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is not necessary for cardiac
hypertrophy
1 Section of Cardiology, Department of Medicine, University of Illinois at Chicago, Illinois 60612; and 2 Max Planck Institut für Immunbiologie, Freiburg D-79011, Germany
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Studies in
human and rodent models have shown that activation of protein kinase
C-
(PKC-) is associated with the development of pathological
hypertrophy, suggesting that ablation of the PKC- pathway might
prevent or reverse cardiac hypertrophy. To explore this, we studied
mice with targeted disruption of the PKC- gene (knockout, KO). There
were no detectable differences in expression or distribution of other
PKC isoforms between the KO and control hearts as determined by Western
blot analysis. Baseline hemodynamics were measured using a closed-chest
preparation and there were no differences in heart rate and arterial or
left ventricular pressure. Mice were subjected to two independent
hypertrophic stimuli: phenylephrine (Phe) at 20 mg · kg
1 · day1 sq infusion
for 3 days, and aortic banding (AoB) for 7 days. KO animals
demonstrated an increase in heart weight-to-body weight ratio (Phe,
4.3 ± 0.6 to 6.1 ± 0.4; AoB, 4.0 ± 0.1 to 5.8 ± 0.7) as well as ventricular upregulation of atrial natriuretic factor mRNA analogous to those seen in control animals. These results demonstrate that PKC- expression is not necessary for the
development of cardiac hypertrophy nor does its absence attenuate the
hypertrophic response.
transgenic mouse; LacZ; cell signaling
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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CARDIAC HYPERTROPHY represents a complex adaptation of the terminally differentiated adult cardiocyte to an imposed mechanical or neurohumoral stimulus. Despite decades of study, the precise cellular signals that are responsible for the initiation and maintenance of this adaptation are poorly understood. Recent attention has focused on the permissive role of chronic activation of regulatory kinases including pathways linked to G protein activation (8, 18, 26) and involving calcineurin, calcium/calmodulin-dependent protein kinase (CaMK), and protein kinase C (PKC), among others. Activation of many of these processes has been shown to be sufficient to affect features of the hypertrophic phenotype in adult cardiocytes, and cardiac-restricted gain-of-function studies using transgenic mouse models have further established these links (8).
Activation of PKC and in particular PKC- in the cardiocyte has been
associated with transcriptional transactivation of atrial natriuretic
factor (ANF) and -myosin heavy chains (-MHC), altered calcium
transients (4), impaired unloaded cell shortening, and
gradual onset of left ventricular hypertrophy in the intact murine
heart (7, 23). The hearts of humans and animals with end-stage heart failure are characterized by activation of this PKC
isoform (3, 21). Moreover, chemical blockade of PKC- in
isolated cells tends to restore normal rates of cell shortening and
calcium cycling. Taken together, these studies strongly suggest that
chronic activation of PKC- in the heart is sufficient to induce a
pathological phenotype, but the studies do not establish whether or not
activation of PKC- is necessary for such an adaptation to occur.
This is a critical issue that must be resolved especially because
agents that block PKC- have been suggested as possible therapies for
chronic cardiac diseases (3, 15, 25). To approach this
question, we have determined whether hearts from mice with targeted
disruption (knockout, KO) of the PKC- gene (16) are
able to manifest a cardiac hypertrophic response to mechanical and
pharmacological stimuli.
Our data demonstrate that PKC- is not necessary for the cardiac
hypertrophic response and suggest that redundant signaling pathways are
responsible for cardiac adaptation and remodeling.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal Care
All animals were bred and maintained in a temperature-controlled room. The mice were provided with food and water ad libitum. All animals used were males, ages 8-12 wk.Generation of PKC- KO mice.
Production of mice with a null mutation for PKC- was described
previously (16). These animals are homozygous for the
PKC- KO and are a mixed background of strains 129/Ola and C57Bl/6
mice. There was no significant difference in body weights between
wild-type (C57Bl/6) and transgenic animals.
