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Background: Although many observational studies have demonstrated significant relationships between obesity and cardiometabolic traits, the causality of these relationships in East Asians remains to be elucidated., Methods: We conducted individual-level Mendelian randomization (MR) analyses targeting 14,083 participants in the Japan Multi-Institutional Collaborative Cohort Study and two-sample MR analyses using summary statistics based on genome-wide association study data from 173,430 Japanese. Using 83 body mass index (BMI)-related loci, genetic risk scores (GRS) for BMI were calculated, and the effects of BMI on cardiometabolic traits were examined for individual-level MR analyses using the two-stage least squares estimator method. The β-coefficients and standard errors for the per-allele association of each single-nucleotide polymorphism as well as all outcomes, or odds ratios with 95% confidence intervals were calculated in the two-sample MR analyses., Results: In individual-level MR analyses, the GRS of BMI was not significantly associated with any cardiometabolic traits. In two-sample MR analyses, higher BMI was associated with increased risks of higher blood pressure, triglycerides, and uric acid, as well as lower high-density-lipoprotein cholesterol and eGFR. The associations of BMI with type 2 diabetes in two-sample MR analyses were inconsistent using different methods, including the directions., Conclusion: The results of this study suggest that, even among the Japanese, an East Asian population with low levels of obesity, higher BMI could be causally associated with the development of a variety of cardiometabolic traits. Causality in those associations should be clarified in future studies with larger populations, especially those of BMI with type 2 diabetes.

Aims: P-wave terminal force in lead V 1 (PTFV 1 ) is an electrocardiogram marker of increased left atrial pressure and may be a noninvasive and early detectable marker for future cardiovascular events in the general population compared to serum B-type natriuretic peptide (BNP) concentration. The clinical significance of PTFV 1 in the contemporary general population is an area of unmet need. We aimed to demonstrate the correlation between PTFV 1 and BNP concentrations in a contemporary representative Japanese population., Methods: Among 2,898 adult men and women from 300 randomly selected districts throughout Japan (NIPPON DATA2010), we analyzed 2,556 participants without cardiovascular disease (stroke, myocardial infarction, and atrial fibrillation). Elevated BNP was defined as a value of ≥ 20 pg/mL based on the definition from the Japanese Circulation Society guidelines., Results: In total, 125 (4.9%) participants had PTFV 1 . Participants with PTFV 1 were older with a higher prevalence of hypertension, major electrocardiographic findings, and elevated BNP concentrations (13.5 [6.9, 22.8] versus 7.8 [4.4, 14.5] pg/mL; P＜0.001). After adjustment for confounders, PTFV 1 was correlated with elevated BNP (odds ratio, 1.66; 95% confidence interval, 1.05-2.62; P=0.030). This correlation was consistent among various subgroups and was particularly evident in those aged ＜65 years or those without a history of hypertension., Conclusions: In the contemporary general population cohort, PTFV 1 was independently related to high BNP concentration. PTFV 1 may be an alternative marker to BNP in identifying individuals at a higher risk of future cardiovascular events in the East Asian population.

The aim of this study is to show the combined effect of weight gain within normal weight range in adulthood and parental HT on the prevalence of HT. The study subjects were 44,998 individuals (19,039 men and 25,959 women) with normal weight (body mass index [BMI] 18.5-24.9) aged 35-69 years who participated in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. They were categorized into six groups by weight gain from age 20 years (<10 kg, and ≥10 kg) and by the number of parents having HT (no parent, one parent, and both parents). Odds ratios for HT were estimated after adjustment for age, sex, current BMI, estimated daily sodium intake, and other confounding factors. The prevalence of HT (31.5% in total subjects) gradually increased with greater weight gain from age 20 years and with greater number of parents with HT. Subjects who gained weight ≥10 kg and having both parents with HT showed the highest risk of having HT compared with those who gained weight <10 kg without parental HT (59.8% vs. 24.9%, odds ratio 4.25, 95% CI 3.53-5.13 after adjustment). This association was similarly observed in any category of age, sex, and BMI. Subjects who gained weight within normal range of BMI and having one or both parent(s) with HT showed the higher risk of having HT independent of their attained BMI in their middle ages. Thus, subjects having parent(s) with HT should avoid gaining their weight during adulthood, even within normal range of BMI, to reduce the risk of having HT.

