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Keywords:

  • correlates;
  • excessive daytime sleepiness;
  • high school adolescents;
  • Korea;
  • prevalence

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

Abstract  The purpose of the present study was to determine the prevalence of excessive daytime sleepiness (EDS) and its associations with sleep habits, sleep problems, and school performance in high school students in South Korea. A total of 3871 students (2703 boys and 1168 girls with a mean age of 16.8 years and 16.9 years, respectively) aged 15–18 years in the 11th grade of high school completed a questionnaire that contained items about individual sociodemographic characteristics, sleep habits, and sleep-related problems. The overall prevalence of EDS was 15.9% (14.9% for boys and 18.2% for girls). Mean reported total sleep time was similar in EDS and non-EDS (6.4 ± 1.6 and 6.4 ± 1.3 h/day, respectively). The increased risk of EDS was related to perceived sleep insufficiency (P < 0.001), teeth grinding ≥ 4 days/week (P < 0.001), witnessed apnea ≥1–3 days/week (P < 0.01), nightmares ≥4 days/week (P < 0.05), low school performance (P < 0.01), and two or more insomnia symptoms (P < 0.05). Students with low school performance had a 60% excess in the odds of EDS compared to those whose school performance was high. These findings suggest that EDS is associated with multiple sleep-related factors in adolescents. Whether interventions to modify associated correlates can alter EDS warrants consideration, especially because it may also improve academic performance in high school students.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

Excessive daytime sleepiness (EDS) has been associated with a decrease in work and school performance, an increased risk for motor vehicle accidents, and psychosocial stress.1–4 Adolescence accompanies various biological and psychological changes including a modification of sleep patterns.5,6 Studies have shown that transition to an earlier school starting time, along with sleep phase delay7,8 due to the late-night academic and social activities,8,9 may cause chronic sleep deprivation and increase the likelihood of daytime sleepiness in adolescents.10–12

Recent epidemiological studies have reported that the prevalence of EDS was 15–26% in the general adult population.13–15 Earlier clinical research has found that several factors such as inappropriate nocturnal sleep, and sleep disorders including obstructive sleep apnea, hypopnea, snoring and insomnia contribute to the daytime sleepiness. However, few studies have examined the prevalence of EDS and its risk factors in adolescents in Asia9,16 and none has been done in Korea. The purpose of the present study was to determine the prevalence of EDS and its associated factors in high school students in Korea.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

Study sample

A cross-sectional study was carried out in a sample of high school students of both genders between September and December 2001. Using the official directory of public and private senior high schools, a total of 11 schools were randomly selected out of 59 schools in the southern part of Seoul, South Korea. Institutional approval for the survey was granted in 10 schools. One girls’ school, however, refused to participate in the study, resulting in a lower response rate for girls. The overall selected sample consisted of 4781 students in the 11th grade from each of the 10 schools.

Procedures

A questionnaire was developed to assess sleep patterns and sleep problems for the student participants. The questionnaire draft was given to 350 senior high school students and their parents as a pretest. To examine test–retest reproducibility, 240 high school students and their parents were given the same draft questionnaire 4 weeks apart. The kappa values for questions on snoring, witnessed sleep apnea, teeth grinding, and nightmares (0.73, 0.89, 0.91 and 0.92, respectively) suggested that reproducibility was high.

The final version for the questionnaire included queries on bedtime, wake-up time, sleep duration and latency, and sleep-related problems such as daytime sleepiness, snoring, witnessed apnea, insomnia, teeth grinding, and nightmares. Sociodemographic data collected included age, gender, height, weight, family income, alcohol consumption, smoking status and school performance.

After a full explanation of the purpose of the study by investigators, questionnaires were distributed to the students in a class and were taken home to fill out. Questions on sociodemographic data, sleep habits, nightmares, insomnia, and daytime sleepiness were answered by the students, while those about the occurrence and frequency of snoring, sleep apnea, and teeth grinding were answered by parents, guardians, sisters or brothers. Participation was on a voluntary basis without teacher input. Subjects were asked to answer sleep habits and sleep-related problems with regard to typical weekdays and nights rather than weekends or holidays. Symptoms were also assessed over a 4-week period to avoid the effects of short-term disturbances.

