Age-dependent response of the electrocardiogram to
K+ channel blockers in
mice
Li
Wang,
Shauni
Swirp, and
Henry
Duff
Department of Medicine, University of Calgary, Calgary, Alberta,
Canada T2N 4N1
 |
ABSTRACT |
Developmental changes in electrocardiogram (ECG) and
response to selective K+ channel
blockers were assessed in conscious, unsedated neonatal (days 1, 7, 14) and adult male mice
(>60 days of age). Mean sinus R-R interval decreased from 120 ± 3 ms in day 1 to 110 ± 3 ms in
day 7, 97 ± 3 ms in
day 14, and 81 ± 1 ms in adult
mice (P < 0.001 by ANOVA; all 3 groups different from day 1). In
parallel, the mean P-R interval progressively decreased during
development. Similarly, the mean Q-T interval decreased from 62 ± 2 ms in day 1 to 50 ± 2 ms in
day 7, 47 ± 8 ms in
day 14 neonatal mice, and 46 ± 2 ms in adult mice (P < 0.001 by
ANOVA; all 3 groups are significantly different from
day 1).
Q-Tc was calculated as
Q-
interval.
Q-Tc significantly shortened from
179 ± 4 ms in day 1 to 149 ± 5 ms in day 7 mice
(P < 0.001). In addition, the J junction-S-T segment elevation observed in day
1 neonatal mice resolved by day
14. Dofetilide (0.5 mg/kg), the selective blocker of
the rapid component of the delayed rectifier
(IKr) abolished S-T segment elevation and prolonged Q-T and
Q-Tc intervals in day 1 neonates but not in adult mice.
In contrast, 4-aminopyridine (4-AP, 2.5 mg/kg) had no effect on
day 1 neonates but in adults prolonged
Q-T and Q-Tc intervals and
specifically decreased the amplitude of a transiently repolarizing
wave, which appears as an r' wave at the end of the apparent QRS
in adult mice. In conclusion, ECG intervals and configuration change
during normal postnatal development in the mouse.
K+ channel blockers affect the
mouse ECG differently depending on age. These data are consistent with
the previous findings that the dofetilide-sensitive
IKr is dominant
in day 1 mice, whereas 4-AP-sensitive
currents, the transiently repolarizing
K+ current, and the rapidly
activating, slowly inactivating K+
current are the dominant K+
currents in adult mice. This study provides background information useful for assessing abnormal development in transgenic mice.
mouse heart; development
 |
INTRODUCTION |
PREVIOUS STUDIES have reviewed the electrocardiographic
effects of dominant-negative functional knockouts of the mouse Kv4, Kv1.5, and human ether-a-go-go-related gene (HERG)
K+ channel genes (1, 2, 13). The
Kv4 functional knockout caused a decrease in the transiently
repolarizing K+ current
(Ito) (2),
whereas the Kv1.5 functional knockout decreased the rapidly activating,
slowly inactivating K+ current
(Islow) (13).
Both of these functional knockouts prolonged action potential duration
(APD) and the Q-T interval in adult mice (2, 13). However, the HERG
functional knockout did not prolong APD nor the Q-T interval in adult
mice (1). These data indicate that the Kv4 and Kv1.5
K+ currents contribute
substantially to repolarization in adult mice, whereas HERG
K+ current does not. These data
are also in keeping with previous in vitro studies, indicating that
Ito and
Islow are the
dominant repolarizing K+ currents
in adult mice, whereas the delayed rectifying
K+ current
(IKr) does not
substantially contribute to repolarization in adult mice (20,
21). However,
IKr is the
dominant repolarizing K+ current
in late fetal and early neonatal mice (19, 21). Thus we hypothesized
that developmental changes in the densities and character of
K+ currents could alter the
surface electrocardiogram (ECG) characteristics of the mouse heart.
Although previous studies have reported the character of the
developmental changes in ECGs in rat (6), no previous study has
examined the character of the developmental changes in mouse ECGs.
