Vascular tone pathway polymorphisms in relation to primary open-angle glaucoma.

AIMS: Vascular perfusion may be impaired in primary open-angle glaucoma (POAG); thus, we evaluated a panel of markers in vascular tone-regulating genes in relation to POAG. METHODS: We used Illumina 660W-Quad array genotype data and pooled P-values from 3108 POAG cases and 3430 controls from the combined National Eye Institute Glaucoma Human Genetics Collaboration consortium and Glaucoma Genes and Environment studies. Using information from previous literature and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we compiled single-nucleotide polymorphisms (SNPs) in 186 vascular tone-regulating genes. We used the 'Pathway Analysis by Randomization Incorporating Structure' analysis software, which performed 1000 permutations to compare the overall pathway and selected genes with comparable randomly generated pathways and genes in their association with POAG. RESULTS: The vascular tone pathway was not associated with POAG overall or POAG subtypes, defined by the type of visual field loss (early paracentral loss (n=224 cases) or only peripheral loss (n=993 cases)) (permuted P≥0.20). In gene-based analyses, eight were associated with POAG overall at permuted P<0.001: PRKAA1, CAV1, ITPR3, EDNRB, GNB2, DNM2, HFE, and MYL9. Notably, six of these eight (the first six listed) code for factors involved in the endothelial nitric oxide synthase activity, and three of these six (CAV1, ITPR3, and EDNRB) were also associated with early paracentral loss at P<0.001, whereas none of the six genes reached P<0.001 for peripheral loss only. DISCUSSION: Although the assembled vascular tone SNP set was not associated with POAG, genes that code for local factors involved in setting vascular tone were associated with POAG.

Comparison of immunological parameters in patients with pemphigus vulgaris following rituximab and IVIG therapy.

BACKGROUND: Information on certain immunological parameters in patients with pemphigus vulgaris (PV) treated with rituximab (RTX) and intravenous immunoglobulin (IVIG) therapy is limited. OBJECTIVE: Comparing immunological parameters in patients who achieved long-term clinical remission (LTR) with those who relapsed. METHODS: Retrospective analysis of 19 patients treated at a single centre using the same protocol. Comparisons were made between patients who went into LTR and those who relapsed following completion of the protocol. Treatments prior to IVIG and RTX included prednisone with or without an immunosuppressive agent. The immunological parameters measured included peripheral blood B cells (CD19+), serum quantitative immunoglobulin levels, and levels of antibodies to desmogleins (Dsg) 1 and 3. RESULTS: Eleven patients achieved LTR. Eight patients developed 15 relapses. The mean follow-up time for the LTR group was 29·6±11·2months, and for the relapse group, 40·0±7·0 months. There were no significant differences in times to B-cell depletion, repopulation, or recovery to pretreatment levels between the patients who achieved LTR and those who relapsed. Recurrences usually occurred after B-cell repopulation. Repeated treatments did not influence the time to B-cell repopulation. IgM levels were decreased after therapy and remained decreased. A consistent increase in anti-Dsg1 antibody levels occurred at the time of relapse in patients with mucocutaneous disease. CONCLUSIONS: The majority of patients treated with rituximab and IVIG therapy achieved LTR. Retreatment of relapses can induce LTR. Decreased serum IgM levels persisted following treatment. Increases in anti-Dsg1 antibodies during therapy in patients with mucocutaneous disease suggests a close follow-up for a potential relapse is required.

Body mass index and the incidence of visually significant age-related maculopathy in men.

