Circulation. 1996;93:866-869
(Circulation. 1996;93:866-869.)
© 1996 American Heart Association, Inc.
Increased Activation of Sympathetic Nervous System and Endothelin by Mental Stress in Normotensive Offspring of Hypertensive Parents
Georg Noll, MD;
René R. Wenzel, MD;
Martin Schneider, MD;
Valerie Oesch, MD;
Christian Binggeli, MD;
Sidney Shaw, PhD;
Peter Weidmann, MD;
Thomas F. Lüscher, MD
From Cardiology, Cardiovascular Research (G.N., R.R.W., V.O., C.B.,
T.F.L.), and Division of Hypertension (M.S., S.S., P.W.), University Hospital,
Bern, Switzerland.
Correspondence to Georg Noll, MD, Cardiology, University
Hospital/Inselspital, CH-3010 Bern, Switzerland.
 |
Abstract
|
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Background The pathogenesis of essential hypertension is
still
uncertain, but genetic factors and the sympathetic nervous system
are
likely to be involved. Sympathetic nerve activity and hormonal
circulatory
control mechanisms, however, are affected by blood pressure
itself.
Hence, early functional changes are best investigated in
normotensive
subjects at risk to develop hypertension, such as
normotensive
offspring of hypertensive parents.
Methods and Results Muscle sympathetic nerve activity (MSA) was
measured in the peroneal nerve of 10 normotensive offspring of parents
with essential hypertension and 8 offspring of normotensive parents.
Measurements were performed under resting conditions, during a
10-minute period of hypoxia (12.5%
O2/87.5% N2), and during a 3-minute
mental stress test. The tests were separated by a 30-minute resting
period. Plasma samples for determination of norepinephrine
and endothelin were collected before and after the tests. Baseline
values of MSA were comparable in offspring of hypertensive and
normotensive parents. During hypoxia, MSA, heart rate, and
norepinephrine and endothelin plasma levels increased in
offspring of hypertensive and normotensive parents to a comparable
degree, whereas no significant changes in blood pressure and plasma
norepinephrine levels were observed in either group. During
mental stress, MSA and plasma norepinephrine and endothelin
increased only in offspring of hypertensive parents (P<.001
to .01). In parallel, blood pressure increased significantly only in
offspring of hypertensive parents (P<.001 to .05), but
heart rate increased in both groups (P<.001 to .05).
Conclusions The activity of the sympathetic nervous system
and plasma norepinephrine and endothelin levels are
increased during mental stress only in offspring of hypertensive
parents, whereas the response to hypoxia was similar in
offspring of hypertensive and normotensive parents, suggesting a
genetically determined abnormal regulation of the sympathetic nervous
system to certain stressful stimuli in offspring of hypertensive
parents. This may play a role in the pathogenesis of essential
hypertension.
Key Words: hypertension nervous system stress hypoxia
 |
Introduction
|
|---|
The pathogenesis of essential
hypertension is still not fully
understood. An increased activity of
the sympathetic nervous
system (SNS) at rest and during hypoxia
has been proposed
1 2 3 ; however, plasma
norepinephrine levels showed inconsistent
results.
4 5 Several reasons may account for this
discrepancy. First,
plasma norepinephrine is a poor
indicator of changes in SNS
activity. Microneurography is more
sensitive in detecting alterations
in SNS activity. Furthermore, SNS
activity is affected by blood
pressure.
6 Hence, in
established hypertension, sympathetic
outflow may be inhibited by the
increase in blood pressure,
thereby obscuring early functional changes.
Endothelin is a
potent vasoconstrictor that enhances
norepinephrine-induced
contractions
7 and
activates the SNS in experimental animals.
8 In
humans, the cold pressor test, which is a potent stimulus
of muscle
sympathetic nerve activity (MSA), increases plasma
endothelin
levels.
9 Measurements of baseline plasma endothelin
levels
in patients with hypertension are inconclusive, and little
is known
about the activation of this pressor system under stress
conditions.
10 Because genetic factors are important in the
pathogenesis of
hypertension, normotensive offspring of hypertensive
parents
may be more suitable for assessing early dysfunction of
cardiovascular
regulation.
11 Such
dysfunction may occur under baseline conditions
or, more likely, during
stress.
12 13 Therefore, we studied
peripheral
MSA and plasma norepinephrine and endothelin under
baseline
conditions, during hypoxia, and during mental stress
in
normotensive offspring of hypertensive parents.
 |
Methods
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We used microneurography to measure MSA in 18 healthy Caucasian
medical
students.
1 14 Ten of them had a genetic
background, ie, one
of their parents had a history of essential
hypertension, and
8 were offspring of two normotensive parents.
