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Objective: To examine the relationships between smoking and the 5-year incidence of new nuclear opacities and between smoking and the progression of nuclear opacities in a prospective study of a cohort of Chesapeake Bay watermen. Methods: A total of 442 men (age, ≥30 years in 1985) with paired, gradable lens photographs in at least one eye in both 1985 and 1990 were studied. Photographs were graded by two readers who used the grading scheme of the Wilmer Institute, Baltimore, Md, with severity ranging in decimal units between 0.0 and 4.0. Data on the smoking history of the subjects were collected by personal interviews that were conducted in 1985 and updated in 1990. Results: The incidence and progression of opacities increased with age. A nonsignificant association was observed between smoking (for both current and exsmokers) and the incidence of a nuclear opacity. The risk of progression of nuclear opacities of less than grade 3 at baseline to grade 3 or worse was 2.4-fold higher among current smokers in 1985, compared with that among exsmokers and nonsmokers (95% confidence limits: 1.0, 6.0) after adjustment for age, baseline opacity status, and alcohol use. An 18% increased risk of progression was significantly associated with each pack-year that a subject smoked between 1985 and 1990. Conclusion: These data confirm previous findings that smoking is associated with a nuclear opacity, particularly with progression to severe opacities.

To compare ofloxacin solution with a combination of fortified antibiotic cefazolin sodium and tobramycin sulfate solutions in the treatment of bacterial keratitis.Patients under care at any one of 28 participating clinical centers who had an eye with suspected bacterial keratitis were randomly allocated in a double-masked manner to treatment with 0.3% ofloxacin solution or a combination of the fortified antibiotics (1.5% tobramycin and 10.0% cefazolin solutions).Time to healing defined as complete re-epithelization, accompanied by a nonprogressive stromal infiltrate for two consecutive visits. Secondary outcome measures included patient symptoms and signs of infection and adverse reactions to study medications. Only patients with a positive bacterial corneal culture were included in most analyses.A positive bacterial corneal culture was obtained in 140 (56%) of the 248 enrolled patients. The time to healing was similar among the 73 patients receiving ofloxacin and the 67 patients receiving fortified antibiotics (P = .70). By 7 days after study entry, the keratitis in 37% of the ofloxacin group and 38% of the fortified antibiotics group had healed. By 28 days, keratitis in 89% of the ofloxacin group and 86% of the fortified antibiotics group had healed. Two patients receiving ofloxacin and one receiving fortified antibiotics discontinued study medication because of lack of efficacy. Patients receiving ofloxacin reported substantially less burning and stinging on instillation than the patients receiving fortified antibiotics (P.001). Five of six patients among the 140 with positive bacterial cultures who had study medications discontinued because of ocular side effects were in the fortified antibiotics group; an additional three patients, all in the fortified antibiotics group, among the remaining 108 receiving study medications had ocular side effects.The efficacy of ofloxacin solution in treating bacterial keratitis is equivalent to that of the fortified cefazolin and tobramycin solutions. The reduced frequency of ocular toxic effects and the relative ease of preparation of ofloxacin are additional considerations.

In reply We thank Dr Tiedeman for his careful reading of our article and his thoughtful comments. As we emphasized in our discussion, advising whether a particular patient should be treated with laser photocoagulation involves consideration of both short- and long-term effects of the treatment and characteristics of the patient such as the condition of the fellow eye. We and Dr Tiedeman are in agreement that the reason that group B patients are good candidates for immediate treatment is the reduced risk for severe loss of vision that begins at 12 months after treatment and endures for at least 3 additional years. This sustained period of lower risk for loss of vision outweighs, in our opinion, the period of increased risk immediately following treatment. Members of the Macular Photocoagulation Study Group are listed in the April issue of theArchiveson page 482.

The Collaborative Corneal Transplantation Studies (CCTS) were designed to evaluate the effect of donor-recipient histocompatibility matching and cross-matching on the survival of corneal transplants in high-risk patients. We now report on the role of symptoms in the detection of corneal allograft reactions in the CCTS and on the relationship between symptom reporting and graft survival. The 456 patients transplanted in the CCTS were followed for a minimum of 2 years or until graft failure. The follow-up protocol included 11 scheduled examinations in the first year, four examinations during the second year, and examinations every 6 months thereafter. Interim examinations were performed in response to patient-reported symptoms. At every examination, patients were asked specifically if they had redness, sensitivity to light, loss of vision, or pain (RSVP). Of the 456 patients transplanted, 62% had at least one graft reaction. Patients diagnosed with reactions at scheduled visits in the first postoperative year were 2.5 times more likely to report symptoms than those without reactions. Reports of red eye and vision loss were strongly associated with allograft reaction. However, these symptoms were neither highly sensitive nor specific for reaction (sensitivity = 46%, specificity = 70% at 6 months). The severity of reaction influenced the reporting of symptoms: 69% of patients with severe reactions reported symptoms versus 48% of patients with mild reactions (p < 0.001). The only patient characteristic associated with reliable symptom reporting was age, with younger patients with reactions being more likely to report symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

