Natural history of cardiovascular manifestations in Marfan syndrome.

AIMS: To investigate the natural history of mitral valve and aortic abnormalities in patients with Marfan syndrome during childhood and adolescence. METHODS: Fifty two patients with Marfan syndrome were followed for a mean of 7.9 years. Occurrence of adverse cardiovascular outcomes was measured clinically and by ultrasound examination. RESULTS: Mitral valve prolapse (MVP) was diagnosed in 46 patients at a mean age of 9.7 years, more than 80% of whom presented as "silent MVP". Mitral regurgitation (MR) occurred in 25 patients, aortic dilatation in 43, and aortic regurgitation (AR) in 13. Both MVP and aortic dilatation developed at a constant rate during the age period 5-20 years. In 23 patients MVP was diagnosed before aortic dilatation, in 18 the reverse occurred, and in 11 patients the two abnormalities were diagnosed simultaneously. During follow up, 21 patients showed progression of mitral valve dysfunction; progression of aortic abnormalities occurred in 13. Aortic surgery was performed in 10; two died of subsequent complications. Mitral valve surgery was performed in six. In sporadic female Marfan patients the age at initial diagnosis of MVP, MR, aortic dilatation, and AR was lowest, the grade of MR and AR most severe, the time lapse between the occurrence of MVP and subsequent MR as well as between dilatation and subsequent AR shortest, and the risk for cardiovascular associated morbidity and mortality highest. CONCLUSIONS: During childhood and adolescence in Marfan syndrome, mitral valve dysfunction as well as aortic abnormalities develop and progress gradually, often without symptoms, but may cause considerable morbidity and mortality by the end of the second decade, especially in female sporadic patients.     

Natural history of cardiovascular manifestations in Marfan syndrome

AIMS—To investigate the natural history of mitral valve and aortic abnormalities in patients with Marfan syndrome during childhood and adolescence.METHODS—Fifty two patients with Marfan syndrome were followed for a mean of 7.9 years. Occurrence of adverse cardiovascular outcomes was measured clinically and by ultrasound examination.RESULTS—Mitral valve prolapse (MVP) was diagnosed in 46 patients at a mean age of 9.7 years, more than 80% of whom presented as "silent MVP". Mitral regurgitation (MR) occurred in 25 patients, aortic dilatation in 43, and aortic regurgitation (AR) in 13. Both MVP and aortic dilatation developed at a constant rate during the age period 5-20 years. In 23 patients MVP was diagnosed before aortic dilatation, in 18 the reverse occurred, and in 11 patients the two abnormalities were diagnosed simultaneously. During follow up, 21 patients showed progression of mitral valve dysfunction; progression of aortic abnormalities occurred in 13. Aortic surgery was performed in 10; two died of subsequent complications. Mitral valve surgery was performed in six. In sporadic female Marfan patients the age at initial diagnosis of MVP, MR, aortic dilatation, and AR was lowest, the grade of MR and AR most severe, the time lapse between the occurrence of MVP and subsequent MR as well as between dilatation and subsequent AR shortest, and the risk for cardiovascular associated morbidity and mortality highest.CONCLUSIONS—During childhood and adolescence in Marfan syndrome, mitral valve dysfunction as well as aortic abnormalities develop and progress gradually, often without symptoms, but may cause considerable morbidity and mortality by the end of the second decade, especially in female sporadic patients.     

The Doppler echocardiographic assessment of valvular regurgitation in normal children

To determine the frequency of valvular regurgitation, 174 children from birth to 18 years old (mean age 7.42+/-4.54 years), with structurally normal hearts were analyzed. Flow patterns across the four valves were examined by pulsed- (PW), continuous-wave (CW) and color Doppler. Regurgitation was detected in 59.7% of the valves. Tricuspid regurgitation (TR) was most commonly found in 32.8% (n=57), pulmonary regurgitation (PR) in 17.2% (n=30), mitral regurgitation (MR) in 8.6% (n=15), and aortic regurgitation (AR) in 1.1% (n=2). The range of peak velocities of the regurgitant flow with CW were as follows: TR:0.98-2.54 m/sec, PR:0.50-1.80 m/sec, MR:0.72-2.30 m/sec, and AR:1.22-1.25 m/sec. The mean peak velocities of the regurgitant flow were similar with CW and PW measurements (p>0.05). The length of the regurgitant flow with color Doppler was less than 1 cm beyond the mitral and aortic valves. It reached up to 1.8 cm behind the pulmonary and 1.83 cm behind the tricuspid valves. Frequency of valvular regurgitation was unchanged with age (p>0.05). Tricuspid regurgitation was more frequent in males (40.9% versus 23.5%; p=0.016). Regurgitation of tricuspid, pulmonary or mitral valves is relatively common in children with structurally normal hearts. Aortic regurgitation is scarce and the possible pathologic cause should always be carefully sought.     

