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Stroke. 2000;31:1588-1601

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(Stroke. 2000;31:1588.)
© 2000 American Heart Association, Inc.

Original Contributions

International Trends in Mortality From Stroke, 1968 to 1994

Cinzia Sarti, MD, PhD; Daiva Rastenyte, MD, PhD; Zygimantas Cepaitis, MSocSc Jaakko Tuomilehto, MD, PhD

From the National Public Health Institute (C.S., Z.C., J.T.), Helsinki, Finland, and the Institute of Cardiology (D.R.), Kaunas, Lithuania.

Correspondence to Dr Cinzia Sarti, Department of Epidemiology and Health Promotion, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland. E-mail cinzia.sarti{at}ktl.fi


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowSubjects and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Background and Purpose—The World Health Organization data bank is an invaluable source of information for international comparison of mortality trends. We present rates and trends in mortality from stroke up to 1994, with a particular emphasis on the last 10-year period. Data are presented for men and women in 51 industrialized and developing countries from different parts of the world.

Methods—We included all deaths from cerebrovascular disease for the population aged 35 to 84 years from all the countries in which death certificates were estimated to be available for at least 80% for the period from 1968 to 1994. Age-standardized mortality rates from stroke were calculated for each country for the last available 5 years. Time trends were calculated by using ordinary linear regression and are presented for the entire study period and for 3 separate time periods: 1968 to 1974, 1975 to 1984, and 1985 to 1994. The last 10-year period was further subdivided into 2 parts of 5 years each. We analyzed data separately for men and women and for groups aged 35 to 74 years and 75 to 84 years.

Results—The highest rates at the end of the study period for the population aged 35 to 74 years were observed in eastern Europe and previous Soviet Union countries (309 to 156/100 000 per year among men and 222 to 101/100 000 per year among women), Mauritius (268/100 000 per year among men and 138/100 000 per year among women), and Trinidad and Tobago (185/100 000 per year among men and 134/100 000 per year among women). Relatively low to average rates (<100/100 000 per year among men and <70/100 000 per year among women) were reported for Western Europe, with an exception of Portugal (162/100 000 per year among men and 95/100 000 per year among women). The countries with lowest stroke mortality rates at the end of the study period, such as the United States, Canada, Switzerland, France, and Australia, experienced steep declining trends. However, the slope of the decline was substantially reduced during the last 5 years in these countries. Mortality from stroke increased most in the eastern European countries, especially during the last 5 years. Among other high-risk populations, no change in stroke mortality trends was observed in Mauritius, whereas somewhat declining trends were seen in Trinidad and Tobago.

Conclusions—We observed large differences in mortality rates from stroke around the world together with a wide variation in mortality trends. A widening gap was observed between 2 groups of nations, those with low and declining stroke mortality rates and those with high and increasing mortality, in particular, between western and eastern Europe. Eastern European countries should initiate actions aiming at the reduction of stroke risk, perhaps by looking at the examples of Japan and Finland and the other countries that have been the most successful in reducing previously very high mortality from stroke.


Key Words: cerebrovascular disorders • mortality • stroke


*    Introduction
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 up arrowAbstract
 *Introduction
down arrowSubjects and Methods
 down arrowResults
 down arrowDiscussion
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Stroke has been the third leading cause of death in most developed countries for many decades. During the 1950s and early 1960s, these countries were characterized by increasing trends in stroke mortality, whereas since the mid 1960s, stroke mortality steeply declined for the next 2 decades.1 2 3 At the same time, most eastern European countries and Portugal and Yugoslavia in southern Europe showed increasing trends in mortality from stroke.1 2 4 5 6 In eastern Asian countries, such as the People’s Republic of China and Japan, stroke has been a principal cause of death for the past few decades.7 Worldwide cerebrovascular accidents are the second leading cause of death.8

During recent years, it has been suggested that the continuing decline in stroke mortality has slowed down in several industrialized countries.9 However, it is not clear whether this observation is temporary or whether it is common for most countries that experienced a decline in stroke mortality in the recent past. Another reason for having a fresh look at international trends is that the world map has changed extensively during the last decade, with a number of new nations emerging into the international arena, and political turmoil might be reflected in the disease statistics. There is a lack of data regarding stroke trends in these countries. In addition, except for an article by La Vecchia et al,10 previous articles on international stroke trends dealt only with middle-aged populations (aged 40 to 69 years)1 or with populations aged <=74 years2 and covered changes in mortality up to 198910 or earlier. There is a lack of knowledge on stroke mortality trends in the elderly. Also, most previous articles included a limited number of countries. The present study, analyzing mortality trends in elderly people, in many countries, and during the last 3 decades, investigates the natural history of stroke mortality around the world.