In reply We thank Dr Bloom for his letter and the opportunity to amplify the explanation we published concerning the definition of an MPS disc area. The MPS disc area and all previous MPS measurements are based on the assumptions that the optic disc is equal to 1500 μm and that the magnification of the photographs on a 35-mm negative is 3.0. These assumptions were made to derive a standard unit for measuring an area because the exact size of each optic disc differs and the magnification of cameras differs, not only by individual camera but also by refractive properties of the eye. 1 Because of these variations, we have been careful to use the term MPS disc areas rather than the unmodified term disc areas. These standard areas have been published, and templates with these standard areas to use on 35-mm negative angiograms derived from a 30° fundus camera

To the Editor. —Published reports by the Macular Photocoagulation Study (MPS) Group 1,2 have documented that laser photocoagulation is helpful in reducing the risk of severe vision loss in patients with ocular histoplasmosis syndrome complicated by choroidal neovascularization that does not involve the center of the fovea. In addition, there is at least one report documenting poor visual prognosis for patients with subfoveal choroidal neovascularization secondary to ocular histoplasmosis syndrome. 3 Accordingly, in 1988, we began to enroll patients in a pilot randomized trial to assess laser treatment for patients with ocular histoplasmosis syndrome and subfoveal choroidal neovascular lesions. Patients and Methods. —To be eligible for this trial, patients were required to have one or more atrophic lesions or "histo spots" in either eye, visual acuity of 20/40 to 20/320, and choroidal neovascularization under the center of the fovea. Eligible eyes could have previously untreated lesions (new membranes) or recurrent

In Reply. —Dr Sugar appropriately emphasizes a point that we made in the "Comment" section of our article. We also mentioned two additional factors that may have contributed to the relatively high success rate for penetrating keratoplasty in the CCTS: a vigorous educational program to assure medication compliance, and frequent, regular follow-up examinations by the transplanting surgeon. The CCTS patients were outstanding in that only 4% of all visits were missed and only 1% of patients were considered unavailable for follow-up. When we formulated the protocol for the CCTS, we were aware that high doses of postoperative steroids could mask any effect of HLA matching on corneal transplant survival. However, our goal was not to design a study that would maximize the likelihood of observing a beneficial HLA matching. Instead, we sought to determine whether HLA matching would improve graft survival when used in addition to the postoperative immunosuppressive regimen

To the Editor. —The Macular Photocoagulation Study (MPS) Group recently reported the results of a randomized clinical trial comparing krypton red laser photocoagulation with no treatment for choroidal neovascular lesions involving the foveal avascular zone in patients with age-related macular degeneration. 1 Although a thorough review of the literature was not the purpose of the report, earlier work by Yassur et al 2 had bearing on the MPS results and should have been cited. Their results from a randomized trial involving 123 eyes with age-related macular degeneration and neovascular lesions involving the foveal avascular zone showed that 37 (67% ) of 55 untreated eyes had deterioration in visual acuity in comparison with only 22 (32% ) of 68 eyes treated with krypton laser. The MPS results for similar eyes showed that 98 (58% ) of 169 untreated eyes in comparison with 86 (49% ) of 174 treated eyes had severe visual loss (six or

• We graded macular features of 127 fellow eyes of participants in the Macular Photocoagulation Study who had an extrafoveal choroidal neovascular membrane secondary to age-related macular degeneration in the first eye and no initial evidence of the neovascular form of age-related macular degeneration in the fellow eye. Our aims were to determine the relationship of drusen characteristics and retinal pigment epithelial abnormalities to the risk of subsequent development of neovascularization in the fellow eye and the risk of subsequent development of recurrent neovascular membranes after photocoagulation in the first eye. Regression analysis demonstrated that the presence of large drusen and focal hyperpigmentation of the retinal pigment epithelium were independent risk factors for the subsequent development of neovascularization in the fellow eye (relative risk, 2.4 and 2.5, respectively). Only 10% of eyes with no large drusen or any retinal pigment epithelial hyperpigmentation compared with 58% of eyes with both large drusen and retinal pigment epithelial hyperpigmentation developed neovascularization in the fellow eye within 5 years. Using multivariate Cox regression analysis, we noted that the risk of developing recurrent neovascular membranes in the first eye was significantly increased when large drusen (relative risk, 2.8) were noted in the fellow eye at the time of laser treatment in the first eye. Fundus features in the fellow eye appear to help identify patients at high risk of developing visual loss from recurrent neovascular membranes following laser treatment in the first eye and from development of a neovascular membrane in the fellow eye.

