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Journal of the American College of Nutrition, Vol. 17, No. 6, 617-624 (1998)
Published by the American College of Nutrition

Effect of UV Exposure and ß-Carotene Supplementation on Delayed-Type Hypersensitivity Response in Healthy Older Men

Laurie A. Herraiz, MS, Wen-Ching Hsieh, MS, Robert S. Parker, PhD, Joy E. Swanson, PhD, Adrianne Bendich, PhD, FACN and Daphne A. Roe, MD

Division of Nutritional Sciences (L.A.H., W-C.H., R.S.P., J.E.S.), Cornell University, New York
New Product Research (A.B.), SmithKline Beecham Consumer Healthcare, Parsippany, New Jersey

Address reprint requests to: Robert S. Parker, PhD, 113 Savage Hall, Cornell University, Ithaca, NY 14853


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS AND MATERIALS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Objectives: The aims of this study were to determine if ultraviolet light (UV) is immunosuppressive in healthy older males, if ß-carotene (ßC) supplementation could prevent any observed UV-induced immunosuppression, and to compare these effects with those observed previously in younger men.

Methods: The study was a placebo-controlled, randomized trial that employed a 2x2 factorial design. Healthy older men (mean age 65.5 years) received 30 mg ßC or placebo daily throughout the 47-day trial, while on a low carotenoid diet. After 28 days, half of each group received 12 suberythemic exposures to UV over a 16-day period. Delayed-type hypersensitivity (DTH) tests and plasma carotenoid assays were performed at baseline, pre-UV and post-UV time points, with DTH testing performed on an area of skin protected from UV exposure.

Results: UV exposure resulted in significantly suppressed DTH response in the placebo group but not in the ßC-UV group. While there was no significant interaction between ßC supplementation and UV on DTH response, there was a significant inverse relationship between final plasma ßC concentration and extent of UV-induced suppression of DTH response. A similar correlation existed among subjects not exposed to UV.

Conclusions: Suberythemic UV exposure was immunosuppressive, as measured by DTH response, in healthy older men as in younger men. Higher plasma ßC was significantly associated with maintenance of DTH response, although the extent of protective effect of ßC appeared less than previously observed in younger subjects. The attenuated effect of ßC in the older UV-exposed subjects may have resulted in part from muted plasma ßC responses to ßC supplementation and/or higher plasma vitamin E levels than those of younger men. The finding that stronger DTH responses were associated with higher plasma ßC concentrations in both UV and non-UV subjects further supports a role for this nutrient in immunomodulation.

Key words: UV, immunosuppression, ß-carotene, delayed-type hypersensitivity, aging


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS AND MATERIALS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Substantial evidence supporting an age-related decrease in immune function has been reported [1–10]. However, there is conflicting evidence regarding the specific nature of these changes. While decreases have been documented in both cellular and humoral immunity [5,6], T cell function appears most susceptible to immunosenescence [7,8]. In particular, delayed-type hypersensitivity (DTH) response declines in the aged [7,10]. A DTH response occurs when an individual is re-exposed to a small dose of previously encountered antigen, and requires the cooperation of a series of cells. Antigen-presenting cells must display the antigen to specific memory T helper cells (CD4+) which in turn must have recognized it and then be stimulated to secrete cytokines. Certain cytokines activate various effector cells, mostly macrophages, which then phagocytize the antigen and consequently lead to a reddening of the application site. A deficient immune response anywhere along this pathway can prevent a positive skin response to the recalled antigen [11]. The DTH response can be quantitated by measuring the number and diameter of reddened areas which appear at the site of topical application of a standard battery of commonly encountered antigens.

The immunosuppressive effects of ultraviolet (UV) light exposure have been previously documented in both humans and animal models. Reported effects of UV have included inhibition of antigen presentation in lymphocytes [12], reduction in CD4+/CD8+ ratios [13], as well as suppression of DTH response [14]. UV-induced immunosuppression, however, has not been investigated in elderly subjects, despite growing concern regarding skin exposure to UV in all age groups.