The aim of the present article is to update and analyze in more detail the available information on international trends in stroke mortality. We present stroke mortality rates for the last available 5 years and trends in stroke mortality during the last 3 decades in men and women aged 35 to 84 years in 51 industrialized and developing countries from different parts of the world.


*    Subjects and Methods
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Subjects and Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Official mortality data and demographic data for countries included in this analysis were provided by the World Health Organization (WHO) data bank for deaths. In the present study, we included all the countries with coverage of deaths estimated by WHO to be >80%. Only deaths from cerebrovascular disease (International Classification of Disease [ICD], 8th and 9th Revision, codes 430 to 438) for the period 1968 to 1994 and for the population aged 35 to 84 years were used in the present analyses. There is a good comparability for the overall category of cerebrovascular disease between these 2 ICD versions, so no adjustments were needed. Thus, the term stroke is used in the present study to denote cerebrovascular disease. The whole category of cerebrovascular disease, including sequelae of stroke, was chosen to be as exhaustive as possible in case ascertainment.

Rates have been standardized by using the Segi’s world population for direct standardization (Waterhouse et al11 ). The trends in rates were calculated from age-standardized annual rates by use of the regression model log rt=a+bt+et, assuming that the annual numbers of deaths within age groups follow Poisson distribution and allowing for additional deviation from the regression line. The instantaneous change rate per year at the time point t is a constant proportion, 100b percentage of the event rate at t; 100b is presented in the tables as the early percentage change. In sum, the annual change in mortality is assumed to be constant and log-linear. The yearly percentage changes in stroke mortality were calculated for the entire study period, from 1968 to 1994, with this period divided into 3 parts: 1968 to 1974, 1975 to 1984, and 1985 to 1994. The mortality trend for a country was calculated if data were available for at least 5 years during a given time period. Time trends for the entire study period were calculated only for the countries that were eligible for the trend analyses during all 3 time periods.


*    Results
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 *Results
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The average age-standardized stroke mortality rates in the 1990s during the last available 5-year period varied markedly among countries for men and women (Tables 1Down and 2Down, respectively). The highest rates among both men and women were observed in eastern Europe, in Mauritius, and in Trinidad and Tobago. Stroke mortality in Portugal was clearly higher than that in any other western European country, among which Finland and Greece showed the next highest rates. Poland had clearly lower stroke mortality than the other eastern European countries. Central and South America, represented by Argentina, Chile, and Uruguay, reported rates approximately twice as high as those observed in western Europe and in Mexico. Cuba also showed relatively high stroke mortality rates, although they were twice lower than those observed in Trinidad and Tobago. The lowest stroke mortality rates were found in Switzerland, Canada, the United States, France, and Australia in both sexes and in both age groups. Stroke mortality was higher in men than in women in most countries, but the differences narrowed considerably above the age of 75 years. In the oldest age group, a few countries (Greece, Cuba, and Uruguay) reported higher rates for women than for men. Both in men and in women, the highest to lowest ratio between countries was >9:1 for the group aged 35 to 74 years and >5:1 for the group aged 75 to 84 years. The absolute rate differences between the countries with the lowest and the highest stroke mortality were >200 per 100 000 population per year in the younger age group and >2000 per 100 000 population per year in the older age group for both men and women.


