Appraisal of lens opacity with mometasone furoate/formoterol fumarate combination in patients with COPD or asthma.

BACKGROUND: Long-term corticosteroid use may increase cataract risk. The Lens Opacities Classification System (LOCS) III ranked lens opacities as Class 1: 0.5-0.9 unit; Class 2: 1.0-1.4 units; or Class 3: ≥1.5 units in clinical trials of combined mometasone furoate and formoterol (MF/F) administered by metered-dose inhaler (MDI). We examined retrospectively shifts in lenticular opacity in patients with chronic obstructive pulmonary disease (COPD) or asthma. METHODS: We analyzed pooled LOCS III data from two COPD studies and separately analyzed LOCS III data from an asthma study. COPD subjects were randomized to twice daily MF/F 200/10 µg, MF/F 400/10 µg, MF 400 µg, F 10 µg, and placebo; asthma subjects were randomized to MF/F 200/10 µg, MF/F 400/10 µg, fluticasone propionate/salmeterol (FP/S) 250/50 µg, and FP/S 500/50 µg. Lenticular opacity changes were analyzed post hoc for proportions of subjects with LOCS III grade increases ≥0.5, ≥1.0, or ≥1.5 units at weeks 26 and 52. RESULTS: Proportions of subjects in the COPD studies with Class 1 (≥0.5 unit), 2 (≥1.0 unit), or 3 (≥1.5 units) increases in LOCS III at week 26 (N = 1675) ranged from 15.5 to 18.6%, 3.3-6.0%, and 0.9-2.2%, respectively. At week 52 (N = 1085), proportions of active-treated subjects with Class 1, 2, or 3 increases in LOCS III ranged from 26.6 to 28.9%, 6.3-10.7%, and 2.6-5.9%, respectively. Treatment differences in lenticular shifts were generally small and nonsignificant in the asthma study. CONCLUSION: No clinically relevant trends were observed in the LOCS III assessment of lenticular shifts during treatment of COPD and asthma patients, although further study may be needed to confirm the findings presented here. In these trials, MF/F effects on lens opacity were not observed. (Clinicaltrials.gov numbers: NCT00383435, NCT00383721, and NCT00379288.).

Long-term efficacy and safety of once-daily treatment with beclomethasone dipropionate nasal aerosol.

Beclomethasone dipropionate (BDP) nasal aerosol has an established efficacy and safety profile for short-term allergic rhinitis (AR) treatment. However, managing perennial AR (PAR) symptoms often requires long-term treatment. This study evaluates efficacy and safety of long-term treatment with BDP nasal aerosol in PAR patients. In this double-blind, placebo-controlled study, patients (≥12 years [n = 529]) were randomized 4:1 to once-daily treatment with BDP nasal aerosol at 320 µg or placebo. The primary efficacy end point was change from baseline in weekly averages of patient-reported 24-hour reflective total nasal symptom score (rTNSS) over 30 weeks. Safety and tolerability of BDP nasal aerosol were also assessed. Ocular safety, including changes in intraocular pressure and severity of lens opacities (nuclear opalescence, nuclear color, cortical lens opacity, and posterior subcapsular lens opacity), was measured for patients who completed 52 weeks of treatment (n = 245). Across 30 and 52 weeks, BDP nasal aerosol significantly improved rTNSS and instantaneous TNSS (iTNSS) versus placebo (least-squares mean treatment difference, rTNSS, -0.97 for 30 weeks and -1.09 for 52 weeks, p < 0.001 for both; iTNSS, -0.96 for 30 weeks and -1.10 for 52 weeks], p < 0.001 for both). BDP nasal aerosol was well tolerated. Incidence of most adverse events with BDP nasal aerosol was similar to that with placebo, except for epistaxis, which occurred more frequently with active treatment. Severity of changes from baseline in ocular lens opacities was comparable between treatments. BDP nasal aerosol at 320 µg once daily was safe and effective for long-term PAR treatment, with no evidence of clinically adverse systemic safety events. This study was a part of the clinical trial NCT00988247 registered at www.ClinicalTrials.gov.

Ocular safety of fluticasone furoate nasal spray in patients with perennial allergic rhinitis: a 2-year study.