Definition

Daytime sleepiness was measured using the Epworth Sleepiness Scale (ESS), a frequently used subjective sleepiness scale that consists of eight items.17 In the present study the ESS was properly adapted to measure adolescent activities such as falling asleep at school rather than at a meeting. Possible ESS scores range from 0 to 24. Higher scores in the ESS represent greater propensity for sleepiness. In the present study, EDS was defined as an ESS score of >10.

The frequency of snoring was classified as never, 1–2 days/week, 3–4 days/week, 5–6 days/week, and always (every night). Students who snored 1–2 days/week or ≥3 days/week were defined as simple snorers and habitual snorers, respectively. To assess sleep apnea, the frequency of breathing cessation during sleep was categorized as never, 1–3 days/week, 4–5 days/week and 6–7 days/week.

Questions about insomnia during the previous month included the following: (i) ‘Do you have difficulty in falling asleep at night?’ (difficulty in initiating sleep); (ii) ‘Do you wake up during the night after you have gone to sleep and have difficulty in getting back to sleep?’ (difficulty in maintaining sleep); (iii) ‘Do you wake up too early in the morning?’ (early morning awakening). Subjects could answer each question as follows: never, 1–2 days/week, 3–4 days/week, 5–6 days/week, or always (every night). The presence of difficulty in initiating sleep, difficulty in maintaining sleep, and early morning awakening was defined when 3–4 days/week or higher was given as an answer to the corresponding question. The presence of insomnia was defined if any insomnia subtypes occurred.

Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Subjects were classified as smokers if they were currently smoking cigarettes, and as non-smokers if they had never smoked or if they had smoked but had quit. Subjects were classified as alcohol consumers if they consumed at least three drinks per month. Here, one drink is equivalent to the intake of 12.5 g of ethyl alcohol. Academic performance was classified as being high-grade if students were ranked among the top quartile of their class, and as being low-grade if students were ranked among the bottom quartile of their class, based on the results of final examination confirmed by school records during the first semester in the 2001 academic year. Student rankings in the middle two quartiles were defined as moderate performance. Computer usage was defined by the number of hours per day for which a computer was used for word-processing, playing computer games, surfing the Internet, and chatting.

Statistical analysis

Data are presented as the mean ± SD for continuous variables and as percentages for categorical variables. The χ2 test was used to test for differences between proportions.

To explore the association of sociodemographic and sleep-related factors with EDS, prevalence rates of EDS within subgroups for each variable were estimated. Both univariate and multiple logistic regression models were examined to identify factors with an overall and independent relationship with EDS. Regression coefficients and standard deviations also allowed the calculation of odds ratios (OR) with 95% confidence intervals (CI). All hypothesis testing was based on two-sided levels of significance.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

Characteristics of study sample

Of 4781 students in the present study sample, 910 were excluded from the analysis because of refusal to complete the questionnaire (n = 587), absence on the day of the survey (n = 14), or incomplete information regarding sociodemographic and sleep-related characteristics (n = 309). Among the remaining 3871 students, 2703 were boys and 1168 were girls, representing an 80.9% response rate.

General characteristics of the study sample are given in Table 1. The mean age of the students was 16.8 years for boys and 16.9 years for girls. Differences in the study characteristics between boys and girls were not markedly large. Although modest, boys tended to use the computer for a significantly longer period of time (30 min/day, P < 0.001).

Table 1.   Study sample characteristics (mean ± SD)
CharacteristicsBoys (n = 2703)Girls (n = 1168)
  • *

    Significantly different from boys (P < 0.001).