BACKGROUND: Reports have suggested relationships of body weight with age-related maculopathy (ARM), particularly its nonneovascular (dry) forms, but results are inconsistent and prospective data are scarce. OBJECTIVE: To examine prospectively relationships of body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters) with visually significant dry and neovascular ARM during an average of 14.5 years of follow-up. METHODS: Incident ARM was assessed by medical record confirmation of self-reported ARM among the 21 121 men participating in the Physicians' Health Study who (1) were followed up for at least 7 years, (2) were free of visually significant ARM at baseline, and (3) had information on BMI and cigarette smoking. We used proportional hazards regression models to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for visually significant dry ARM (256 cases) and neovascular ARM (84 cases) within 4 categories of BMI: lean (< 22.0), normal (22.0-24.9), overweight (25.0-29.9), and obese (> or = 30.0). RESULTS: Adjusting for age, randomized aspirin and beta carotene assignments, and cigarette smoking, the incidence for visually significant dry ARM was lowest in men with a normal BMI. Compared with these men, the RRs (95% CIs) were as follows: 1.43 (1.01-2.04) for lean, 1.24 (0.93-1.66) for overweight, and 2.15 (1.35-3.45) for obese men. Although there was no significant relationship of BMI with the diagnosis of neovascular ARM, due to the small number of cases these analyses could not rule out an important relationship. CONCLUSIONS: Obesity is a risk factor for visually significant ARM in men, in particular for dry ARM. However, the relationship of BMI with dry ARM appears to be J-shaped, and the leanest individuals also appear to be at increased risk.

Age-related maculopathy in a randomized trial of low-dose aspirin among US physicians.

OBJECTIVE: To examine the development of age-related maculopathy (ARM) in a large-scale trial of low-dose aspirin treatment. METHODS: The Physicians' Health Study I was a randomized, double-masked, placebo-controlled trial of low-dose aspirin (325 mg every other day) and beta carotene (50 mg every other day) in the prevention of cardiovascular disease and cancer conducted among 22 071 US male physicians aged 40 to 84 years in 1982. A total of 21 216 participants did not report ARM at baseline, were followed up for at least 7 years, and are included in this analysis. MAIN OUTCOME MEASURES: Total ARM, defined as a self-report confirmed by medical record evidence of an initial diagnosis subsequent to randomization, and ARM with vision loss, defined as total ARM but with vision loss to 20/30 or worse attributable to ARM. RESULTS: Early termination of the randomized aspirin component of the Physicians' Health Study I, after an average of 60.2 months of treatment and follow-up due to a statistically extreme 44% reduced risk of first myocardial infarction, resulted in a far lower number of incident cases of ARM during the aspirin treatment period than would have accrued without early termination. Thus, during an average of 60.2 months of follow-up, a total of 117 cases of ARM were confirmed, including 57 cases responsible for vision loss to 20/30 or worse. There were 51 cases of ARM in the aspirin group and 66 in the placebo group (relative risk, 0.77; 95% confidence interval, 0.54-1.11). For ARM with vision loss, there were 25 cases in the aspirin group and 32 in the placebo group (relative risk, 0.78; 95% confidence interval, 0.46-1.32). CONCLUSIONS: These randomized trial data tend to exclude any large beneficial effect of 5 years of low-dose aspirin treatment on ARM. However, a smaller, but potentially important, beneficial effect cannot be ruled out and would require testing in randomized trials of adequate size and duration.

Aspirin use and risk of cataract in posttrial follow-up of Physicians' Health Study I.

