Hypoxia tolerance and preconditioning are not additive in the trout (Oncorhynchus mykiss) heart
1 Department of Biology, Portland State University, PO Box 0751, Portland,
OR 97207-0751, USA
2 Department of Biological Sciences, Idaho State University, Pocatello, ID
82309-8007, USA
* Author for correspondence at present address: Ocean Sciences Center, Memorial University of Newfoundland, St John's, NF, Canada A1C 5S7 (e-mail: kgamperl{at}mun.ca)
Accepted 26 April 2004
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Summary |
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Key words: rainbow trout, Oncorhynchus mykiss, myocardial hypoxia, stretch, hypoxia tolerance, functional recovery
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Introduction |
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However, the importance and indeed existence of preconditioning in
hypoxia-tolerant vertebrate hearts is unclear. Ischaemic preconditioning
failed to improve contractile function following 40 min of global ischaemia in
hypoxia-tolerant neonatal rat hearts (1 or 4 days post-partum), and only
slightly (by 7%) improved contractile function in relatively hypoxia-sensitive
rat hearts tested 7 days post-partum
(Ostadalova et al., 1998).
Further, Baker et al. (1999
)
showed that hearts from 710-day-old rabbits that were reared in a
hypoxic environment (12% oxygen) developed a degree of myocardial
ischaemia-tolerance (60% recovery of contractile function following 40 min of
ischaemia), and no longer experienced increased functional recovery in
response to preconditioning. In contrast, both Tajima et al.
(1994
) and Neckár et
al. (2002
) demonstrated that
although hearts from chronically hypoxic adult rats had increased resistance
to ischaemia-related damage, preconditioning conferred an additional amount of
protection. These results question whether long-term and short-term mechanisms
of ischaemic protection in the mammalian heart share the same signal
transduction pathways and end-effectors, and whether the relationship between
inherent hypoxia/ischaemia tolerance and preconditioning is fundamentally
different between life stages.
The rainbow trout is generally considered to be a hypoxia-sensitive fish
species (Gesser, 1977;
Dunn and Hochachka, 1986
;
Gamperl et al., 2001
).
However, Faust et al. (2004
)
recently identified a group of rainbow trout with a significant degree of
inherent myocardial hypoxia tolerance. For example, hearts from these trout
required twice the duration of severe hypoxia (15 min vs 30 min) and
5 times the workload during hypoxia (output pressure 1 kPa vs 5 kPa)
to get the same amount of post-hypoxic loss (25%) of function as in Gamperl et
al. (2001
). In the present
study, we used an in situ heart preparation as a comparative model to
investigate whether (1) hypoxic preconditioning can improve post-hypoxic
myocardial functional recovery in these trout, i.e. whether the protection
afforded by inherent hypoxia tolerance and preconditioning are additive; and
(2) whether stretch and exposure to low levels of adrenaline confer any
protection against hypoxia-related myocardial dysfunction.
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Materials and methods |
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Surgical procedures
All procedures were approved by the Animal Care Committee at PSU, and
conformed with the Guide for the Care and Use of Laboratory Animals published
by the US National Institutes of Health (NIH Publication No. 85-23, revised
1996). Trout were anaesthetized in an oxygenated, buffered, solution of
tricaine methane sulfonate (0.1 g l-1 MS-222; 0.1 g l-1
sodium bicarbonate) and transferred to an operating table where their gills
were irrigated with a maintenance level of oxygenated and buffered anesthetic
(0.05 g l-1 MS-222; 0.05 g l-1 sodium bicarbonate) at
46°C. Fish were then injected with 1.0 ml of heparinized (100 i.u.
ml-1) saline via the caudal vessels, and an in
situ heart preparation was obtained as detailed in Farrell et al.
(1986). Briefly, an input
cannula was introduced into the sinus venosus through a hepatic vein and
perfusion with heparinized (10 i.u. ml-1) saline containing 5 or 15
nmol l-1 adrenaline (see Experimental protocols) was begun
immediately. Silk thread (30) was then used to secure the input cannula
in place, and to occlude any remaining hepatic veins. An output cannula was
inserted into the ventral aorta at a point confluent with the bulbus
arteriosus and firmly tied in place with 1-O silk thread. Finally, silk
ligatures (1 silk) were tied around each ductus Cuvier to occlude these veins
and to crush the cardiac branches of the vagus nerve. This procedure left the
pericardium intact, while isolating the heart in terms of saline and autonomic
nervous inputs and outputs.