BACKGROUND: This is the first study, to our knowledge, to evaluate the ocular effects of an intranasal corticosteroid during 2 years of treatment for perennial allergic rhinitis (PAR). OBJECTIVE: To assess ocular safety in adult and adolescent patients 12 years and older with PAR after 2 years of continuous treatment with fluticasone furoate nasal spray (FFNS), 110 µg once daily, and placebo. METHODS: This was a 2-year, randomized, double-blind, placebo-controlled study of once-daily FFNS, 110 ìg, and placebo in 548 patients 12 years and older with PAR. The primary ocular safety end points were time to first occurrence of an event for the Lens Opacities Classification System, Version III (LOCS III), posterior subcapsular opacity (PSO) and time to first occurrence of an event for intraocular pressure (IOP). RESULTS: On the basis of survival analyses, the difference between the treatment groups for time to first occurrence of a LOCS III PSO and time to first occurrence of an IOP event was not statistically significant (P = .39 and P = .34, respectively). Changes from baseline in visual acuity, LOCS III PSO, cortical opacity, LOCS III nuclear opacity and nuclear color, IOP, and horizontal cup-to-disc similar between treatment groups. There were no ophthalmic-related adverse events of LOCS III PSO or IOP that led to early withdrawal. The most common drug-related adverse event was epistaxis (FFNS, 28%; placebo, 14%). CONCLUSION: These data neither support nor negate current recommendations for regular ophthalmic monitoring in patients treated with intranasal corticosteroids. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00682643.

NASCA report 2: Longitudinal study of relationship of exposure to space radiation and risk of lens opacity.

The NASA Study of Cataract in Astronauts (NASCA) was designed to measure the impact of exposure to space radiation on progression rates of cortical, nuclear, and posterior subcapsular cataract in U.S. astronauts who have flown in space and comparison groups of astronauts who had not flown in space, and subjects with a history of military aviation. We present our analyses of 5 years of data with an average of 3.8 exams per subject. All subjects had digital lens images with the Nidek EAS 1000 Lens Imaging System. Because of high variability and skewness of opacity measures, nonparametric methods were used to test for association between rates of opacification and space radiation exposure. First, median regression was used to collapse longitudinal data into robust estimates of progression rates (opacity severity compare to time for each eye of each subject). To quantify and test for a radiation effect, median regression with the dependent variable being the maximum of the two slopes (OD and OS) per subject was then used, adjusting for the confounding variables of age, nutritional, and sun-exposure histories. Median regression showed evidence of an association between the rate of cortical progression in the worse eye with radiation dose and age. The estimated median progression rate from space radiation being 0.25 ± 0.13% lens area/Sv/year (P = 0.062). We found no relationship between radiation exposure and progression of aggregate area of posterior subcapsular cataract or nuclear progression rates. However, longer follow-up may be needed to further understand any impact of space radiation on progression rates for posterior subcapsular cataracts and nuclear cataracts, and to characterize changes to visual acuity.

NASA study of cataract in astronauts (NASCA). Report 1: Cross-sectional study of the relationship of exposure to space radiation and risk of lens opacity.

The NASA Study of Cataract in Astronauts (NASCA) is a 5-year longitudinal study of the effect of space radiation exposure on the severity/progression of nuclear, cortical and posterior subcapsular (PSC) lens opacities. Here we report on baseline data that will be used over the course of the longitudinal study. Participants include 171 consenting astronauts who flew at least one mission in space and a comparison group made up of three components: (a) 53 astronauts who had not flown in space, (b) 95 military aircrew personnel, and (c) 99 non-aircrew ground-based comparison subjects. Continuous measures of nuclear, cortical and PSC lens opacities were derived from Nidek EAS 1000 digitized images. Age, demographics, general health, nutritional intake and solar ocular exposure were measured at baseline. Astronauts who flew at least one mission were matched to comparison subjects using propensity scores based on demographic characteristics and medical history stratified by gender and smoking (ever/never). The cross-sectional data for matched subjects were analyzed by fitting customized non-normal regression models to examine the effect of space radiation on each measure of opacity. The variability and median of cortical cataracts were significantly higher for exposed astronauts than for nonexposed astronauts and comparison subjects with similar ages (P=0.015). Galactic cosmic space radiation (GCR) may be linked to increased PSC area (P=0.056) and the number of PSC centers (P=0.095). Within the astronaut group, PSC size was greater in subjects with higher space radiation doses (P=0.016). No association was found between space radiation and nuclear cataracts. Cross-sectional data analysis revealed a small deleterious effect of space radiation for cortical cataracts and possibly for PSC cataracts. These results suggest increased cataract risks at smaller radiation doses than have been reported previously.