Background: Atrial premature complexes (APC) are among the most frequently encountered electrocardiographic abnormalities. However, their prognostic value among healthy individuals is unclear. This study aimed to clarify the role of APC in predicting cardiovascular events in a large Japanese community cohort using long-term follow-up data., Methods: National Integrated Project for Prospective Observation of Non-communicable Disease And its Trends in the Aged, 1990-2005, (NIPPON DATA 90) was a large cohort study of cardiovascular disease (CVD) in Japan. A total of 7692 otherwise healthy participants with no history of myocardial infarction, stroke, atrial fibrillation, or atrial flutter were enrolled (men, 41.5%; mean age, 52.5 ± 13.7 years)., Results: A total of 64 (0.8%) participants had at least one beat of APC on screening 12-lead electrocardiogram. During the follow-up of 14.0 ± 2.9 years (total, 107,474 patient-years), 338 deaths occurred due to CVD. The association between APC and CVD outcome was assessed using Cox proportional hazard models. Cox regression analysis revealed that the presence of APC was an independent predictor for CVD deaths (HR: 2.03, 95% CI: 1.12-3.66, P = 0.019). The association of APC on CVD death was more evident in participants with hypertension (P-value for interaction, 0.03)., Conclusions: APC recorded during the screening electrocardiogram are significantly associated with an increased risk of CVD deaths in a Japanese community-dwelling population and are a strong prognostic factor for hypertensive participants.

Data from animal studies clearly indicate an association between leptin and hypertension; results of human studies are less concordant. We investigated the role of leptin in obesity-related higher blood pressure (BP) in Japanese Americans living in Hawaii and Japanese in Japan. Serum leptin and BP were examined by standardized methods in men and women ages 40 to 59 years from 2 population samples, one Japanese American in Hawaii (88 men and 94 women) and the other Japanese in central Japan (123 men and 111 women). Multiple linear regression models were used to assess role of leptin in obesity-related higher BP. Across quartiles of leptin, there were significantly higher mean body mass index levels, systolic BP, and diastolic BP for both sexes and sites (P<0.01 to 0.02). In multivariate regression analyses using all of the data combined, relations of body mass index and leptin to systolic BP and diastolic BP remained significant with the interaction term (body mass index x log-leptin) in the models (P<0.01 to <0.05). These findings are consistent with the inference that leptin may be an independent mediator for obesity-related elevations in BP.

A family history of stroke seems to be related with increased risk of stroke although the relationship is not always significant. Increased risk of stroke is strongly associated with hypertension, which might be also associated with family history. However, investigations into the relationship between family history of hypertension and stroke mortality are scarce. We investigated whether a family history of stroke and that of hypertension evaluated using a simple questionnaire could predict stroke mortality in Japanese. We obtained parental histories of stroke and of hypertension from 8,037 randomly selected general Japanese without history of cardiovascular disease and followed them for 19 years. The multivariate adjusted hazard ratios (HRs) for total stroke mortality, intra-cerebral hemorrhage mortality and for cerebral infarction mortality according to family history were estimated using the Cox proportional hazards model. The prevalences of family histories of stroke and of hypertension were 20.6% and 31.1%, respectively. A family history of stroke was not related to total stroke mortality, intra-cerebral hemorrhage mortality or to cerebral infarction mortality. Meanwhile, a family history of hypertension was positively related to total stroke mortality among women aged less than 60 years and men aged 60 or more years (women: HR=3.41, 95% confidence interval [CI]: 1.49-7.81; men: HR=1.50, 95% CI: 1.00-2.24) even after adjustment for systolic blood pressure. In conclusion, a family history of stroke could not predict total stroke mortality. However, a family history of hypertension might predict an increased risk for total stroke.

