© 1995 American Heart Association, Inc.
Articles |
Abnormal Reverse Cholesterol Transport in Controlled Type II Diabetic Patients
Studies on Fasting and Postprandial LpA-I Particles
From the Service de Médecine Interne, Nutrition, Métabolisme Lipidique (E.C., N.N., B.J.), Hôpital Henri-Mondor Créteil, France; the Department of Clinical Biochemistry (F.B., R.W.), Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Argentina; and INSERM (B.D., C.D., C. De G., J.-C.F., G.C.), Institut Pasteur de Lille, France.
Correspondence to Graciela Castro, INSERM Unité 325, Institut Pasteur, 1, rue du Professeur Calmette, Lille Cedex, France.
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Abstract |
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Abstract The high incidence and prevalence of coronary heart disease in diabetes mellitus is clearly established. The usual lipid pattern found in type II diabetic patients is a moderate increase in fasting triglyceride levels associated with low HDL cholesterol levels. These abnormalities are further amplified in the postprandial state. To study the effect of these alterations on reverse cholesterol transport, we isolated lipoprotein containing apoA-I but not apoA-II (LpA-I) particles by immunoaffinity chromatography from the plasma of well-controlled type II diabetic patients and nondiabetic matched control subjects. Different parameters involved in this antiatherogenic pathway were measured in both fasting and postprandial states. Diabetic patients had reduced levels of LpA-I particles that were protein enriched and phospholipid depleted. Gradient gel electrophoresis showed that control LpA-I particles had five distinct populations, whereas diabetic particles lacked the largest one. LpA-I isolated from diabetic plasma exhibited a decreased capacity to induce cholesterol efflux from Ob 1771 adipose cells both in fasting (15.1±10.0% versus 7.5±2.7%, P<.05) and postprandial (17.7±11.2% versus 7.7±3.9%, P<.05) states, whereas only control particles showed significantly higher ability to promote cholesterol efflux after the test meal (P=.02). Lecithin:cholesterol acyltransferase activity measured with an exogenous substrate showed a 54% increase and an 18% decrease postprandially for control subjects and patients, respectively. Thus, the different abnormalities found in the fasting state were further amplified in the postprandial situation. This resulted in LpA-I particles with aberrant size and composition and decreased ability to accomplish their antiatherogenic role in type II diabetic patients.
Key Words: type II diabetes • postprandial • LpA-I • cholesterol efflux
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Introduction |
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The high incidence and prevalence of coronary heart disease in diabetes mellitus has been firmly established by numerous epidemiological studies.1 2 3 However, the underlying mechanisms of this increased risk in type II diabetic patients remain unclear,4 and many factors seem to be implicated.5 The usual lipid pattern found in type II diabetics is a moderate increase in fasting TG levels associated with low HDL-C levels, whereas the incidence of hypercholesterolemia does not differ from that in nondiabetic subjects.1 Moreover, plasma TG levels are an independent predictive factor of mortality from coronary heart disease in diabetic and glucose-intolerant subjects.6
In spite of adequate nutritional and hypoglycemic therapy, type II diabetics with slight-to-moderate increases in fasting TG levels have increased postprandial lipemia and associated abnormalities in lipoprotein levels and composition, particularly in the postprandial state, compared with nondiabetic control subjects.7 8 These changes, primarily cholesteryl ester depletion and TG enrichment, are positively related to the magnitude of postprandial lipemia. Untreated type II diabetics with severe obesity and hyperglycemia have increased postprandial lipemia compared with obese nondiabetic control subjects.9
Patsch et al10 have established the relations between increased postprandial lipemia and reduced HDL2 pool, and the same authors have demonstrated that postprandial TG levels accurately predict the presence of coronary artery disease as verified by angiography in nondiabetic subjects.11 The mechanisms explaining the higher risk of atherosclerosis in patients with increased postprandial lipemia are not completely understood and may be at least partially explained by the antiatherogenic role attributed to HDL together with reduced reverse cholesterol transport from peripheral cells to the liver.