Various reports have demonstrated the restorative effects of ß-carotene (ßC) on immune function [15–21]. Both CD4+ (16) and natural killer (NK) cell populations are increased with ßC supplementation [17]. Evidence of increased T cell function, such as mitogen-induced proliferation [18], interferon production [19], and IL2 receptor secretion [20] have also been demonstrated in vivo in supplemented individuals. Animal studies have shown that ßC reduces UV-induced tumor development [21]. ßC has also been shown to inhibit UV-induced peroxidation of linolenic acid micelles in vitro [22]. In vitro studies have shown that canthaxanthin and ßC protect peripheral blood monocytes from functional damage due to UV exposure [23]. In the only previous study of the interaction between ßC, UV and immune function in humans, we demonstrated that ßC supplementation protected young men from photosuppression of DTH response caused by UV exposure [24].

To follow up on our previous study with younger men, we conducted a placebo-controlled study of the effect of UV exposure and ßC supplementation on DTH responsiveness in older men. The objectives of this study were to: 1) determine if UV exposure causes significant immunosuppression in healthy older males; 2) determine if ßC could modulate any observed UV-induced changes in DTH response; and 3) compare the plasma ßC response to ßC supplementation in older men with that previously observed in younger men. We also investigated the effects of ßC supplementation and UV exposure on the concentration of other micronutrients in plasma, including other carotenoids, {alpha}-tocopherol, and retinol.


   METHODS AND MATERIALS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS AND MATERIALS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Subjects
The study protocol was approved by the Cornell University Committee on Human Subjects. Individual consent was obtained from all subjects. Thirty-two healthy elderly males, ranging in age from 55 to 79 years, were recruited from a volunteer pool. Pre-selection screening included a medical history, physical exam, smoking history, and blood chemistry profile. Tests of light sensitivity were carried out to determine each individual’s minimum erythemic dose (MED) of UV light from a solar simulator. Subjects were excluded if their MED was less than 3 J/cm2. Volunteers were also excluded if they had an acute infection or inflammatory disease, were taking medication that might interfere with the study protocol, or had a history of phototoxic disorders associated with photosensitivity or cutaneous light damage, including skin cancer. The subjects were randomized into four treatment groups, as described below. The mean age of the subjects was 65.5 years. There was no statistically significant difference between treatment groups with respect to age, body weight, % body fat, and MED.

Pre-study, 3-day food records were obtained from subjects, analyzed for caloric and nutrient content and used to determine energy needs while on the study diet. A food frequency questionnaire was administered to determine usual intake of carotenoid-containing foods. Subjects agreed to discontinue the use of vitamin supplements 30 days prior to the start of the study. Subjects also agreed to abstain from alcohol consumption throughout the duration of the study. To determine sample size, power calculations were performed using existing data from the previous study in younger men [24].

Subjects were randomly assigned to receive either 30 mg ßC/day, (10% ßC water dispersible beadlets), or placebo (similar beadlets without ßC), which they were instructed to take with breakfast. The beadlet preparations, packaged in gelatin capsules containing 15 mg ßC, were provided by Hoffmann-La Roche, Inc., Paramus, NJ. After 28 days of ßC or placebo treatment, referred to as the pre-UV period, each group was further divided, such that half of each group received 12 ultraviolet (UV) light exposures (Fig. 1). This resulted in a total of four groups, in a complete 2x2 factorial design: Group 1, placebo/non-UV (P-nonUV); Group 2, placebo/UV (P-UV); Group 3, ßC/non-UV (ßC-nonUV); Group 4, ßC/UV (ßC-UV).



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  		Fig. 1. Study design. Arrows indicate duration of dietary intervention, ß-carotene or placebo treatment, and UV exposure, and X indicates times of DTH testing and blood sampling.

 
Diet
The subjects consumed a single menu, low carotenoid basal diet used previously in the study with younger men [24] starting from day 0, after completion of the baseline DTH test. Subjects were supplied with foods on a daily basis, which they consumed at home. In addition, all subjects were given one serving of cooked carrots daily (supplied frozen, from the same lot) containing 1.5 mg ßC. This was done in an effort to stabilize plasma ßC levels during the UV treatment period in order to better ascertain any effect of UV on plasma ßC concentration. To maintain body weight, an additional low carotenoid snack and/or frozen entree was added to the menu. The additional food had approximately the same macronutrient ratio as the basal diet.