The saline used to perfuse the heart contained (in mmol l-1):
124 NaCl; 3.1 KCl; 0.93 MgSO47H2O; 2.52
CaCl22H2O; 5.6 glucose; 6.4 TES salt; and 3.6 TES acid
(Keen et al., 1993). These
chemicals were purchased from Fisher Scientific (Fair Lawn, NJ, USA), with the
exception of the TES salt, which was purchased from Sigma Chemical Co. (St
Louis, MO, USA). The TES buffer system was used to simulate the buffering
capacity of trout plasma, and the normal change in blood pH with temperature
(pKa/dT=0.016 pH units °C-1)
(Keen et al., 1993
).
Adrenaline bitartrate (5 or 15 nmol l-1; Sigma Chemical Co.) was
added to the perfusate throughout the experiments, to ensure the long-term
viability of the perfused trout heart
(Graham and Farrell, 1989
).
The saline was bubbled with 100% O2 for a minimum of 45 min prior
to use. Although the coronary circulation was not perfused, prior research
shows that this level of oxygenation can supply sufficient O2 to
the outer myocardium such that the maximum performance of the in situ
heart is comparable (Farrell et al.,
1986
) and perhaps even higher
(Farrell et al., 1991
) than
that measured in vivo. For the hypoxic exposures, the perfusate was
bubbled with 100% N2 for a minimum of 2 h prior to the experiments
to ensure that PO2 was 510 mmHg (1
mmHg=0.133 kPa). Potential oxygen transfer from the experimental bath to the
heart was minimized by covering the bath with a loose fitting plastic lid, and
by bubbling 100% N2 into the bath beginning 5 min prior to the
onset of hypoxia.
Experimental protocols Experiment 1: Can hypoxia-tolerant trout hearts be preconditioned?
This experiment examined whether 5 min of hypoxic pre-exposure could
improve myocardial functional recovery following 30 min of severe hypoxia, and
each treatment protocol was separated into three main sections: (1)
stabilization and maximum cardiac function test 1
(MAX1); (2) the
experimental period; and (3) recovery and
MAX2. All cardiovascular
variables (input pressure, PIN; output pressure,
POUT; cardiac output,
) were manipulated in an identical
manner during the initial and final portions of each treatment. However, the
treatments were unique in terms of the number of severe hypoxia periods
administered during the experimental period (see
Fig. 1).
|
Stabilization and MAX1
Once the fish was placed into the experimental bath and connected to the
perfusion apparatus, PIN was set to achieve a
physiologically relevant (1617
ml min-1 kg-1;
Kiceniuk and Jones, 1977
), and
POUT was maintained at 1 kPa for 5 min. Thereafter,
POUT was raised to 5 kPa, a level comparable to in
vivo arterial pressures (Kiceniuk and
Jones, 1977
). After allowing the heart to stabilize at a
POUT of 5 kPa for 5 min, PIN was
gradually increased until
reached 30
ml min-1 kg-1. This initial cardiac stretch, which was
maintained for 20 s, allowed any air bubbles to be cleared from within the
heart and provided an initial assessment of cardiac viability. Hearts were
discarded if they required more than a 0.3 kPa increase in
PIN to reach a
of
30 ml min-1 kg-1, and were assumed to have poor cannula
placement, cannula obstruction or cardiac damage.
Following the cardiac stretch, all hearts were maintained at a
of 1617 ml min-1
kg-1 for 20 min before their initial maximum cardiac output
(
MAX1) was determined.
Maximum cardiac output
(
MAX) was achieved by
increasing PIN in a stepwise fashion from that required to
achieve resting
to 0.3 kPa, to 0.4
kPa, and finally to 0.45 kPa (Fig.
1). Each stepwise increase in PIN was
maintained for approximately 20 s, and resting
was quickly re-established after
MAX was reached. The entire
MAX test took approx. 5 min
to complete. After
MAX1 was
measured, hearts were randomly assigned to a treatment group.