Because the pattern of expression of various K+ channels varies even among
closely related species, such as the mouse and rat, and because
recombinant mice are being widely used to study structure-function
relationships, the developmental changes in the mouse ECG and its
response to pharmacological agents were assessed. These
electrocardiographic data contribute information for detecting and
understanding the alteration of ECGs in transgenic mice with ionic
channel defects.
 |
METHODS |
FVB mice at the following developmental stages were evaluated:
days 1, 7, and
14 neonatal and male adults >60 days
old. The mice were handled in accordance with our institutional
guidelines for animal use in research. The mice were fed a standard
rodent chow.
Recording ECGs.
Previous studies have reported the character of ECGs in adult
conscious, unsedated mice instrumented with a telemetry devise (15).
However, implantation of the currently available telemetry devise in
day 1 neonatal mice is not feasible
because of its mass. Accordingly a method was devised to record ECGs in
conscious, unsedated neonatal (1, 7, and 14 days old) and adult mice.
Unsedated conscious mice were placed in a custom-designed restraining
tube. Multiple perforations were cut in the tube so that the forelimbs and the hindlimbs would protrude through the perforations. The limbs
were coated with electrocardiographic gel and electrodes were placed on
the surface of the skin. Three standard leads of ECG were recorded
using CV Soft (Calgary, Canada). To minimize stress, mice were
accustomed to the restrainer by placing them in the restrainer for at
least 15 min before obtaining the ECG. Because body temperature of
day 1 neonatal mice drops rapidly toward ambient temperature, ECGs were recorded both at room temperature and in an Isolatte Infant Incubator (Healthdyne, Hatboro, PA). Thus ECG
from all age groups could be recorded at a body temperature of
37°C. Measurements included sinus cycle length (R-R interval), P-R
interval, and Q-T interval. The end of the T wave was measured as time
when the repolarization process returns to the isoelectric point. The
isoelectric point was defined as the position between the end of the P
wave and the beginning of the QRS (5). The definition of the
isoelectric point in this study is compatible with that used in human
electrocardiography (5). Similarly, Mitchell et al. (15) assigned the
end of the T wave as the isoelectric point, which follows a terminal
negative T wave vector in the surface ECGs of mice. The
Q-Tc interval was calculated as
the Q-T/
interval (seconds). The P-R interval was defined as the interval from the beginning of the P wave to the
onset of the QRS.
Statistics.
All data are presented as means ± SE. Statistical significance
among groups was determined using one-way ANOVA.
P < 0.05 was considered
significantly different. To define the difference between the subgroups
compared within ANOVA, such as day 1 neonatal group vs. adult group, the Dunnett's multiple range test was
used. All subgroups were compared.
 |
RESULTS |
Validation of measurements.
One investigator made all initial electrocardiographic measurements.
This investigator was blinded to the developmental stage of the ECG.
Another investigator checked the validity of each measurement, and any
measurement discrepancies were corrected by consensus.
To assess intraobserver variability, three sets of records from each
developmental stage were measured on two separate occasions separated
from each other by at least 48 h. The intraobserver variability was
2.3%.
Effect of temperature on age-dependent changes in ECGs.
Figure
1A
illustrates representative ECG leads I, II, and III recorded from
conscious nonsedated day 1 neonatal
mice at room temperature. We noted that the core body temperature of
day 1 neonates progressively decreased
when the neonatal mouse was separated from siblings and the maternal
mouse and exposed to room temperature. In contrast, the body
temperature of adult mice remained constantly at 37°C. Thus
observed ECG difference between day 1 and adult mice may be simply due to temperature effect but not age.
Therefore in all subsequent experiments neonatal mice were placed in an infant incubator set to control neonatal body temperature to 36.5 ± 0.5°C. Figure 1, B and
C, displays the representative ECGs of day 1 neonatal mice recorded at a body
temperature of approximately 37°C and adult mice, respectively.

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Fig. 1.
Representative electrocardiograms (ECGs) in leads I, II, and III
recorded from conscious 1-day-old and adult mice at room temperature
(RT) and 37°C. In day 1 neonates
heart rate was 208 beats/min at room temperature
(A) but increased to 432 beats/min
with a significant shortening of P-R, R-R, and Q-T intervals at
37°C (B). However, changing body
temperature did not alter configuration of day
1 neonatal ECGs (B),
which was distinguished from adult mouse ECGs
(C) in many aspects as described in
text.