Induction of cardiac hypertrophy. Hypertrophy was induced in all animals by two different mechanisms: pharmacology and pressure overload. Pharmacological hypertrophy was induced by subcutaneous injections of phenylephrine (Phe) (22). Control and transgenic mice were given subcutaneous injections of Phe for 3 days (22). This level of Phe is toxic to rats but not to mice. Pressure-overloaded hearts were established by constriction of the transverse aorta as previously described (20). Once the animals were intubated and ventilated, a thoracotomy at the second intercostal space and the ascending aorta was dissected free of surrounding tissue. The transverse aorta was banded with 4-0 silk suture placed around extruded polyethylene-50 (PE-50) tubing next to the aorta; when the suture was tied, the tubing was removed, leaving constriction of ~30% of the original lumen diameter. The chest cavity was sutured closed in three layers and negative pressure was reestablished, allowing the animal to recover and breathe on its own. The animals were maintained for 7-10 days at which point they were killed by cervical dislocation. Their hearts were removed to measure the extent of hypertrophy and then frozen in liquid nitrogen for subsequent biochemical analyses. Histologic sections were obtained from each group that demonstrate an increase in myocyte size as a result of Phe stimulation and aortic banding (data not shown).
Biochemical Analysis
Western analysis.
Tissue samples were homogenized in ice-cold sucrose buffer (in mM: 320 sucrose, 20 Tris · HCl, 2 EDTA, 10 EGTA, 10 µl/ml
-mercaptoethanol, 0.3 phenylmethylsulfonyl fluoride; and 20 µg/ml
of leupeptin) with protease inhibitors. This total homogenate
was assayed spectrophotometrically (Bradford assay) for protein
content. Equal amounts of protein were isolated and tricarboxylic acid
was extracted and then resuspended in SDS sample buffer. In addition to
this total PKC sample, the homogenate was fractionated by differential
centrifugation into cytosolic and particulate fractions. Protein
(60-80 µg) was loaded onto 10% acrylamide gels to separate the
constituent proteins. PKC-purified enzymes (positive control) and
molecular weight markers were run in parallel. The proteins were
transferred to nitrocellulose using a semidry blot apparatus (Bio-Rad).
The membranes were blocked overnight at 4°C in 5% dry milk and the
primary antibody was applied for 1-2 h at room temperature. PKC
polyclonal antibodies for the 
-, -, 
- and 
-isoforms
(1:3,000 dilution, Santa Cruz; and 1:1,000 dilution, Transduction
Laboratories) were used. After a 30-min wash, the membrane was probed
with secondary antibody (1:10,000-1:20,000 dilution) conjugated to
horseradish peroxidase for 1 h at room temperature. The membrane
was then washed for 30 min and exposed to chemiluminesence reagents
(Pierce) for 10 min and developed on radiographic film.
Semiquantitative densitometric analysis was performed using the Bio-Rad
Gel Doc system.
Northern blot analysis. ANF mRNA was used as a marker of cardiac hypertrophy. Atrial and ventricular tissues were isolated from freshly excised hearts of both control and hypertrophied wild-type and transgenic mice. RNA was isolated using TRIzol reagent (GIBCO-BRL) according to the protocol supplied by the manufacturer. The cDNA probes for ANF and GAPDH have been previously published and 32P labeling was done using the Stratagene primer kit. A GAPDH probe was used for normalization and was prepared in the same manner.
PKC- -galactosidase fusion protein
expression.
Generation of the PKC- KO mice is described elsewhere in detail
(16). In brief, the second exon of the PKC- gene was
disrupted by homologous recombination with a LacZ-neo cassette. This
insertion provides an endogenous marker of PKC- expression by
quantification of LacZ expression. Because LacZ is not expressed in
nontransgenic tissue, the background signal is low and therefore is
very sensitive to defining PKC- expression. Hearts and brains
harvested from animals subjected to hypertrophic stimuli were infused
with paraformaldehyde, isolated, and frozen. The tissue was
cryosectioned (5-µm sections were acquired). Tissue sections were
stained for -galactosidase activity using standard techniques. LacZ
mRNA levels were measured by standard RT-PCR protocols (GeneAMP,
Perkin-Elmer) using primers designed to specifically amplify the LacZ
cassette used for gene disruption.
In situ hemodynamics. For in situ measurements, the animals were anesthetized with an initial dose of methoxyflurane (Metofane) and sedation was maintained after intubation with 1% isoflurane using a Harvard small-animal ventilator (respiratory rate 2 Hz, respiratory volume, 0.1-0.03 ml). Body temperature was monitored using a rectal thermistor and maintained at 39°C using a warming blanket placed under the animal. An incision lateral to the right carotid was made and the carotid artery was exposed. The vessel was opened and a 1.4-Fr Millar pressure transducer was passed through the carotid artery and into the left ventricle. Arterial pressure and waveform was measured before the heart was entered; after this the ventricular waveform was obtained, which indicated the location of the transducer. Baseline hemodynamic measurements of wild-type and transgenic mice were obtained in this manner. All data were acquired and analyzed through the Gould/Ponemah system (Gould, Columbus, OH).