BACKGROUND: In Physicians' Health Study I, randomized trial results indicated no major beneficial effect of 5 years of low-dose aspirin treatment on total cataract (relative risk [RR], 0.94; 95% confidence interval [CI], 0.79-1.13) or cataract extraction (RR, 0.81; 95% CI, 0.65-1.01) during the period of treatment. OBJECTIVE: To examine the effect of assigned aspirin treatment and posttrial, self-selected aspirin use on the risk of age-related cataract over the 15 years of follow-up of Physicians' Health Study I. METHODS: Participants were 20 968 US male physicians enrolled in Physicians' Health Study I who did not report cataract at baseline. At 7 years, after termination of the randomized aspirin component of the trial, self-selected aspirin use was computed from annual questionnaires. The main outcome measures were age-related cataract and extraction of age-related cataract, defined as an incident, age-related lens opacity responsible for a reduction in best-corrected visual acuity to 20/30 or worse based on self-report confirmed by medical record review. RESULTS: During a median of 14.9 years of follow-up, there were 2081 cataracts and 1198 cataract extractions. Overall, the age- and beta carotene-adjusted RR of cataract in men assigned to aspirin compared with those assigned to placebo was 1.09 (95% CI, 1.00-1.18). For cataract extraction, the RR was 1.09 (95% CI, 0.98-1.22). During a median posttrial follow-up of 7.9 years, a total of 1225 incident cataracts and 635 cataract extractions were documented. The multivariate RR of cataract in men who reported using aspirin frequently (>/=180 days per year) at 7 years compared with nonusers (0-13 days per year) was 1.20 (95% CI, 1.03-1.40). For cataract extraction, the multivariate RR was 1.22 (95% CI, 0.98-1.51). Results for diagnosis and extraction of cataract subtypes were similar. CONCLUSIONS: Analyses based on randomized aspirin assignment indicated no long-term benefit of 5 years of low-dose aspirin treatment on total cataract or cataract extraction. Posttrial, observational data also indicated no decreased risk of cataract in aspirin users and suggested a small increased risk of cataract in aspirin users. Further randomized trial data to investigate the effect of longer term treatment with low-dose aspirin are being collected as part of the ongoing Women's Health Study, a randomized trial of low-dose aspirin and vitamin E among 39 876 apparently healthy, postmenopausal US female health professionals.

Periodontal disease and risk of subsequent cardiovascular disease in U.S. male physicians.

OBJECTIVES: We sought to prospectively assess whether self-reported periodontal disease is associated with subsequent risk of cardiovascular disease in a large population of male physicians. BACKGROUND: Periodontal disease, the result of a complex interplay of bacterial infection and chronic inflammation, has been suggested to be a predictor of cardiovascular disease. METHODS: Physicians' Health Study I was a randomized, double-blind, placebo-controlled trial of aspirin and beta-carotene in 22,071 U.S. male physicians. A total of 22,037 physicians provided self-reports of presence or absence of periodontal disease at study entry and were included in this analysis. RESULTS: A total of 2,653 physicians reported a personal history of periodontal disease at baseline. During an average of 12.3 years of follow-up, there were 797 nonfatal myocardial infarctions, 631 nonfatal strokes and 614 cardiovascular deaths. Thus, for each end point, the study had >90% power to detect a clinically important increased risk of 50%. In Cox proportional hazards regression analysis adjusted for age and treatment assignment, physicians who reported periodontal disease at baseline had slightly elevated, but statistically nonsignificant, relative risks (RR) of nonfatal myocardial infarction, (RR, 1.12; 95% confidence interval [CI], 0.92 to 1.36), nonfatal stroke (RR, 1.10; CI, 0.88 to 1.37) and cardiovascular death (RR, 1.20; CI, 0.97 to 1.49). Relative risk for a combined end point of all important cardiovascular events (first occurrence of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death) was 1.13 (CI, 0.99 to 1.28). After adjustment for other cardiovascular risk factors, RRs were all attenuated and nonsignificant. CONCLUSIONS: These prospective data suggest that self-reported periodontal disease is not an independent predictor of subsequent cardiovascular disease in middle-aged to elderly men.

A prospective study of blood pressure and risk of cataract in men.