HDL is not a homogenous entity; two main subfractions, LpA-I and LpA-I:A-II, can be isolated by using immunoaffinity chromatography.12 Clear evidence indicates that LpA-I and LpA-I:A-II are metabolically distinct.13 14 Different in vivo kinetics of apoA-I on LpA-I and LpA-I:A-II have been demonstrated by Rader et al,15 and both subfractions differ in their substrate qualities with regard to their esterifying and lipolytic enzymes.16 It is generally accepted that LpA-I is the antiatherogenic fraction of HDL.17 This could be related to the capacity of the pre-ß migrating species of LpA-I to accept the cholesterol released from cells.18 The effluxed cholesterol is immediately esterified by the LCAT that is mainly associated with the LpA-I particles.19 Cholesteryl esters are then transferred to lower density lipoproteins by the cholesteryl ester transfer protein that is also present in LpA-I particles. Modifications in plasma concentration20 and size distribution21 of LpA-I are reported in patients with coronary artery disease. Women, who are better protected from atherosclerosis than men, have higher levels of LpA-I particles.22 Furthermore, human apoA-I transgenic mice are less susceptible to atherosclerosis than transgenic mice overexpressing both human apoA-I and apoA-II.23
In spite of these related findings, neither LpA-I levels nor their capacity to induce reverse cholesterol transport has been explored in type II diabetic patients. The general aim of this study was to evaluate the metabolic activities that occur in reverse cholesterol transport under fasting and postprandial conditions in type II diabetics under optimized glycemic and metabolic control compared with healthy control subjects. To gain further insights into this metabolic pathway, we specifically investigated the plasma concentration, chemical composition, and size distribution of LpA-I particles; the capacity of LpA-I to promote cholesterol efflux from cultured adipose cells; and LCAT activity within LpA-I particles.
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Methods |
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Subjects
We studied 14 type II diabetic patients and 12 control subjects aged 35 to 60 years old. All 26 subjects were male. Patients who were under optimized metabolic control, had no major complications, and according to previous results8 were probable hyperresponders to a fat load were selected from outpatient consultation if they satisfied the following criteria: clinical diagnosis of type II diabetes (non–insulin-dependent diabetes mellitus)24 ; fasting C peptide >1.2 ng/mL and fasting TG >1.42 mmol/L and/or HDL-C <1.04 mmol/L and/or apoB >1.15 g/L; normal thyroid, renal, and liver functions and absence of macroproteinuria (defined as urine protein excretion >0.5 g/d on at least two consecutive collection days) and clinical evidence of neuropathy; body mass index <27, or <30 in the case of patients who had previously followed a hypocaloric dietary treatment for at least 6 months without significant weight loss; waist-hip ratio >0.95; and tobacco consumption <10 cigarettes/d. Special care was taken to avoid patients with additional causes of dyslipidemia such as excessive ethanol intake (>20 g/d), therapy with drugs that could affect lipoprotein metabolism, or associated familial dyslipemia; even without familial history, patients were excluded if presenting cholesterol levels >7.7 mmol/L or TG levels >4.46 mmol/L. Four patients were current smokers, and 6 others had stopped smoking 2 to 16 years before. Four patients (1 smoker and 3 former smokers) had microalbuminuria (protein excretion, 20 to 200 µg/min as measured by radioimmunodiffusion assay). Optimized metabolic control had a three-part definition: HbA1c levels <6.5% (normal range, 3.65% to 4.35%) under the patient's usual hypoglycemic therapy (biguanides alone or combined with sulfonylureas), good adherence to a program of standardized physical activity (minimally, a 45-minute walk every day), and good adherence to a balanced normocaloric diet for at least the 8 weeks preceding the metabolic study. The recommended diet composition was 35% fat with a 1:1:1 relative distribution of saturated, monounsaturated, and polyunsaturated fatty acids, 45% to 50% carbohydrate, 15% to 20% protein, and <20 g alcohol/d. Adherence to this nutritional treatment was evaluated twice by means of a 3-day dietary record that was analyzed by a nutritionist.
Control subjects were selected from the hospital staff as healthy subjects without familial or personal history of diabetes or dyslipemia and with normal thyroid, hepatic, and renal functions. In addition, an oral glucose tolerance test was performed in all subjects to exclude those with glucose intolerance (glycemia levels >7.8 mmol/L 2 hours after a 75-g glucose load) or hyperinsulinism (insulin >100 U/L during the glucose tolerance test). Control subjects were not taking any drugs known to affect carbohydrate or lipid metabolism, and they adhered to the same nutritional and physical activity program as patients. Informed consent was obtained from all participants, and the protocol was approved by the ethical committee from H. Mondor Hospital.