UV Light Treatment
During days 29–44, subjects randomized to the UV light groups (groups 2 and 4) received 12 exposures to UV light (Hönle Blue Light, Model 2004, Dermalight, Studio City, CA). The source contained two 400 watt metal halide lamps and a filter that excluded wavelengths <280 nm. UV-A irradiance at skin level was determined with an IL-1700 light meter and UV-B irradiance was determined with an IL-443 meter (both from International Light, Newburyport, MA). These determinations were performed daily to calculate the time of exposure necessary to deliver the intended dose. UV-B irradiance was 10% of the UV-A value. Light exposures were to the anterior and posterior sides of the body with the subjects lying first supine and then prone. Subjects wore shorts of uniform length and protective eyewear. A 10x15 cm area of skin on the subjects’ backs was consistently protected from UV exposure using an index card. This area served as the site of application of the DTH test antigens. The initial dose to each side of the body was 0.5 J/cm2 and increased to 2 J/cm2 as tolerated. Subjects were under the light from between 2 to 6 minutes/day. The mean total UV dose was 15.0 J/cm2. Individuals presenting with signs of erythema from a previous UV exposure were not exposed on that day.

Plasma Analyses
Fasting venous blood samples were collected into opaque heparinized tubes, immediately placed on ice, and centrifuged to separate plasma. Plasma was subdivided in a dimly lit laboratory and stored at -70°C until analyzed. Total carotenoids extracted from ethanol-precipitated plasma with hexane containing 0.01% BHT and 40 µM {alpha}-tocopheryl acetate (internal standard). Plasma levels of {alpha}- and ß-carotene, lutein, lycopene, ß-cryptoxanthin, retinol, and {alpha}-tocopherol were determined by HPLC by a modification of the method of Thurnam et al [25]. Plasma extracts (20 µL) reconstituted in mobile phase were injected into a 15.0 cmx4.6 mm, 5 mm ODS2 column (LKB Instruments Ltd., South Craydon, Surrey, UK) using a Perkin-Elmer 250 binary pump interfaced to a Spectroflow 783 programmable absorbance detector (ABI Analytical, Kratos Division) and a 3390A integrator/chart recorder (Hewlett Packard). The mobile phase was composed of HPLC grade acetonitrile:methanol:chloroform (47:47:6 by volume), 0.05 M ammonium acetate and 0.05% triethylamine. Carotenoids, retinol, and tocopherols were separated isocratically at a flow rate of 1.5 ml/minute. Each sample was injected twice, using two different detection protocols. One analysis used automated multiple wavelength programming: 325 nm from 0 to 3 minutes (for retinol), 292 nm from 3 to 7.25 minutes (for {alpha}-tocopherol and {alpha}-tocopheryl acetate), and 450 nm from 7.25 to 20 minutes (for lycopene, {alpha}-carotene, all-trans-ßC, and cis-ßC). The second analysis used detection at 450 nm throughout, for quantification of ß-cryptoxanthin, lycopene, {alpha}-carotene, all-trans-ßC, and cis-ßC. Standards were constituted in methanol with concentrations similar to those expected in the plasma extracts. The internal standard, ({alpha}-tocopheryl acetate) was used to determine recovery. Since each of the duplicate extracts was analyzed using both detection programs, some analytes (lycopene, {alpha}-, ß-, and cis-ß-carotenes) were calculated as the average of four values and others (retinol, {alpha}-tocopherol, lutein, and ß-cryptoxanthin) as the average of two values.

Delayed-Type Hypersensitivity Tests
Delayed type hypersensitivity responsiveness (DTH) was measured using Multitest CMI kits (Merieux Institute, Miami, FL). The test antigens were applied to the protected skin site on the back. Seven antigens were administered simultaneously: tetanus toxoid, diphtheria toxoid, streptococcus, tuberculin (old), Candida albicans, Proteus mirabilis, Trichophyton mentagrophytes, and a glycerin control. Induration of >=2 mm was considered a positive reaction. Responses were assessed 48 hours after application and were recorded both as total number of positive reactions and the cumulative diameter (induration, mm) of the positive reactions, as measured by caliper. Each test was administered and read by one investigator who was unaware of the subjects’ treatment group.