Cardiovascular changes in children with mucopolysaccharide disorders

The aims of this study were to evaluate cardiac involvement, assess risk factors and mortality, and define the outcome of cardiac abnormalities with age in the different types of mucopolysaccharidoses (MPS). The echocardiograms of 99 patients with MPS, aged 1-24 y (median age 10.3 y) were reviewed between 1978 and 2000. Mitral regurgitation (MR) was detected in 29 patients (29%). MR was more frequent in types IH [ n = 11 (38%)], II [ n = 10 (24%)] and III [ n = 4 (20%)]. Sixteen patients (16%) developed aortic regurgitation (AR), seen mostly in types II [ n = 9 (56%)] and IV [ n = 4 (24%)]. AR and/or MR was detected in 37 patients and 8 had both abnormalities of borderline significance (odds ratio 2.95, 95% confidence interval 1.0-8.85, p = 0.05). Of 99 patients, 47 had a normal study on their first echocardiogram, whereas only 7 had a normal study on subsequent echocardiograms. Fifty-four (54%) had a single echocardiogram. Of these, 27 (50%) were abnormal and 27 normal. Forty-five patients had more than one echocardiogram, of which 25 (56%) were abnormal and 20 normal. In 13/20 (65%) a cardiac abnormality developed on a subsequent echocardiogram which was statistically significant ( p = 0.002). Overall mitral and aortic valve abnormalities showed a positive association with age. Univariate analysis of risk factors showed that increasing age, MPS I and ejection fraction were significant risk factors for death. However, left ventricular hypertrophy, mitral valve abnormalities and type II MPS were not significant risk factors for death, with borderline significance for aortic valve abnormalities.

Conclusion: This study demonstrates the evaluation of ventricular function, which is a significant risk factor for death, along with increasing age and MPS I, and outlines the borderline significance of aortic valve abnormalities, which has not been mentioned in previous studies. It also shows that mitral valve lesions, commonly seen in MPS, were not a significant risk factor for death. The results emphasize the importance of performing serial echocardiograms in patients with MPS to assess ventricular function and the progression of cardiac abnormalities with age.     

Impact of Age and Gender on Cardiac Pathology in Children and Adolescents With Marfan Syndrome

Cardiac pathologies are the major aspect in the treatment strategies for Marfan syndrome (MFS). In this progressive disease, less is known about manifestations and progression of cardiovascular symptoms in children. To define a certain decision regarding therapeutic options, knowledge concerning the onset of cardiovascular findings is essential. From 1998 to 2011, suspected pediatric Marfan patients were subjected to a standardized diagnostic program. Cardiovascular findings were analyzed in terms of age at first clinical manifestation, prevalence and gender differences, morbidity, mortality, and treatment. Marfan syndrome was diagnosed in 82 patients (46 boys; mean age at diagnosis, 9.0 ± 5.7 years). At first presentation, aortic root dilation was found in 56 % of patients, mitral valve prolapse in 31 %, whereas pulmonary artery dilation was detected in 22 % and tricuspid valve prolapse in only 17 % of patients. Aortic (2.5 %) and mitral valve regurgitations (22 %) are significantly correlated with aortic root dilation (p < 0.01) and mitral valve prolapse (p < 0.05) but without relevant progression during childhood. Prophylactic medication was initiated for 42 % of the patients (mean age, 8.0 ± 4.5 years) because of progressive aortic root dilation. Aortic dissection did not appear. Aortic root surgery was needed for 4 % of the patients. Gender-specific differences in cardiovascular findings, progression of disease, or treatment did not appear. Comparable with adults, aortic root dilation is the most frequent cardiovascular finding in children and associated with relevant morbidity, whereas aortic and mitral valve regurgitation are of minor clinical relevance. Manifestation at an early age and slow progression of cardiovascular findings underscore the necessity of repeated echocardiographic examinations for early diagnosis and start of prophylactic treatment.     