Study Protocol
The day before the test, patients and control subjects were
instructed to eat a standardized meal (500 kcal, 20 g fat). After a
12-hour overnight fast, venous blood was collected into EDTA-containing
or clot-activator evacuated tubes for the fasting
sample. Both groups then received the test meal, and blood samples were
drawn 6 hours later for the postprandial sample. Hourly samples were
obtained for an additional 8 hours to evaluate postprandial TG
responses. After the extraction, tubes were centrifuged at
1500g for 15 minutes at 4°C and immediately used for
lipoprotein studies. Aliquots were stored at -80°C for
determination of LpA-I concentration.
Test Meal
The test meal contained 32.5 g lipid/m2 of body
surface.8 The relative fatty acid composition had a 1:1:1
distribution of saturated, monounsaturated, and
polyunsaturated fatty acids. Mean cholesterol content was
100 mg. The meal consisted of milk, coffee, cheese, bacon, margarine,
and a fruit. It was well tolerated and ingested within 15 minutes.
Lipoprotein Separation
Fasting and postprandial LpA-I particles were isolated by
immunoaffinity chromatography12 from HDL
fractions separated by ultracentrifugation. Eight
milliliters fresh EDTA plasma was adjusted to d=1.063 g/mL
and ultracentrifuged for 18 hours at 10°C in a 50-Ti
Beckman rotor (Beckman L8-55, Beckman Instruments). Floating
apoB-containing lipoproteins were discarded. HDL was obtained after a
second spin (d=1.210 g/mL), and the floating HDL fraction
was collected with a syringe. HDL was dialyzed at 4°C in a buffer
containing (in mol/L) Tris 0.01, NaCl 0.15, and EDTA 0.01, pH 7.4. A
mixture of three lipoprotein preservatives (aprotinin, benzamidine, and
gentamicin) was immediately added to the HDL fractions, which were
stored at 4°C until analysis.
A mixture of three different monoclonal antibodies to apoA-I (A05, A17, and A30) was found to effectively recognize all plasma apoA-I. This mixture was covalently coupled to CNBr-activated Sepharose 4B (Pharmacia) as instructed by the manufacturer (5 mg/g gel). A mixture of three different monoclonal antibodies to apoA-II (G03, G05, and G11) recognizing all plasma apoA-II was coupled in the same fashion. HDL protein (11 to 13 mg) was depleted of apoA-II by passing it through the anti–apoA-II column. The nonretained fraction from the anti–apoA-II column was chromatographed on the anti–apoA-I column. The retained apoA-I–containing particles (ie, LpA-I) were eluted from the column with 3 mol/L NaSCN. The LpA-I fraction was desalted immediately by passing it onto a Sephadex G25 column and then dialyzing it against PBS pH 7.4. The LpA-I fraction was concentrated, and its purity was tested by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (gradient, 8% to 25%, Phast Gel, Pharmacia Biotech).
Analytical Procedures
HbA1c (normal range, 3.65% to 4.35%) was
determined by liquid-phase chromatography. Total
cholesterol, TG, and phospholipid measurements in total
plasma and LpA-I particles were carried out by using enzymatic reagents
(Boehringer Mannheim). Protein was quantified according to the
Lowry method by using bovine serum albumin (BSA) as
standard.25 Plasma apoA-I and apoB levels were measured by
using an immunoturbidimetric method (Daïchi kits). Quantitative
determination of LpA-I was performed by electroimmunoassay of serum
with ready-to-use plates (Hydragel LpA-I, Sebia).
LpA-I size distribution was evaluated by employing a nondenaturing polyacrylamide gel electrophoresis (gradient 8% to 25%, Phast Gel, Pharmacia Biotech) in acetate and Tris (each 112 mmol/L), pH 7.4. The samples (4 µg protein) were applied by using loading applicators of 1 µL. The buffer strips (Phast-Gel native buffer strips, Pharmacia) were 2% agarose in 0.88 mol/L l-alanine and 0.25 mol/L Tris, pH 8.8. Electrophoresis was performed in a Phast-System apparatus (Pharmacia) at 400 V for 40 minutes at 15°C. Gels were stained with Phast-Blue R335 (0.2% mass/vol) in 10% (by volume) acetic acid solution. The staining and destaining steps were automatically performed using the Phast-System development kit. Thyroglobulin (665 kD), ferritin (440 kD), catalase (232 kD), lactate dehydrogenase (140 kD), and albumin (67 kD) (high-molecular-mass calibration mixture, Pharmacia) were used as calibrating proteins on each gel. Stained gels were scanned by using a CCD scanner with 512x512 pixels with 256 gray levels. Data was analyzed by using the lecphor program (Biocom).