Experimental period
In situ trout hearts were exposed to one of four experimental
treatments: (A) control (oxygenated perfusion) (N=7), (B) 5 min of
severe hypoxia (N=7), (C) 30 min of severe hypoxia (N=8) or
(D) 5 min of severe hypoxia (preconditioning) followed 20 min later by 30 min
of severe hypoxia (N=8) (Fig.
1). Throughout the experimental period, POUT
was set at 5.0 kPa. A period of 30 min, with POUT left at
5 kPa, was chosen as the main hypoxic insult because Faust et al.
(2004) showed that this results
in an approx. 25% reduction in maximum cardiac function
(
; stroke volume,
VS) in this population of trout, and we wanted
post-hypoxic myocardial function after the main hypoxic period to be similar
to that experienced by the hearts in Gamperl et al.
(2001
). This similarity in
post-hypoxic myocardial function allowed for a direct comparison on the
preconditioning effects of 5 min of hypoxia in hypoxia-sensitive
(Gamperl et al., 2001
)
vs hypoxia-tolerant (present study) trout hearts. During all periods
of oxygenated perfusion
was
maintained at a resting level of 1617 ml min-1
kg-1 body mass by adjusting PIN. However,
PIN was not increased to maintain
during severe hypoxia because Faust
et al. (2004
) showed that the
in situ hearts failed to regain contractile function when an attempt
was made to maintain pre-hypoxic workloads.
Recovery and MAX2
Immediately following the 30 min hypoxic period, the in situ heart
was perfused with oxygenated saline, and a resting
of 1617 ml min-1
kg-1 was quickly restored (within 24 min). This was
accomplished by setting POUT at a subphysiological level
(1 kPa) and gradually increasing PIN. Following this 10
min period of reduced after-load, POUT was restored to 5.0
kPa and the heart was allowed to recover for 20 min before the final maximum
cardiac output test (
MAX2)
was administered (Fig. 1). This
test was performed using the same procedures as described for the
MAX1 test.
Experiment 2: Validation of preconditioning protocol.
In mammalian studies it has been shown that the stimulation of - and
ß-adrenergic receptors (Bankwala et
al., 1994
; Lochner et al.,
1999
; Yabe et al.,
1998
) and stretch (Ovize et
al., 1994
) can precondition the myocardium. Because the hearts in
Experiment 1 were volume-loaded prior to the preconditioning stimulus (at the
stretch and during
MAX1,
see Fig. 1), and the perfusate
contained 15 nmol l-1 adrenaline, we wanted to ensure that the lack
of preconditioning in these hypoxia-tolerant hearts was not due to inadvertent
preconditioning (Kloner et al.,
1995
). Therefore, we determined the minimum adrenaline
concentration at which myocardial viability could be maintained long-term (5
nmol l-1), and then repeated the preconditioning experiment without
the initial stretch or
MAX1. In this experiment
(Fig. 2), each treatment
protocol was only divided into two main sections: (1) stabilization and
experimental period and (2) recovery and
MAX. All other
methodological details were the same as in Experiment 1.
|
Data collection and analysis
Cardiac function was continuously monitored throughout each experiment by
measuring , PIN and
POUT. Cardiac output (ml min-1) was measured
using a Model T206 small animal blood flow meter in conjunction with a
pre-calibrated in-line flow probe (2 N, Transonic Systems Inc., Ithaca, NY,
USA). Gould Statham pressure transducers (P23 ID, Oxnard, CA, USA) were used
to measure PIN and POUT. Signals from
the Transonic® flow meter and the pressure transducers were
amplified and filtered using a Model MP100A-CE data acquisition system (BIOPAC
Systems Inc., Santa Barbara, CA, USA). The acquired signals were then analyzed
and stored using Acqknowledge Software (BIOPAC Systems Inc.). Heart rate
(fH) was calculated by measuring the number of systolic
peaks during a 2030 s interval and stroke volume
(VS) was calculated as
/fH.