A randomized, controlled trial to investigate the effect of ciclesonide and beclomethasone dipropionate on eye lens opacity.

BACKGROUND: Inhaled corticosteroids (ICS) are recommended first-line therapy for the treatment of persistent asthma. However, reports from observational studies have suggested that the use of ICS may be associated with systemic adverse events, such as glaucoma and cataract (opacity of the lens) formation. OBJECTIVE: To compare two ICS over 1 year regarding the formation/progression of lenticular opacities in patients with asthma. METHODS: Adults (>or=18 years of age) with moderate-to-severe asthma were randomized to ciclesonide 640 micro g/day (n = 785) or beclomethasone dipropionate 640 micro g/day (n = 783) in a multinational, double-blind, active-controlled, parallel-group study. The primary endpoint was the occurrence of a positive Class I grading shift (increase [worsening] in Lens Opacities Classification System [LOCS] III score of >or= 0.5 for nuclear opalescence, >or= 0.8 for cortical opacification, or >or= 0.5 for posterior subcapsular opacification, or cataract surgery) in either eye at any visit over the 12-month, double-blind treatment period. RESULTS: Mean changes (+/- standard error) in nuclear opalescence and cortical and posterior subcapsular opacification were small and similar between groups (ciclesonide 640 micro g/day: 0.10 +/- 0.02, 0.07 +/- 0.02 and 0.04 +/- 0.01, respectively; beclomethasone dipropionate 640 micro g/day: 0.11 +/- 0.02, 0.09 +/- 0.02 and 0.03 +/- 0.01, respectively). Class I shifts were observed in 34.3% versus 36.8% of ciclesonide-treated and beclomethasone dipropionate-treated patients, respectively. Ciclesonide 640 micro g/day was non-inferior to beclomethasone dipropionate 640 micro g/day regarding Class I shifts (risk ratio of ciclesonide to beclomethasone dipropionate, 0.940 [95% confidence interval, 0.820-1.077]); the 95% confidence interval upper bound was lower than the pre-specified non-inferiority bound of 1.333 (p < 0.0001), thereby excluding the possibility of higher risk ratio values. CONCLUSIONS: Mean changes in LOCS III scores were very small in both groups. Treatment with ciclesonide 640 micro g/day or beclomethasone dipropionate 640 micro g/day for 1 year has a minimal impact on lenticular opacities development and/or progression.

Protein-protein interactions between lens vimentin and alphaB-crystallin using FRET acceptor photobleaching.

PURPOSE: The R120G mutation of alphaB-crystallin is known to cause desmin-related myopathy, but the mechanisms underlying the formation of cataract are not clearly established. We hypothesize that alteration of protein-protein interaction between R120G alphaB-crystallin and lens intermediate filament proteins is one of the mechanisms of congenital cataract. METHODS: Protein-protein interactions were determined by confocal fluorescence resonance energy transfer (FRET) microscopy using green fluorescence protein (GFP) as the donor and red fluorescence protein (RFP) as the acceptor. The lens vimentin gene was fused into a GFP vector and the alphaB-crystallin (WT or R120G mutant) gene was fused into the RFP vector. The donor-acceptor plasmid pairs of intermediate filament (IF)-GFP and alphaB-RFP were co-transfected into HeLa cells. After incubation, confocal fluorescence images of the transfected cells were taken. FRET was estimated by the acceptor photobleaching method. Protein-protein interaction was evaluated by FRET efficiency. RESULTS: The confocal fluorescence images showed that the cells expressing vimentin and R120G alphaB-crystallin contained large amounts of protein aggregates while few vimentin fibers were observed. FRET efficiency analyses indicated that vimentin had a significantly greater protein-protein interaction with R120G alphaB-crystallin than with WT alphaB-crystallin. CONCLUSIONS: Our results show that the R120G alphaB-crystallin mutant promoted vimentin aggregation through increased protein-protein interaction. This process may contribute to the formation of congenital cataract.