Cholesterol Efflux
The characterization of the Ob 1771 preadipocyte clonal line has
been reported.26 Cells were plated at 2.5x103
cells/cm2 in multiwell plates (Nunc) and grown in
Dulbecco's modified Eagle's medium supplemented with 10% (vol/vol)
fetal calf serum, 200 U/mL penicillin, 50 µg/mL streptomycin, 33
µmol/L biotin, 17 µmol/L pantothenate, 15 mmol/L HEPES, and 1.2 g/L
NaH2CO3, pH 7.4. After reaching
confluence, the cells were maintained in the same medium supplemented
with 17 nmol/L insulin and 2 nmol/L triiodothyronine.
Isobutylmethylxanthine (100 µmol/L) was added
to the medium during the first 2 days postconfluence. Under these
conditions, differentiation occurred within 10 days. The medium was
changed every other day. To promote cholesterol
accumulation in the cells, differentiated Ob 1771 cells were first
maintained at 37°C for 48 hours in a medium containing 10%
lipoprotein-deficient serum and then exposed for 48 hours to the
same medium supplemented with LDL labeled with
[3H]cholesteryl linoleate (400 cpm/µg
cholesterol and 150 µg cholesterol/mL)
according to the method of Craig et al.27 Subsequently,
the cells were washed with PBS (pH 7.4) containing 1% BSA and then
twice with PBS. In the cholesterol efflux experiment, 50
µg/mL protein LpA-I was incubated for 3 hours with the cultured cells
at 37°C in humidified 5% CO2. After incubation, media
were removed and centrifuged to discard cell debris and then
counted for radioactivity. The cells were washed twice with PBS and
BSA, washed twice with PBS alone, and dissolved in 1 mL of 0.1 mol/L
NaOH. The alkaline digest (0.5 mL) was used for radioactivity counts,
and the remainder was used to assay the protein concentration.
LCAT Activity
LCAT activity was determined according to the exogenous
substrate method of Chen and Albers.28 Protein LpA-I
(50 µg) was incubated with a proteoliposome substrate containing
apoA-I, [14C]cholesterol, and egg
phosphatidylcholine at a molar ratio of 0.8:12.5:250 for 1 hour at
37°C.
Data and Statistical Analysis
Data are presented as mean±SD. TG postprandial
incremental and total areas were calculated by using the trapezoidal
rule. The Mann-Whitney nonparametric U test was
used to compare patients and control subjects, and differences were
considered significant at P<.05 in the bilateral situation.
The Wilcoxon nonparametric test was used to compare
fasting and postprandial states within the same group of subjects.
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Results |
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Subjects
Both diabetic and control subjects had similar ages (49.9±8.5 [range, 39 to 60] versus 48.9±8.1 [range, 35 to 60] years) and body mass index (27.0±2.0 [range, 24 to 30] versus 25.6±1.5 [range, 23 to 28] kg/m2). The distribution of apoE phenotypes was also similar; one patient had been excluded because he presented the phenotype E4/E4. As expected, HbA1c differed significantly between diabetic and control subjects (5.1±0.9% [range, 3.9% to 6.5%] versus 4.2±0.3% [range, 3.7% to 4.4%], P<.001).
Lipid and Apolipoprotein Levels
Plasma lipid and apolipoprotein levels from the 14 type II
diabetic patients and 12 healthy control subjects are shown in Table 1
. As expected, HDL-C was significantly lower in
diabetic than in control subjects (P=.002), and total
cholesterol concentration was comparable in both groups.
Fasting TG levels were higher in patients than healthy subjects
(P=.002), although the increase in fasting TG in patients
was moderate (range, 1.07 to 3.29 mmol/L). Larger overall 8-hour
postprandial TG total and incremental area responses were also found in
diabetics (P=.002). ApoB was significantly higher in
patients than in control subjects (P=.002); only a
nonsignificant decrease in apoA-I was observed. One major finding was
the significantly decreased LpA-I particle level in diabetic subjects
(0.37±0.06 versus 0.49±0.13 g/L, P<.05).
