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Blood, Vol. 91 No. 11 (June 1), 1998:
pp. 4158-4163
Methylenetetrahydrofolate Reductase C677T Mutation,
Plasma Homocysteine, and Folate in Subjects From Northern Italy
With or Without Angiographically Documented Severe Coronary
Atherosclerotic Disease: Evidence for an Important
Genetic-Environmental Interaction
By
Domenico Girelli,
Simonetta Friso,
Elisabetta Trabetti,
Oliviero Olivieri,
Carla Russo,
Renzo Pessotto,
Giovanni Faccini,
Pier Franco Pignatti,
Alessandro Mazzucco, and
Roberto Corrocher
From the Institute of Medical Pathology, Chair of Internal Medicine,
the Institute of Biology and Genetics, the Institute of Cardiovascular
Surgery, and the Institute of Clinical Chemistry, University of Verona,
Verona, Italy.
 |
ABSTRACT |
Moderate elevation of plasma total homocysteine (tHcy) is a strong
and independent risk factor for coronary artery disease (CAD). It can
result from genetic or nutrient-related disturbances in the
transsulfuration or remethylation pathways for Hcy metabolism. A point
mutation (C677T; Ala-to-Val) in the gene encoding the 5,10-methylenetetrahydrofolate reductase (MTHFR) has been recently reported to render the enzyme thermolabile and less active. Studies on
the role of this mutation as a risk factor for CAD have given conflicting results. We studied a total of 415 subjects, 278 with angiographically documented multivessel CAD and 137 with
angiographically documented normal coronary arteries. The overall
frequency of the MTHFR V/V homozygous genotype was 15.7% (with 52.5%
heterozygous and 31.8% normal). Subgroup analysis showed no
significant differences between CAD and CAD-free subjects. A
genotype/phenotype correlation study showed a marked effect of folate
on the association between MTHFR genotypes and tHcy. Among individuals
with folate levels below the median (11.5 nmol/L), fasting
tHcy was significantly increased not only in V/V homozygotes (by 59%)
but also, at intermediate values, in A/V heterozygotes (by 21% on
average). Conversely, the mutation resulted neutral with respect to
tHcy levels in subjects with adequate folate levels. We conclude that,
in our population, the MTHFR C677T mutation is rather
common, but it does not appear to be associated per se to CAD. A
genetic-environmental interaction may contribute to the vascular risk
by elevating tHcy when folate status is low.
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INTRODUCTION |
HOMOCYSTEINE is a non-protein-forming,
thiol-containing amino acid that results from the demethylation of the
essential amino acid methionine.1 Elevated levels of plasma
total homocysteine (tHcy) can result from genetic or nutrient-related
disturbances in the two pathways for homocysteine metabolism,
remethylation or transsulfuration. In remethylation, the primary methyl
donor for the vitamin B12-dependent conversion of Hcy to methionine is
5-methyltetrahydrofolate, which in turn is formed from 5,10 methylenetetrahydrofolate by means of the enzyme
methylenetetrahydrofolate reductase (MTHFR). In transsulfuration, Hcy
is irreversibly catabolized to cystathionine by means of the vitamin
B6-dependent enzyme cystathionine  -synthase (CBS) and eventually
excreted as inorganic sulphate. Fasting levels of tHcy reflect mainly
the remethylation pathway, whereas transsulfuration is thought to be
reflected by the increase in tHcy above fasting levels after an oral
methionine load.