Intake of zinc and antioxidant micronutrients and early age-related maculopathy lesions.

BACKGROUND: Macular degeneration, the end stage of age-related maculopathy (ARM), is the leading cause of legal blindness worldwide, and few modifiable risk factors are known. The high concentration of carotenoids in the macula, plus evidence linking oxidative stress to ARM and carotenoids to antioxidation, generated the hypothesis that higher antioxidant intakes can prevent ARM. Results of observational and intervention studies have been inconsistent. OBJECTIVE: To evaluate associations between intakes of zinc and antioxidant micronutrients and early ARM. METHODS: Between 1993 and 1995, ARM was assessed in 398 Boston-area women aged 53-74 y using the Wisconsin Age-related Maculopathy System of grading retinal fundus photographs. The women were a subset of the Nurses' Health Study cohort. Micronutrient intake was assessed by semi-quantitative food frequency questionnaires administered four times between 1980 and the baseline eye examinations. RESULTS: After multivariate adjustment for potential confounders, 1980 energy-adjusted intakes of alpha-carotene, beta-carotene, lycopene, total retinol, total vitamin A, and total vitamin E were significantly inversely related to the prevalence of pigmentary abnormalities (PA). Furthermore, increasing frequency of consuming foods high in alpha-or beta-carotene was associated with lower odds of PA; compared to women consuming these foods < 5 times/wk, odds ratios (95% CI) were 0.7 (0.3-1.6) for 5-6 times/wk, 0.6 (0.2-1.3) for 7-9.5 times/wk, and 0.3 (0.1-0.7)for > or =10 times/wk. Lutein/zeaxanthin intakes and more recent intakes of most carotenoids were unrelated to PA, and intakes of zinc and antioxidant micronutrients were unrelated to having large or intermediate drusen alone.

Dietary linolenic acid intake is positively associated with five-year change in eye lens nuclear density.

OBJECTIVE: Dietary fat may affect lens cell membrane composition and function, which are related to age-related cataract. The present study was designed to examine the associations between dietary fat and the change in nuclear lens opacification over five years. METHODS: Women aged 52 to 73 years without previously diagnosed cancer, diabetes and cataracts from the Boston, Massachusetts area were selected from the Nurses' Health Study cohort. Four hundred forty women participated in a baseline (1993-95) and a follow-up (1998-2000) eye examination. Intakes of total fat and selected fatty acids were calculated as the average intake from five food frequency questionnaires that were collected between 1980 and baseline. Change in the degree of nuclear density (opacification) was characterized by the difference between baseline and follow-up in pixel density at the central clear zone in the Scheimpflug slit image of the lens. RESULTS: Intake of alpha-linolenic acid (ALA) was positively associated with change in nuclear density. The geometric mean nuclear density change was 16% greater in the highest quartile category of ALA intake than in the lowest quartile category (P for trend = 0.05). For women in the high tertile category of baseline nuclear lens opacification, the geometric mean change in the highest quartile category of ALA acid intake was 70% higher than the change in the lowest quartile category (P for trend = 0.01). There were no significant associations between other dietary fats and change in nuclear density. CONCLUSION: Higher ALA intake was associated with a greater age-related change in lens nuclear density.

Topical ocular hypotensive medication and lens opacification: evidence from the ocular hypertension treatment study.

PURPOSE: To determine whether topical ocular hypotensive medication is associated with refractive changes, visual symptoms, decreased visual function, or increased lens opacification. DESIGN: Multi-center clinical trial. METHODS: We compared the medication and observation groups of the Ocular Hypertension Treatment Study (OHTS) during 6.3 years of follow-up with regard to the rate of cataract and combined cataract/filtering surgery, and change from baseline in visual function, refraction, and visual symptoms. A one-time assessment of lens opacification was done using the Lens Opacities Classification System III (LOCS III) grading system. RESULTS: An increased rate of cataract extraction and cataract/filtering surgery was found in the medication group (7.6%) compared with the observation group (5.6%) (hazard ratio [HR] 1.56; 95% confidence interval [CI] 1.05 to 2.29). The medication and observation groups did not differ with regard to changes from baseline to June 2002 in Humphrey visual field mean deviation, Humphrey visual field foveal sensitivity, Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity, refraction, and visual symptoms. For the medication and observation groups, LOCS III readings were similar for nuclear color, nuclear opalescence, and cortical opacification. There was a borderline higher mean grade for posterior subcapsular opacity in the medication group (0.43 +/- 0.6 SD) compared with the observation group (0.36 +/- 0.6 SD) (P = .07). CONCLUSIONS: We noted an increased rate of cataract extraction and cataract/filtering surgery in the medication group as well as a borderline higher grade of posterior subcapsular opacification in the medication group on LOCS III readings. We found no evidence for a general effect of topical ocular hypotensive medication on lens opacification or visual function.