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Progressive age-dependent changes in mouse ECGs.
Figure 2A
illustrates developmental changes in ECGs in lead I recorded at four
developmental stages: neonatal days 1, 7, and 14 and adult
mice, and the arrows indicate the end of the T waves for each example
measurement. Progressive changes in the configuration of the J
junction-S-T segment-T wave complex are shown in the boxes in Fig.
2A. Elevation of the J junction and
the plateau portion of the S-T segment was observed in
day 1 mice. The entire J junction-S-T
segment-T wave complex shortens during development. In
addition the elevation of the plateau portion of the S-T segment-T wave
complex seen in day 1 animals resolves
by day 14. In adult mice much of the
repolarization process is truncated to a large transient repolarizing
wave (TRW), which appears as an r' wave at the end of the
apparent QRS. The TRW is evident in ECGs from day
14 mice but increases in magnitude and becomes shorter
in duration in the adult mice.

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Fig. 2.
Representative ECGs of lead I recorded from conscious mice at 4 developmental stages: days 1, 7, 14 neonatal and adult mice. A: ECGs
illustrate representative examples of ECGs recorded in
days 1, 7, 14 neonatal and adult mice.
Arrows indicate end of Q-T intervals for each developmental stage.
Expanded view of J junction-S-T segment-T wave complex is shown in
boxes. Day 1 mouse shows elevation of
J junction and elevation of plateau portion of S-T segment. J
junction-S-T segment-T wave complex in day
14 and adult mice shows resolution of elevation of
plateau phase of S-T segment to near isoelectric values.
B: progressive developmental
shortening of mean R-R, P-R, Q-T, and
Q-Tc intervals
(n 8 for each group).
* Significant difference compared with day
1 by ANOVA and Dunnett's multiple range test.
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The mean R-R, P-R, Q-T and Q-Tc
intervals observed during normal development are shown in Fig.
2B. Progressive and significant shortening of R-R interval was observed comparing measurements at
day 1 to measurements at all other
developmental stages (P < 0.01).
However, there was no significant difference comparing R-R intervals at
14 days old to adult mice. In parallel with the changes in R-R
intervals, there were significant changes in the P-R intervals during
normal development (Fig. 2B).
Although significant differences were noted comparing
day 1 to adult mice, no significant decrease was observed comparing data from day
14 to adult mice. In addition the mean Q-T intervals
significantly decreased comparing data from day
1 mice to any other developmental stage; however, there
was no difference comparing Q-T interval in day
7 and 14 to adult mice
(Fig. 2B). The
Q-Tc interval significantly
decreased comparing day 1 and
day 7 mice; however, there was no
subsequent significant developmental change. Specifically the
Q-Tc interval was not
significantly different comparing values in days
7 and 14 and adult mice.
Q-T intervals at matched R-R intervals in neonatal and adult mice.
To assess whether developmental changes in P-R and Q-T intervals were
predominantly due to the slower mean heart rate of the early neonates,
we compared neonatal mice with unusually fast sinus rates (cycle length
less than 100 ms) to adult mice with comparable sinus cycle lengths.
Figure 3 shows an example of ECG records
from such a day 1 neonate and an adult
mouse. At a similar sinus cycle length, the Q-T interval was longer in
day 1 (n = 2) vs. adult
(n = 2). In addition, the
morphological differences as previously described were still present
comparing neonatal and adult mice. These data indicate that the
developmental changes in Q-T intervals are present even at matched
cycle lengths. These data also parallel the changes in
Q-Tc interval, which is another method to correct for changes in R-R interval. These data indicate that
developmental changes in Q-T interval occur independent of changes in
heart rate.

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Fig. 3.
ECGs obtained from day 1 neonatal and
adult mice with similar heart rates. Examples of ECGs recorded in
day 1 neonatal mouse with unusually
rapid heart rate is compared with ECG of adult mouse at virtually
matched sinus heart rates. P-R and Q-T intervals were longer in
day 1 neonate even at heart rates
equivalent to that of adult. Ends of the Q-T intervals are shown by
arrows.
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Effects of selective
K+ channel
blockers on ECGs in neonatal and adult mice.