In accordance with pioneer investigations,2,3 several
recent studies have established that an elevated plasma level of tHcy
is an independent risk factor for vascular disease, both in the
coronary circulation and elsewhere (reviewed in Ueland et
al,4 D'Angelo and Selhub,5 Boers,6
and Boushey et al7). With respect to coronary
atherosclerotic disease (CAD), the evidence for a detrimental role of
tHcy is striking. Based on a meta-analysis considering both
case-control and prospective studies, it has been calculated that 10%
of the population's risk for CAD may be attributable to elevated
tHcy.7 As with cholesterol levels, the risk gradually
increases with increasing tHcy levels, and the enhanced risk associated
with a 5 µmol/L elevation of tHcy was estimated to be the same as
that associated with a 0.5 mmol/L increase in total cholesterol. More
recently, a prospective study found a strong, graded association
between tHcy and mortality in 587 patients with angiographically
confirmed CAD.8 By virtue of this background, investigation
of the determinants of even moderate hyperHcy has intensified. Early
biochemical studies by Kang et al9,10 identified a
thermolabile variant of MTHFR with reduced enzymatic activity; this
defect was reported to be associated with both elevated tHcy levels and
increased CAD risk. In 1995, the defect responsible for the
thermolabile MTHFR was characterized, consisting of a missense mutation
(C677T) that results in a valine substitution for an
alanine.11 Given that homozygous mutants were reported to
have increased plasma tHcy levels, the C677T mutation was
proposed as a candidate genetic risk factor for CAD. However,
subsequent studies (reviewed in Rozen12) have given
remarkably conflicting results. These discrepancies might relate to
both population-specific factors (ie, differences in the geographical
distribution of the mutation and/or in the nutritional status)
and to heterogeneity of study conditions (ie, differences in the
selection of cases and controls and, sometimes, lack of adequate
information on folate and tHcy levels).
In this report, we investigated the frequency of the C677T
genotype and its association with tHcy levels before and after methionine loading in Italian patients with angiographically documented severe CAD compared with subjects with angiographically documented normal coronaries. Because an adequate folate status may counterbalance the defective MTHFR activity,13 we also examined the
influence of plasma folate concentration on the relation between the
MTHFR thermolabile polymorphism and plasma tHcy concentrations.
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MATERIALS AND METHODS |
Study population.
Between May 1996 and May 1997, we studied 415 consecutive unrelated
adult patients of both sexes recruited from those referred to the
Institute of Cardiovascular Surgery of Verona (Verona, Italy). Of
these, 278 were candidate to coronary artery bypass grafting (CABG),
having angiographically documented severe multivessel CAD. One hundred
thirty-seven subjects examined for reasons other than suspected CAD
(mainly valvular heart disease) and having angiographically documented
normal coronary arteries were considered as the control group. Both CAD
patients and controls came from the same geographical area (Northern
Italy), with a similar socioeconomic background. At the time of the
blood sampling, a complete clinical history including cardiovascular
risk factors such as smoking and hypertension was collected in all
participating subjects. We excluded only subjects with conditions known
to influence homocysteine levels (thus interfering with
genotype/phenotype correlation study), such as current or recent use of
a folate or vitamin B12 supplement or of any multivitamin preparation;
current or recent use of drugs interfering with homocysteine levels
(ie, anticonvulsivants, methotrexate, and penicillamine); any major
systemic acute illness (including myocardial infarction in the CAD
group) in the last 3 months; serum creatinine level  1.8 mg/dL.
Moreover, control subjects were enrolled providing that they had not
only a normal coronary angiogram at cardiac catheterization, but also
neither history nor clinical or instrumental evidence of
atherosclerosis in vascular districts other than the coronary bed.
Hypertension was defined as systolic blood pressure 160 mmHg or
diastolic blood pressure 95 mmHg or on the basis of medical history
and the use of antihypertensive medication. Among the CAD patients, the
diagnosis of previous myocardial infarction (in 66% of them) was based
on the medical history, previous ECG, and enzyme documentation
and/or based on the finding of typical sequelae of infarction
on ventricular angiography. The severity of CAD was determined by the
number of significantly stenosed coronary arteries, ie, lesions with
greater than 50% luminal stenosis. The angiograms were assessed by two
cardiologists who were unaware that the patients were to be included in
the study. Most of the CAD patients (76%) had severe CAD involving all
the three major coronary arteries, 19% had two stenosed vessels and
5% had one. The majority of the women enrolled (n = 93) were in the
menopausal status (88%), and none of them assumed hormone replacement
therapy. Informed consent was obtained from every subject after a full
explanation of the study.
Biochemical analysis.
Samples of venous blood were drawn from each subject in the free-living
state, at scheduled ambulatory evaluation few days before surgery.