PURPOSE: Cataract is the leading cause of blindness worldwide. Blood pressure has been identified as a risk factor in some, but not all, previous studies. We aimed to test prospectively the hypothesis that high blood pressure increases risk of age-related cataract. METHODS: Participants in the Physicians' Health Study of 22,071 men aged 40 to 84 years in 1982 completed annual questionnaires that provided medical history including self-reported blood pressure, treatment for hypertension, and cataract. Over 12 years, 1392 cataracts were confirmed by medical record review among 17,762 physicians with complete data and no reported cataract at baseline. We used proportional hazards regression models to examine relations of systolic blood pressure (SBP), diastolic blood pressure (DBP), hypertension, as well as antihypertensive medications with cataract, after control for potential confounding factors. RESULTS: In models adjusting for age and randomized treatment assignment, there was a significant relationship of SBP, but not DBP, hypertension, or antihypertensive medications (each p > or = 0.23) with incident cataract. Estimates were attenuated after adjusting for multiple potential confounders, although the relationship of SBP with incident cataract remained significant. The multivariate adjusted rate ratio (95% confidence interval) of cataract for SBP > or = 150 versus < 120 mm Hg was 1.31 (1.04-1.66), p for trend = 0.04. For DBP > or = 90 versus < 70 mm Hg, the estimate was 1.11 (0.84-1.45), p for trend = 0.33. CONCLUSIONS: Overall, these data suggest that the relationship of blood pressure with cataract is not strong, and is subject to confounding by other risk factors. The modest magnitude of the association with SBP and lack of significant relationships with DBP and hypertension may suggest a non-causal relationship of blood pressure with cataract.

HLA-B27-associated uveitis and cystoid macular edema.

OBJECTIVE: To determine which ocular and systemic characteristics are associated with cystoid macular edema (CME) in patients with HLA-B27-associated uveitis. METHODS: The authors reviewed the records of 129 patients (157 eyes) with HLA-B27-associated uveitis seen at the Massachusetts Eye and Ear Infirmary from June 1980 to June 1995. Data obtained from the records included: age, gender, duration of uveitis, follow-up duration, ocular and systemic findings, presence of CME, therapeutic intervention, and visual outcome. RESULTS: Twenty-one of 157 eyes (13.4%) with HLA-B27-associated uveitis presented with or subsequently developed CME. In 14 (67%) eyes with CME, vitreous cells were noted either at presentation or during follow-up. Forty-nine of 136 eyes (36%) without CME had vitreous cells at presentation or developed vitreous cells during follow-up. The estimated odds ratio for developing CME associated with the presence of vitreous cells was 2.9 (95% confidence interval: 1.0-8.3). No other demographic, ocular, or systemic characteristics appeared to be associated with the presence of CME. CONCLUSION: The presence of vitreous cells in patients with HLA-B27-associated uveitis may indicate an increased risk of CME development.

Relations of body fat distribution and height with cataract in men.

BACKGROUND: Cataract is the leading cause of blindness worldwide. Body mass index (BMI; in kg/m(2)) is a risk factor for cataract, but other anthropometric measurements may also be important. OBJECTIVE: We tested relations of alternative measures of body size, including height and waist-to-hip ratio (WHR), as well as BMI, with cataract. DESIGN: This was a prospective follow-up study. We analyzed data from 20271 participants in the Physicians' Health Study who did not have cataract at baseline and for whom there was complete information on weight, height, and other risk factors. For analyses concerning WHR, we excluded 3121 additional men for whom we did not have these measurements, assessed at the ninth year of follow-up. The main outcome measures were incident cataract and cataract surgery. RESULTS: Among the 17150 men for whom there were complete data, we confirmed an incident cataract in 1727 during an average of 14 y of follow-up. In proportional hazards regression models that adjusted for many known or suspected risk factors, higher BMI [rate ratio (RR) = 1.25 for >/=27.8 compared with <22, P: for trend = 0. 03], height (RR = 1.23 for >/=184 cm compared with

Blood levels of homocysteine and atherosclerotic vascular disease.

In contrast to cross-sectional and case-control studies, which tend to report strong positive associations between plasma homocysteine and vascular risk, many prospective epidemiologic studies indicate modest associations at most, whereas other prospective studies report no evidence of association. Thus, while homocysteine may represent a causal factor in atherothrombosis, it is also possible that homocysteine is a marker of preclinical disease, or a consequence of other factors more closely linked to risk. Randomized trials are necessary to test reliably whether lowering homocysteine levels will decrease risks of atherosclerotic vascular disease. Current guidelines from the American College of Cardiology and the American Heart Association do not support population-based homocysteine screening to determine cardiovascular risk.

Secondary glaucoma in patients with juvenile rheumatoid arthritis-associated iridocyclitis.