Marfanoid children. Etiologic heterogeneity and cardiac findings

The clinical, cardiac, and echocardiographic test results of 20 children with marfanoid features are reviewed. Fifteen were diagnosed as having Marfan syndrome, two had "possible" Marfan syndrome, and three had other diagnoses. On first evaluation, eight patients with Marfan syndrome (53%) had mitral regurgitation and none had aortic regurgitation. Echocardiography showed aortic root enlargement in 12 (80%) of 15 patients and mitral valve prolapse in 12 (80%) of 15. None had a normal echocardiogram. At follow-up examination, one patient had developed aortic root enlargement, and one patient, mitral valve prolapse. Thus, although aortic root enlargement is usually present in early childhood in patients with Marfan syndrome, it is not considered specific because in this study it also occurred in one child with Alport's syndrome and in one with marfanoid features. Four patients with aortic root enlargement were treated with propranolol and their echocardiograms showed no further increase in the aortic root diameter for several years. We recommend echocardiography in the diagnosis and routine management of children in whom Marfan syndrome is suspected.     

Five-Year Clinical Course of Aortic Regurgitation Without Coronary Aneurysm Following Kawasaki Disease

Kawasaki disease has recently been considered as a major cause of acquired valvular diseases in infants and children. But there have been few reports on the clinical course of the lesions caused by this disease, particularly aortic regurgitation. In February 1982, we examined a six-month-old male infant who had Sellers third degree aortic regurgitation (AR) and Sellers first degree mitral regurgitation (MR) without discernible dilatation, aneurysm formation or stenosis of the coronary arteries, and in January 1987 we performed a second cardiac catheterization in order to estimate the progress of these lesions. The results were: 1) His AR showed no apparent worsening; 2) His MR had completely recovered; 3) His volume and pressure studies were almost normal. The catheterization data were compatible with those of other clinical examinations. He no longer had cardiac enlargement as seen on a chest roentgenogram, and there were no signs of left ventricular hypertrophy on an electrocardiogram (ECG). ( Acta Paediatr Jpn 1989; 31: 198 - 204)     

Paradoxical relationship between mitral valve prolapse and left ventricular function in Marfan's syndrome

Summary A child with Marfan's syndrome had cardiac failure during infancy. Aortic sinus aneurysms, mitral prolapse with severe regurgitation, and atrial septal defect were present. After myocardial infarction at age 4 years, the mitral prolapse became less and the regurgitation disappeared. After recovery of left ventricular function, mitral regurgitation reappeared. The unusual relationship between mitral valve and left ventricular function could be related to redundant chordae and leaflet. Myocardial infarction occurs in Marfan's syndrome even during childhood.Supported by grant RR-305 from the General Clinic Research Centers Program of the Division of Research Resources, National Institutes of Health, Bethesda, Maryland     

Surgical Treatment of Aortic Root Aneurysm Related to Marfan Syndrome in Early Childhood

The prognosis of Marfan syndrome in both adult and pediatric patients is primarily related to the cardiovascular complications. In infantile Marfan syndrome, although involvement of the mitral valve is the most frequently encountered cardiovascular lesion, the aortic root can be more worrisome because of its excessive dilatation, leading to aortic insufficiency or dissection. If the role of elective surgery is relatively well defined for adult patients, it is still debated during childhood. We report two patients, aged 22 months and 5 years, each presenting an aortic root aneurysm related to Marfan syndrome, and each treated with the Bentall procedure without specific age-related mortality or morbidity. These two patients experienced normal growth and were free of any complication for a follow-up period of 8 and 2 years, respectively. More than an absolute value of the aortic root dimension, it is the conjunction of the rate of progression of the aortic root dilatation, the degree and the duration of the aortic valve regurgitation, and its resulting left ventricular dysfunction that must be taken into consideration in choosing the surgical option.     