For tHcy (which refers to the sum of homocysteine, homocystine, and
homocysteine-cysteine mixed disulfide, free and protein bound), blood
was collected after an overnight fast into EDTA-containing vacuum tubes
and kept on ice and in the dark; plasma was separated within 90 minutes; tHcy levels were determined by high-performance liquid
chromatography (HPLC) with fluorescent detection,
according to Araki and Sako.14 After the first blood
sampling, a standardized methionine-loading test was performed by
administering orally L-methionine (100 mg/kg) mixed with 200 mL of
orange juice, together with a standardized low-protein breakfast; blood
was then collected 6 hours later for the determination of the
postmethionine loading (PML) tHcy level. Plasma folate and vitamin B12
concentrations were measured by an automated chemiluminescence method
(Chiron Diagnostics, East Walpole, MA). Plasma triglycerides and total and high-density lipoprotein (HDL) cholesterol were determined by using
a Technicon DAX 96 automated analyzer (Technicon Instruments, Tarrytown, NY); low-density lipoprotein (LDL) cholesterol
levels were calculated using the Friedewald formula.
Mutation analysis.
DNA was extracted from peripheral lymphocytes using
phenol/chloroform protocol and the analysis of the C677T
mutation in the MTHFR gene was performed by PCR and HinfI
digestion.11 Because the C677T mutation results
in a valine (V) substitution for an alanine (A), the three genotypes
were defined as follows: A/A, normal homozygous; A/V, heterozygous; and
V/V, mutant homozygous.
Both biochemical and mutation analysis were conducted blind as to
whether a sample came from a CAD or CAD-free subject.
Statistical analysis.
Statistical analysis was performed by the Systat 5.2.1 package (Systat
Inc, Evanston, IL) working on Macintosh Performa 5300 (Apple Computer Inc, Cupertino, CA). Because of the skewness of the
distributions of values for tHcy, folate, and vitamin B12, analyses
were performed using natural log-transformed data; thus, geometric
means of such variables are presented. Quantitative data were analyzed
using the Student's t-test or by AN(C)OVA with Tukey's post
hoc comparison of the means when appropriate. Qualitative data were
analyzed using a  2 test. A value of P < .05 was considered significant.
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RESULTS |
The relevant characteristics of the population studied are
summarized in Table 1. As expected, CAD
patients had more conventional risk factors (higher body mass index
[BMI], total and LDL cholesterol, a higher prevalence of
hypertension and smoking, and lower HDL cholesterol) as compared with
CAD-free controls. The two groups were matched for age, but there were
more women in the control group compared with the patient group.
Geometric mean fasting tHcy levels were significantly higher in CAD
than in CAD-free subjects, also after adjusting for both sex and age
(Table 1). Geometric mean PML increase in tHcy (absolute PML value
minus fasting) levels were not significantly different between the two groups. Although the measures of fasting and PML tHcy were highly correlated (r = .68; P < .001), different persons
with elevated homocysteinemia were identified by each measure. By
analyzing tHcy level as a categorical variable, the prevalence of
hyperhomocysteinemia (defined as at least 1 of the 2 values in the top
fifth of the control distribution, ie, fasting tHcy 19 µmol/L and
PML increase in tHcy 31.7 µmol/L) was higher in CAD than in
CAD-free subjects (41% v 28.8%, respectively; P < .05). There was no statistically significant difference in either
plasma folate or in vitamin B12 concentrations between CAD and CAD-free
subjects, although both the values tended to be lower in CAD subjects.
Both in the whole population and in each of the two subgroups, fasting
tHcy levels were inversely correlated with the concentrations of folate
and vitamin B12 (r =  .38 and .25, respectively,
in the whole population, n = 415; P < .001 for both). Among
the CAD patients, there was no difference in either tHcy values
(fasting and PML increase) or in the concentrations of vitamins when
subjects with or without previous myocardial infarction were compared
(data not shown).
The distribution of the MTHFR genotypes in the whole population was
compatible with the Hardy-Weinberg equilibrium. Allele and genotype
frequencies were as follows: V allele frequency, 41.9%; A/A, 31.8%;
A/V, 52.5%; and V/V, 15.7%. There was no sex-dependent variation in
the prevalence of the V allele frequency or V/V genotype. Table 2 indicates the allele frequencies
and genotype distributions in CAD and CAD-free subjects. The frequency
distribution of the genotypes between CAD and CAD-free subjects was not
significantly different (2 = 1.04, df = 2, P = .59). It was also not significantly different between CAD
subjects with or without previous myocardial infarction (A/A 33.3%,
A/V 55.1%, and V/V 11.6% in CAD without myocardial infarction
[MI]; A/A 32.9%, A/V 51%, and V/V 16.1% in CAD with MI; 2 = .9, df = 2, P = .63).