Objective: We investigated the factors contributing to whether or not hypertensive patients brought their home blood pressure records to the outpatient clinic., Method: We studied 325 hypertensive patients [169 men (66.3+/-11.4 years old) and 156 women (68.1+/-11.2 years old)] who had received medical treatment for hypertension in our outpatient clinic from June to August 2006., Results: Of the 325 patients studied, 206 (63.4%, 101 men, 105 women) brought their home blood pressure records to our outpatient clinic. Logistic analysis showed age [odds ratio (OR) =0.95; 95% confidence interval (CI): 0.93-0.98; p=0.0002], systolic blood pressure in outpatient clinic (OR=1.02; 95% CI: 1.00-1.04; p=0.0488) and the number of medicines prescribed (OR=1.94; 95% CI: 1.37-2.75; p=0.0002) were independent factors contributing to whether or not hypertensive patients bring along their home blood pressure records to the outpatient clinic., Conclusion: The contributing factors determining whether the patients bring their home blood pressure records to the outpatient clinic were: younger age, higher systolic blood pressure in the outpatient clinic, and a higher number of antihypertensive drugs. In conclusion, our results suggest that physicians should further motivate older patients, with well-controlled blood pressure in the outpatient clinic, to bring their home blood pressure records to the outpatient clinic.

Hypertension and smoking are major risk factors for death due to cardiovascular disease (CVD). These attributions for CVD mortality should be higher in the countries where obesity-related conditions are uncommon. However, the joint effect of these risk factors on CVD and all-cause mortality have not been described. We followed a representative 8,912 Japanese men and women without a history of stroke and heart disease. Participants were categorized into 4 groups as follows: a group of individuals who neither smoked nor had hypertension (HT), a group of current smokers, a group with HT, and a group of current smokers with HT. We further calculated population-attributable fractions (PAF) of CVD and all-cause mortality based on relative hazards assessed by proportional hazard regression models. After 19 years of follow-up, we observed 313 and 291 CVD and 948 and 766 all-cause deaths for men and women, respectively. The PAF of CVD mortality due to smoking or HT were 35.1% for men and 22.1% for women. The PAF of CVD mortality was higher in participants <60 years of age (57.4% for men and 40.7% for women) vs. those who were older (26.3% for men and 18.1% for women). Aggressive attempts to discourage smoking and to curb HT could yield large health benefits in Japan and throughout Asia, particularly for those aged <60 years. Efforts to warn about the adverse consequence of HT and smoking during adolescence and youth could yield the greatest health benefits, since positive behaviors adopted early are more easily continued into middle adulthood and later life.

Background: The association of obesity measures (ie, body mass index (BMI), waist circumference (WC) and waist-to hip ratio (WHR)) with metabolic risk factors in community-based populations has not been well studied., Methods and Results: In the present study 759 men and 1,255 women aged between 30 and 79 years, without histories of stroke or coronary heart diseases, were dichotomized at the medians of BMI-WHR, WC-WHR and BMI-WC. The accumulation of 4 metabolic risk factors (risk &#95; sum) were examined: high blood pressure (> or =130/85 mmHg or on antihypertensive therapy); high triglycerides (> or =170 mg/dl); low high-density lipoprotein-cholesterol (<40 mg/dl); and impaired glucose tolerance (hemoglobin A1c > or =5.6% or on antidiabetic therapy). BMI and WC correlated well in both men (r=0.871) and women (r=0.874). All 3 obesity measures related with the metabolic risk factors. The area under the receiver-operating characteristic curve for BMI, WC and WHR to predict the risk &#95; sum > or =2 for men was 0.683, 0.709, and 0.700, respectively, and 0.715, 0.739, and 0.746, respectively, for women., Conclusions: BMI may be used instead of WC if the latter is not available. When WC is measured, hip circumference also should be measured because the WHR may be the most valuable measure of obesity.

Morning hypertension (MHT) and metabolic syndrome (MS) have been reported as important risk factors for stroke and cardiovascular events. We investigated the prevalence of MHT and MS among hypertensive patients in our outpatient clinic from June to August, 2005. We studied 181 hypertensive patients (91 men and 90 women) in our outpatient clinic using home-use electronic sphygmomanometers. Seventy-nine of these 181 patients (43.6%) demonstrated MHT, defined as systolic blood pressure (SBP) > or = 135 mmHg in the morning. Only 48.1% of the patients demonstrated normal SBP both at the clinic and in the morning at home, whereas 72.9% of the patients demonstrated normal diastolic blood pressure (DBP) under the same conditions. Sixty-one patients (33.7%) had MS, and 34 patients had both MHT and MS. Twenty-seven of the 102 patients (26.5%) without MHT had MS. The frequency of MS was significantly higher among those with MHT than those without MHT (p = 0.019). Multiple logistic regression analysis including smoking, alcohol consumption, sex, and age as confounding factors showed significant association between MHT and MS (odds ratio: 1.99; 95% confidence interval: 1.04-3.80; p = 0.039). In conclusion, although 1 year has passed since the JSH 2004 guidelines, 43.6% of our patients still showed MHT, and there was a significantly higher prevalence of MS among those with MHT. Our results suggest the need for a more vigorous intervention for controlling BP.