The product limit method of Kaplan and Meier for estimating survival functions and the logrank test of Mantel are widely employed for analysis of longitudinal medical data. Developed for analysis of one-time events such as death, survival analysis is also commonly adapted to more complex states such as loss of vision or cancer remission by restricting analysis to first occurrences. The nonparametric discrete time nonhomogeneous Markov process is proposed as a better model for any applications of the latter type. This simple stochastic model allows for an arbitrary number of possible states and for transitions in any direction. Maximum likelihood estimators are easily computed for the stochastic model and are identical to the product-limit estimates in the special case represented by the Kaplan-Meier model. The logrank test extends to evaluation of differences between populations with respect to any specified transition.

The authors present results of a study in which certified visual acuity examiners in the Macular Photocoagulation Study Group, performed independent replicate refractions and visual acuity measurements on both eyes of patients whose visual acuities ranged from 20/20 to

We analyzed a consecutive series of 596 eyes that underwent vitrectomy for complications of diabetic retinopathy to determine the postoperative incidence of iris neovascularization and neovascular glaucoma. Survival curves for various factors were plotted, showing the cumulative incidence of these complications at various postoperative times up to one year. Eyes in which the lens was removed during vitrectomy had a statistically significant (P less than .001 by log-rank test) increase in the postoperative incidence of both iris neovascularization and neovascular glaucoma compared to eyes in which the lens was not removed. Lens removal at vitrectomy increased the risk of postoperative iris neovascularization by a factor of more than three and the risk of neovascular glaucoma by a factor of more than four. Other factors associated with a significantly increased incidence of postoperative iris neovascularization were severe preoperative retinal neovascularization and the absence of preoperative scatter retinal photocoagulation. Neither of these two factors nor postoperative retinal detachment invalidated or reduced the effect of lensectomy on increased postoperative iris neovascularization when all factors were considered simultaneously. This study showed a statistically significant increase in the postoperative incidence of neovascular glaucoma in eyes undergoing combined lensectomy and vitrectomy compared to eyes in which the lens was not removed.

The Macular Photocoagulation Study (MPS) Fundus Photograph Reading Center has developed a standard set of methods for assessing color photographs and fluorescein angiograms on study patients. For pretreatment angiograms, these methods are used to determine the location and extent of the choroidal neovascularization. For posttreatment color fundus photographs, these methods are used to assess the extent and intensity of treatment. Although these methods were developed to judge eligibility and treatment of patients enrolled in the MPS, they provide an excellent way for all treating ophthalmologists to evaluate their patients' angiograms and to assess immediately the intensity and extent of laser photocoagulation. The technique requires a microfilm reader or slide projection device to determine the completeness of treatment. The authors superimpose independent drawings made from pre- and posttreatment photographs. The techniques described can be applied readily in clinical practice. Since persistent neovascularization is highly correlated with incomplete and/or inadequate photocoagulation treatment, clinicians may adopt these Reading Center techniques to minimize the frequency of persistent neovascularization and, possibly, to reduce the frequency of visual loss in treated eyes.

This report extends an earlier analysis of a case-control study of the relationship of oral contraception (OC) to thrombosis in 104 idiopathic cases 357 other thrombosis cases (excluding cerebrovascular) and 1302 matched controls which described a 7-fold increase in risk for OC users in the idiopathic series and a 2-fold increase for the whole series. This report analyzes factors which predispose or precipitate thrombosis related to risk with OC use. In the initial study the control patients had not been matched with the cases for the presence or absence of 6 factors (history of thrombosis of vascular disease of central vascular disorders of blood abnormalities of metabolic disease and of surgery or trauma) thought to predispose or precipitate thrombosis. In this report 2 methods of analysis (matched set and logistic regression) gave closely similar results. Where the case series consisted of idiopathic cases the revised estimate of relative risk was reduced form 7.2 to 4.7 by these procedures; for predisposed cases it increased from 1.2-2.2. Variation in relative risk was examined for 4 separate diagnostic categories: venous thrombosis alone pulmonary embolism alone venous thrombosis and pulmonary embolism together and myocardial infarction. Overall the relative risk estimates were greater than unity for each thrombosis category for both predisposed and nonpredisposed cases. The relative risk was not found to vary significantly according to age or smoking status.