Statistics. The are the sample means ± SD. The results were compared by an unpaired Student's t-test with the significance established at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Characterization of PKC- KO
hearts: PKC expression and compensation.
Figure 1 shows a composite Western blot
from extracts of normal and transgenic hearts. Each lane has similar
amounts of total protein loaded. The level of expression was measured
to investigate the effect of the null mutation of PKC- on the
expression of the other PKC isoforms. There was no significant
difference between wild-type and transgenic mice in the expression of
PKC- or PKC- (the major isoforms expressed in the heart) as a
result of the absence of PKC- in the transgenic hearts. Although
expressed in lower amounts, PKC- was also examined and there was no
change in expression level compared with the wild-type heart.
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In situ hemodynamics.
Pooled hemodynamic data from several animals are shown in Table
1. There was no significant difference in
either carotid or intraventricular pressure between wild-type and
transgenic animals. The pressures measured were expected and similar to
those seen in other studies involving mice (4, 20). The
wild-type mouse had a carotid pressure of 91 ± 8 mmHg and an
intraventricular pressure of 109 ± 2 mmHg (n = 6)
compared with the transgenic mice, which had a carotid pressure of
99 ± 6 mmHg and an intraventricular pressure of 103 ± 5 mmHg (n = 6).
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Development of cardiac hypertrophy.
The mice used in this study were subjected to hypertrophic stimuli to
examine the effect of targeted PKC- disruption on cardiac hypertrophy. The wild-type heart weight-to-body weight ratio (HW/BW) was 4.1 ± 0.2 and the PKC- KO HW/BW was 4.3 ± 0.6; this
indicated no baseline hypertrophy due to the PKC- deficiency (Table
2). Cardiac hypertrophy was induced by
two different mechanisms: -adrenergic stimulation via Phe injection
and pressure overload via aortic banding. The hearts were removed and
the wet weights were obtained. Both groups of animals had significant
increases in heart weight (Table 2).
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translocation, is illustrated in Fig. 2.
PKC- expression in the membrane fraction increased 35% compared
with baseline saline-treated hearts. Acute physiological response to
this dose of Phe is shown in Fig. 3.
There is an overall stimulation of cardiac performance with heart rate
returning to near-baseline levels at 15 min postinjection; however, the
left ventricular pressure and contractility indexes remain elevated for
a prolonged period. Hearts were examined for gross necrosis and edema
and none was observed. Gross edema was also ruled out by measuring dry
tissue weights, which showed conservation of an increase in HW/BW
independent of being derived by wet or dry weight. Cellular hypertrophy
was confirmed by histological assessment (data not shown).
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Pressure overload-induced cardiac hypertrophy.
Banding of the aorta in control and PKC- KO mice was performed to
induce a hypertrophic response (Table 2). After 7 days of coarctation,
there was a measurable increase in cardiac mass in both wild-type
(HW/BW, 4.1 ± 0.2 at baseline and 5.1 ± 0.1 banded) and
PKC- KO mice (HW/BW, 4.0 ± 0.1 at baseline and 5.8 ± 0.6 banded). There was no significant change in body weight for any of the
animals in either group. The animals that survived the banding
represent ~65% of those banded. Those animals that did not survive
the surgery died 3-4 days postbanding.
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PKC- expression via -galactosidase and
RT-PCR.
Brain and cardiac ventricular tissue sections were obtained from
hypertrophic PKC- KO animals. -Galactosidase staining was readily
apparent in the brain sections and was primarily localized to the
hippocampus (Fig. 5). In comparison,
there was no detectable -galactosidase staining in the heart
sections (data not shown). However, the RT-PCR results in Fig. 5
indicate expression of LacZ mRNA in hearts and brains from PKC- KO
and control animals. Lanes 1-3 are from wild-type
animals and show the absence of LacZ message in both brain and heart
tissue. In contrast, lanes 4-7 are from PKC- KO
brain and heart tissue and show positive expression of the LacZ
message, thereby confirming the expression of PKC- in the adult
murine myocardium. Lane 8 is a positive control for the
RT-PCR method and the results from the same PKC- KO heart sample
minus the reverse transcriptase used in lane 6 are shown in
lane 9. The presence of signal in lane 8 and the
absence of signal in lane 9 demonstrate that the results are
due to RT of mRNA and not contaminating DNA. The high sensitivity of
this technique provided a positive signal in the ventricle and brain
tissue of PKC- KO animals, but no signal was seen in wild-type
tissue.
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Hypertrophic marker: ANF.