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Table 2.
Frequencies of MTHFR Normal (Alanine) and Mutant
(Valine) Alleles and of the Three Genotypes (A/A, A/V, and V/V) in
CAD-Free (n = 137) and CAD (n = 278) Subjects
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A genotype/phenotype correlation study focused on the effect of the
MTHFR mutation on tHcy levels was performed using combined data of the
entire study population. Because a mutation in the MTHFR gene might
alter folic acid requirements in mutant individuals, we divided the
sample into two groups on the basis of plasma folate levels, using the
median value (11.5 nmol/L, which was similar in both groups) as the
cutoff. Results are summarized in Table 3.
Regardless of the folate levels, V/V homozygotes had significantly higher fasting tHcy as compared with the A/A and the A/V genotypes. However, the latter genotype had intermediate values that were not
statistically different from the A/A group. After stratification by
folate levels, it became evident that there was a marked effect of
folate on the association between genotype and fasting
tHcy. In individuals with folate levels above the median,
there was no significant difference between genotypes. Conversely, the
low-folate V/V subjects had fasting tHcy levels 59% greater than
low-folate A/A subjects and 38% greater than the intermediate levels
of low-folate A/V subjects. Noteworthy, after exclusion of the
low-folate V/V group with extremely high fasting tHcy values,
low-folate A/V heterozygotes had fasting tHcy levels significantly
higher (by 21% on average) as compared with all the other
genotype/phenotype categories (Table 3 and
Fig 1).
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Table 3.
Plasma Hcy Levels in the Whole Population as a
Function of MTHFR Genotype and Folate Levels (Stratification by
Folate Values Above and Below the Median)
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| Fig 1.
Fasting tHcy for genotypes of Ala-to-Val
(C677T) MTHFR mutation, stratified by low and high plasma
folate levels, in the total study population.
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The PML increase in tHcy concentration was unrelated to MTHFR genotype,
irrespective of plasma folate level (Table 3).
Table 4 summarizes the biological
parameters in CAD subjects with different MTHFR genotypes. With respect
to the conventional risk factors, there was no significant difference
among patients with different genotypes for any of the listed variables
except a lower prevalence of hypertensives in the heterozygous group. Differences in tHcy levels were similar to those observed in the entire
population group. Folate levels were not significantly different
between genotypes, either in this group or when considering the entire
population study or the CAD-free subjects (data not shown).
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DISCUSSION |
The primary objectives of this study were (1) to assess the frequency
distribution of the MTHFR C677T mutation in a large population of patients with angiographically documented severe CAD, in
comparison to subjects with angiographically documented absence of CAD;
and (2) an attempt to clarify the relative contribution of this genetic
factor to plasma tHcy level, with particular reference to the
interaction with an environmental factor potentially modifiable, such
as folate status.
Since the original report from Frosst et al,11 the MTHFR
C677T mutation has been object of intensive investigation
as a possible genetic risk factor for vascular disease. An early study, including a mixture of subjects with premature cerebrovascular, peripheral, and coronary disease, reported a frequency of V/V homozygosity significantly higher in cases as compared with selected controls without conventional risk factors.15 To the best
of our knowledge, the studies restricted to CAD patients reported so
far are somewhat conflicting: some found a higher prevalence of the
mutation than in controls,16,17 whereas others did
not.18-26 However, these studies were remarkably
heterogeneous with respect to several important conditions that could
influence the results. First, most of them used subjects from the base
population as control group, without objective angiographic information
about their coronary arteries.18-24 Using this approach,
one is never sure about the extent of the coronary narrowing, because
those controls might have substantial (although not clinically
manifest) coronary atherosclerosis, which in turn might contribute to
attenuate the association between the MTHFR polymorphism and CAD.