Long-term prognosis of acute rheumatic carditis with combined aortic and mitral regurgitation

Thirty-one patients with acute rheumatic carditis associated with aortic (AR) and mitral regurgitation (MR) who received corticosteroid anti-inflammatory therapy for an average of nine weeks were followed up for 332 patient-years (mean: 10.71 years). The age of onset was 9.34 (1 SD = +/- 1.94) years. The patients were classified according to degree of left ventricular volume overloading (LVH), duration of pre-treatment interval and regularity of penicillin prophylaxis. The probability of the yearly disappearance of MR, AR and both lesions were calculated for the total group and in relation to affecting subgroups. The mean yearly rate of disappearance of AR was 2 percent after a 10 percent probability in the first year. This rate was 6.83 percent per year for MR, and it increased to 10.15 percent per year in the patients in whom therapy was initiated in less than three weeks, and decreased to 3.14 percent in the patients in whom therapy was initiated after three weeks. The disappearance of both AR and MR was observed in only two patients (about 1% per year); MS developed in two patients (6.45%) and the mortality rate was 3.2 percent in 332 patient-years (0.0001/year).     

Long term follow-up results of 139 Turkish children and adolescents with rheumatic heart disease

We aimed to evaluate the predictors of the severity of chronic rheumatic valvar disease. The long term follow-up records of 139 patients with chronic rheumatic carditis were reviewed. Children were followed-up on an outpatient basis for a period ranging from 1-16 years (5.0 +/- 3.7 years). Mitral regurgitation either isolated (51%, n=71) or combined with aortic regurgitation (AR) (49%, n=68) was observed in all cases of the initial attack of rheumatic carditis. AR at initial attack of the rheumatic carditis was found to be affected by gender (AR was more associated with males, p = 0.032), combined mitral and aortic regurgitation (CMAR), and presence of MR at initial attack (p = 0.000 and p = 0.012, respectively) with univariate analysis. The effect of CMAR on AR at initial attack was also significant by multivariate analysis (p = 0.000). CMAR, MR, and AR at initial attack had significant effects on CMAR at final evaluation (p = 0.000, p = 0.020, and p = 0.000, respectively) in univariate analysis. Multivariate analysis revealed the significant effects of CMAR and MR at initial attack on CMAR at final evaluation (p = 0.000 and p = 0.005, respectively). Univariate analysis showed that MR and AR at initial attack, and CMAR at final evaluation, had significant effects on MR at final evaluation (p = 0.000, p = 0.029, and p = 0.000, respectively). MR at initial attack and CMAR at final evaluation had significant effects on MR at final evaluation with multivariate analysis (p = 0.001 and p = 0.003, respectively). AR at final evaluation was affected by CMAR and AR at initial attack (p = 0.000 and p = 0.000, respectively), and CMAR and MR at final evaluation (p = 0.000 and p = 0.000, respectively) with both univariate and multivariate analysis. Mitral valve prolapsus was more common in patients with a longer duration (37.5%, 6 out of 16) than those with a shorter duration (11%, 14 out of 123) and the difference was significant (p = 0.020). In conclusion, the initial severity of valve involvement and the presence of CMAR at initial attack were found to be the best predictors for the severity of chronic rheumatic valvar disease in this study.     

Osteogenesis imperfecta in childhood: cardiac and renal manifestations

We examined 58 children aged 1–16 years with various forms of osteogenesis imperfecta (OI). Congenital cardiac malformations were diagnosed in 4 children (valvular aortic stenosis, 2 with atrial septal defect II, Fallot Tetralogy). Two additional children developed holosystolic mitral valve prolapse and regurgitation. Children suffering from a severe clinical course (type III according to the Sillence classification) showed aortic root dilatation (28%) and increased septal (40%) and posterior left ventricular wall thickening (68%) on initial evaluation. All three parameters were significantly correlated to body surface area.Kidney stones and renal papillary calcifications were detected in 4 children. Cardiovascular abnormalities and nephrolithiasis may be important extraskeletal manifestations of childhood OI.     

Ventricular dysrhythmias in children with Marfan's syndrome

A teenager with Marfan's syndrome required resuscitation and was found to have multiform premature ventricular contractions and ventricular tachycardia. Of 24 children with Marfan's syndrome, eight (33.3%) were found to have ventricular dysrhythmias, including three with ventricular tachycardia. Six of these eight patients had mitral valve prolapse, and five had prolonged QT or QTU intervals corrected for heart rate. However, only two patients had severe mitral regurgitation, five had only mild heart disease, and one had no detectable heart lesion. The role of mitral valve prolapse and/or delayed repolarization in the development of ventricular dysrhythmia was explored. Delayed repolarization, especially when combined with mitral valve prolapse, is associated with occurrence of ventricular dysrhythmia. Serious ventricular dysrhythmia can occur in children with Marfan's syndrome with or without substantial valve disease, and the dysrhythmia appears to progress with age.     