Figure 6 illustrates the expression of
ANF in the ventricle of the mouse heart in response to isoproterenol
and Phe. Figure 6 (left) illustrates the ANF expression from
the wild-type ventricle. The left lane demonstrates that
there is a very low level of ANF expression in the ventricle under
normal conditions. When the ventricle is stimulated to hypertrophy,
there is an increase in ANF expression due to both isoflurane (14 ± 2%) and Phe (12 ± 3%) stimulation. Figure 6
(right) shows that the increase in ANF expression in the
ventricle of the PKC- KO heart recapitulates the wild-type response
to isoflurane (15 ± 2%) and Phe (16 ± 5%). These results
indicate that the correlation of cardiac hypertrophy and ANF mRNA is
conserved in mice lacking PKC- expression.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The development and persistence of cardiac hypertrophy under a
multiplicity of conditions involves a cascade of cellular events including G proteins, protein kinases, and transcription factors, many
of which interact in a temporal and spatial manner resulting in a
complex regulatory network. The importance of PKC in the modulation of
cellular processes has been clearly delineated in several model systems
(1-5) and specifically in the heart, the regulation
of PKC expression has been shown to be involved in protection from
ischemia (24) as well as in the induction of cardiac hypertrophy (4). Only recently has the specific
role of particular PKC isoforms in the heart been investigated
(4, 12, 24). Attention has centered on PKC-, which has
been implicated in the preservation of function during ischemic
preconditioning in the adult heart and in phosphorylation of troponin
I. The role of PKC- is less well defined (especially in the adult
heart) although its expression has been linked to cardiac hypertrophy in animals (4) and to heart failure in humans
(3). The goal of the present work was twofold: to
ascertain the extent of PKC- expression in the adult murine
myocardium and to establish whether expression of PKC- is necessary
for the cardiac hypertrophic response. The major results of the study
were the following: 1) using a PKC- KO mouse model, we
have established that expression of PKC- is not necessary for the
development of both quantitative and qualitative features of cardiac
hypertrophy; and 2) PKC- is expressed in the adult mouse
heart albeit at lower levels than in other species.
Characterization of PKC- KO
hearts.
For these studies we chose to use a PKC- gene KO transgenic mouse
model. This approach avoids the question of chemical inhibitor specificity and allows the investigation of specific PKC isoform function. The integrity of the mutated PKC- transgene was checked for its ability to be activated by endogenous transcription signals. The brain has an abundant amount of PKC- (14, 17), and
therefore the brains of the PKC- KO mice should express a high level
of LacZ and be amenable to -galactosidase staining. Figure 5
illustrates -galactosidase staining of brain tissue from a PKC-
KO mouse. The longitudinal section clearly shows specific expression of the LacZ gene in the hippocampus of the brain. This indicates that the
transcription factors for the PKC- gene are functional, and
therefore LacZ is expressed in the same manner as PKC- in the brain.
This is the same in the myocardium as demonstrated by the RT-PCR
results in Fig. 5. These data are significant because PKC-
expression in the adult myocardium has been linked to heart failure
(3), although the positive LacZ results indicate that it
is also present under basal conditions. The baseline hemodynamics of
these mice were measured to rule out any predisposition toward the
development of cardiac hypertrophy and/or any compensatory physiological adaptation due to the absence of the gene. Because PKC- has been shown to be expressed in arterial smooth muscle, it
was conceivable that gene ablation might have altered arterial resistance. As shown in Table 1, there was no overt baseline hemodynamic phenotype present in these mice. There was no difference between the wild-type and PKC- KO control hearts in terms of heart
rate, aortic pressure, or left ventricular pressure and contractility.
These data preclude the hypothesis that there is an alteration in
baseline hemodynamics that would predispose these hearts to develop
heart failure. It does not, however, exclude a predisposition to an
enhanced response to hypertrophic stimuli.
, the other classical
calcium-dependent PKC expressed in the heart is PKC-. Figure 1
illustrates that this isoform is expressed in both wild-type and
PKC- KO murine hearts, and there appears to be equivalent expression
of this isoform. Additionally two members of the novel class of PKCs,
PKC- and PKC-, were identified in hearts. Similar to the results
for PKC-, there was no change in the expression level of either
PKC- or PKC- in the KO hearts. A lack of expression adaptation is
not indicative of a defect in the PKC system as a whole. The PKC system
in these mice is still active and will respond to activation via the
classic mechanism of protein translocation. When activated, PKC
(PKC- in particular) translocated from the cytosolic to the membrane fraction as illustrated in Fig. 2. When the amount of each isoform was
quantitated by reference to a known purified protein standard, it was
apparent that small amounts of PKC- were expressed relative to the
other two isoforms, so it is conceivable that small changes might have
been masked. Although not all of the PKC isoforms were measured in
these hearts, it is apparent from the data represented here that there
was no overt compensatory response to the absence of PKC- in the
heart. We focused on those PKC isoforms of known cardiac importance,
and it is apparent that adult murine hearts haves a similar PKC-isoform
profile yet not at the same level of expression that is seen in other species.