Previous in vitro studies have reported that
IKr is the
dominant repolarizing current in fetal and early neonatal mice, whereas Ito and
Islow are the
dominant repolarizing currents in adult mice (19-21). To assess
the functional role of these K+
currents on cardiac electrical activities in vivo, we treated day 1 and adult mice with the
selective IKr
blocker dofetilide (7) and the selective
Ito and
Islow blocker
4-aminopyridine (4-AP) (22).
After dofetilide (0.5 mg/kg ip) was given, ECGs were recorded from
day 1 and adult mice at 5, 10, 15, and
20 min. Figure 4, A and
B, shows representative ECGs recorded
from day 1 neonatal mice and Fig.
4C is adult mice at baseline and after
exposure to dofetilide. Before dofetilide treatment, an elevation of
the baseline J junction-S-T segment-T wave complex is shown as the striped area in the top box in Fig.
4A. Dofetilide treatment reversed the
elevation of the plateau portion of the S-T segment to an isoelectric
position as shown in the bottom box of Fig.
4A. This dofetilide-induced change in
configuration appeared 5 min after treatment, persisted for more than 2 h, and fully recovered within 16 h. In addition, Mobitz 1, Wenckebach
block was observed in some day 1 neonates treated with dofetilide (in 25% of records, Fig.
4B). Dofetilide did not
substantially change the ECG configuration and intervals in adult mice
(Fig. 4C). Figure
5 shows the effect of dofetilide on mean
ECG intervals. Dofetilide prolonged R-R, Q-T and
Q-Tc intervals in
day 1 neonates (Fig.
5A) but not in adult mice (Fig.
5B). In day
1 mice, dofetilide prolonged
Q-Tc interval from 181 ± 4 ms
at baseline to 196 ± 6 ms (n = 6, P < 0.05).

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Fig. 4.
Effects of dofetilide, a selective delayed rectifying
K+ current
(IKr) channel
blocker on ECGs recorded from day 1 and adult mice. A: representative ECG
before and after dofetilide (0.5 mg/kg ip) in day
1 neonatal mouse. Dofetilide substantially suppressed
plateau of S-T segment in day 1 mouse
as shown in boxes. B: illustrative
example of dofetilide-induced Wenckebach in day
1 neonatal mice. However dofetilide at same dose did
not affect ECGs in adult mice (C).
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Fig. 5.
Effects of dofetilide on mean ECG intervals in day
1 neonatal and adult mice. Mean R-R, P-R, Q-T, and
Q-Tc intervals before and after
treatment with dofetilide (0.5 mg/kg ip) are shown for
day 1 neonates
(A) and for adults
(B). * Change that is
significantly different from control
(n = 4 for each group).
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|
Figure 6 shows representative examples of
the effects of 4-AP (2.5 mg/kg ip) on ECGs of both day
1 and adult mice. ECGs were recorded at 5, 10, 15, and
20 min after 4-AP treatment. In day 1 neonatal mice, 4-AP had no significant effect on the configuration of
the QRS-T complex (Fig. 6A) for up
to 20 min following injection. In contrast, 4-AP changed the
configuration of the QRS-T complex in adult mice (Fig.
6B). Specifically, 4-AP reduced the
amplitude and widened the duration of the TRW shown in the striped area (Fig. 6B, bottom box). These data
indicate that 4-AP-sensitive currents contribute to TRW. The effect of
4-AP on mean electrocardiographic intervals is shown in Fig.
7A for
day 1 neonatal mice and in Fig. 7B for adult mice. 4-AP prolonged Q-T
and Q-Tc intervals in adult animals but had no effect on neonatal day
1 mice. In adult mice, 4-AP prolonged
Q-Tc interval from 155 ± 4 ms
at baseline to 177 ± 4 ms (P < 0.05, n = 6).

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Fig. 6.
Effects of 4-aminopyridine (4-AP), a selective transiently repolarizing
K+ current and slowly inactivating
K+ current channel blocker on ECGs
recorded from day 1 neonate and adult
mice. Effects of 4-AP (2.5 mg/kg) on representative ECGs in
day 1 neonate and adult mice are
shown. 4-AP had no effect on ECG configuration in day
1 neonatal mice (A).