PURPOSE: The prevalence and management of glaucoma were evaluated in patients with juvenile rheumatoid arthritis (JRA)-associated iridocyclitis. METHODS: The records of 69 patients with JRA-associated iridocyclitis were reviewed. RESULTS: Twenty-nine (42%) of these patients had secondary glaucoma or ocular hypertension. Glaucoma was controlled with topical treatment in only 7 of the 41 affected eyes (17%); systemic carbonic anhydrase inhibitor therapy resulted in control of another 8 eyes. Surgery controlled all but one of the remainder. CONCLUSION: Glaucoma is a common complication of JRA-associated iridocyclitis. It results from prolonged, inadequately treated intraocular inflammation and in some instances, from steroid use. Medical and surgical therapy for the glaucoma associated with JRA-uveitis is challenging and incompletely effective. We suspect that a more aggressive approach to the treatment of JRA-associated uveitis, earlier in the course of the disease may reduce this vision robbing contribution to the process.

Baseline self-reported cataract and subsequent mortality in Physicians' Health Study I.

PURPOSE: To examine whether a reported history of cataract, a possible marker of aging, is associated with future mortality. METHODS: Participants were 18,669 of the 22,071 U.S. male physicians enrolled in the Physicians' Health Study I who had complete information at study entry, including self-report of presence or absence of baseline cataract. Participants were without a previous history of myocardial infarction, stroke, transient cerebral ischemia, or cancer (except non-melanoma skin cancer). Reported deaths were confirmed by an End Points Committee of physicians. RESULTS: A total of 581 participants reported a personal history of cataract at baseline. During an average of 12.4 years of follow-up, there were 1,514 deaths including 496 due to cardiovascular (CV) and 1,018 due to non-CV causes. After adjustment for differences in age, men who reported cataract at baseline had a non-significant 9% increased risk of death from any cause compared to men who did not report cataract (RR, 1.09; 95% CI, 0.91-1.30). The RRs were 1.03 (95% CI, 0.75-1.41) for CV death and 1.12 (95% CI, 0.90-1.40) for non-CV death. Adjustment for other risk factors had little effect on these estimates. Similar results were obtained in analyses conducted separately among those with and without self-reported diabetes at baseline. CONCLUSIONS: These results from a population of generally healthy physicians indicate that a report of a history of cataract is not associated with any material increase in mortality after adjustment for differences in age between men with and without cataract. Additional investigation of this cohort is in progress to determine whether incident age-related cataracts as well as their subtypes, confirmed by medical record review, are associated with increased mortality.

Smoking cessation and risk of age-related cataract in men.

CONTEXT: Although cigarette smoking has been shown to be a risk factor for age-related cataract, data are inconclusive on the risk of cataract in individuals who quit smoking. OBJECTIVE: To examine the association between smoking cessation and incidence of age-related cataract. DESIGN: Prospective cohort study conducted from 1982 through 1997, with an average follow-up of 13.6 years. SETTING AND PARTICIPANTS: A total of 20,907 US male physicians participating in the Physicians' Health Study I who did not have a diagnosis of age-related cataract at baseline and had reported their level of smoking at baseline. MAIN OUTCOME MEASURES: Incident age-related cataract defined as self-report confirmed by medical record review, diagnosed after study randomization and responsible for vision loss to 20/30 or worse, and surgical extraction of incident age-related cataract, in relation to smoking status and years since quitting smoking. RESULTS: At baseline, 11% were current smokers, 39% were past smokers, and 50% were never smokers. Average reported cumulative dose of smoking at baseline was approximately 2-fold greater in current than in past smokers (35.8 vs 20.5 pack-years). Two thousand seventy-four incident cases of age-related cataract and 1193 cataract extractions were confirmed during follow-up. Compared with current smokers, multivariate relative risks (RRs) of cataract in past smokers who quit smoking fewer than 10 years, 10 to fewer than 20 years, and 20 or more years before the study were 0.79 (95% confidence interval [CI], 0.64-0.98), 0.73 (95% CI, 0.61-0.88), and 0.74 (95% CI, 0.63-0.87), respectively, after adjustment for other risk factors for cataract and age at smoking inception. The RR for never smokers was 0.64 (95% CI, 0.54-0.76). The reduced risk in past smokers was principally due to a lower total cumulative dose (RR of cataract for increase of 10 pack-years of smoking, 1.07; 95% CI, 1.04-1.10). A benefit of stopping smoking independent of cumulative dose was suggested in some analyses. Results for cataract extraction were similar. CONCLUSION: These prospective data indicate that while some smoking-related damage to the lens may be reversible, smoking cessation reduces the risk of cataract primarily by limiting total dose-related damage to the lens. JAMA. 2000;284:713-716