Age (years) 16.8 ± 0.8 16.9 ± 0.8
Height (cm)173.6 ± 5.7161.8 ± 5.1
Weight (kg) 64.3 ± 10.8 51.3 ± 7.0
Body mass index (kg/m2) 21.3 ± 3.1 19.6 ± 2.5
Current smoker (%) 13.29.2
Current alcohol drinker (%) 28.732
Computer usage (h/day)  2.8 ± 2.2  2.3 ± 1.7*

Prevalence of excessive daytime sleepiness, sleep habits, and sleep-related problems

Table 2 shows the prevalence of EDS, sleep habits, and reported sleep-related problems of subjects by gender. The prevalence of EDS was 14.9% for boys and 18.2% for girls. The difference in reported sleep duration between boys and girls (6.3 h vs 6.5 h per day) was statistically significant (P < 0.001), although modest. In contrast, sleep latency was longer in girls (P < 0.01), as was the frequency of nightmares (P < 0.001). The prevalence of insomnia symptoms was also significantly higher in female students than in male students (14.5% vs 11.9%, P < 0.01). Boys, however, experienced a greater prevalence of habitual snoring compared with girls (12.4% vs 8.5%, P < 0.001).

Table 2.   Prevalence of EDS, sleep habits, and sleep-related problems (mean ± SD)
VariablesBoys (n = 2703)Girls (n = 1168)
  • EDS, excessive daytime sleepiness.

  • *

    Significantly different from boys (P < 0.05).

  • **

    Significantly different from boys (P < 0.01).

  • ***

    Significantly different from boys (P < 0.001).

EDS (%)14.918.2*
Bedtime0:19 a.m. ± 1:080:13 a.m. ± 1:11*
 Before 11:00 p.m. (%) 3.9 5.8
 11:01–12:00 a.m. (%)14.212.7
 12:01–1:00 a.m. (%)49.351.3
  1:01–2:00 a.m. (%)20.918.2
  2:01–3:00 a.m. (%)11.712.0
Wake-up time6:27 a.m. ± 0:376:32 a.m. ± 0:38***
 Before 6:00 a.m. (%) 3.3 3.8
 6:01–7:00 a.m. (%)51.542.0
 7:01–8:00 a.m. (%)40.448.8
 8:01–9:00 a.m. (%) 4.8 5.5
Night sleep duration (h/day) 6.3 ± 1.5 6.5 ± 1.6***
Sleep latency (min)17.4 ± 15.419.0 ± 15.7**
Insomnia symptoms (%)11.914.5*
Habitual snoring (%)12.4 8.5***
Witnessed apnea (%) 0.9 0.9
Teeth grinding (%) 2.4 1.5
Nightmares (%) 3.5 6.5***

Table 3 provides the general characteristics of EDS and non-EDS students. Average ages were the same between EDS and non-EDS groups. Mean BMI were also similar. The EDS subjects, however, were significantly more likely to smoke cigarettes or drink alcohol than those without EDS. Students with EDS also spent more time on the computer than non-EDS students by nearly 25 min/day. School performance was also associated with EDS. Here, students without EDS were less likely to be low-grade performers than those with EDS (25.9% vs 35.5%, P < 0.001).

Table 3.   General characteristics of EDS and non-EDS students (mean ± SD)
CharacteristicsEDS (n = 614)Non-EDS (n = 3257)
  • EDS, excessive daytime sleepiness.

  • *

    Significantly different from the EDS group (P < 0.001).

Age (years)16.8 ± 0.816.8 ± 0.8
Body mass index (kg/m2)20.7 ± 3.320.8 ± 3.0
Current smoker (%)16.411.2*
Current alcohol drinker (%)36.328.5*
Computer usage (h/day) 3.0 ± 2.5 2.6 ± 2.0*
School performance
 High grade (%)21.825.3*
 Moderate grade (%)42.748.8*
 Low grade (%)35.525.9*

Table 4 shows the comparison of sleep habits and sleep-related factors between EDS and non-EDS students. Although EDS students had significantly later bedtime and later wake-up time than non-EDS students, there were no significant differences in nocturnal sleep duration and sleep latency. In contrast, EDS students had a significantly greater prevalence of habitual snoring (P < 0.001), witnessed apnea (P < 0.001), insomnia (P < 0.01), teeth grinding (P < 0.001) and nightmares (P < 0.001) compared with non-EDS students.