Dietary glycemic index and carbohydrate in relation to early age-related macular degeneration.

BACKGROUND: Several dietary factors have been linked to age-related maculopathy (ARM), the early form of age-related macular degeneration, and there is reason to think that dietary carbohydrate may play a role in the development of ARM. OBJECTIVE: The purpose of the present study was to examine the relation between dietary carbohydrate quality, as measured by dietary glycemic index (GI) or total carbohydrate intake, and ARM. DESIGN: From the Nurses' Health Study, 1036 eyes from 526 Boston-area participants without a previous ARM diagnosis were included in the present study. The presence and degree of ARM were classified by the Age-Related Eye Diseases Study system. Long-term dietary information was based on data from an average of 4 food-frequency questionnaires collected over a 10-y period before the assessment of ARM. With eyes as the unit of analysis, we used a generalized estimating approach to logistic regression to estimate the odds ratios for ARM in a manner that accounted for the lack of independence between the 2 eyes from the same subject. RESULTS: After multivariate adjustment, dietary GI was related to ARM (specifically to retinal pigmentary abnormalities), whereas total carbohydrate intake was not. The odds ratio for ARM being in the highest tertile of dietary GI (> or =77.0) versus the lowest (<74.6) was 2.71 (95% CI: 1.24, 5.93; P for trend = 0.01). Neither dietary GI nor total carbohydrate intake was related to drusen. CONCLUSION: Our results suggest that dietary GI may be an independent risk factor for ARM.

DNA binding domains and nuclear localization signal of LEDGF: contribution of two helix-turn-helix (HTH)-like domains and a stretch of 58 amino acids of the N-terminal to the trans-activation potential of LEDGF.

Lens epithelium derived growth factor (LEDGF), a nuclear protein, plays a role in regulating the transcription of stress-associated genes such as heat shock proteins by binding to consensus core DNA sequences nAGGn or nGAAn or their repeats, and in doing so helps to provide cyto-protection. However, additional information is required to identify the specific structural features of LEDGF involved in gene transcription. Here we have investigated the functional domains activating and repressing DNA-binding modules, by using a DNA binding assay and trans-activation experiments performed by analyzing proteins prepared from deletion constructs. The results disclosed the DNA-binding domain of N-terminal LEDGF mapped between amino acid residues 5 and 62, a 58 amino acid residue stretch PWWP domain which binds to stress response elements (STRE; A/TGGGGA/T). C-terminal LEDGF contains activation domains, an extensive loop-region (aa 418-530) with two helix-turn-helix (HTH)-like domains, and binds to a heat shock element (HSE; nGAAn). A trans-activation assay using Hsp27 promoter revealed that both HTH domains contribute in a cooperative manner to the trans-activation potential of LEDGF. Interestingly, removal of N-terminal LEDGF (aa 1-187) significantly enhances the gene activation potential of C-terminal LEDGF (aa 199-530); thus the N-terminal domain (aa 5-62), exhibits auto-transcriptional repression activity. It appears that this domain is involved in stabilizing the LEDGF-DNA binding complex. Collectively, our results demonstrate that LEDGF contains three DNA-binding domains, which regulate gene expression depending on cellular microenvironment and thus modify the physiology of cells to maintain cellular homeostasis.

Carbohydrate intake and glycemic index in relation to the odds of early cortical and nuclear lens opacities.