Informed consent
was obtained from all subjects. The study was approved
by the
ethics committee of the University Hospital (Inselspital), Bern,
Switzerland.
The investigators performing the experiments were blinded
to
the history of the subjects. All subjects were studied in a
randomized
fashion under the same conditions, ie, in the morning (9
AM)
after a light breakfast. After micturition to avoid any
increase
of sympathetic nerve activity through bladder
distension,
15 subjects were asked to resume a supine
position. The left or
right leg was fixed by a vacuum cushion, and ECG,
blood pressure
cuff, and respiration strain gauge were fixed. A
catheter (Venflon,
Ohmeda) was inserted into a cubital vein. Multifiber
recordings
of MSA were obtained from the peroneal nerve
posterior to the
fibular head with tungsten microelectrodes (200-µm
shaft
diameter; 1- to 5-µm uninsulated tip; University of
Iowa).
1 14 A reference electrode was inserted
subcutaneously 1 to 2
cm from the recording electrode.
Electrodes were connected to
a preamplifier (gain, 1000) and amplifier
(variable gain, 10
to 50). Neural activity was fed through a
band-pass filter (bandwidth,
700 to 2000 Hz) and then a
resistance-capacitance integrating
network (time constant, 0.1
second) to obtain a mean voltage
neurogram. The signal was displayed on
an oscilloscope and registered
on a thermocoupled printer at a paper
speed of 5 mm/s (Graphtec
Inc). Three criteria for acceptance
of MSA recording were required:
(1) electrical stimulation (0.1
to 1.0 V, 0.2 ms, 1 Hz) through
the electrode in the peroneal nerve
elicited involuntary muscle
contractions in the peroneal nerve but no
paresthesia; (2) tapping
or stretching the innervated
muscle region elicited afferent
mechanoreceptor discharges, whereas
stroking the skin did not;
and (3) the neurogram revealed spontaneous,
intermittent, pulse-synchronous
sympathetic bursts that increased
during apnea.
1 16 17 18
Neurograms
with cutaneous sympathetic
activity or mixed cutaneous sympathetic
activity and MSA were not
accepted. This was assessed by the
response to arousal stimuli that
elicited single reflex bursts
of cutaneous sympathetic activity but not
MSA. If there was
any evidence of a dislocation of the electrode
position, the
experiment was discarded from the study. The number of
bursts
was counted manually. MSA was expressed as bursts per minute.
In
addition, the analog signal was digitized by use of an
analog-digital
board (MIO-16L, National Instruments) and a program
written
in LabView (National Instruments) with a sampling rate of 500
Hz.
Digitized data were used to assess the sum of the amplitude
of
bursts in the mean voltage neurogram. For that purpose, a
program
written in MatLab (MathWorks) was used. The results
were expressed as
cumulative volts per minute. Blood pressure
was measured at 3-minute
intervals with an oscillometric method
(Dynamap, Critikon). After an
equilibration period of 30 minutes,
baseline values were registered
over a period of 3 minutes;
then subjects were exposed to
hypoxia for 8 minutes. They were
breathing a gas mixture of
12.5% O
2/87.5% N
2. Capillary
P
O2 was measured in blood obtained from the
subject's earlobe before
and at the end of exposure to hypoxia
with an automated gas
analyzer (Radiometer ABL 505, IG
Instrumenten Gesellschaft AG).
After a resting period of 30 minutes, a
mental stress test was
performed by unexpectedly asking the subject to
perform mental
arithmetic consisting of continuous subtractions for 3
minutes.
Venous blood samples were drawn from a venous cannula in the
brachial
vein before and immediately after (mental stress) or 25
minutes
after (hypoxia) the end of the tests and stored at
-70°C.
Plasma norepinephrine was measured by
high-performance liquid
chromatography and
plasma endothelin by radioimmunoassay.
19 Ambulatory blood
pressure measurements were performed for 10
to 12 hours at intervals of
30 minutes (CH-Druck Recorder, Disetronic
Medical Systems). Data
are mean±SEM. Paired and unpaired
Student's
t tests were
used for statistical evaluation of intragroup
and intergroup
differences, respectively.
 |
Results
|
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Subject Characteristics
Age, waist-to-hip ratio, and body
mass index were
comparable
in both groups (offspring of normotensive parents: 27±4
years,
0.80±0.01, and 21.8±0.6 kg/m
2; offspring of
hypertensive
parents: 27±3 years, 0.84±0.01, and 22.4±0.6
kg/m
2;
P=NS). Ambulatory blood pressure averaged
125±4/81±3
mm Hg in offspring of normotensive parents and
126±3/85±2
mm Hg in offspring of hypertensive parents
(
P=NS). Heart rate
was 75±2 and 72±3 beats per
minute,
respectively
(
P=NS).