Demographic predictors of eye care utilization among women.

BACKGROUND: Visual impairment may be preventable or treatable with timely intervention. Differences in the use of eye care services may play a role in fostering the racial and socioeconomic gap in the burden of visual impairment in the United States. OBJECTIVE: The objective of this study was to examine the frequency of eye examinations in women and how this varies with age, race, marital status, geographic region, profession, education, and income. SUBJECTS AND METHODS: We used logistic regression models to examine data obtained by mailed questionnaires from 39,876 female health professionals participating in the Women's Health Study. RESULTS: Most women (83%) had an eye examination within the past 2 years. The likelihood of having an eye examination in the past 2 years increased with age (odds ratio [OR] = 2.59 for age > or =75 years versus those <50 years; P [trend] <0.0001), higher education (OR = 1.27 for master's degree versus licensed nurse training; P [trend] = 0.0004), and higher household income (OR = 1.85 for > or =$100,000 versus <$10,000; P [trend] <0.0001). Women from the south were less likely to have had an eye examination than those from the west (OR = 0.92; P = 0.03). Compared with whites, Asian/Pacific Islanders were less likely (OR = 0.76; P = 0.02) and blacks more likely (OR = 1.27; P = 0.02) to have had an eye examination within 2 years. CONCLUSIONS: Age, education, income, race/ethnicity, and region of residence were independent predictors of having had an eye examination in the past 2 years. Known medical and ocular problems appeared to explain the association with age but not the other findings, although the clinical significance of these associations was not determined in the present study. Additional research on determinants of eye care-seeking behavior could help in devising new strategies to encourage preventive behaviors, especially among groups at higher risk of visual impairment.

Correlation of metalloproteinase-2 and -9 with proinflammatory cytokines interleukin-1b, interleukin-12 and the interleukin-1 receptor antagonist in patients with chronic uveitis.

PURPOSE: Matrix metalloproteinases have been shown to play a role in active uveitis. Transcription of MMPs is induced by a number of growth factors and cytokines. This study investigates the role of MMPs in chronic uveitis and correlates the amounts of MMP-2 and -9 in intraocular samples to the intraocular levels of proinflammatory cytokines (Interleukin-1 [IL-1], Interleukin-12 [IL-12] and Interleukin-1 receptor antagonist [IL-1ra]). METHODS: Aqueous humor of 16 patients was collected during surgical or diagnostic procedures (control group: cataract patients). MMP-2 and -9 were measured using zymography. IL-1beta, IL-12 and IL-1ra were evaluated by ELISA. RESULTS: We found MMP-2 and -9 in all of our uveitis patients. In the control group only MMP-2 was seen. Higher levels of MMP-2 and -9 were found in patients with higher activity of uveitis (p < 0.014 for MMP-2, p < 0.0054 for MMP-9). The amounts of IL-1beta, IL-12 and IL-1ra detected in our uveitis patients correlated with levels of MMP-2 (p < 0.07, p < 0.0004, p < 0.03) and MMP-9 (p < 0. 003, p < 0.0001, p < 0.002), and IL-12 (p < 0.004, p < 0.0001). Patients with moderately active uveitis presented with twice the level of MMP-2 as the control group; MMP-9 levels reached up to 92% of the amounts found in patients with active uveitis. Two patients in remission for almost one year still had detectable intraocular MMP-9 levels. CONCLUSION: Our data suggests that the high levels of MMPs found in patients with chronic uveitis might contribute to the damage often seen in these eyes. Since MMPs are capable of releasing proinflammatory cytokines bound to components of the extracellular matrix, and facilitate the secretion of active TNF-alpha by cleavage of the membrane bound form, it is conceivable that MMPs contribute to the chronicity of some uveitis cases.