Second, some studies included only MI survivors as
patients.18-21 Such a phenotype may be too selective,
leading to possible underrepresentation of the V/V genotype in CAD
patients, if the mutation is related to early mortality after MI.
Third, several studies lacked adequate information on the levels of
homocysteine,24 folate,17 or both.18,22,25 Finally, it has become clear that the
prevalence of the C677T mutation is specific to
populations. Reported frequencies of the V/V MTHFR genotype in control
populations varied from 1.4% in African Americans27; to
5% in Dutch15,28; to about 10% in Japanese17
and in Australians24,25; to 12% to 13% in
French-Canadians,11 in people in the United States,19,21 and in people in the United
Kingdom.18 In Italy, the frequencies of V/V homozygotes in
two series of apparently healthy subjects from the
Southern29 and the Northern30 part of the
country were 15.1% and 21%, respectively. Our data confirm that the
C677T mutation in our country is quite common (homozygosity in the entire population study and in controls was 15.7% and 18.2%, respectively), with a prevalence that is one of the highest reported so
far. Such a high frequency argues per se against a possible role of
this mutation as a single factor involved in the pathogenesis of CAD, a
potentially lethal disease that is known to be multifactorial. In line
with this view, in our population, the distribution of the MTHFR
genotypes was not statistically different between patients with
angiographically documented severe CAD and controls (Table 2). An
important peculiarity that strengthens the negative results of our
study relies on the fact that it included only subjects with objective angiographic information. Noteworthy, most of our CAD
patients, recruited among those who were candidates to have CABG, had
severe triple-vessel disease (76%). Only one of the two
studies that found a positive association between MTHFR polymorphism and CAD reported angiographical data of CAD patients.17 In
this study on a large sample of Japanese CAD patients, the frequency of
the V/V genotype was correlated with the angiographical severity of
CAD, and most of this association was due to patients with triple-vessel disease. On the other hand, in our study, the control population was chosen to provide a contrasting population with angiographically documented absence of CAD. In this way, having considered extreme and objective conditions, we feel confident to
reduce the chance of spurious results, an inherent problem of allelic
association studies.31 In agreement with previous data18-21 and keeping in mind the above-mentioned
limitations, our study also excluded any relationship between the MTHFR
C677T mutation and myocardial infarction, the major
thrombotic complication of CAD.
Whereas it is now becoming clear that, at least in most of the
populations studied so far, the C677T mutation cannot be
considered as a single genetic risk factor for CAD, this polymorphism
remains of great potential interest because of its influence on plasma homocysteine concentrations. This is particularly relevant to CAD
patients, by virtue of the striking results of a recent prospective trial that found a strong graded and independent association between plasma tHcy and mortality in patients with angiographically confirmed CAD,8 confirming and extending a previous meta-analysis of observational studies.7 Actually, Nygård et
al,8 after a median follow-up of 4.6 years,
found that the mortality ranged linearly from 24.7% in patients with
high tHcy levels to 3.8% in patients with low tHcy levels. The
genotype/phenotype correlation study in our population confirms that
the MTHFR polymorphism is a major determinant of plasma tHcy levels,
but also clearly shows that it is not important as a single factor.