Table 4.   Comparison of sleep habits and sleep-related problems (mean ± SD)
VariablesEDS (n = 614)Non-EDS (n = 3257)
  • EDS, excessive daytime sleepiness.

  • *

    Significantly different from EDS group (P < 0.05).

  • **

    Significantly different from EDS group (P < 0.01).

  • ***

    Significantly different from EDS group (P < 0.001).

Bedtime0:22 a.m. ± 1:160:16 a.m. ± 1:08*
 Before 11:00 p.m. (%) 4.7 4.4
 11:01–12:00 a.m. (%)13.713.8
 12:01–1:00 a.m. (%)49.050.0
  1:01–2:00 a.m. (%)19.220.3
  2:01–3:01 a.m. (%)13.411.5
Wake-up time (h:min)6:32 a.m. ± 0:416:28 a.m. ± 0:37*
 Before 6:00 a.m. (%) 4.7 3.2
 6:01–7:00 a.m. (%)43.849.7
 7:01–8:00 a.m. (%)42.742.8
 8:01–9:00 a.m. (%) 8.9 4.3
Night sleep duration (h/day) 6.4 ± 1.6 6.4 ± 1.3
Sleep latency (min)18.3 ± 16.817.7 ± 15.0
Insomnia symptoms (%)16.012.0**
Habitual snoring (%)17.310.0***
Witnessed apnea (%) 2.4 0.6***
Teeth grinding (%) 6.0 1.4***
Nightmares (%) 8.5 3.6***

Independent correlates of excessive daytime sleepiness

Table 5 provides the estimated odds ratios of EDS according to differences in key characteristics associated with EDS. Here, sleep duration, perceived sleep insufficiency, school performance, insomnia, snoring, witnessed apnea, teeth grinding, and nightmares were significantly associated with an increased risk of EDS in univariate logistic analyses. After adjustment for age, gender, and factors that were significantly related to EDS in the univariate analyses, effects of snoring were no longer statistically significant. In contrast, there was a threefold excess risk of EDS in students with teeth grinding ≥4 days/week versus students without teeth grinding. Students with witnessed apnea ≥4 days/week had a 2.1-fold excess risk of EDS compared with students without an apnea. The EDS prevalence consistently increased with increasing number of insomnia symptoms. When three symptoms were present, the odds ratio of EDS was nearly doubled, as compared to when symptoms were absent. Students with  nightmares  ≥4 days/week  had  a  61% excess  in the odds of EDS as compared to those without nightmares.  Other  factors  that  continued  to  have  significant relations with EDS were ≥7 h/day of nocturnal sleep, low school performance, and perceived sleep insufficiency.

Table 5.   Estimated odds ratios of excessive daytime sleepiness for sleep-related factors
VariablesEDS %Crude valuesAdjusted values
Odds ratio95%CIOdds ratio95%CI
  • EDS, excessive daytime sleepiness.

  • Insomnia symptoms were difficulty in initiating sleep, difficulty in maintaining sleep, and early morning awakening.

  • Adjusted for age, gender, and significant variables in univariate logistic analyses.

  • *

    Excess of EDS (P < 0.05);

  • **

    excess of EDS (P < 0.01);

  • ***

    excess of EDS (P < 0.001).

