human lens an increased susceptibility to osmotic stress via the sorbitol pathway. It is also reassuring to note that an AR inhibitor is no less effective in blocking the more active AR in the diabetic than in the nondiabetic lens. The therapeutic implications of this are discussed.

The American Cooperative Cataract Research Group (CCRG) has adopted a system of classifying human cataractous changes that is based on separate and independent photographic documentation of opacification and nuclear color. This system has been extremely useful to the laboratory scientist who wishes to know the significance of associations between laboratory data and the extent or type of cataractous change. It has been applied to the analysis of nearly 2500 cataracts since 1976. This study presents the details of the instrumentation and technique of this new system and the results of classifying 2231 intracapsularly-extracted cataracts.

Four groups of female Dutch-belted rabbits (Oryctulagus cuniculus) were given methoxsalen (12 mg/kg) or placebo by oral intubation and 1 hr later were exposed to UVA for either 2 or 8 hr. This procedure was repeated 5 days each week for 18 mo. A fifth group received no drug and no UVA exposure. The skin of the animals given methoxsalen and UVA showed signs of acute and chronic phototoxicity. Multiple peripheral blood parameters of hepatic, renal and hematologic function were normal and were not different between groups. Complete ophthalmoscopic examinations were performed periodically. No cataracts were seen in any of the animals. This data provides the perspective that in one species the daily dose of methoxsalen and UVA required to induce chronic cutaneous photosensitization is lower than the daily dose required to induce cataracts. It is inadvisable to interpret this data as suggesting that no risk exists for patients being treated with oral methoxsalen photochemotherapy. The experimental evidence supporting photosensitization as a cause of cataracts and implicating a role of lens DNA in this cataractogenesis is reviewed. Because methoxsalen-UVA alterations of lens DNA or protein could lead to delayed onset of cataracts, and because of the serious nature and potential preventability of phototoxic lens opacification, appropriate protective eye wear is recommended for all patients receiving oral psoralen photochemotherapy.

The polyol pathway has been implicated in the process of diabetic cataractogenesis. We report the use of deuterium (2H) spectroscopy for dynamically monitoring the polyol and glycolytic pathways in the single intact rabbit lens. Using 2H labeled C-1 D-glucose, the formation of sorbitol from glucose and the metabolism of sorbitol to fructose was dynamically monitored at 5.5 mM and 35.5 mM glucose concentrations. The accumulation of sorbitol at 35.5 mM glucose concentration was prevented by the inhibition of aldose reductase using an inhibitor (Sorbinil). 2H spectra were obtained in short acquisition times because of the short T1's of deuterated metabolites. A further advantage of 2H spectroscopy is that the natural abundance resonance of water (HDO) can be used as an internal reference standard. These findings confirm previous studies and demonstrate for the first time by NMR spectroscopy activity in the polyol pathway at low glucose concentrations.

Reduction of nonprotein disulfides required both glucose or glucose-6-phosphate (G6P) and nicotinamide adenine dinucleotide phosphate (NADP). However, hexokinase (HK) was found to be the rate-limiting step: the glucose-supported reduction rate was only 50% of that of G6P-supported activity. This disulfide-reducing activity seemed to decline in the aging lens. Further, the glucose-supported activity dropped substantially if HK was deactivated with diamide; the deactivation was partially reversible. HK activity in aging clear and cataractous human lenses had greatly diminished. This might explain the disproportionate decrease in glucose-supported reduction in the aging lens. The components of the disulfide-reducing mechanism in human lens were reviewed and discussed.

When rat lens is incubated in 30 mM galactose overnight, the extent of accumulation of rubidium ions (Rb) and myoinositol (MI) are affected, as well as the Na-K ATPase activity. Rb accumulation and Na-K ATPase activity are only slightly affected compared to the dramatic drop in MI accumulation. These changes are completely abolished by sorbinil, which blocks polyol formation, or by rendering the galactose medium hypertonic to offset the osmotic effect of polyol formation. On the other hand, the addition of excess MI to the galactose medium had no effect on correcting these changes. The results obtained are consistent with the polyol-osmotic theory of sugar cataract formation.