We examined the interactions between lifestyle and polymorphisms of salt-sensitive genes and their effects on hypertension in a general Japanese sample (The Shigaraki Study). The study group consisted of 2,902 subjects who underwent a medical examination in 1999 in Shigaraki, a suburban area in Shiga. Among 1,647 subjects not receiving antihypertensive medication, in a combined analysis of angiotensinogen (AGT) and adducin (ADD1) polymorphisms, double homozygosity of 235Thr or 460Trp was not found to be associated with hypertension. A multiple logistic regression analysis showed that age (odds ratio [OR]: 1.07, 95% confidence interval [95% CI]: 1.06-1.08), body mass index (BMI) (OR: 1.18, 95% CI: 1.13-1.23), alcohol consumption (OR: 1.39, 95% CI: 1.16-1.66), family history of hypertension (OR: 1.57, 95% CI: 1.18-2.07), and combined AGT M235T Thr/Thr and ADD1 Trp/Trp polymorphisms (OR: 1.37, 95% CI: 1.03-1.82) were associated with hypertension. However, there was no interaction between eating salty food and combined AGT and ADD1 polymorphisms. Furthermore, eating salty food was not associated with hypertension in a multivariate analysis. Therefore, a combination of the AGT and ADD1 polymorphisms appears to be associated with hypertension. However, a simple questionnaire regarding salt intake was not sufficient to confirm the relationship between salt intake and hypertension and/or salt-sensitive genes.

To examine whether the response to the angiotensin II receptor antagonist losartan varies depending on the angiotensin converting enzyme (ACE) genotype, we prospectively studied the effect of losartan in 42 hypertensive patients (20 men, 22 women; mean age: 60.4 years). After a 4-week observation period, losartan was administered at 50 mg/day and blood pressure was measured every 2 to 4 weeks for 12 weeks. Among the 42 patients, 19, 11, and 12, respectively, had the II, ID, and DD ACE genotypes. The baseline plasma ACE activity in patients with the ID or DD genotype was significantly higher than that in patients with the II genotype (13.8 +/- 4.2 vs. 9.6 +/- 2.3 IU/l; p = 0.0002). However, age, gender, baseline systolic and diastolic blood pressure (SBP/DBP), and body mass index (BMI) were not different among the groups. After 12 weeks of treatment with losartan alone, DBP in the ID+DD group was significantly higher than that in the II group (85.0 +/- 9.0 vs. 77.8 +/- 9.6 mmHg, p = 0.018), while the percent reduction in DBP in the ID+DD group was significantly smaller than that in the II group (7.9 +/- 8.8 vs. 14.3 +/- 10.1%, p = 0.035). Multiple regression analysis showed that the significant predictors of the DBP at 12 weeks were age (p = 0.030), ACE genotype (p = 0.029) and baseline DBP (p = 0.0001). The ACE genotype may be a determinant of the response to losartan in hypertensive patients.

In Japanese and other Asians, the prevalence of genetically decreased mitochondrial aldehyde dehydrogenase (ALDH2) activity is higher than in Caucasians. The aim of this study was to elucidate the relation between ALDH2 genotypes and blood pressure levels or hypertension in Japanese. After obtaining informed consent for genetic analysis from 917 men and 1,478 women who lived in a mountainous farming region near Kyoto and who were free from cardiovascular disease and liver dysfunction, the authors identified the ALDH2 genotype in all subjects. Differences in blood pressure level among genotypes were then compared by analysis of covariance, and the relation between genotypes and hypertension was also analyzed by logistic regression analysis. The frequencies of genotypes *1/*1, *1/*2, and *2/*2 were 44.7%, 46.9% and 8.4% in men, and 50.1%, 43.2% and 6.8% in women, respectively. In men, systolic and diastolic blood pressures tended to decrease in the order of *1/*1>*1/*2>*2/*2. However, adjustment for confounding factors including alcohol consumption resulted in the disappearance of significance. Logistic regression analysis adjusted for the same confounding factors for men showed that the odds ratios (OR) of being hypertensive in the *2 allele to not having *2 allele were 0.67 (95% confidence interval (CI): 0.47-0.96). However, in the subgroup analyses, this relation was not observed in the group having a below-median level of alcohol consumption (OR = 0.92; 95% CI: 0.53-1.62) or in the group not taking antihypertensive agents (OR = 0.77; 95% CI: 0.52-1.15). Furthermore, we did not observe any relation between the ALDH2/*2 allele and hypertension in women (OR = 1.07; 95% CI: 0.80-1.42). The results suggest that there may be no causal relation between hypertension and the ALDH2 genotype per se, after excluding for some confounding factors, especially for alcohol drinking.