Sleep duration (h/day)
 <617.3 (176/1018)1.34*1.06–1.681.210.96–1.53
 6–13.5 (173/1282)1.0 1.0 
 ≥716.9 (265/1571)1.30*1.05–1.601.301.05–1.60
Sleep insufficiency
 No12.4 (202/627)1.0 1.0 
 Yes18.4 (412/2244)1.58***1.32–1.901.45***1.20–1.75
School performance
 High grade14.0 (135/967)1.0 1.0 
 Moderate grade14.2 (275/1936)1.010.81–1.271.060.38–1.31
 Low grade20.5 (198/968)1.59**1.25–2.011.58**1.17–1.91
Insomnia symptoms
 No15.3 (516/3381)1.0 1.0 
 Only one symptom161. (53/330)1.710.82–3.651.010.79–1.30
 Two symptoms25.2 (30/119)3.01**1.49–6.071.51*1.02–2.24
 Three symptoms36.6 (15/41)3.20***1.68–6.081.92*1.09–3.59
Snoring
 No14.7 (400/2717)1.0 1.0 
 1–3 days/week15.5 (112/721)1.060.84–1.331.050.85–1.30
 ≥4 days/week24.4 (106/433)1.87***1.47–2.391.320.91–1.91
Witnessed apnea
 No14.6 (516/3483)1.0 1.0 
 1–3 days/week23.5 (83/353)2.44*1.19–4.971.48**1.12–1.95
 ≥ days/week42.9 (15/35)4.31***2.19–8.472.12**1.19–4.49
Teeth grinding
 No14.6 (490/3350)1.0 1.0 
 1–3 days/week19.8 (87/440)1.43*1.11–1.851.210.93–1.59
 ≥4 days/week45.7 (37/81)4.90***3.13–7.673.08***1.88–5.05
Nightmares
 No14.5 (490/3350)1.0 1.0 
 1–3 days/week22.1 (77/349)1.67***1.27–2.191.310.98–1.74
 ≥4 days/week30.6 (52/170)2.60***1.85–3.661.61*1.10–5.05

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

In the current report, the prevalence of daytime sleepiness and its associated factors in a sample of 3871 students was examined by using questionnaires that contained items about individual sociodemographic characteristics, including school performance, sleep habits, and sleep-related problems.

Adolescent sleep-wake patterns were found to be affected by increased demand of schoolwork,9,10 increased extracurricular activities and part-time jobs,18,19 pubertal development,8,20–22 and changes in circadian rhythm.23 Many studies have consistently demonstrated that bedtime is delayed with increase in age throughout adolescence, while wake-up time remains constant due to school starting times. Consequently, total sleep time is decreased during high school, while daytime sleepiness is increased.8,24 The present study also found an insufficient amount of sleep for adolescents during puberty. More than 80% of students went to bed at midnight or later and >50% rose before 7 a.m. As a result, reported nocturnal sleep duration was 6.3 h/day for boys and 6.5 h/day for girls, which seems comparable to those of Japanese high school students.25 However, this nocturnal sleep duration is much shorter than those of adolescents in China,16 North America,26 and Israel.27 It is likely that a rapid diffusion of computer, video games, and late-night cinemas during the past decade in South Korea have contributed to this lack of nocturnal sleep time. In addition, uniquely high academic demands for South Korean adolescents caused by hard competition for college admission may be another reason for widespread sleep deficiency reported in the present study.

Sleep deficiency during adolescence deserves special concern because it is known that adolescence requires an adequate amount of sleep, which otherwise can have detrimental outcomes. Carskadon has shown that more sleep is required during adolescence than during the prepubertal period, thus puberty itself imposes a burden of increased daytime sleepiness with no change in nocturnal sleep.19 It is reported that adolescents need >8 h of sleep per night for optimal daytime alertness.19,20 When sleep duration is reduced below this level, alertness and school performance become objectively impaired,28,29 and this impairment can impact on normal development and quality of life.11,30 As expected, our results also show that the prevalence of EDS increased significantly (P < 0.001) with a decline in school performance, which is consistent with other studies.10,12

Previous studies reported that the prevalence of EDS ranged from 0.5 to 36%, depending upon study population, definition, and methodology. In the majority of the studies, however, the range is 10–20%. In a questionnaire survey by Saarenpaa-Heikkila et al., the prevalence of EDS (defined as daytime sleepiness ‘always’ or ‘often’) was found to be 20% for boys and 22% for girls between the ages of 7 and 17 years.31 In a sample of 1125 adolescents aged 15–18 years, using the Sleep-EVAL system, Ohayon et al. demonstrated that the prevalence of daytime sleepiness was 19.9%.32 Liu et al. reported that EDS (defined as feeling excessively sleepy ‘always’ or ‘often’ during the daytime) occurred in 18.7% of men and in 20.7% of women aged 20–39 years.13 In contrast, the prevalence of EDS (defined as excessive daytime sleepiness ‘always’ or ‘often’) was 35.8% in army draftees between the ages of 17 and 29 years.33 Although there have been various subjective and objective methods for measuring daytime sleepiness, one of the most widely used instruments to assess the EDS is the ESS.17,34 In the present report, 15.9% of students (14.9% of boys and 18.2% of girls) reported EDS, defined as an ESS score of >10. Because of the variability in operational definitions, sample population, and assessment techniques, it is difficult to interpret the prevalence rates of EDS between the studies.