In contrast, in adult mice 4-AP decreased amplitude of transient
repolarizing wave as shown in boxes
(B).
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Fig. 7.
Effects of 4-AP on mean ECG intervals in day
1 neonatal and adult mice. Mean R-R, P-R, Q-T, and
Q-Tc intervals during control and
after treatment with 4-AP are shown for day
1 neonates (A) and
for adults (B). * Change that
is significantly different from control
(n = 4 for each group).
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|
We cannot exclude that developmental differences in absorption,
distribution, and metabolism of the dofetilide and 4-AP could contribute to differences in the pharmacological response.
 |
DISCUSSION |
The new findings of this study include
1) a method was devised that allows
noninvasive measurements of ECGs in conscious, unsedated mice at
various ages of development; 2)
significant changes in the configuration of the J junction-S-T
segment-T wave complex, and the R-R, P-R, Q-T, and
Q-Tc intervals were observed during normal postnatal development;
3) a dofetilide-sensitive current,
likely IKr,
appears to contribute to spatial gradients that result in elevation of
the plateau portion of the S-T segment in day
1 neonatal mice; 4)
4-AP-sensitive currents appear to contribute to the TRW in adult mice.
S-T segment elevation in neonatal day 1 mouse ECG.
The surface ECG is a useful, nontraumatic method to obtain information
about depolarization and repolarization of the heart in intact animals
and humans. During depolarization of the heart an activation wave
propagates through the heart, creating a potential difference between
depolarized and not-yet-depolarized areas of the heart. The potential
differences seen during activation of the heart have been represented
as a moving depolarizing dipole vector of variable magnitude and
direction. After depolarization the cells repolarize, again as a
propagation wave, creating a repolarizing dipole vector. The direction
and magnitude of the repolarization vector are determined by the
spatial gradients of action potential configurations (4-8). Action
potential is shorter in the epicardium than the endocardium in many
species, resulting in a upright T wave (4-8). S-T segment
elevation can result from multiple causes, including congenital
abnormalities of the sodium channel such as the Brugada syndrome (8, 9) and some class 1C drugs (12) and transmural ischemia (10, 16).
The available data suggest that loss of the action potential dome in
right ventricular epicardium but not endocardium underlies the S-T
segment elevation associated with Brugada syndrome. Similarly, using
simulations Wohlfart (23) reconstructed S-T segment elevation by
calculating differences between subendocardial and epicardial action
potentials. Indeed spatial heterogeneity of action potential configurations appears to be the common underlying mechanism of S-T
segment elevation.
Day 1 neonatal mice manifest elevation
of the J junction and a plateau phase of the S-T segment-T wave
complex. One possible mechanism of S-T segment elevation in
day 1 neonatal mouse heart is the
presence of a gradient of unopposed depolarizing forces early during
the action potential. In day 1 neonatal mouse,
IKr is the
dominant repolarizing current. However,
IKr
characteristically manifests a substantial latency to activation.
Therefore early in the action potential the depolarizing currents are
unopposed by any substantial repolarizing forces. During the first 2 wk of normal development a progressive resolution of this elevation in the
J junction-S-T segment-T wave complex occurs. Over this same time the
density of Ito
increases progressively. The
Ito activates
very rapidly and thus can oppose the depolarizing forces. Thus the S-T
segment elevation in day 1 neonates
may result from gradients of unopposed depolarizing forces and
developmental resolution of the S-T segment elevation may result from a
greater balance of repolarizing and depolarizing forces early in the
action potential. However this mechanism cannot explain how dofetilide
resolves the S-T segment elevation in day
1 neonatal heart. Indeed, pharmacologically inhibiting
IKr might be
expected to leave more of the initial depolarizing forces unopposed and
thus might be expected to exaggerate S-T segment elevation.