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LpA-I Chemical Composition and Size
Table 2 shows the chemical composition of fasting
and postprandial LpA-I particles isolated by immunoaffinity
chromatography. LpA-I particles from diabetic patients
appeared depleted in cholesterol and phospholipids and
relatively enriched in proteins compared with LpA-I particles from
control subjects. In the postprandial state, we observed an increase in
LpA-I TG content that was significant for the whole group but not
within subgroups (patients plus control subjects,
P<.05).
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When the sizes of fasting and postprandial LpA-I particles were analyzed, we found that patients showed a different particle size distribution than did normal subjects. In healthy subjects, we were able to visualize five different subpopulations with approximate molecular weights of 55, 70, 110, 170, and 270 kD and relative distributions for fasting LpA-I of 6.9±0.6%, 13.1±2.5%, 10.8±0.8%, 5.7±1.5%, and 63±0.5%, respectively, and for postprandial LpA-I of 5.8±1.4%, 13.3±0.3%, 11.0±3.6%, 8.7±4.0%, and 67.5±4.5%, respectively. In contrast, diabetic subjects presented a distribution of four subpopulations with approximate molecular weights of 55, 70, 110, and 170 kD and relative distributions for fasting LpA-I of 13.6±6.7%, 24.4±9.0%, 21.0±4.3%, and 44.0±8.5% respectively, and for postprandial LpA-I of 11.6±1.0%, 15.7±15.0%, 23.2±8.0%, and 51.8±14.7%, respectively.
Cholesterol Efflux and LCAT Activity
The Figure shows the percentage of efflux of
[3H]cholesterol from adipose cultured cells
induced by fasting and postprandial LpA-I obtained from patients and
control subjects. LpA-I isolated from diabetic patients exhibited
decreased capacity to induce cholesterol efflux both in
fasting (15.1±10.0% versus 7.5±2.7%, P<.05) and
postprandial (17.7±11.2% versus 7.7±3.9%, P<.05)
states. When fasting and postprandial samples were compared, only
normal subjects showed a significant increase in
cholesterol efflux capacity after the meal
(P=.02).
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LCAT activity within LpA-I particles increased by 54% in the postprandial state in control subjects (n=12; P=.01), whereas it decreased slightly (18%) in diabetics (n=12; NS).
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Discussion |
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To gain insight into the mechanisms that could explain the higher cardiovascular risk in type II diabetics with lipid intolerance, this study explored LpA-I levels and their capacity to promote the reverse transport of cellular cholesterol in patients under optimized glycemic control compared with a matched group of healthy nondiabetic control subjects. The fasting lipid abnormalities we found in these patients are in agreement with previous reports and consist mainly in a slight-to-moderate increase in TG and decrease in HDL-C levels. This pattern is associated with high postprandial lipemia after a standardized lipid-rich meal.
The decreased LpA-I levels found in diabetics in our study are consistent with the observation that HDL-C in hypertriglyceridemic patients is mainly composed of HDL2,10 as the proportion of LpA-I associated with HDL2 is greater than that of LpA-I:A-II.29 30 A negative correlation between plasma LpA-I levels and the magnitude of postprandial lipemia is reported in normolipidemic subjects,30 whereas postprandial lipemia positively correlates with the TG content of HDL particles both in diabetics8 and nondiabetics.10
Horowitz et al31 have shown that HDL enrichment with TGs and exposition to lipases increase the apoA-I fractional catabolic rate because increased proportion of apoA-I is present in a more easily dissociated pool that can be rapidly catabolized by the kidney.
The apparent molecular weight and size distribution of the major LpA-I particles from diabetics differed from those of control subjects' particles, as the patients completely lacked the largest LpA-I subfraction of apparent molecular weight 270 kD. Accordingly, LpA-I chemical composition analysis showed that both fasting and postprandial LpA-I particles from diabetics had a low lipid-to-protein ratio. Cheung et al21 report size alterations of LpA-I particles, with a preponderance of smaller, protein-rich particles, in patients with angiographically proven coronary heart disease. Interestingly, reduced levels of the larger and increased levels of the smaller LpA-I subfractions, obtained from whole plasma or ultracentrifuged HDL, were seen in a study by Cheung and Wolf32 in a diabetic subject.