Mental Stress Test
Under baseline conditions, MSA expressed
as number of bursts per
minute tended to be lower in offspring of hypertensive compared with
offspring of normotensive parents (19.0±2.8 versus 25.9±3.9
bursts
per minute; P=NS; Figs 1
and 2
).
Similar results were obtained expressing MSA as the
sum of burst amplitude per minute (offspring of normotensive parents,
54±20 V/min; offspring of hypertensive parents, 24±6 V/min; Fig
2
).
During mental stress, a significant increase in MSA was observed in
offspring of hypertensive parents, whereas in offspring of normotensive
parents, MSA remained unchanged (Figs 1
and 2
).
In parallel, plasma
norepinephrine, which was lower in offspring of
hypertensives under baseline conditions (Table 1
),
increased during mental stress only in offspring of hypertensives
(Table 1
). Similarly, endothelin levels were comparable under
resting
conditions in offspring of normotensive and hypertensive parents but
increased significantly during mental stress only in offspring of
hypertensive parents (Table 1
). There was a significant
increase in
systolic and diastolic blood pressures during
mental stress in offspring of hypertensive parents only (Table
1
),
whereas heart rate increased to a comparable degree in both groups
(Table 1
).

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Figure 1. Original recordings of muscle sympathetic
activity (MSA) in an offspring of normotensive parents (L.B.; left) and
an offspring of a hypertensive parent (R.R.; right) at rest and during
mental arithmetic (mental stress). BP indicates blood pressure; HR,
heart rate; and bpm, beats per minute.
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Table 1. Blood Pressure, Heart Rate, Plasma
Norepinephrine, and Endothelin-1 During MS in Offspring of
Hypertensive and Normotensive Parents
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Hypoxia
Resting MSA was slightly but not significantly higher
in offspring
of normotensive compared with offspring of hypertensive parents
before exposure to the hypoxic gas mixture (offspring of normotensives:
18.6±2.4 bursts per minute, 35±17 V/min; offspring of
hypertensives:
23.5±3.5 bursts per minute, 20±7 V/min; P=NS;
Fig 3
). During hypoxia, capillary
PO2 decreased in both groups to the same extent
(Table 2
), whereas MSA increased significantly in both
groups (offspring of normotensives: 29.4±4.1 bursts per minute,
54±21
V/min; offspring of hypertensives: 22.3±2.6 bursts per minute,
31±10
V/min, P<.05). Blood pressure and heart rate did not change
during hypoxia (Table 2
). There was a slight but statistically
insignificant increase in plasma norepinephrine levels
during hypoxia (Table 2
). Endothelin-1 plasma levels increased
significantly in both groups to the same extent after exposure to the
hypoxic gas (Table 2
).
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Table 2. Blood Pressure, Heart Rate, Capillary
PO2, and Plasma
Norepinephrine and Endothelin-1 During Hypoxia in
Offspring of Hypertensive and Normotensive Parents
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 |
Discussion
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|---|
This study demonstrates for the first time that in normotensive
offspring
of hypertensive parents compared with offspring of
normotensive
parents, SNS activity and plasma endothelin increased to a
greater
extent from respective baseline levels in response to mental
stress,
whereas the response to hypoxia was similar in the two
groups.
The groups were comparable with respect to age, blood pressure,
waist-to-hip
ratio, and body mass index. Hence, common
confounding factors
that may affect SNS activity and plasma endothelin
levels were
excluded. The fact that the offspring of hypertensive
parents
were still normotensive indicates that the observed changes
in
cardiovascular responsiveness occur at an early stage,
are
probably of genetic origin, and could play a role in the
pathogenesis
of hypertension. Indeed, a hyperreactivity of the SNS has
long
been suspected in the development of hypertension, but most
studies
have yielded inconsistent results.
4 In
addition to methodological
problems, it is likely that the activity of
the SNS changes
during the natural history of high blood pressure. On
the basis
of our results and those of the literature, it is likely that
in
normotensive individuals with a genetic background for hypertension,
MSA
is increased only in response to factors such as stress, becomes
increased
even under unstimulated conditions in borderline
hypertension,
1 and eventually returns to normal levels in
established hypertension.
2 14 It has been
demonstrated
previously that offspring of normotensive
parents react to
psychological stress with a slightly greater
pressure response than
offspring of normotensive
parents.