Blood levels of homocysteine and increased risks of cardiovascular disease: causal or casual?

BACKGROUND: Accumulating data from epidemiological studies suggest that individuals with elevated blood levels of homocysteine have increased risks of cardiovascular disease. We reviewed the currently available evidence of an association between homocysteine and cardiovascular disease and examined whether the strength of the evidence varies according to study design. METHODS: We used a computerized MEDLINE literature search, 1966 through September 1998, to identify all epidemiological studies that examined the relationship of homocysteine level with risks of coronary heart or cerebrovascular disease. Two measures of plasma homocysteine level and its association with risk of cardiovascular disease were extracted: mean homocysteine level in cases and controls, and relative risk of cardiovascular disease for elevated homocysteine level. RESULTS: A total of 43 studies were reviewed. Most crosssectional and case-control studies indicated higher mean homocysteine levels (either fasting or after methionine load) and/or a greater frequency of elevated homocysteine level in persons with cardiovascular disease as compared with persons without cardiovascular disease. Results of most prospective studies, however, indicated smaller or no association. The few prospective studies that reported a positive association between homocysteine level and risks of cardiovascular disease included patients with preexisting vascular disease. CONCLUSIONS: In contrast to cross-sectional and case-control studies, results of prospective studies indicated less or no predictive ability for plasma homocysteine in cardiovascular disease. Instead, elevated homocysteine level may be an acute-phase reactant that is predominantly a marker of atherogenesis, or a consequence of other factors more closely linked to risks of cardiovascular disease. Randomized trials are necessary to test reliably whether lowering homocysteine levels will decrease risks of cardiovascular disease.

A randomized trial of low-dose, topical mitomycin-C in the treatment of severe vernal keratoconjunctivitis.

OBJECTIVE: To evaluate the efficacy and safety of low-dose, topical mitomycin-C in patients with severe vernal keratoconjunctivitis. DESIGN: Placebo-controlled, double-masked, randomized clinical trial. PARTICIPANTS: Twenty-six patients with vernal keratoconjunctivitis refractory to combination of steroid and mast-cell stabilizer treatment. INTERVENTION: Patients were randomly assigned (2:1) to treatment with topical 0.01% mitomycin-C eye drops (n = 17) or placebo (n = 9) three times daily for 2 weeks. MAIN OUTCOME MEASURES: Symptoms (itching, tearing, photophobia, ropy mucous discharge, foreign body sensation) and signs (conjunctival hyperemia, epithelial punctate keratitis, Trantas' dots, limbal edema, and palpebral conjunctival giant papillae) of vernal keratoconjunctivitis recorded on the day of enrollment and at the end of the treatment period. RESULTS: There was a statistically significant decrease in ropy mucous discharge, photophobia, conjunctival hyperemia, and limbal edema in the mitomycin-C treated group compared with the placebo group at the end of the 2-week treatment period. In addition, none of the 17 treated patients, but all 9 of the placebo patients, required medication during the 4-week posttreatment follow-up period. No adverse effects of treatment with mitomycin-C were observed. CONCLUSIONS: Short-term, low-dose, topical mitomycin-C may be considered in the acute exacerbation periods of patients with severe vernal keratoconjunctivitis refractory to conventional treatment.

Design of Physicians' Health Study II--a randomized trial of beta-carotene, vitamins E and C, and multivitamins, in prevention of cancer, cardiovascular disease, and eye disease, and review of results of completed trials.