Early studies by Kang et al9,32 reported that not all the
individuals with biochemically demonstrated thermolabile MTHFR had
increased tHcy levels and that, among those who had it, normalization was seen after folate supplementation. Consistent with these
observations, the interaction between MTHFR thermolabile genotype and
folate status was first pointed out by Jacques et al13 on
356 individuals from the NHLBI Family Heart Study. They found that tHcy
increased only in those V/V homozygous individuals who had concomitant
plasma folate levels below the median (15.4 nmol/L in that population). Similar data were then obtained in other US19,20 and
French-Canadian23 populations by several, but not
all,21 investigators. Sequence homology studies suggest
that the region in MTHFR relating to the C677T mutation is
involved in folate binding and that the enzyme may be stabilized in the
presence of adequate folate levels.33 Our data confirm that
the mutation is neutral with respect to tHcy levels when folate status
is adequate. Moreover, we found that in subjects with low folate status
tHcy increased significantly not only in V/V homozygotes, but also, at
intermediate values, in subjects with only one copy of the mutant
allele (Fig 1). To our knowledge, this is the first study reporting
increased plasma tHcy levels also in MTHFR C677T
heterozygotes with concomitant low plasma folate levels. Our results
are consistent with previous studies that correlated the MTHFR
polymorphism to the biochemical phenotype, by means of in vitro
evaluation of the enzyme activity and thermolability in
lymphocytes.11,15,23,28 These studies demonstrated that the
effects of the two alleles on MTHFR activity are codominant, with A/V
heterozygotes having an enzyme activity intermediate between the two
homozygote groups. Interestingly, it has been calculated that a plasma
folate level of 15 nmol/L is that which ensure adequate tissue
folate.34,35 Our data are also consistent with a
longitudinal observational study that found that, at plasma folate
levels markedly low (< 3.7 nmol/L), even the heterozygous A/V
subjects have an increased likelihood of being significantly
hyperhomocysteinemic.36 The discrepancies with the
above-mentioned genotype/phenotype correlation studies may relate to
different folate status in our population as compared with North
Americans, in which the use of vitamin supplements and/or the
consumption of folate fortified cereals is more common.35
Indeed, the median folate level in our population (11.5 nmol/L) was
lower than that reported, although this extrapolation needs to be
followed with caution because of the different
biochemical methods used for the determination of folate. It is
noteworthy that interventional studies have clearly demonstrated that
folic acid supplementation is effective in reducing plasma tHcy levels, particularly in subjects carrying the C677T
mutation.36,37 Because of the high prevalence of the
mutation (allele frequency of 42% in our population) and the linear
association between tHcy and CAD from prospective
studies,7,8 our results point out that a substantial
proportion of people may have increased folate needs to maintain a low
plasma level of tHcy. We add evidence to the view that both the low
normal threshold values for plasma folate levels and the recommended
dietary allowance (RDA) should be reconsidered,38
especially in populations with a substantial number of mutants. It
should be stressed that we are talking about a nutritional deficiency
that has to be intended as marginal and limited to subjects with a
genetically determined enzyme isoform, who may require an increased
folate intake to stabilize the enzyme and/or to counteract the
folate consumption needed to compensate the reduced MTHFR activity. In
our series, the 65 V/V homozygotes had average plasma folate levels
that tended to be lower, although not statistically significant, than
the other genotypes (Table 4). However, 38% of them had plasma folate
levels above the median and low plasma tHcy (Table 3), probably due to
adequate dietary intake, because none of our subjects assumed any
vitamin supplement.
It has been suggested that the determination of PML tHcy is also a
useful tool to assess the risk of vascular disease attributable to
moderate hyperhomocysteinemia.39,40 Only two
studies13,26 have investigated also the relationship of the
C677T mutation with PML tHcy, giving conflicting results.
The increase in plasma tHcy levels after PML is generally thought to
primarily reflect abnormalities in the transsulfuration pathway, both
genetically determined (heterozygous CBS deficiency) or
nutrient-related (inadequate B6 status).41 According to
this hypothesis and to Jacques et al,13 we found that the
thermolabile MTHFR genotype is not associated with the PML increase
(Table 3).
Finally, according to the majority of studies,17,18,21,24
we cannot confirm the association between the MTHFR genotype and other
conventional risk factors, such as BMI and/or hypertension, reported by some investigators.25
In conclusion, our findings are against a role of the V/V MTHFR
genotype as an independent genetic risk factor for CAD in our
population. However, they are consistent with an important genetic-environmental interaction between folic acid and MTHFR, which
may have detrimental effects, especially in subjects with angiographically documented CAD.8
| |
FOOTNOTES |
Submitted November 4, 1997;
accepted January 19, 1998.
Supported by grants from the Veneto Region, from the Cariverona
Foundation, from MURST 60%, and from CNR Project Biotechnologies.
Address reprint requests to Domenico Girelli, MD, PhD, Institute of
Medical Pathology, Chair of Internal Medicine, Policlinico Borgo Roma,
37134 Verona, Italy.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank Maria Luisa Zenari and Diego Minguzzi for their
excellent technical assistance and Mirella Chesini for helpful assistance in collecting data.
| |
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Abstract
Introduction
Abstract