12 20 21 22 23 24
Differences in
cardiovascular reactivity were
more pronounced during
active stressors such as mental arithmetic
or stressful
interview
12 21 22 23 24
than during passive stressors
such as
the cold pressor test or watching a stressful
film.
21 24 25 26 27 28 29 30
Our results are in line with these
observations
and demonstrate that a hyperreactivity of the SNS to
mental
stress is a likely mediator. Since the response of the SNS and
hemodynamics
to hypoxia did not differ between
normotensive and hypertensive
offspring, the abnormal reactivity of the
latter group to mental
stress must represent a rather specific
abnormality.
Endothelin is a locally released vascular regulator that at very low
concentrations enhances contractions to norepinephrine and
at higher concentrations has potent direct vasoconstrictor
properties.7 In experimental animals, endothelin
stimulates sympathetic outflow.8 Hence, alterations in the
local release of endothelin could alter the activity and vascular
effects of the SNS. In human hypertension, normal and increased plasma
levels have been reported under baseline conditions.10
Endothelin levels during stimulation of the
cardiovascular system have not been reported in
hypertensive individuals, although hypoxia and exercise
increase endothelin plasma levels in normal subjects.19 In
our study, we observed an increase in plasma endothelin-1 levels during
exposure to hypoxic gas mixture, in line with a previous observation
during hypoxia at high altitude.19 These changes
of plasma endothelin to hypoxia were not influenced by the
genetic background for essential hypertension. Since blood pressure did
not change in either normotensive or hypertensive offspring but
pulmonary pressure does, as demonstrated in a previous
study,19 the hypoxia-induced increase in
endothelin appears to be important for the regulation of the
pulmonary but not the systemic circulation. In contrast, mental
stress caused a parallel increase in endothelin and MSA as well as
blood pressure in offspring of hypertensive but not in those of
normotensive parents, suggesting that it might contribute to this
abnormal circulatory response to mental stress. These early functional
changes of central and local cardiovascular regulation
may be important in the pathogenesis of essential hypertension.
 |
Acknowledgments
|
|---|
This study was supported by grants from the Swiss National
Research
Foundation (No. 32-042 560.94 and SCORE No. 32-35591.92) and
the
German Research Association (DFG No. WE 1772/1-1).
Received October 30, 1995;
revision received December 28, 1995;
accepted January 2, 1996.
 |
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R. A. Mangiafico, L. S. Malatino, T. Attina, R. Messina, and C. E. Fiore
Exaggerated Endothelin Release in Response to Acute Mental Stress in Patients with Intermittent Claudication
Angiology,
July 1, 2002;
53(4):
383 - 390.
[Abstract]
[PDF]
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L. E. Spieker, D. Hurlimann, F. Ruschitzka, R. Corti, F. Enseleit, S. Shaw, D. Hayoz, J. E. Deanfield, T. F. Luscher, and G. Noll
Mental Stress Induces Prolonged Endothelial Dysfunction via Endothelin-A Receptors
Circulation,
June 18, 2002;
105(24):
2817 - 2820.
[Abstract]
[Full Text]
[PDF]
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C. Binggeli, R. Corti, I. Sudano, T. F. Luscher, and G. Noll
Effects of Chronic Calcium Channel Blockade on Sympathetic Nerve Activity in Hypertension
Hypertension,
April 1, 2002;
39(4):
892 - 896.
[Abstract]
[Full Text]
[PDF]
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T. Quaschning, F. Ruschitzka, B. Niggli, C. M. B. Lunt, S. Shaw, M. Christ, M. Wehling, and T. F. Luscher
Influence of aldosterone vs endothelin receptor antagonism on renovascular function in liquorice-induced hypertension
Nephrol. Dial. Transplant.,
November 1, 2001;
16(11):
2146 - 2151.
[Abstract]
[Full Text]
[PDF]
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F. Ruschitzka, T. Quaschning, G. Noll, A. deGottardi, M. F. Rossier, F. Enseleit, D. Hurlimann, T. F. Luscher, and S. G. Shaw
Endothelin 1 Type A Receptor Antagonism Prevents Vascular Dysfunction and Hypertension Induced by 11{beta}-Hydroxysteroid Dehydrogenase Inhibition : Role of Nitric Oxide
Circulation,
June 26, 2001;
103(25):
3129 - 3135.
[Abstract]
[Full Text]
[PDF]
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L. E. Spieker, G. Noll, F. T. Ruschitzka, and T. F. Luscher
Endothelin receptor antagonists in congestive heart failure: a new therapeutic principle for the future?
J. Am. Coll. Cardiol.,
May 1, 2001;
37(6):
1493 - 1505.