We examined the relationship between age and pathological stage in 444 consecutive patients who underwent pelvic lymphadenectomy and radical retropubic prostatectomy for clinically localized adenocarcinoma of the prostate. Pathological stage of cancer was determined postoperatively as organ-confined, capsular penetration (cancer through prostatic capsule), seminal vesicle involvement or lymph node metastases. Patient age ranged from 34 to 75 years. The majority of the patients had clinical stage B1 disease with induration confined to less than 1 lobe of the gland. In this group a statistically significant (p equals 0.001, chi-square test for trend) correlation between increased age and higher pathological stage was found. We also found that older men with clinical stage B1 disease had a statistically significant trend toward higher Gleason grade. An explanation for our findings might be the masking of prostatic induration by benign prostatic hypertrophy, clearly a disease of aging men. We suggest that increased age is a relative risk factor for advanced pathological findings in men with clinical stage B1 prostatic cancer.

• Central visual function is characteristically reported as Snellen acuity at distance and near. We performed functional tests in a group of patients with visual acuity of 20/100 or worse due to macular disease to determine whether there was a relationship between Snellen acuity and functional performance among these patients with poor visual acuity. Our tests of functional performance included currency discrimination, color recognition, reading a clock, and reading large print. Our results suggest that there is a correlation between Snellen acuity and functional vision, even among patients with poor visual acuity. Hence, therapeutic efforts to keep patients' visual acuity at 20/200 rather than 20/400, tor example, appears to be justifiable in that better acuity levels seem to be associated with improved functional performance.

• A prospective, clinical study of patients with suspected carotid artery disease compared the accuracy of compression and suction ophthalmodynamometry (ODM) with carotid artery stenosis determined by arteriography. Results were analyzed with respect to current criteria for classification and determination of "substantial" carotid artery disease. The best correlation for both procedures with arteriography was a ratio of the corrected intraocular pressure to the systolic brachial pressure. Both suction and compression ODM findings are equally accurate, with levels approaching 80%; however, neither test is sensitive enough to be used alone as a screening technique. Arteriography remains the best procedure for the determination of carotid artery disease.

• This study was undertaken to determine whether the treatment benefit reported in randomized trials for patients with extrafoveal choroidal neovascular membranes (NVMs) secondary to age-related macular degeneration (AMD) or the ocular histoplasmosis syndrome (OHS) can be duplicated in other clinical settings. The visual results and recurrence rates in treated extrafoveal NVMs of 70 patients with AMD and 21 patients with OHS were similar to those reported by the Macular Photocoagulation Study Group, in which all treated patients received argon blue-green laser photocoagulation after the administration of retrobulbar anesthesia. In this study, 78% (71/ 90) of the patients were treated with krypton laser and only 35% (32/90) had retrobulbar anesthesia. These results suggest, but do not prove, that the wavelength of the laser used or the administration of retrobulbar anesthesia may not be critical variables in determining the success of treatment in patients with extrafoveal NVMs.

• The visual function of 100 eyes with low visual acuity of 100 patients with age-related macular degeneration was examined using measurements of visual acuity, peak contrast sensitivity, and the ability to read, to tell time, and to distinguish colors, products, and facial expressions. Visual acuity and peak contrast sensitivity were correlated ( r =.62); however, a range of peak contrast sensitivities was observed at each level of acuity. When considered individually, visual acuity and peak contrast sensitivity were related to the ability to perform each of the tasks. When multivariate methods were applied, both visual acuity and peak contrast sensitivity contributed independently to the ability to read and tell time. Among patients with the same contrast sensitivity, visual acuity had little or no relationship to the ability to identify colors, products, and faces.

Sixty-eight eyes in 67 patients with a histoplasmic neovascular membrane treated with Argon laser photocoagulation between 1972 and 1978 are reviewed. Factors affecting visual outcome and causes of visual failure are discussed. Twenty of 68 eyes (nearly 30%) experienced a recurrent or new SRNVM after initially successful treatment. Final evaluation of Argon laser photocoagulation for histoplasmic neovascular membrane must await the outcome of the Macular Photocoagulation Study.