Data Analysis
Group comparisons of baseline values for age, body mass index, and plasma constituent values were carried out using t-tests for normally distributed measures. Because DTH responses were not normally distributed, non-parametric tests were used to analyze the absolute values from these measurements: Mann Whitney for inter-group comparisons of DTH values among time points, and Wilcoxon signed rank test for intra-group comparisons of DTH values at each time point. Changes in DTH were normally distributed, therefore, Spearman rank correlation was used to test for a relationship between changes in DTH and plasma ßC concentration. Regression analysis was used to test for an interaction between ßC supplementation and UV light exposure on DTH response. In the ßC-UV group, one subject developed a viral infection and was excluded from the analyses.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS AND MATERIALS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
Effects of Dietary Treatment on Plasma Micronutrient Levels
The placebo groups (P-non-UV and P-UV) exhibited declines of about 50% in plasma ßC levels between the baseline and pre-UV sampling times (Fig. 2) in spite of the daily carrot serving in the low carotenoid diet. The ßC supplemented groups (ßC-nonUV and ßC-UV), consuming 30 mg ßC per day, exhibited substantial increases in plasma ßC concentration between baseline and the pre-UV sampling points. Group 3 (ßC-non-UV) mean level increased 10-fold and apparently reached equilibrium by pre-UV. The mean level in group 4 (ßC-UV) continued to rise slightly during the UV exposure period and ultimately increased 12-fold. The two ßC groups did not differ statistically in pre-UV plasma ßC concentration.



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  		Fig. 2. Mean plasma ß-carotene concentrations in treatment groups at baseline, pre-UV and post-UV time points.

 
Plasma levels of lutein and lycopene declined substantially in all groups from baseline to pre-UV in response to the low carotenoid diet, as did those of ß-cryptoxanthin (data not shown). There was no effect of ßC supplementation on the extent of the decline in these carotenoids. Plasma {alpha}-carotene levels gradually increased over time from baseline to post-UV in the two ßC supplemented groups, but not in the placebo groups (data not shown). This was attributed in part to low levels of {alpha}-carotene (or a carotenoid co-eluting with {alpha}-carotene) in the ßC beadlet preparation, as shown by HPLC analysis.

Effects of UV Exposure on Plasma Carotenoids
In the placebo groups, plasma ßC levels did not change from the pre-UV to post-UV sampling periods (Fig. 2). This stability was attributed to the daily serving of carrots in the diet, which prevented the progressive decline in plasma levels of this carotenoid previously seen with this low carotenoid diet [24]. UV treatment had no effect on plasma ßC concentration over this period. A comparison of UV with non-UV groups over the UV exposure period indicated that UV treatment had no effect on the extent of decline in plasma lutein, ß-cryptoxanthin, or lycopene levels (data not shown). In addition, there were no changes in plasma retinol or {alpha}-tocopherol levels in any group over the course of the study, attributable to either dietary or UV treatment.

Delayed-type Hypersensitivity Response
The mean DTH response in each of the four treatment groups at baseline, pre-UV, and post-UV time points are presented in Table 1. All groups were similar with respect to DTH parameters at baseline and pre-UV time points. During the baseline to pre-UV interval, three groups tended to increase in number of positive responses and/or induration, but none of these changes were significant. The magnitude of change in induration (cumulative diameter of responsive antigen sites) between the pre-UV and post-UV time points among the four treatment groups is shown in Fig. 3. UV exposure resulted in a decrease in mean DTH response in both P-UV and ßC-UV groups, but only the decrease in the P-UV group was significantly different from zero (p=0.01). The magnitude of decline in the placebo-UV group was not significantly different from that of the ßC-UV group, and regression analysis revealed no significant interaction between UV and ßC treatments. There were no significant changes in DTH induration in the two non-UV-exposed groups. Similar results were observed with respect to the mean total number of positive antigen responses (P-UV decrement, p=0.04; data not shown).


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  		Table 1. Comparison of Delayed Type Hypersensitivity Responses in Older Men Assigned to Placebo, UV or ß-Carotene Treatment Groups

 


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  		Fig. 3. Change in delayed-type hypersensitivity induration between pre-UV and post-UV time points. Values are mean±SEM.