BACKGROUND: Animal studies suggest a role for dietary carbohydrate in cataractogenesis. However, few published human studies have evaluated associations between carbohydrate nutrition and lens opacification. OBJECTIVE: Our objective was to test the hypothesis that long-term carbohydrate intake and dietary glycemic index are associated with the odds of early cortical and nuclear opacities. DESIGN: Subjects were 417 Boston-area members of the Nurses' Health Study cohort aged 53-73 y. Dietary information was based on an average from 5 semiquantitative food-frequency questionnaires collected over a 14-y period. Opacities were assessed by using the Lens Opacity Classification System III (LOCS III). We used eyes (n = 711) as the unit of analysis and generated odds ratios by using a generalized estimating approach to logistic regression to account for the lack of independence between the 2 eyes of each subject. RESULTS: After multivariate adjustment, the odds of cortical opacities (LOCS III >/=1.0) among women in the highest tertile of carbohydrate intake (>/=200 g/d) was 2.46 times (95% CI: 1.30, 4.64; P for trend = 0.005) that among women in the lowest tertile (<185 g/d). This association was not affected by adjustment for dietary glycemic index, which was not associated with early cortical opacities. Carbohydrate nutrition was not associated with the odds of nuclear opacities (LOCS III >/=2.5). CONCLUSIONS: These data suggest that carbohydrate quantity, but not carbohydrate quality, is associated with early cortical opacities, and that neither the quantity nor the quality of dietary carbohydrate affects the risk of nuclear opacities in middle-aged women.

Dietary fat intake and early age-related lens opacities.

BACKGROUND: Dietary fat may affect lens cell membrane composition and function, which are related to age-related cataract. OBJECTIVE: The objective of the study was to examine the association between long-term dietary fat intake and the prevalence of age-related nuclear, cortical, and posterior subcapsular lens opacities. DESIGN: Women (n = 440) aged 53-73 y from the Boston area without previously diagnosed cancer, diabetes, or cataract were selected from the Nurses' Health Study cohort. Intakes of total fat and selected fatty acids were calculated as the average of intake data from 5 food-frequency questionnaires collected between 1980 and the study eye examination (1993-1995). Nuclear opacity was defined as grade >/=2.5, cortical opacity as grade >/=1.0, and posterior subcapsular opacity as grade >/=0.5 according to the Lens Opacities Classification System III. RESULTS: There were significant positive associations between linoleic and linolenic acid intakes and the prevalence of nuclear opacity. The odds ratios for nuclear opacity in women with intakes in the highest quartile and women with intakes in the lowest quartile were 2.2 (95% CI: 1.1, 4.6; P for trend = 0.02) for linoleic acid and 2.2 (95% CI: 1.1, 4.5; P for trend = 0.05) for linolenic acid. There were no significant associations between intakes of any type of fat and either cortical or posterior subscapular opacity. CONCLUSIONS: High intake of the 18-carbon polyunsaturated fatty acids linoleic acid and linolenic acid may increase the risk of age-related nuclear opacity. Further study is needed to clarify the relation between dietary fat and cataract risk.

Long-term nutrient intake and 5-year change in nuclear lens opacities.

OBJECTIVE: To determine if usual nutrient intake is related to a 5-year change in the amount of lens nuclear opacification assessed by computer-assisted image analysis. DESIGN: A sample of 408 Boston, Mass-area women from the Nurses' Health Study aged 52 to 74 years at baseline participated in a 5-year study related to nutrition and vision. Usual nutrient intake was calculated as the average intake from 5 food frequency questionnaires that were collected over a 13- to 15-year period before the baseline evaluation of lens nuclear density. Duration of vitamin supplement use before baseline was determined from 7 questionnaires collected during this same period. We assessed the degree of nuclear density (opacification) using computer-assisted image analysis of digital lens images with amount of nuclear density measured as a function of average pixel gray scale, ranging from 0 (clear) to 255 (black). RESULTS: Median (range) baseline and follow-up nuclear densities were 44 (19 to 102) and 63 (32 to 213). The median (range) 5-year change in nuclear density was 18 (-29 to 134) and was positively correlated with the amount of opacification at baseline (Spearman correlation coefficient = 0.35; P<.001). Geometric mean 5-year change in nuclear density was inversely associated with the intake of riboflavin (P trend = .03) and thiamin (P trend = .04) and duration of vitamin E supplement use (P trend = .006). CONCLUSION: Our results suggest that long-term use of vitamin E supplements and higher riboflavin and/or thiamin intake may reduce the progression of age-related lens opacification.