Statistics
All statistical analyses were performed using StatView Software (SAS
Institute Inc., Cary, NC, USA). One-way ANOVAs, followed by Fisher's protected
least significant difference (PLSD) post hoc tests, were used to
compare parameters between the treatment groups, including: (1) body and
ventricular mass; (2) resting cardiac function
(, VS and
fH) prior to
MAX1 in Experiment 1; (3)
maximum cardiac function (
,
VS and fH) at
MAX1 in Experiment 1; (4)
the percentage change in maximum cardiac performance
(
MAX2 vs
MAX1) in Experiment 1; (5) the
percentage change in resting PIN prior to
MAX1 vs
MAX2 in Experiment 1; and (6)
maximum cardiac function (
,
VS and fH) at
MAX in Experiment 2.
Repeated-measures ANOVAs were performed for comparisons of (1) maximum
myocardial performance
(
MAX1 vs
MAX2) within each treatment
group in Experiment 1; (2) the loss of cardiac function
(
and fH) during
30 min of severe hypoxia between the treatment groups in Experiment 1; and (3)
resting PIN (prior to
MAX2 vs prior to
MAX1) within each treatment
group in Experiment 1. All percentage data were arc-sine transformed prior to
running any statistical tests. The level of statistical significance used in
each analysis was P<0.05, and data reported in the text, figures
and tables represent means ± S.E.M.
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Results |
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Experiment 1
Initial cardiac function under oxygenated conditions
Prior to MAX1, resting
was maintained at 16.9±0.2 ml
min-1 kg-1 (Table
1), using a PIN of 0.15±0.03 kPa
(Fig. 3). At this resting
, fH was
66.4±3.4 beats min-1 and VS was
0.26±0.01 ml kg-1 (Table
1). In situ hearts in the 30 min of severe hypoxia
treatment had a significantly higher resting VS (by
0.050.07 ml kg-1) as compared with the other treatment
groups, probably due to their marginally lower fH
(P<0.09) (Table 1).
However, there were no significant differences in
(55.5±2.8 ml min-1
kg-1), VS (0.99±0.05 ml
kg-1), or fH (56.5±2.3 beats
min-1) between groups at
MAX1
(Fig. 5A).
|
|
|
Cardiac function during severe hypoxia
Cardiac output decreased by 34.5% (Fig.
4) during the 5 min of hypoxic pre-exposure (preconditioning).
However, 5 min of hypoxic pre-exposure (preconditioning) had no effect on the
loss of cardiac function during the subsequent 30 min period of severe
hypoxia. Resting decreased by 79.5%
(Fig. 4), and
fH and VS fell by 41% and 61.4%,
respectively (data not shown). These data indicate that: (1) myocardial
function during the main hypoxic challenge was not altered by 5 min of hypoxic
pre-exposure; and (2) any effects of hypoxic pre-exposure on post-hypoxic
maximum myocardial function were not the result of differences in cardiac
workload during severe hypoxia.
|
Cardiac function following severe hypoxia
The PIN required to maintain a resting
of 1617 ml min-1
kg-1 increased significantly in all groups (by 0.08 kPa to 0.14
kPa) over the duration of the experiment
(Fig. 3A). Maximum
fH also increased slightly following the control treatment
(by 3.4±1.4 beats min-1;
Fig. 5A). However, there were
no significant differences between the changes in resting
PIN or maximum fH when all groups were
compared (Figs 3B and
5B, respectively). Maximum
VS fell slightly over the course of the experiment in both
the control (by 0.05±0.01 ml kg-1) and the 5 min of hypoxic
pre-exposure (preconditioning) treatments (by 0.09±0.02 ml
kg-1) (Fig. 5).
However, it is unlikely that these changes were the result of reduced
myocardial function because the reduction in maximum VS
was slight (approx. 59%), and there was no significant decrease in
MAX following either of
these two treatments. 30 min of severe hypoxia significantly decreased
MAX (by approx.
1520%), independent of whether the hearts were pre-exposed to 5 min of
severe hypoxia (Fig. 5).
Further, the decrease in maximum VS in the group
pre-exposed to 5 min of severe hypoxia was significantly greater (by 7.5%)
when compared with the group only exposed to 30 min of severe hypoxia.