Aim: The present study aimed to clarify the association between body mass index (BMI) and the activities of daily living (ADL). Although BMI is likely to be concerned regarding the relationship with specific diseases or mortality, few studies have focused on the relationship of BMI and ADL. Methods: A total of 3353 Japanese participants of a 22‐year cohort study from 1990 to 2012 aged 45–74 years at baseline were divided into four groups according to their BMI levels: ≤18.5, 18.5–21.9 (reference), 22.0–24.9 and ≥25.0 kg/m2. Outcomes were becoming dependent in ADL (including death after ADL decline) and death without observation of ADL decline as a competing risk. Sex‐specific multinomial logistic regression analysis was carried out in 2017 to estimate the odds ratios (OR) after adjusting for age, smoking, alcohol drinking, hypertension, hypercholesterolemia, diabetes and serum albumin. Results: After multivariable adjustment, though the relationship between BMI and risk of ADL decline was U‐shaped among women, only those with BMI ≥25.0 showed a higher risk for ADL decline (OR 1.39, 95% CI 1.01–1.92) compared with the reference. The OR for death without observation of ADL decline was significantly lower for men with BMI ≥25.0 (OR 0.70, 95% CI 0.50–0.98). Conclusions: This study suggests being overweight is a good predictor of future decline in ADL for women, whereas men with BMI 22.0–24.9 had lower risks of ADL decline. Appropriate management of weight in older women could prevent disabilities. Geriatr Gerontol Int 2018; 18: 799–805 [ABSTRACT FROM AUTHOR]

Characterization of the time of stroke onset has been plagued by the problem of determining the time of the onset of events that are detected when the patient awakens. Our aim was to evaluate the characteristics, risk factors and acute fatality associated with wake-up stroke. Data was obtained from Takashima Stroke Registry covering approximately 55,000 residents in central Japan. During the period 1988-2003, information about the situation at stroke onset was available for 897 cerebral infarction (CI) and 335 intracerebral hemorrhage (ICH) events. Differences in characteristics and outcome between stroke during sleep and stroke while awake were explored. Among CI and ICH cases, 9.7 and 11.9% suffered from stroke during sleep, respectively. Hypertension and experiencing a severe event were associated with stroke during sleep among CI. Smoking and experiencing a severe event were associated with stroke during sleep and a drinking history reduced the chance of stroke during sleep among ICH. Acute fatality risks did not differ between stroke during sleep and stroke while awake among both CI and ICH cases. About 1 in 10 stroke patients had an onset of stroke during sleep. Hypertensive, smoker and clinically more severely affected patients had a higher prevalence of stroke during sleep. There were no differences between the 2 groups with respect to acute-case fatality. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

OBJECTIVE -- Metabolic syndrome is diagnosed according to several criteria. Of these, some require glucose intolerance and others require obesity for the diagnosis. We investigated the relationship between metabolic risk factor clustering and cardiovascular disease (CVD) mortality stratified by high blood glucose or obesity. RESEARCH DESIGN AND METHODS-- We followed 7,219 Japanese men and women without a history of CVD for 9.6 years. We defined high blood pressure, high blood glucose, high triglycerides, low HDL cholesterol, and obesity as metabolic factors. The multivariate adjusted hazard ratio (HR) for CVD mortality according to the number of clustering metabolic factors was calculated using the Cox proportional hazards model. RESULTS -- During follow-up, 173 participants died of CVD. The numbers of metabolic risk factors and CVD mortality were positively correlated (Ptrend = 0.07). The HR was obviously higher among participants with than among those without high blood glucose and clustering of ≥2 other metabolic risk factors (HR 3.67 [95% CI 1.49-9.03]). However, the risk increase was only modest in participants without high blood glucose even if they had ≥2 other metabolic risk factors (1.99 [0.93-4.28]). Conversely, metabolic risk factor clustering was related to CVD mortality irrespective of obesity. CONCLUSIONS-- Our findings suggest that glucose tolerance plays an important role in CVD mortality. Because the prevalence of nonobese participants with several metabolic risk factors was quite high and their CVD risk was high, excluding them from the diagnosis of metabolic syndrome because of the absence of obesity might overlook their risk. [ABSTRACT FROM AUTHOR]