LEDGF regulation of alcohol and aldehyde dehydrogenases in lens epithelial cells: stimulation of retinoic acid production and protection from ethanol toxicity.

Retinoic acid (RA) is required for the normal growth and maintenance of many cell types, including lens epithelial cells (LECs). Alcohol (ADH) and aldehyde (ALDH) dehydrogenases are implicated in cellular detoxification and conversion of vitamin A to RA. Lens epithelium-derived growth factor (LEDGF) provides cellular protection against stress by transactivating stress-associated genes. Here we show evidence that LEDGF binds and transactivates heat shock (nGAAn) and stress response (A/TGGGGA/T) elements in the promoters of ADH1, ADH4, and retinaldehyde 2 (RALDH2) genes. Electrophoretic mobility and supershift assays disclosed specific binding of LEDGF to nGAAn and A/TGGGGA/T elements in these gene promoters. Transfection experiments in LECs with promoters linked to a chloramphenicol acetyltransferase (CAT) reporter gene along with LEDGF cDNA revealed higher CAT activity. RT-PCR results confirmed that LECs overexpressing LEDGF contained increased levels of ADH1, ADH4, and RALDH2 mRNA. Notably, LECs displayed higher LEDGF mRNA and protein expression during ethanol stress. Cells overexpressing LEDGF typically exhibited elevated RA levels and survived well during ethanol stress. The present findings indicate that LEDGF is one of the transcriptional activators of these genes that facilitates cellular protection against ethanol stress and plays a role in RA production.

Overall adherence to the dietary guidelines for americans is associated with reduced prevalence of early age-related nuclear lens opacities in women.

Few studies have examined the efficacy of the Dietary Guidelines for Americans in the prevention of age-related chronic disease, such as age-related cataract. We examined whether adherence to the Guidelines was associated with a lower prevalence of age-related nuclear lens opacities in women. Eye exams were conducted in 479 Nurses' Health Study participants aged 52 to 73 y without previously diagnosed cataract or diabetes living in the Boston, MA area. Four FFQs, collected during a 9- to 11-y period before evaluation of lens status, were used to define diet quality according to the following: 1) daily number of servings of fruits, vegetables, and whole grains; 2) Recommended Foods Score (RFS); and 3) Healthy Eating Index (HEI). Nuclear opacities were defined as scores >/= 2.5 using the Lens Opacification Classification System III. After adjusting for age, smoking, and other risk factors, women in the highest quartile category of HEI scores were significantly less likely to have nuclear opacities than those in the lowest category [odds ratio (OR) = 0.47; 95% CI: 0.26-0.84]. This association appeared to be stronger among nonusers of supplemental vitamin C (OR = 0.23; 95% CI: 0.10-0.52). Decreased prevalence odds of nuclear opacities were also observed with high intake of fruit (OR = 0.58; 95% CI: 0.32-1.05) and whole grains (OR = 0.64; 95% CI: 0.36-1.15). These results suggest that overall compliance with the Dietary Guidelines, as measured by the HEI, protects against nuclear opacities.

Moderate alcoholic beverage intake and early nuclear and cortical lens opacities.

PURPOSE: To study the relationship between alcoholic beverage intake and early lens opacities. METHODS: 556 Boston-area women aged 53-74 years were sampled from the Nurses' Health Study cohort. Degree of opacity was assessed by eye examinations including lens photography. RESULTS: After multivariate adjustment, the odds of a nuclear opacity grade > or =2.3 increased by 30% (OR=1.3, 95% CI: 1.10-1.54) per 10-g increase in total alcohol intake. Furthermore, after control for intake of other alcoholic beverages, the odds of a higher nuclear opacity grade increased by 13% (OR=1.13, 95% CI: 1.02-1.26) for every two additional hard-alcoholic drinks consumed per week, and by 17% (OR=1.17, 95% CI: 1.03-1.33) for every two additional glasses of wine consumed per week. The odds of a cortical opacity grade > or =0.4 decreased by 12% (OR=0.88, 95% CI: 0.79-0.98) for every two additional glasses of wine consumed per week, but intake of other alcoholic beverages was unrelated to cortical opacity. CONCLUSIONS: Consumption of alcoholic beverages, particularly hard liquor and wine, was positively related to nuclear opacity. Wine drinking was inversely related to cortical opacity.