Experiment 2
Prior to the determination of maximum cardiac output
(MAX), the
PIN required to maintain resting cardiac output was not
significantly different between treatments, and averaged
0.03±0.020 kPa. In the control group
MAX, VS
and fH at the end of the protocol averaged 62.5±4.3
ml min-1 kg-1, 1.2±0.1 ml kg-1 and
51.4±2.0 beats min-1, respectively. Exposure to 5 min of
severe hypoxia (preconditioning) alone had no significant effect on any
cardiovascular parameter. In addition, preconditioning with 5 min of hypoxia
failed to prevent the approx. 2530% decrease in both
MAX and
VS that followed the 30 min period of exposure to hypoxia
(Fig. 6).
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Discussion |
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Two previous studies looking at neonatal/immature mammals have also shown
that ischaemic pre-exposure (preconditioning) fails to protect the recovery of
contractile function in hypoxia-tolerant hearts. First, preconditioning did
not improve functional recovery in inherently hypoxia-tolerant neonatal
(14 days post partum) rat hearts, following 4060 min of
ischaemia (Ostadalova et al.,
1998). Second, preconditioning failed to improve contractile
function, following 30 min of ischaemia, in neonatal rabbit hearts (710
days post partum) that were exposed to a hypoxic environment (12%
O2) from birth (Baker et al.,
1999
). The data from these two studies suggests that the cellular
pathways and/or end-effectors that confer protection against ischaemic/hypoxic
damage are maximally stimulated in hypoxia/ischaemia-tolerant hearts, and
support the results for rainbow trout generated in this study. However,
studies on adult mammalian hearts do not support this conclusion. Both Tajima
et al., (1994
) and
Neckár et al. (2002
)
demonstrated that although hearts from chronically hypoxic adult rats had
increased resistance to ischaemia-related damage, preconditioning conferred an
increased amount of protection. Taken together, these results suggest that the
relationship between inherent hypoxia tolerance and the ability to be
preconditioned in lower vertebrates and neonatal/immature mammals is similar,
but that these two groups differ as compared with adult mammals. Numerous
mechanisms and signal transduction pathways appear to be involved in
preconditioning the mammalian heart
(Lawson and Downey, 1993
;
Parratt, 1995
;
Yellon et al., 1998
;
Baines et al., 1999
;
Okubo et al., 1999
;
Nakano et al., 2000
;
Yellon and Downey, 2003
).
Thus, it is possible that inherent hypoxia tolerance in lower vertebrates and
neonatal/immature mammals is associated with stimulation of all the signal
transduction pathways that are shared with preconditioning, while in adult
mammals only a portion of them are stimulated by exposure to chronic hypoxia.
Clearly, this is a hypothesis that warrants further investigation.
Although there appear to be differences in how inherently hypoxia/ischaemia
tolerant fish, neonatal/immature mammal and adult mammal hearts respond to
preconditioning, our results are in line with those of both Baker et al.
(1999) and Neckár et al.
(2002
), who showed that the
level of protection achieved by the combination of hypoxic adaptation and
preconditioning in the mammalian heart was not additive (i.e. there was no
increase in the total capacity of myocardial protective mechanisms). Thus, our
results suggest that the non-additivity of these two forms of myocardial
protection is a common feature of vertebrate hearts.
Alternative explanations for the failure of 5 min of hypoxic pre-exposure
(preconditioning) to improve cardiac function following 30 min of severe
hypoxia include: (1) 5 min ofhypoxia was an insufficient period of time to
elicit a preconditioning response in these trout hearts; and/or (2) these
in situ hearts were inadvertently preconditioned due to myocardial
stretch and/or exposure to adrenaline. However, we are confident that 5 min of
hypoxia was a sufficient stimulus to precondition these in situ trout
hearts. Several mammalian experiments have demonstrated that 5 min of either
hypoxia or ischaemia are equipotent in their ability to protect the heart from
ischaemia-induced contractile dysfunction
(Lasley et al., 1993;
Zhai et al., 1993
) and cardiac
infarction (Shizukuda et al.,
1992
). 5 min of hypoxic preconditioning completely eliminated the
myocardial dysfunction that normally follows 15 min of hypoxic perfusion in
hypoxia-sensitive in situ rainbow trout hearts
(Gamperl et al., 2001
).