 
The main effects of UV exposure or ßC supplementation on DTH responses are presented in Table 2, with both UV groups or both ßC groups combined because of the lack of interaction between UV and ßC treatment. The combined UV group (placebo-UV plus ßC-UV) exhibited a significant decline in DTH responsiveness over the UV exposure period. The mean number of positive responses and the cumulative induration each declined by 36% over this period (p=0.007 and p=0.02, respectively) as a result of UV exposure. DTH responsiveness, as reflected by either cumulative induration or total positive responses, remained unchanged in the group not exposed to UV.


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  		Table 2. Comparison of Delayed Type Hypersensitivity Response by ß-Carotene or UV Treatment

 
Over the duration of the study (baseline to post-UV) the combined placebo groups (P-UV and P-non-UV) (Table 2) exhibited a significant decline in number of positive DTH responses (p=0.02), and a marginal decline in cumulative induration (p=0.07). The combined ßC-supplemented groups (ßC-UV and ßC-non-UV) remained unchanged over time with respect to both DTH outcomes. The mean final (post-UV) number of positive DTH responses in the combined ßC groups was significantly higher than that of the combined placebo groups (p=0.05). However, because of variation between subjects in each group, the overall effect of ßC supplementation, as assessed by comparison of overall change in DTH response between groups, was not statistically significant.

In subjects exposed to UV light, the correlation between change in DTH response (induration) over the UV exposure period and final plasma ßC concentration was statistically significant (Pearson r=0.54, p-0.04; Fig. 4). Similarly, among those subjects not exposed to UV, there was a significant correlation between change in DTH induration over the course of the study (baseline to post-UV) and final plasma ßC level (Spearman r=0.60, p=0.02; Fig. 5). In both cases, lower plasma ßC concentrations were associated with greater declines in induration of the DTH response.



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  		Fig. 4. Relationship between post-UV plasma ß-carotene concentration and change in delayed-type hypersensitivity induration between pre-UV and post-UV among subjects exposed to UV.

 


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  		Fig. 5. Relationship between post-UV plasma ß-carotene concentration and change in delayed-type hypersensitivity induration between baseline and post-UV among subjects not exposed to UV.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS AND MATERIALS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
This study examined the individual and interactive effects of ultraviolet light exposure and ßC supplementation on a measure of cellular immune competence, delayed-type hypersensitivity response, in a group of healthy older men. We previously reported that DTH response in healthy young men was significantly suppressed as result of UV exposure [24]. A similar effect of UV was observed in this older cohort. Groups exposed to UV exhibited decreased DTH responsiveness both in terms of total number of positive antigen responses, and cumulative induration of response, while the mean responses in groups not exposed to UV remained virtually unchanged. To our knowledge this represents the first controlled metabolic study of the effects of UV light exposure on DTH response in older men. However, while qualitatively similar in response to UV, the older cohort exhibited a less pronounced DTH suppression compared to the younger cohort, as reflected by the postUV-pre-UV difference in number or induration of positive antigen responses. This may be the result of the daily administration of a portion of carrots in the older cohort which did not occur in younger cohort study, as discussed below. As the UV treatment was adjusted to be suberythemic, the cumulative doses used here are relevant to doses to which people may be exposed through recreational or other exposures to sunlight.

The results of this study suggest a protective role for ßC in UV-induced DTH suppression. In the UV group, the magnitude of suppression of DTH response was significantly correlated with plasma ß-carotene concentration such that subjects with higher plasma ßC levels were more resistant to the immunosuppressive effects of UV (Fig. 4). This association between maintenance of DTH response and higher plasma levels was first observed in the previous study of younger men exposed to suberythemic UV [24]. Furthermore, UV exposure resulted in a significant decline in DTH response (induration or number of positive responses) in the placebo-UV group but not in the ßC-UV group. However, unlike the previous trial in which ßC was depleted from the diets and consequently, the serum of the younger men, the current study found no significant difference in the magnitude of UV-induced DTH suppression between the ßC-supplemented and placebo groups.