Our working hypothesis is that spatial gradients in the balance of
depolarizing versus repolarizing currents likely contributes to the
elevation of the J junction-S-T segment complex and may explain the
response to dofetilide. Suppose that dofetilide is the dominant
repolarizing current in most day 1 neonatal ventricular myocytes but not in one particular region of the
mouse heart (say the endocardium). Indeed we have reported that the
dofetilide-sensitive IKr is the
dominant repolarizing current in most ventricular cardiac myocytes but
that the APD of some endocardial cells are substantially different,
suggesting a different balance of depolarizing and repolarizing
currents in these cells (19, 21). When dofetilide blocks
IKr in most of
the day 1 neonatal myocytes it may
spatially homogenize action potential repolarization and thus decrease
the spatial voltage gradient that leads to J junction-S-T segment elevation. However, no experimental study has evaluated spatial heterogeneity of action potentials in neonatal heart, so this explanation is speculative.
Transiently repolarizing wave in adult mouse ECG.
A transiently repolarizing wave appears as an r' wave at the end
of the apparent QRS complex and is a dominant repolarizing vector in
the ECGs of adult mice. The evidence that the TRW is a part of the
repolarization includes 1) the
timing of the TRW would temporally align with phase
1 repolarization and
Ito is responsible for phase 1 repolarization
in many species and is the dominant repolarizing current in adult mice
(22); 2) 4-AP blocks
Ito and
Islow in vitro
(21) and decreases the magnitude and slows the time course of the TRW
in vivo; 3) our conviction that
Ito contributes
to the TRW is supported by the data in Fig. 5 of the study by Barry et
al. (2) that shows that the Kv4 functional knockout results in a
decrease in the amplitude and slowing of the time constant of the TRW.
From these data we conclude that the
Ito contributes
to the TRW in vivo.
Developmental changes in Q-Tc intervals
and Q-T intervals at matched R-R intervals in neonates and adults.
Previous studies have reported developmental shortening of APD at
matched cycle lengths (20, 21). In the present study, developmental
shortening in mean sinus R-R interval is a confounding factor to an
assessment of whether developmental Q-T interval shortening was due to
an intrinsic shortening of APD or due to more rapid heart rates. To
address this issue we calculated the rate-corrected Q-T interval
(Q-Tc) and compared the ECGs of
day 1 neonatal mice with unusually
rapid heart rates to adult mice at matched rates. The two methods for
rate correction provide similar results. Q-T interval in adults was
shorter than in neonates even at matched sinus R-R intervals. Similarly
the Q-Tc interval was
significantly shorter in adults than neonates. These data provide
evidence that the developmental shortening of the Q-T interval is at
least in part related to intrinsic shortening of APD.
Relevance of these data to
K+ channel
knockout mice.
Transgenic and knockout mouse models allow an assessment of the
physiological sequelae of over- or underexpression of gene products or
the sequelae of changes in the structure of a protein. Transgenic
knockout mice may provide insights into the contribution of ion
channels to normal growth and development. Before a study of transgenic
mice, it is necessary to understand the correspondence between the
currents underlying the action potential and the ECG waves recorded
from the body surface. The method reported herein will allow recording
of ECGs in conscious, unsedated mice and thus can avoid the potential
confounding effects of anesthetic drugs, instrumentation, or signal
averaging on the ECG. The present study provides insights for studying
transgenic mouse with altered K+
channel expression in the heart. For example, 4-AP-mediated reductions in Ito and
Islow result in a
reduction in the amplitude of the TRW. This information may be helpful
for recognizing phenotypes of appropriate functional knockouts.
In conclusion, changes in the ECG morphology and changes in R-R, P-R,
Q-T, and Q-Tc intervals occur
during normal development in mice. Electrocardiographic responses to
K+ channel blockers differ
dependent on developmental age in mice.
 |
ACKNOWLEDGEMENTS |
We thank Dr. H. E. D. J. ter Keurs and Alan Davidoff for helpful suggestions.
 |
FOOTNOTES |
This work was funded by the Medical Research Council of Canada Grant
CBBA-18083 and by the Canadian Heart and Stroke Foundation and the
Andrew's Family Professorship for Cardiovascular Research .
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: H. J. Duff,
Dept. of Medicine, Univ. of Calgary, 3330 Hospital Dr., NW, Calgary,
Alberta, Canada, T2N 4N1 (E-mail: hduff{at}ucalgary.ca).
Received 29 April 1999; accepted in final form 27 August 1999.
 |
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