The chemical composition and particle size of the apoA-I–containing particles are regulated by the concerted action of LCAT, cholesteryl ester transfer protein, and the lipolytic enzymes lipoprotein lipase and hepatic lipase. Studies using HDL subfractions or reconstituted particles have shown that lipoprotein lipase and LCAT are involved in the conversion of smaller to larger particles, whereas hepatic lipase and cholesteryl ester transfer protein are believed to facilitate the conversion of larger to smaller particles.33 34 35 Decreased activity of lipoprotein lipase and high hepatic lipase activity have been described in type II diabetes.36 37 38 Precisely how the various enzymes and particles interact in vivo to determine the modifications observed in the particles from diabetic subjects remains to be clarified. However, the long-lasting and elevated mass of TG-rich lipoproteins observed in the postprandial state and the impaired LCAT activity must be important contributors to the diabetic pattern.
Our study demonstrated that LpA-I particles from diabetics show a reduced capacity to induce cholesterol efflux from Ob 1771 cells in both the fasting and postprandial states, but mainly in the postprandial state. Whether these changes are due to the modifications in size distribution reflected by the lack of the 270-kD subpopulation or the composition of the different LpA-I particles remains to be shown. The facts are that diabetics have fewer LpA-I particles and that these are less effective in promoting cholesterol efflux. When percentage of difference between both conditions was analyzed in individual subjects, control subjects had a significantly increased percentage of cholesterol efflux in the postprandial state, but diabetic patients experienced a slight decrease (20.4±18.5% versus -0.5±20.6%, P<.05).
One study, which explored the cholesterol net transport between cultured fibroblasts and plasma from uncontrolled type II diabetic patients, demonstrated an inhibition that was normalized after either removal of plasma apoE or effective control of hyperglycemia with insulin.39 Diabetic patients in our study were well controlled, and the apoE levels in their particles were very low (<0.01% of the total protein) and did not differ from control subjects' apoE levels. Another mechanism that could be implicated concerns the glycation of apoA-I. LpA-I and HDL3 from severely hyperglycemic type I diabetics induce cholesterol efflux less efficiently than normal fractions.40 41 Even though the type II diabetics in our study were under optimized metabolic control, their level of glycated apoA-I was still increased. Differences in the activation of LCAT by glycated apoA-I become already detectable even when the degree of glycation of lysine residues reaches 3% to 5%.42 Nevertheless, the degree of apoA-I glycation is expected to be identical in both fasting and postprandial samples.
The rate of esterification of cholesterol in normal plasma is stimulated during the postprandial state with no difference in the absolute LCAT mass.43 The exogenous substrate method that we used could be considered as a measurement of the mass of LCAT associated with the LpA-I particles. When the percentage of difference between both conditions was analyzed in individual subjects, we obtained results indicating that in the postprandial state there is an increase of LCAT within the LpA-I particle from control subjects but not from patients; this pattern mimics the changes observed for cholesterol efflux experiments in the same particles.
All diabetic subjects in this study received metformin to optimize their metabolic control because of the capacity of the drug to improve insulin resistance. Although detailed data on biguanide effects on lipoprotein metabolism are still lacking, a majority of studies show that biguanides effectively reduce fasting TG and VLDL levels in type II diabetics44 and nondiabetic dyslipidemic subjects.45 If anything, biguanides would probably improve lipoprotein metabolism, making it unlikely that the LpA-I abnormalities found in this study could be related to this treatment.
In summary, even under optimized glycemic control type II diabetic patients have reduced LpA-I levels with abnormal composition. LpA-I particles from diabetic subjects show decreased ability to induce reverse cholesterol transport and are unable to increase this capacity in the postprandial state. These abnormalities are conducive to the formation of unstable, phospholipid-depleted, and less functional particles and to the generation of small particles easily cleared from plasma, thus contributing to hypoalphalipoproteinemia and to the increased risk of coronary heart disease observed in this type of patient.
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Acknowledgments |
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Fernando Brites was supported in part by a grant from Ministerio de Cultura y Educación from Argentina and is a Research Fellow from the University of Buenos Aires. The expert technical assistance of Philippe Poulain and Claude Martin are acknowledged.
Received March 6, 1995; accepted September 14, 1995.
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References |
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