Mitral and aortic regurgitation in 84 patients with mucopolysaccharidoses

In echocardiographic and necropsy studies nodular thickening of the mitral valve and, less frequently, of the aortic valve has been found in 60%–90% of patients with mucopolysaccharidoses (MPS). Little is known about the haemodynamic consequences of these morphological changes. In this study 84 unselected patients with different enzymatically proven MPS and 84 age and sex matched, healthy persons were studied prospectively by colour Doppler flow mapping. The patients' age ranged from 1 to 47 years (median 8.1 years). Mitral and aortic regurgitation were defined as a holosystolic or holodiastolic jet originating from the valve into the left atrium or the left ventricular outflow tract, respectively, with peak velocities exceeding 2.5 m/s. Of the 84 patients with satisfactory studies, mitral regurgitation was detected in 64.3% and aortic regurgitation in 40.5%, respectively. Regurgitation was severe in 4.8% of mitral valves and 8.3% of aortic valves. The frequency of aortic and/or mitral regurgitation was 75% in all patients, 89% in MPS I, 94% in MPS II, 66% in MPS III, 33% in MPS IV, and 100% in MPS VI. Combined mitral and aortic regurgitation was present in 29% of our patients. None of the control persons showed mitral or aortic regurgitation.     

Mucocutaneous lymph node syndrome with coronary artery aneurysm.

A white North American girl with clinical features of the mucocutaneous lymph node syndrome had a myocardial infarct and angiographic evidence of a coronary artery aneurysm and mitral regurgitation. The mucocutaneous lymph node syndrome has been extensively diagnosed in Japan in recent years. It appears to be a distinct entity, although not precisely separated from polyarteritis nodosa in childhood. The condition may be more common than previously realized.     

Neonatal Atrial Fibrillation After Surgical Repair of Tracheoesophageal Fistula With Esophageal Atresia

Atrial fibrillation is rare in childhood that had not been reported in neonates with normal cardiac morphology and function. The authors present a newborn who underwent surgical repair of a tracheoesophageal fistula with esophageal atresia at the age of 2 days and experienced atrial fibrillation 16 days after the procedure. A report of 35 pediatric patients in a single center over a period of 22 years identified atrial fibrillation in children with a variety of ailments including congenital cardiac anomalies before and after corrective surgery, rheumatic valve disease, Marfan's syndrome with mitral regurgitation, infective endocarditis, cardiomyopathy, endocardial fibroelastosis, paroxysmal atrial tachycardia of infants, and cardiac tumors [2]. All these patients had underlying cardiac disease.     

Difficulties in diagnosing Marfan's syndrome in childhood and adolescence

BACKGROUND: The diagnosis of Marfan's syndrome in childhood and adolescence is made by the criteria of the Gent nosology, which evaluates genetic data, family history and a spectrum of clinical criteria. Due to the age dependent manifestations of the clinical symptoms, combined with the extreme heterogeneity of Marfan's syndrome diagnosis in early childhood remains sometimes difficult. PATIENTS: Prospectively, we analyzed the clinical symptoms of all patients where Marfan's syndrome was suspected. We evaluated those patients between January 1997 and April 2002 by an interdisciplinary approach. METHODS: We compared the clinical datas of the patients by using the Gent nosology and the Berlin nosolgy. RESULTS: 34 patients underwent full follow-up. The median age was 10,32 years with a range of 0,01 to 37,31 years, 19 patients were male, 15 patients were female. In eight patients Marfan's syndrome could be rouled out, 9 of 26 patients (34,6 %) fullified the criteria of the Gent nosology, in 17 of 26 patients (65,4 %) Marfan's syndrome remained just suspected, but was not fullified by the criteria of the Gent nosology. Concerning the Berlin nosology 14 of 26 patients (53,8 %) fullified the criteria, 12 of 26 patients (46,2 %) failed. Due to the criteria of the Gent nosology 14 patients (53,8 %) fullified the criteria of skeletal involvement, 21 patients (80,8 %) fullified cardiovascular major manifestation, 6 patients (23,1 %) had an ophthalmic major manifestation, and 9 patients (34,6 %) had an affected first degree relative or were genetically determined. CONCLUSIONS: On the basis of the data of our patients the diagnosis of Marfan's syndrome in childhood and adolescence can be made more sensitive by the criteria of the Berlin nosology compared to the Gent nosology. This seems to be caused by the age dependent manifestations of the symptoms. Until diagnostic algorhythms of Marfan's syndrome in childhood remain suboptimal, continuous clinical follow-up for all cases even those only in the case of suspected Marfan's syndrome are necessary to exclude complicated course and to improve outcome.     