A man is as old as his arteries and the vascular remodeling is a common problem in the elderly. Aortic pulse wave velocity (PWV) provides noninvasive measurement of the mechanical properties of arteries. Objective: We measured the effects of HMA-CoA inhibitor (pravastatin) on arterial stiffness, ankle brachial index, PWV, and blood pressure (BP) in patients with hyperlipidemia. Design and Methods: The present study involved 15 patients (mean age 65 ± 2.7 years) with hyperlipidemia who were not on any medication. Aortic pulse wave velocity was evaluated at baseline and following 3 months of drug intake (pravastatin 10 mg/day). Twenty healthy volunteers constituted a control group. Results: Following 6 months of conventional treatments of hyperlipidemia. brachial systolic BP and diastolic BP did not change significantly with pravastatin from baseline (Not significant: NS). The PWV decreased significantly after treatment with pravastatin (1912 ± 90.3 vs 1755 ± 96.9 cm/sec. P < 0.001). There was no significant difference in control subjects (1677 ± 71.5 vs 1796 ± 56 cm/sec, NS). The decrease in PWV with pravastatin was independent of blood pressure (P < 0.05). Conclusions: The study shows that HMA-CoA inhibitor might improve arterial wall stiffness in patients with hyperlipidemia. [ABSTRACT FROM AUTHOR]

Background and Objective: Recently, attention has been focused on endothelin-1 (ET-1) as an indicator of atherosclerosis. However, normal levels of ET-1 are frequently found in elderly patients. We investigated the relationships between echocardiographic findings and ET-1 in 117 inpatients for rehabilitation. Methods: The patients were 34 men and 83 women, 83.4 ± 0.8 years old (mean ± SE), with the following diseases: cerebrovascular diseases (n = 83), cardiovascular diseases of New York Heart Association Class I or II (n = 57), diabetes mellitus (n = 11) and hyperlipidemia (n = 12). Ejection fraction (EF) and left ventricular mass index (LVMI) were calculated by echocardiographic studies. Results: The average ET-1 was within the normal range, but a significant positive correlation was observed between age and ET-1 (ET-1 = 1.8 ± 0.1 pg/ml, r = 0.248, p < 0.01). Moreover, plasma ET-1 was positively correlated to total cholesterol and to low density lipoprotein cholesterol in patients with a history of hypertension (n = 41, r = 0.318 and r = 0.314, both p < 0.05). Gender was not a significant factor. There was no significant difference in ET-1 between patients with mild renal dysfunction (n = 54) and patients with normal renal function (n = 63) (blood urea nitrogen = 30.9 ± 2.4 vs. 15.1 ± 0.5 mg/dl, serum creatinine = 1.03 ± 0.06 vs. 0.59 ±0.02 mg/dl, ET-1 = 1.7 ± 0.1 vs. 1.8 ± 0.1 pg/ml), or between patients with (n = 50) and without (n = 67) left ventricular hypertrophy (LVMI = 146 ± 6 vs. 83 ± 2 g/m[sup 2] , ET-1 = 1.8 ± 0.1 vs. 1.8 ± 0.1 pg/ml). There was no difference in ET-1 between patients with EF <50% (n = 27) and EF ≥50% (n = 90) (ET-1 = 1.8 ± 0.2 vs. 1.7 ± 0.1 pg/ml). Conclusion: There were no significant relationships between echocardiographic findings and ET-1 in elderly subjects without overt heart failure. However, in patients with a history of hypertension, measuring ET-1 may be useful for estimating the extent of atherosclerosis.Copyright © 1999 S.Karger AG, Basel [ABSTRACT FROM AUTHOR]