The reports that PKC- is upregulated in human heart failure as well
as indications that PKC- overexpression causes cardiac hypertrophy
in transgenic models suggest that activation of PKC- may be
sufficient to effect the hypertrophic phenotype; however, the question
of necessity remains unanswered. Because the PKC- gene has been
knocked out in the mice used in these studies, this can be addressed by
subjecting the animals to common and robust hypertrophic stimuli such
as pharmacological and surgical interventions. This strategy was used
because these two different stimuli initiate hypertrophic response via
different mechanisms. The data clearly demonstrate no qualitative
difference between wild-type and PKC- KO mice in response to these
stimuli (Table 2). This reveals that PKC- expression is not
necessary for developing cardiac hypertrophy.
This result does not exclude the presence of other, subtler phenotypic
changes. Although morphologically similar, it is conceivable that the
PKC- KO hypertrophic myocytes may differ in function from wild-type
myocytes, particularly as relates to the suggested substrates of
PKC- (ion channels, gene expression, and contraction) (6, 10,
11, 13, 19) and their role in the hypertrophic heart. To begin
to address these issues, we looked at markers of gene expression and
contractility in hypertrophic wild-type and PKC- KO hearts. ANF, a
standard marker of hypertrophy, message was detected in the ventricle
of hypertrophied hearts but not in the untreated hearts. This is
similar to results seen in wild-type hearts and demonstrates that the
classic transcriptional response to a hypertrophic stimuli was
conserved in the PKC- KO hearts.
A final issue relates to the level of PKC expression and isoform
distribution in the heart. This has been controversial, as some
investigators have been able to detect PKC- in adult cardiocytes, whereas others have not. The discordant data may reflect technical issues related to specific antibodies and/or real species differences in isoform expression. Our lab and others have shown that in mice the
isoform is present albeit at low levels. This discrepancy may reflect
technical aspects and/or real species differences. We and others have
established that the PKC- protein is present although at low levels
because it is necessary to load 65-80 ug from a total-heart
homogenate to define a clear signal via Western analysis. This is in
contrast to data derived from other species including rat, rabbit, and
dog. The low concentration of PKC in general in murine hearts raises
questions about species differences, and it is conceivable that larger
animals are more reliant on this signal messenger cascade to effect
phenotypic changes than are smaller animals. It is not yet clear due to
the limited number of studies currently in the literature, but it is
clear that PKC has a role in the developmental process (9)
and this may speak to the hierarchical role of the PKC signaling system
in different species. Pasquet (19a) has demonstrated that
when murine hearts are separated into myocyte and fibroblast fractions
at various stages of development, the apparent decrease in PKC
expression is actually an artifact that is corrected by loading an
equivalent number of cells (as opposed to total protein). It is clear
in these cell-fractionation studies that PKC- is expressed in the myocyte as well as in the fibroblasts, a result that is similar to that
represented here (Fig. 1).
In summary, our data indicate that PKC- is not a necessary factor
for the development of cardiac hypertrophy either in response to
pharmacological stimuli or to pressure-overload methods. Although more
"key" hypertrophic pathways and factors are being continuously elucidated, understanding the complexity of the cardiac hypertrophic response remains elusive and it appears to be the case that no single
factor is necessary. This is an important observation especially as
pharmacological techniques are proposed that target only unique points
of regulation.
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ACKNOWLEDGEMENTS |
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The authors thank Paul H. Goldspink for help and discussions of the RT-PCR experiments and Ron D. McKinney for technical assistance.
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FOOTNOTES |
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This work is supported by National Institutes of Health Grant R01-15498 (to P. M. Buttrick).
Address for reprint requests and other correspondence: B. B. Roman, Dept. of Medicine, Section of Cardiology, Univ. of Illinois at Chicago, 840 S. Wood St. (M/C 787), Chicago, IL 60612 (E-mail: broman{at}uic.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 30 May 2000; accepted in final form 8 December 2000.
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RESULTS
DISCUSSION
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