To the Editor. —The principal investigators of the Collaborative Corneal Transplantation Studies (CCTS), a National Eye Institute-sponsored multicentered clinical trial of histocompatibility matching in high-risk keratoplasty, have received several inquires regarding our position on recommendations for tissue matching and sharing of typed tissue. We believe that the available data do not, at this time, allow us to determine whether histocompatibility matching improves the prognosis for penetrating keratoplasty in high-risk recipients. Available data do not allow us to determine whether histocompatibility matching, if effective, should be based on HLA-A matches, HLA-B matches, HLA-DR matches, or ABO matches. It is the purpose of the CCTS to address these and other questions. The CCTS is a masked, prospective, randomized clinical trial. Consequently, none of the investigators is aware of the degree of tissue match that any of his patients receive. Data are reviewed biannually by the CCTS Data and Safety Monitoring Committee. At

• We determined the visual prognosis of 94 eyes in 92 patients having (1) agerelated macular degeneration, (2) a discrete choroidal neovascular membrane directly under the center of the foveal avascular zone (subfoveal), and (3) an initial visual acuity of 20/100 or better. Of the patients who were reexamined 24 months following their initial presentation, 77% had lost at least four lines of vision and 64% had lost at least six lines. Estimation of visual loss using a conservative assessment procedure showed four-line visual loss in 65% of the patients and six-line loss in 50%. In general, the better the visual acuity at the initial examination, the more likely the patient was to have a smaller choroidal neovascular membrane. These results suggest that it may be reasonable to consider a randomized clinical trial of laser photocoagulation for this group of patients with a relatively poor visual prognosis.

To the Editor. —In response to Sabates et al, 1 who recently voiced some concerns about the Macular Photocoagulation Study (MPS), 2 we offer the following comments: The authors stated that we did not consider time of treatment as a factor in evaluating the outcome of laser treatment. In fact, the vast majority of patients enrolled in the National Eye Institute-supported Ocular Histoplasmosis Study had newly diagnosed cases. We recognized at the outset of the trial that if laser photocoagulation were to be effective, it would be preferable to treat as early as possible. Consequently, patients with visual symptoms and a new vessel membrane who were considered eligible by the principal investigator were issued treatment assignments by telephone consultation with the MPS Coordinating Center in Baltimore. We agree with the authors that there is no documented evidence that steroids have a role in managing patients with the ocular histoplasmosis syndrome.

Methods are presented for dealing with screening or diagnostic variables which exhibit trends over time. The number and spacing of observations is assumed to vary among patients. Criteria for establishing 'normal' trends, and for detecting extremes and pattern deviations, are developed. The methods are applied to a pregnancy study in which longitudinal data on alpha-fetoprotein in material were obtained in 1501 patients.

To the Editor. —Transmission of cytomegalovirus (CMV) from infected donors to recipients is a serious concern in the transplantation of bone marrow, kidneys, and other vascularized organs. Because the immune systems of these recipients are severely compromised by cytotoxic drug and systemic steroid therapies, primary or secondary infection with CMV may cause a variety of clinical diseases, such as hepatitis, pneumonitis, and retinitis. Usually, serologic testing of corneal donors and recipients for antibodies to CMV is not performed. However, when presented with a positive serologic test result from a multiple organ donor, the corneal surgeon may feel uncomfortable in accepting a cornea for transplantation into a patient whose serologic CMV status is unknown. In fact, we know of at least two instances in which tissue was refused by a corneal surgeon solely on the basis of a positive CMV test result from the donor. Since seropositivity in the general population

In Reply. —Drs Tornambe and Poliner raise interesting questions about the treatment strategy for NVMs within the foveal avascular zone. However, we do not believe that "treatment inside the foveal vascular zone remains a dilemma." Results in our initial report on the effectiveness of krypton laser photocoagulation in preventing loss of vision 1 showed that among eyes with neovascularization within 200 μm of the foveal center, 8% of treated eyes in comparison with 32% of untreated eyes had large losses in visual acuity (≥ 6 lines). While intentional partial treatment of the neovascularization to spare receptors within the foveal avascular zone is appealing, we have misgivings about the strategy. The proposed partial treatment is far less extensive than treatment applied to eyes that were not completely covered in the Krypton Ocular Histoplasmosis Study. Subsequent persistent leakage from the NVM and its vision-threatening effects may overwhelm the benefit of sparing some