PURPOSE: To assess the balance of benefits and risks of supplementation with beta-carotene, vitamin E, vitamin C, and multivitamins on cancer, cardiovascular (CVD), and eye diseases. DESIGN: Physicians' Health Study II (PHS II) is a randomized, double-blind, placebo-controlled trial enrolling 15,000 willing and eligible physicians aged 55 years and older. PHS II will utilize a 2 x 2 x 2 x 2 factorial design to test alternate day beta-carotene, alternate day vitamin E, daily vitamin C, and a daily multivitamin, in the prevention of total and prostate cancer, CVD, and the age-related eye diseases, cataract and macular degeneration. PRIOR RESULTS: The final results of the recently completed Physicians' Health Study I (PHS I), a randomized, double-blind, placebo-controlled trial in 22,071 healthy US male physicians, indicated that beta-carotene supplementation (50 mg on alternate days) had no significant benefit or harm on cancer or CVD during more than 12 years of treatment and follow-up. In regards to cancer, there were possible benefits on total and prostate cancer in those with low baseline levels assigned to beta-carotene, a finding compatible with the Chinese Cancer Prevention Study for combined treatment with beta-carotene, vitamin E, and selenium in a poorly nourished population. Further, with respect to CVD, there were apparent benefits of beta-carotene supplementation on subsequent vascular events among a small subgroup of 333 men with prior angina or revascularization. The currently available data from randomized trials of primary prevention are sparse and inconsistent for vitamin E and non-existent for vitamin C and multivitamins. For eye diseases, namely cataract and age-related macular degeneration, there are no completed large-scale randomized trials of antioxidant vitamins. CONCLUSIONS: PHS II is unique in several respects. PHS II is the only primary prevention trial in apparently healthy men testing the balance of benefits and risks of vitamin E on cancer and CVD. In addition, PHS II is the only primary prevention trial in apparently healthy men to test the balance of benefits and risks of vitamin C, multivitamins, as well as any single antioxidant vitamin, alone and in combination, on cancer, CVD, and eye diseases. Finally, PHS II is the only trial testing a priori the hypotheses that beta-carotene and vitamin E may reduce the risks of prostate cancer. Thus, PHS II will add unique as well as importantly relevant and complementary information to the totality of evidence from other completed and ongoing large-scale randomized trials on the balance of benefits and risks of beta-carotene, vitamin E, vitamin C, and multivitamins alone and in combination on prevention of cancer, CVD and eye diseases.

Risk factors for progression of distal symmetric polyneuropathy in type 1 diabetes mellitus. Sorbinil Retinopathy Trial Research Group.

In a prospective cohort study, the authors examined risk factors for progression of distal symmetric polyneuropathy (DSP) in type 1 (insulin-dependent) diabetes mellitus. The study population consisted of participants in the Sorbinil Retinopathy Trial, a randomized trial of aldose reductase inhibition among patients aged 18-56 years with type 1 diabetes mellitus of 1-15 years' duration. Diagnosis of DSP was based on standardized clinical neurologic evaluation. A total of 407 participants who did not have definite DSP at randomization and had at least one follow-up visit were included in the analysis. Stepwise Cox proportional hazards models were used to examine the independent contribution of baseline variables to progression of DSP. During follow-up (median, 40 months), 68 participants (17%) showed progression to definite DSP. After adjustment for age and treatment assignment, independent predictors of progression to definite DSP were total glycosylated hemoglobin (relative risk (RR) for increase of one percentage point = 1.25; 95% confidence interval (CI) 1.12, 1.39), height (RR associated with being one inch (2.54 cm) taller = 1.15; 95% CI 1.05, 1.26), cigarette smoking (ever vs. never) (RR = 1.87; 95% CI 1.09, 3.21), and female gender (RR = 2.26; 95% CI 1.09, 4.67). These data indicate that, in addition to the previously established role for total glycosylated hemoglobin, other factors including height, cigarette smoking, and female gender may also be independent risk factors for progression of DSP in type 1 diabetes mellitus.