Two factors may have contributed to the apparently attenuated effect of ßC in this older cohort. First, less marked decrements in DTH response over the UV exposure period were observed in the older cohort. This was entirely due to lower baseline and pre-UV DTH responsiveness in the older group (Table 3), since post-UV DTH responses were similar between the two age groups. This indicates that the older cohort was relatively immunosuppressed prior to UV challenge. This result is consistent with other evidence that aging is associated with suppression of certain aspects of cellular immune function [2–10]. The consequence in this case was that less marked decrements in DTH would render potential treatment effects more difficult to detect.


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  		Table 3. Comparison of Baseline Delayed-Type Hypersensitivity (DTH) and Plasma ß-Carotene Response to Supplementation Between Younger and Older Subjects

 
Secondly, the older cohort exhibited less marked changes in plasma ßC in response to either ßC supplementation or to the restricted carotenoid diet. The trial in younger men employed a diet which was very low in all carotenoids, including ßC, whereas the older cohort consumed this basal diet plus 1.5 mg ßC per day as a serving of carrots. Consequently, the overall decline in plasma ßC concentration in placebo subjects was more pronounced in the younger men than in the older men. In addition, older subjects supplemented with ßC exhibited less of an increase in plasma ßC concentrations compared to younger men (Table 3). The mean increase in plasma ßC concentration over the course of the study in supplemented older men was 2.4 µM, while that of the younger men was 3.8 µM (Table 3). Two-thirds of the older subjects achieved a plasma ßC level of 2 µM during the study, while 90% of younger subjects met or exceeded this level. The basis for this difference in plasma response is unknown, as there are no reports demonstrating an age-related decrease in absorption efficiency or plasma response to ßC supplementation [26, 27]. Differential rates of compliance cannot be ruled out. The lower plasma ßC responsiveness in the older group may have contributed to the difference in the observed effect of ß-carotene supplementation on UV-induced suppression of DTH responsiveness between the two trials.

Among subjects not exposed to UV, we observed a significant correlation between plasma ßC concentration and extent of change in DTH induration, with lower plasma concentrations associated with greater declines in response over the duration of the trial. In the previous trial with young men, such an effect of ßC independent of UV exposure could not be probed since all subjects were exposed to UV. Bogden et al [28] reported a significant correlation between change in number and induration of positive DTH responses and increase in serum ßC concentration in older subjects given a daily multivitamin/mineral supplement containing 0.75 mg ßC for 12 months. That effect, however, could not be attributable solely to ßC.

The mechanism of influence of ßC on immune function is not known. T cell cytokine production and response to mitogens are known to be reduced after UV exposure [29, 30], but the effect of ßC on these indicators has not been investigated within the context of UV exposure. The effect of ßC apparently cannot be attributed to a light filtering effect [31]. Radical trapping or other antioxidant effects may be involved, in that reactive species generated by UV exposure may suppress immune function by damaging cutaneous or circulating cells which are important in antigen presentation and/or cytokine production. To this end, the observation that the mean baseline plasma vitamin E concentration was significantly higher in the older men (38 µM) compared to the young men (23 µM) may be relevant to the observed differences in outcome between the two studies.

There were no observed effects of either supplemental ßC or of UV light on plasma concentration of other carotenoids, vitamin E, or retinol. White et al [32] previously reported a reduction in plasma carotenoid levels resulting from similar UV exposure in younger subjects. Since the duration of UV exposure was suberythemic and relatively short, these data do not rule out potential adverse effects of long-term or acute high doses of UV on these other nutrients.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS AND MATERIALS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
In summary, this trial clearly demonstrates that exposure to UV light impairs DTH response in healthy older males, consistent with previous findings in healthy younger subjects. Effects of UV on other indicators of immune function in the elderly have yet to be investigated, and the comparative effects of UV on males and females is likewise unknown. Furthermore, both in the presence and absence of UV challenge, DTH responses was associated with plasma ß-carotene levels when the latter were manipulated over a wide range of concentrations, supporting the concept that ß-carotene can be immunomodulatory under certain circumstances.


   ACKNOWLEDGMENTS
 
Supported in part by a grant from Hoffmann-La Roche, Inc., Nutley, NJ. LA Herraiz was supported by a National Science Foundation Minority Graduate Fellowship. We gratefully acknowledge the technical assistance of Dr. Abdur Rahman, and wholeheartedly thank all of the participants for their diligence and compliance.

Received August 1, 1997. Accepted May 1, 1998.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS AND MATERIALS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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