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  		Table 1. Stroke Mortality in Men Aged 35–84 Years During the Last Available 5 Years, by Country and Age Group


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  		Table 2. Stroke Mortality in Women Aged 35–84 Years During the Last Available 5 Years, by Country and Age Group

The annual percentage change in mortality from stroke in men and women aged 35 to 74 and 75 to 84 years during the 3 consecutive time periods is presented in Tables 3 through 6DownDownDownDown and during the entire period of 1968 to 1994 in Figures 1Down and 2Down. Throughout the entire study period, the largest decline was observed in Japan, Australia, France, Switzerland, and the United States (for men and women) and in Israel (for women) (Figures 1Down and 2Down). In most western European countries, Australia, Japan, the United States, and Canada, a clear decline in stroke mortality had already occurred during the 1970s, and it accelerated in the 1980s and still continued to decline at the beginning of the 1990s (Tables 3 through 6DownDownDownDown). Slowing down of the decreasing trend during the last study period, especially during the last 5 years (Tables 7Down and 8Down), was observed in Denmark, Norway, Sweden, the Netherlands, Israel, the United States, and Canada. In addition, the same pattern could also be observed in Japan and Australia. In general, the countries with the lowest stroke mortality rates at the end of the study period had also experienced a steep decline in mortality during the previous 10 or 20 years. Also, some countries for which still moderate or high stroke mortality rates were observed during 1990 to 1994 showed a continuing declining trend (Japan, Finland, Portugal, Greece, and Trinidad and Tobago).


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  		Table 3. Percentage Change per Annum in Mortality From Stroke in Men Aged 35–74 Years During 1968–1994, by the 3 Time Periods and Country


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  		Table 4. Percentage Change per Annum in Mortality From Stroke in Women Aged 35–74 Years During 1968–1994, by the 3 Time Periods and Country


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  		Table 5. Percentage Change per Annum in Mortality From Stroke in Men Aged 75–84 Years During 1968–1994, by the 3 Time Periods and Country


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  		Table 6. Percentage Change per Annum in Mortality From Stroke in Women Aged 75–84 Years During 1968–1994, by the 3 Time Periods



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  		Figure 1. Annual percentage change in mortality from stroke in men (left) and women (right) aged 35 to 74 years in selected countries during the entire study period of 1968 to 1994.



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  		Figure 2. Annual percentage change in mortality from stroke in men (left) and women (right) aged 75 to 84 years in selected countries during the entire study period of 1968 to 1994.


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  		Table 7. Percentage Change per Annum in Mortality From Stroke in Men and Women Aged 35–74 Years During 1985–1994, by the 2 Time Periods


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  		Table 8. Percentage Change per Annum in Mortality From Stroke in Men and Women Aged 75–84 Years During 1985–1994, by the 2 Time Periods

Only a few countries in eastern Europe, such as Poland, Bulgaria, former Yugoslavia, and Romania, presented an increasing trend in mortality from stroke among men aged 35 to 74 years during all 3 time periods studied. Among women aged 35 to 74 years, only Poland had a significantly increasing trend during the first study period, from 1968 to 1974, and Mauritius had a significantly increasing trend during the second period, from 1975 to 1984. Similar patterns were observed for the group aged 75 to 84 years, for both men and women, except for Mauritius and Mexico, who joined the group of a few eastern European countries showing an increasing trend in mortality from stroke throughout the entire study period.

In general, among people aged 35 to 74 years, the temporal trends in stroke mortality were more favorable in women than in men. In the countries with increasing trends, the increase was smaller in women than in men in most, but not all, cases. Conversely, in the countries with declining trends, the decline tended to be steeper in women than in men (Tables 3 through 6UpUpUpUp). The trends observed among people aged 75 to 84 years were in the same direction as in the younger people, but the relative changes were smaller in the older age group. This is confirmed by the high correlation in stroke mortality trends observed between the younger and older age groups in men (r=0.85, P=0.0001) and in women (r=0.85, P=0.0001) (Figure 3Down). Similarly, high correlations (ie, trends in the same direction) were also observed between men and women in both age groups (35 to 74 years, r=0.95, P=0.0001; 75 to 84 years, r=0.92, P=0.0001) (Figure 4Down).



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  		Figure 3. Correlation in stroke mortality trends during the entire study period of 1968 to 1994 between the age groups of 35 to 74 and 75 to 84 years in men (left) and women (right).



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  		Figure 4. Correlation in stroke mortality trends during the entire study period of 1968 to 1994 between men and women aged 35 to 74 years (left) and 75 to 84 years (right).