[Abstract]
[Full Text]
[PDF]
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P. Kienbaum, T. Heuter, M. C. Michel, N. Scherbaum, M. Gastpar, and J. Peters
Chronic {micro}-Opioid Receptor Stimulation in Humans Decreases Muscle Sympathetic Nerve Activity
Circulation,
February 13, 2001;
103(6):
850 - 855.
[Abstract]
[Full Text]
[PDF]
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P. FORTE and N. BENJAMIN
Does an impaired flow mediated vasodilatation predict hypertension in offspring hypertensive parents?
Heart,
February 1, 2001;
85(2):
131 - 132.
[Full Text]
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T. Quaschning, F. Ruschitzka, S. Shaw, and T. F. Luscher
Aldosterone Receptor Antagonism Normalizes Vascular Function in Liquorice-Induced Hypertension
Hypertension,
February 1, 2001;
37(2):
801 - 805.
[Abstract]
[Full Text]
[PDF]
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F. Elijovich, C. L. Laffer, E. Amador, H. Gavras, M. R. Bresnahan, and E. L. Schiffrin
Regulation of Plasma Endothelin by Salt in Salt-Sensitive Hypertension
Circulation,
January 16, 2001;
103(2):
263 - 268.
[Abstract]
[Full Text]
[PDF]
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L. Ghiadoni, A. E. Donald, M. Cropley, M. J. Mullen, G. Oakley, M. Taylor, G. O'Connor, J. Betteridge, N. Klein, A. Steptoe, et al.
Mental Stress Induces Transient Endothelial Dysfunction in Humans
Circulation,
November 14, 2000;
102(20):
2473 - 2478.
[Abstract]
[Full Text]
[PDF]
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L. E. Spieker, R. Corti, C. Binggeli, T. F. Luscher, and G. Noll
Baroreceptor dysfunction induced by nitric oxide synthase inhibition in humans
J. Am. Coll. Cardiol.,
July 1, 2000;
36(1):
213 - 218.
[Abstract]
[Full Text]
[PDF]
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R. Corti, C. Binggeli, I. Sudano, L. E. Spieker, R. R. Wenzel, T. F. Luscher, and G. Noll
The Beauty and the Beast: Aspects of the Autonomic Nervous System
Physiology,
June 1, 2000;
15(3):
125 - 129.
[Abstract]
[Full Text]
[PDF]
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F. A. Treiber, R. W. Jackson, H. Davis, J. S. Pollock, G. Kapuku, G. A. Mensah, and D. M. Pollock
Racial Differences in Endothelin-1 at Rest and in Response to Acute Stress in Adolescent Males
Hypertension,
March 1, 2000;
35(3):
722 - 725.
[Abstract]
[Full Text]
[PDF]
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C. Dodt, B. Keyser, M. Molle, H. L. Fehm, and M. Elam
Acute Suppression of Muscle Sympathetic Nerve Activity by Hydrocortisone in Humans
Hypertension,
March 1, 2000;
35(3):
758 - 763.
[Abstract]
[Full Text]
[PDF]
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E. L. Schiffrin
Role of Endothelin-1 in Hypertension
Hypertension,
October 1, 1999;
34(4):
876 - 881.
[Abstract]
[Full Text]
[PDF]
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R. R. Wenzel, L. Spieker, S. Qui, S. Shaw, T. F. Luscher, and G. Noll
I1-Imidazoline Agonist Moxonidine Decreases Sympathetic Nerve Activity and Blood Pressure in Hypertensives
Hypertension,
December 1, 1998;
32(6):
1022 - 1027.
[Abstract]
[Full Text]
[PDF]
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A. Radaelli, L. Mircoli, I. Mori, G. Mancia, and A. U. Ferrari
Nitric Oxide–Dependent Vasodilation in Young Spontaneously Hypertensive Rats
Hypertension,
October 1, 1998;
32(4):
735 - 739.
[Abstract]
[Full Text]
[PDF]
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U. Scherrer and C. Sartori
Insulin as a Vascular and Sympathoexcitatory Hormone : Implications for Blood Pressure Regulation, Insulin Sensitivity, and Cardiovascular Morbidity
Circulation,
December 2, 1997;
96(11):
4104 - 4113.
[Abstract]
[Full Text]
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Y. Lampl, G. Fleminger, R. Gilad, R. Galron, I. Sarova-Pinhas, and M. Sokolovsky
Endothelin in Cerebrospinal Fluid and Plasma of Patients in the Early Stage of Ischemic Stroke
Stroke,
October 1, 1997;
28(10):
1951 - 1955.
[Abstract]
[Full Text]
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