Lens epithelium-derived growth factor (LEDGF/p75) expression in fetal and adult human brain.

Lens epithelium-derived growth factor (LEDGF/p75) is a novel transcription co-activator that is critically involved in lens epithelial cell gene regulation and stress responses. Recent evidence indicates that LEDGF/p75 may play an important role in lens epithelial to fibre cell terminal differentiation. Since the lens and the brain are both ectodermally derived organs generated from epithelioid progenitor cells, we hypothesize that LEDGF/p75 is expressed and subserving similar functions in both organs. To investigate this hypothesis, we studied LEDGF/p75 expression and localization in the human brain. We detected LEDGF/p75-specific RT-PCR reaction products in both fetal and adult human brain. LEDGF/p75 mRNA expression in the brain exhibited differential developmental and regional specificity. LEDGF/p75 transcript was markedly elevated in fetal as compared to adult brain. In the adult brain, LEDGF/p75 mRNA expression was substantial in the subventricular zone (SVZ), scant in hippocampus, and undetectable elsewhere. To study LEDGF/p75 protein expression and localization, we developed and purified a new anti-LEDGF/p75 polyclonal antibody directed against a unique C-terminal region of LEDGF/p75. Western blot analysis of fetal and adult human brain revealed a approximately 75 kDa protein that demonstrated developmental and regional specificity similar to that detected by RT-PCR analysis. LEDGF/p75 protein expression was high in fetal brain and in the adult SVZ. Immunohistochemical studies of human fetal brain showed prominent LEDGF/p75-immunoreactive cells in the germinal neuroepithelium and cortical plate regions. Analysis of adult and aged human brain revealed LEDGF/p75-immunoreactive cell enrichment in the SVZ adjacent to the ventral region of the lateral ventricle at the level of the anterior commissure, a region implicated in adult neurogenesis. We utilised a primary mixed cortical cell culture system to identify LEDGF/p75 in neurons, but not astrocytes. Neuronal LEDGF/p75 exhibited a predominantly perinuclear distribution pattern. These data demonstrate that LEDGF/p75 is expressed in discrete regions and cell types within the fetal and adult human brain. Moreover, the developmental and regional expression patterns of LEDGF/p75 suggest that this transcriptional co-activator may be involved in neuroepithelial stem cell differentiation and neurogenesis.

Weight status, abdominal adiposity, diabetes, and early age-related lens opacities.

BACKGROUND: The association between weight status and the risk of lens opacities has received little attention. OBJECTIVE: We examined the cross-sectional relations of body mass index (BMI; in kg/m(2)), waist circumference, and diabetes with the presence of age-related lens opacities. DESIGN: Eye examinations were conducted in 466 Boston-area women aged 53-73 y who were without previously diagnosed cataracts and were part of the Nurses' Health Study cohort. Weight, height, waist, and hip measurements were obtained by self-report. Lens status was evaluated by using the Lens Opacification Classification System III (LOCS III). BMI and waist circumference were used as measures of overweight and abdominal adiposity, respectively. Nuclear, cortical, and posterior subcapsular (PSC) opacities were defined as LOCS III scores > or = 2.5, > or = 1.0, and > or = 0.5, respectively. Diabetes was defined as a history of type 2 diabetes or as a fasting plasma glucose concentration > or = 7.0 mmol/L. RESULTS: Women with diabetes were significantly more likely to have PSC opacities [odds ratio (OR): 4.1; 95% CI: 1.8, 9.4] than were women with fasting plasma glucose concentrations < 6.1 mmol/L. Women with a BMI > or = 30 had a higher prevalence of PSC opacities than did women with a BMI < 25 (OR: 2.5; 1.2, 5.2), and women with a waist circumference > or = 89 cm had a higher prevalence of PSC opacities than did those with a waist circumference < 80 cm (OR: 2.3; 1.0, 5.2). Diabetes and measures of adiposity were unrelated to the prevalence of cortical and nuclear opacities. CONCLUSIONS: Diabetes is a strong risk factor for PSC opacities, and overweight and abdominal adiposity may be risk factors for PSC opacities.