For the countries that used to belong to the former Soviet Union, we had data for only the last 10 years. All of them showed increasing stroke mortality in both men and women and in both age groups (Tables 3 through 6UpUpUpUp). Because all these countries experienced enormous socioeconomic and political changes during the early 1990s with the fall of Soviet Union, we decided to explore whether there was any notable effect of these changes on trends in mortality from stroke by dividing the last 10 years into two 5-year periods: before and after the collapse of the Soviet Union (Tables 7Up and 8Up). All of these former republics of the Soviet Union experienced a marked unfavorable change in the overall trend in mortality from stroke since 1991. This further subdivision also showed that the declining trend in stroke mortality has indeed been slowing down after 1990 in Japan, Australia, Austria, the Netherlands, Switzerland, Canada, and the United States. Several other countries, such as Finland, Spain, Portugal, Sweden, and the United Kingdom, were still showing a steep downward trend in mortality from stroke in both men and women in all age groups during the latter period, from 1991 to 1994.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
 up arrowResults
 *Discussion
down arrowReferences
 
Although studies based on routine statistics are always open to criticism as to the reliability of the database, official mortality statistics are invaluable in providing comparable secular information from countries around the world,1 even though the point estimates of mortality rates might not be fully comparable. It is true that a questionable quality of routine mortality statistics in some countries might result in a bias in estimates of cause-specific mortality.2 Poor coverage, however, is more likely to result in a bias at a certain point in time rather than to affect temporal trends, which are dependent on sudden changes in registration methods at least as much as on coverage in total. In the present report, we included all the countries in which the estimated coverage of all deaths reported in the routine mortality statistics was >=80%.

The WHO data bank does not provide information on mortality rates from different subtypes of stroke. On the other hand, it is not likely that the adoption of the 9th revision of ICD has influenced the death rates from cerebrovascular disease, because this overall category of stroke deaths is essentially similar in the 8th and 9th revisions of ICD. Furthermore, increasing trends in mortality from stroke in eastern European countries are not isolated. On the contrary, they are strongly associated with an increase in cardiovascular mortality and total mortality reported independently by other authors.5 12 13 In addition, in the present study, a clear correlation was observed between the stroke mortality trends in men and women, which also speaks against the possible inconsistency of the data presented. Therefore, we are confident that the findings related to trends in stroke mortality observed in the countries included in our analyses are real.

Sex Differences
Although we observed trends mainly in the same direction in men and women, the magnitude of the change differed by sex and age. The temporal trends in stroke mortality were more favorable in women than in men, and in the countries with increasing trends, the increase was smaller in women than in men in most cases. Conversely, in the countries with declining trends, the decline tended to be steeper in women than in men. The trends observed among people aged 75 to 84 years were in the same direction, but the relative changes were smaller in the older age group. Hormonal differences have been postulated to sex differences in cerebrovascular disease, but the studies are conflicting. An increased risk for ischemic stroke has been suggested for postmenopausal women who use oral estrogen replacement therapy.14 Clinical studies, on the other hand, have suggested that estrogen replacement therapy enhances the cognitive function and protects against brain injuries, such as stroke.15 However, other studies did not confirm an increase or a decrease in the risk of ischemic stroke associated with hormone replacement therapy.16

Western Europe and Other Industrialized Countries
All the countries with low stroke mortality rates or those that showed steep declines from the previously high stroke mortality rates during the last 25 years are affluent industrialized countries. Countries such as Japan and Finland, which had, respectively, the highest and the second highest rate of stroke mortality in the world in the beginning of the 1970s, did particularly well.1 2 3 The magnitude of the decline was also remarkable in some countries (eg, Australia and the United States) starting from a more favorable position. Moreover, this declining trend could be also seen among people aged >74 years, indicating a general improvement in the risk of stroke and not only a shift of stroke mortality toward the older ages. The difference between the trends observed in the 2 age groups can be roughly attributed to a shift of stroke onset to the latter age group.