Surgical Correction of Mitral Valve Prolapse

We describe the case of a 3-year-old child with neonatal Marfan syndrome complicated by mitral valve prolapse with regurgitation, marked aortic root dilatation, and ventricular tachycardia. The patient had resolution of ventricular tachycardia following surgical intervention consisting of a valve-sparing aortic root replacement and mitral valve annuloplasty.     

Clinical Outcome,Valve Dysfunction,and Progressive Aortic Dilation in a Pediatric Population With Isolated Bicuspid Aortic Valve

The aim of this study was to explore the medium-term clinical outcome and the risk of progression of aortic valve disease and aortic dilation in pediatric patients with isolated bicuspid aortic valve (BAV). 179 pediatric patients with isolated BAV were prospectively followed from January 1995 to December 2010. Patients with severe valve dysfunction at baseline were excluded. Clinical outcome included cardiac death, infective endocarditis, aortic complications, cardiac surgery and percutaneous valvuloplasty. Echocardiographic endpoints were: progression of aortic stenosis (AS) or regurgitation (AR) and progressive aortic enlargement at different levels of the aortic root, evaluated as z-score. The median age at diagnosis was 7.8 [2.7–12.0] years. After a median followup of 5.4 [2.3–9.2] years, all patients were alive. The clinical endpoint occurred in 4 (2.2 %) patients (0.41 events per 100 patient-years). A progression of AS and AR was observed in 9 (5.0 %) and 29 (16.2 %) patients, respectively. The z-scores at the end of follow-up were not significantly different from baseline at the annulus, Valsalva sinuses and sinotubular junction, whereas a slight increase was observed at the level of the ascending aorta (1.9 vs 1.5, p = 0.046). Significant progressive aortic dilation occurred in a minority of patients (10.6, 5.6, 9.5, and 19.0 % respectively). The clinical outcome in pediatric patients with isolated BAV is favourable and the progression of aortic valve dysfunction and aortic dilation is relatively slow. These findings may be taken into account to better guide risk assessment and clinical follow-up in these patients.     

Cardiovascular changes in children with mucopolysaccharide storage diseases and related disorders – clinical and echocardiographic findings in 64 patients

Cardiovascular abnormalities were evaluated in 64 children aged between 1 year 9 months and 25 years with mucopolysaccharidoses (MPS) and related disorders. A heart murmur was heard in 18 patients, but in only 6 was it characteristic for specific valvular lesions. Echocardiography was performed in 63 children. In one girl cardiac lesions were diagnosed on autopsy. In 46 patients (72%), valvular lesions and/or different types of cardiomyopathy were detected. There were no characteristic changes for different types of MPS. In the majority of children in whom dermatan sulphate accumulated, cardiac involvement was the most frequent (88%) and severe. The most common lesion, regardless of MPS type, was thickening of the mitral valve (66%), with regurgitation or stenosis in 28 (44%). Aortic valve thickening was detected in 17 patients (27%), asymmetric septal hypertrophy or hypertrophic cardiomyopathy in 18, congestive cardiomyopathy in 1 and endocardial thickening in 13 patients. Cardiac involvement was less frequent in children with Sanfilippo disease. Two or more echocardiographic examinations were performed in 23 patients. In 19 of them (83%) cardiac changes were more severe during the second examination. One 7-year-old boy with Hunter disease underwent successful mitral valve replacement. Conclusions Cardiac involvement is present in most patients with MPS although there are few clinical signs and symptoms. The most common and severe changes are in Hurler, Hunter, Maroteaux-Lamy and I-cell disease, rarely in Sanfilippo disease. Mitral valve deformation is most frequent in all patients. The cardiac lesions are progressive. Received: 15 March 1997 / Accepted: 20 January 1998