Overgaard et al. (2004
) were
unable to precondition hypoxia-tolerant trout hearts with 1x 5 min or
even 2x 5 min of severe hypoxia. Finally, neither preconditioning with
1x 5 min or 3x 5 min of ischaemia improved the recovery of left
ventricular developed pressure in immature rabbit hearts that were inherently
hypoxia tolerant (Baker et al.,
1999
).
As discussed by Kloner et al.
(1995), the meaningful
interpretation of preconditioning experiments depends upon the exclusion of
confounding stimuli that may inadvertently precondition the myocardium.
Several mammalian studies have shown that adrenergic stimulation protects the
ischaemic myocardium (Bankwala et al.,
1994
; Yabe et al.,
1998
; Hearse and Sutherland,
1999
) and Ovize et al.
(1994
) showed that stretching
the myocardium via volume overloading induces preconditioning in
canine hearts. The in situ trout hearts used in Experiment 1 were
perfused with saline containing 15 nmol l-1 of adrenaline. In
addition, these hearts were volume-loaded twice before exposure to severe
hypoxia (at stretch and at
MAX1). Although it is
possible that the in situ trout hearts in Experiment 1 were
inadvertently preconditioned, it is difficult to reconcile this possibility
with the results of Experiment 2 (this study) or those of Gamperl et al.
(2001
). Hypoxic pre-exposure
did not improve cardiac performance following the main hypoxic period when the
initial stretch and
MAX
were eliminated, and the perfusate adrenaline concentration was reduced to 5
nmol l-1 [a level comparable to that measured in resting trout
(14 nmol l-1; Gamperl et
al., 1994
)] (Fig.
6). Further, the presence of both adrenergic stimulation (15 nmol
l-1) and a myocardial stretch
(
MAX1) did not prevent 5
min of hypoxia from completely ameliorating post-hypoxic myocardial
dysfunction in hypoxia-sensitive in situ trout hearts
(Gamperl et al., 2001
). The
inability of stretch (volume loading) to precondition hypoxia-tolerant trout
hearts (Figs 5 vs
6) or to prevent hypoxic
preconditioning in hypoxia-sensitive trout hearts
(Gamperl et al., 2001
) is in
direct contrast to the results of Ovize et al.
(1994
) for the canine heart,
but is not surprising. Fish hearts can increase stroke volume to a much
greater degree than mammals, and venous pressure/the Starling response are
primary determinants of changes in stroke volume
(Farrell, 1991
;
Franklin and Davie, 1992
).
These results suggest that while the phenomenon of preconditioning is common
to both vertebrate groups (fish and mammals), there may be fundamental
differences in the type of stimuli that can trigger or promote the signal
transduction pathways that mediate preconditioning.
Limitations of this study
In this study, 5 min of hypoxic pre-exposure (preconditioning) did not
improve the recovery of trout cardiac function following 30 min of severe
hypoxia. Some investigators might argue that it is unclear whether this
represents an absence of myocardial preconditioning, because the recovery of
myocardial function only provides an indirect assessment of myocardial
viability. However, the recovery of contractile function has often been used
as an index of myocardial preconditioning
(Asimakis et al., 1992;
Kolocassides et al., 1996
;
Gamperl et al., 2001
) and
recent studies indicate that improved cardiac function represents a specific
end-point of preconditioning. First, Mosca et al.
(1998
) showed that
ischaemic/hypoxic preconditioning improved contractility in rat hearts
independently of reduced myocardial necrosis. Second, the results of Perez et
al. (1999
) strongly suggest
that preconditioning improves the calcium responsiveness of individual
myofilaments, which might in turn promote cardiac performance. Finally, at
present we have been unable to show using a number of biochemical parameters
that the in situ trout heart is irreversibly damaged when exposed to
prolonged (<30 min) periods of severe hypoxia at 10°C
(Gamperl et al., 2001
;
Faust et al., 2004
;
Overgaard et al., 2004
).
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Acknowledgments |
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Footnotes |
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References |
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