In the application of Topcon SL-45 Scheimpflug slit and Neitz CTR retroillumination photography to in vivo documentation of cataractous change, several sources of variance affect the results of each technique. We have measured the between-person, between-photographer, between-focal plane (Neitz), between-photo session, replicate photograph (Topcon), between-image analyst and replicate image analysis variances encountered in in vivo documentation of human cataracts with the Topcon SL-45 and Neitz-CTR cameras and our system of computerized image analysis.

We examined the aqueous/vitreous tonicity in "sugar' cataracts. Four sets of eyes and their controls were examined: diabetic human eyes, eyes from rabbits and rats fed 50% galactose for up to 1 week, and eyes from streptozotocin-diabetic rats of up to 21 days after diabetes induction. The results showed no statistically significant increase of aqueous/vitreous tonicity in the diabetic human eye and eyes from galactose-fed rats and rabbits. Diabetic rats, on the other hand, showed large tonicity increase in the vitreous, although treatment of the diabetic rats with an aldose reductase inhibitor or insulin completely normalized the tonicity. Seven days after feeding, the galactose-fed animals already showed lens opacities, while diabetic rat lenses remained clear even after 21 days after diabetes induction. These results indicate insignificant osmotic changes in the human eye. In the rat eye, the increase of lens tonicity can be offset by a concomitant increase in the vitreous tonicity. However, this phenomenon is not observed in the galactose eyes. The nature of the osmolytes in the diabetic eye is unclear, although both glucose and sorbitol have been ruled out. The presence of an osmotic regulatory mechanism in the eye is implied.

Steroids that inhibit glucose-6-phosphate dehydrogenase (G6PD) were used to examine the correlation between the loss of GSSG-reducing activity and G6PD deficiency in the lens. The correlation was found to be nonlinear. In senile cataracts, which had lost 36% of NADPH-generating activity as compared to clear lenses, the estimated loss of GSSG reduction was only 20%. On the other hand, lenses with severe G6PD deficiency (i.e. 93% loss) retained at least 28% GSSG-reducing activity. The declined reducing activity, however, suggested a possible role of G6PD deficiency in cataract formation in young patients.

Assay of the activities of hexokinase, phosphofructokinase, and pyruvate kinase showed that the first two declined in aging human lens cortex and all three enzymes retained constant activities in the epithelium throughout life. Moreover, both clear and cataractous aging lenses contained the same enzyme activities. ATP contents in cataracts, however, were lower than in clear lenses; in fact, after incubation at 37.5 degrees C in isotonic (290 to 300 mOsm), glucose-containing media, ATP was rapidly lost from cataracts (but not from clear lenses), suggesting excessive ATP expenditure in cataracts for osmotic balance. Cataracts incubated in media containing either glucose-6-phosphate or fructose-1, 6-diphosphate produced significantly higher ATP than with glucose in the media, indicating that glucose metabolism in human senile cataracts could be supplemented with hexose phosphates. Fructose-1, 6-diphosphate appeared to be more efficient than glucose-6-phosphate in preventing lens swelling during incubation.

Diabetic cataractogenesis, a multifactorial process, was examined with nuclear magnetic resonance (NMR). P-31 NMR spectroscopic studies showed substantial alteration of both energy and membrane metabolism in the diabetic lens. Findings from a C-13 NMR spectroscopic determination of the sorbitol pathway flux in lenses incubated in 35.5 mmol/L glucose revealed that (1) one-third of total glucose consumed was channeled through this pathway, and (2) the turnover rate of NADPH to NADP was 3,000%/hr. Furthermore, a competition for NADPH between aldose reductase and glutathione reductase was demonstrated. It is important to note that all metabolic changes in hyperglycemic/diabetic lenses can be prevented by aldose reductase inhibitors, eg, sorbinil.