A number of studies have been conducted to document and to explain the accelerated decline in stroke mortality during the late 1970s and the early 1980s in a number of industrialized countries. Earlier studies also reported the declining trends in both the incidence and case fatality of stroke during the 1970s.17 18 19 However, more recent studies supported by the data from the population-based stroke registers have not been able to show any significant decline in the incidence of stroke.20 21 22 23 Nevertheless, mortality from stroke has continued to decline throughout the 1970s and the 1980s in these countries, suggesting that acute stroke events have become milder and that the prevalence of stroke survivors in these communities is increasing. Whether this decline in mortality from stroke can be attributed to an improvement in the control of hypertension has been debated.24 25 There is evidence suggesting that a decrease in the prevalence of some environmental factors, presumably the decrease in the intake of dietary salt and saturated fat, has contributed more to the decrease in stroke mortality than has pharmacological treatment of hypertension alone.24 26 27 It has also been postulated that a reduction in salt intake by 50 mmol/d in the entire population would be 1.5 times more effective than pharmacological treatment of all hypertensive patients to reduce stroke mortality in the community.28 Flat or even increasing trends in the incidence of stroke are in sharp contrast to the results from a number of the clinical trials involving the treatment of hypertension, which have consistently documented significant reductions in the expected numbers of new cases of stroke.29 30 31 It could be speculated that efforts directed to the effective control of hypertension have contributed to the decline in mortality from stroke by reducing the severity of acute stroke events but also by reducing the incidence of stroke. Only a study on trends in different subtypes of stroke could tell us whether this assumption is correct or not, because different subtypes of stroke have different prognoses. Unfortunately, routine mortality data collected from so many countries are not reliable enough to allow subtype-specific analyses. This limits the possibility of an interpretation of the temporal trends. Another severe limitation is the lack of information on case fatality, which requires incidence data to be calculated. Without case-fatality and subtype analyses, we can only speculate on the reasons for the changes in trends. For example, in Finland, subarachnoid hemorrhage and intracerebral hemorrhage represent {approx}20% of all strokes but account for {approx}40% of all stroke deaths.32 Because hypertension is the most important risk factor for intracerebral and subarachnoid hemorrhage, changes in the level of hypertension control my produce large changes in case fatality from different subtypes of stroke. In sum, it is very important that studies on routinely collected data be accompanied by population-based studies collecting incidence data and accurate data on the subtypes on stroke.

In spite of the generally favorable trends in stroke mortality observed in many industrialized countries, some of these countries seem to have experienced a slowdown of the declining trend during the last 10 and especially during the most recent years. Most of these countries currently have the lowest stroke mortality rates. This may indicate that without intensified application of the available measures for primary and secondary prevention of stroke or without new methods yet to be identified, the maximum results have already been obtained. This slowing down of the decline in stroke mortality may also in some countries mask a relapse in hypertension detection and control. It is also possible that some risk factors for stroke are increasing, which might have led to the slowdown in the mortality decline and a possible upturn in stroke incidence. The data available seem to support this hypothesis, inasmuch as the incidence of diabetes,33 34 abdominal obesity,35 36 and alcohol drinking37 are increasing in most countries. In addition, although the prevalence of hypertension has not increased, the incidence of congestive heart failure seems to be rising,38 and the prevalence of atrial fibrillation, an important risk factor for stroke, might also be increasing.39 40 Both of them are important risk factors for stroke. These trends may be primarily related to the improved long-term survival of patients with hypertension and also those with ischemic heart disease, who are at very high risk of stroke.41

Eastern European Countries: A Special Case for Stroke
There is a clear difference in stroke trends between western and eastern European countries. Because hypertension is the main determinant of stroke, this difference suggests that environmental factors causing high blood pressure have not decreased or have even increased in eastern European countries. Also, inadequate control of hypertension on a population level is still widespread in eastern Europe.42 Differences in trends in risk factors, such as smoking, alcohol consumption, and diet, probably have the primary role in explaining the diverging trends in stroke mortality in different parts of Europe.5 6 The early 1990s were characterized by economic uncertainty and political instability in eastern Europe. Psychological disorders, especially depression, are important determinants of mortality, particularly that due to cardiac causes.43 44 Depression, increased alcohol consumption, and an impoverished health care system seem to be associated with the degrading health of the population. More affluent western European countries have more comprehensive and better funded health care systems. However, the allocation of available resources is at least as important in health promotion as is the increase of resources. Eastern European countries could find good and relatively inexpensive methods to limit this problem of high stroke mortality by observing the examples of the countries that have successfully tackled the problem (such as Japan and Finland) through large community-based risk factor control and salt reduction in the diet in the previous decades.45 46