Daytime sleepiness is caused by qualitative and quantitative sleep deficiencies, central nervous system dysfunctions, misalignments of the body's circadian pacemaker with the environment (e.g. jet lag or shift work), and drugs.35 Although it is known that short sleep duration is a strong predictor of EDS and that the degree of daytime sleepiness is related to the amount of nocturnal sleep,35 there was no significant difference in total sleep hours between EDS and non-EDS students in the current study. Several factors may have caused this result. First, school schedules require waking up early, while academic work loads, social activities, and work patterns require staying up late. Compressed in this daily lifestyle is a very narrow window for sleep, which may have removed the possibility of difference in sleep duration between the two groups. Second, EDS in the present subjects was mainly caused by poor sleep quality due to the significantly higher prevalence of insomnia, habitual snoring, witnessed apnea, teeth grinding, and nightmares. Third, students may misreport sleep duration during night. Therefore, our results may indicate that EDS is affected by sleep quality as well as sleep quantity.

Among sleep problems included in multiple regression analyses in the present study, teeth grinding contributes the most to increased risk of EDS, followed by witnessed apnea. Students with teeth grinding ≥4 days/week and witnessed apnea ≥4 days/week reported a greater  prevalence  of  EDS  (OR,  3.1;  OR,  2.1)  than did those without teeth grinding or witnessed apnea. Although the underlying mechanism resulting in EDS by teeth grinding is not fully known, it is generally recognized that teeth grinding may cause electroencephalogram (EEG) arousals and sleep fragmentation, which produce subsequent daytime sleepiness. The increased daytime sleepiness following nights of fragmented sleep is due to the changes in total sleep time and/or changes in sleep architecture, such as increased stage I sleep, decreased slow-wave sleep, and decreased rapid eye movement sleep.36 Other factors such as stress and psychosocial influences, and craniofacial structure of adolescents may also be involved in increased risk of EDS.37,38 Although the prevalence of teeth grinding decreases with age after peaking during adolescence,37 no study using biological recordings has been conducted to measure the frequency of teeth grinding and/or to evaluate its persistence in a given individual with respect to age. Further studies are needed to elucidate the etiological pathophysiology of teeth grinding in a prospective study.

To our knowledge, this report provides the first information about prevalence and correlates of daytime sleepiness for adolescents in South Korea. Several limitations, however, must be considered in the interpretation of our results. Above all, our data on sleep-disordered breathing and sleep-related symptoms were collected from a questionnaire. To compensate for this limitation, we examined the test–retest reliability of the question responses on sleep, and the results show that their reproducibility was high. In addition, Korean parents commonly check on their sleeping adolescents during the night and/or the family sleeps in close proximity to one another. Thus, our data on sleep is likely to be reasonably reliable. The use of objective measures (a multiple sleep latency test, polysomnography etc.) to validate our data collected by questionnaire is still in need of further investigation. The generalization of our results to all of the adolescents needs to be carefully considered because this study is based on a cross-sectional survey of urban high school students in Korea, and the EDS-associated factors such as sedating medications and psychiatric depression were not fully assessed in the present study.

In conclusion, our findings show that EDS is common  in  adolescents  in  Korea,  and  the  increased  risk of EDS is significantly associated with perceived sleep insufficiency, higher frequency of teeth grinding ≥4 days/week, witnessed apnea ≥4 days/week, nightmares ≥4 days/week, low school performance, and the presence of two or more insomnia symptoms. Whether interventions to modify associated correlates can alter EDS warrants consideration, especially because it may also improve academic performance in high school students.

ACKNOWLEDGMENT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

This work was supported by a grant no. 2000-n6 from the Korea University Medical Science Research Center.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES
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