Other Countries
Although there is a lack of studies directly addressing the issue of stroke risk in Trinidad and Tobago, there are strong indications that the high mortality from stroke in this country is due to the high stroke risk profile of its population, as reported in a study comparing subjects hospitalized for coronary heart disease in Trinidad and the United Kingdom.47 A high prevalence of hypertension and non–insulin-dependent diabetes mellitus has been found especially among the Asian Indian population, followed by the population of African descent; the lowest has been found in European offspring.48 49 Conversely, it is possible that the relatively lower mortality from stroke in Cuba (compared with Trinidad and Tobago) could be ascribed to different patterns of risk factors for stroke in this country, especially diabetes.50 51 Also, Mauritius reported stroke mortality rates among the highest, with no declining trend during the most recent years. Thus far, there are no specific studies on cerebrovascular disease in this country; however, a large survey of cardiovascular risk factors has been ongoing for several years, showing that this population has high levels of risk factors, especially diabetes.52 It is worth noting that the populations of Mauritius and of Trinidad and Tobago consist of Asian Indians and Creoles (with a strong African admixture) and that in these countries a very high prevalence of diabetes has been found.49

Different genetic background probably explains part of the differences observed in stroke mortality worldwide. For example, stroke appears to affect black people disproportionately, and many authors agree that the excess risk factor burden does not completely explain the differences in blacks and whites.25 53 54 It has also been observed that intracranial atherosclerosis occurs predominantly in the black population, whereas extracranial disease is relatively more common in whites.55 Intracranial atherosclerosis and hemorrhagic stroke are also more common in oriental populations compared with white populations.55 56 Weather conditions may also influence stroke occurrence, triggering a stroke event or affecting its outcome, and thus explain part of the differences in mortality observed. Several studies have addressed this issue, but the results are not definitive: although a winter excess of ischemic strokes, which is supposedly linked to cold weather, has been reported,57 58 this has not been confirmed in all studies.59 A Chinese study, for example, found that thrombotic stroke deaths were more frequent in hot (>32°C) and in cold (<26°C) weather, whereas the risk of dying from hemorrhagic stroke decreased with increasing temperatures.60

We did not provide stroke mortality rates for China because these data are not available in the WHO database. However, it is known that for the past few decades, stroke has been a principal cause of death in China, as in other eastern Asian countries.7 The burden of stroke in the entire eastern Asian region is predicted to increase, both in absolute terms and as a proportion of total disease burden.7 Although the reasons for the greater burden of stroke in eastern Asian populations remain unclear, the recent available data have suggested that the association between blood pressure and stroke may be stronger there than in western populations.61 Asian populations are also particularly prone to diabetes, which is rapidly increasing in all Asian countries.33 In the study by the Eastern Stroke and Coronary Heart Disease Collaborative Research Group,61 a decrease of 5 mm Hg in usual diastolic blood pressure was associated with a 44% decrease in the risk of stroke in eastern Asia compared with a 34% decrease in stroke risk in a similar study of 9 western populations,62 and it was associated with a 27% lower stroke risk in another study, mostly of western populations.63 The observed association of blood pressure with stroke was so strong that the decline in average diastolic blood pressure of {approx}4 mm Hg reported for Japan over the past few decades could explain most of the decrease of stroke, particularly hemorrhagic stroke, observed during the study period.64

Information based on official mortality statistics, such as in the present study, is very useful. Nevertheless, trends in mortality from stroke do not necessary reflect stroke occurrence in many countries. We know that trends in stroke incidence do not always parallel the trends in mortality from stroke. Although declining trends have been observed in mortality, trends in incidence can be flat or even increase.48 Keeping in mind that {approx}70% of stroke patients survive >=1 month after acute stroke,65 official mortality data might depict a too optimistic picture of the situation. Thus, to investigate the reasons behind stroke trends, it is essential that we also maintain data on the incidence of stroke and on case fatality and that we have reliable data on the subtypes of stroke. Because these data should be obtained only on a population basis, well-organized and standardized population-based stroke registers are of the greatest importance. They require more manpower and funds compared with the maintenance of the official mortality statistics, but such efforts are very small compared with the entire burden of stroke.

Received September 24, 1999; revision received April 20, 2000; accepted April 20, 2000.


*    References
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 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
 up arrowResults
 up arrowDiscussion
 *References
 

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