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Departments of 1 Health and Kinesiology and 2 Medical Physiology and Cardiovascular Research Institute, Texas A&M University, College Station, Texas 77843
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Hindlimb unloading of rats results in a diminished ability of skeletal muscle arterioles to constrict in vitro and elevate vascular resistance in vivo. The purpose of the present study was to determine whether alterations in the mechanical environment (i.e., reduced fluid pressure and blood flow) of the vasculature in hindlimb skeletal muscles from 2-wk hindlimb-unloaded (HU) rats induces a structural remodeling of arterial microvessels that may account for these observations. Transverse cross sections were used to determine media cross-sectional area (CSA), wall thickness, outer perimeter, number of media nuclei, and vessel luminal diameter of feed arteries and first-order (1A) arterioles from soleus and the superficial portion of gastrocnemius muscles. Endothelium-dependent dilation (ACh) was also determined. Media CSA of resistance arteries was diminished by hindlimb unloading as a result of decreased media thickness (gastrocnemius muscle) or reduced vessel diameter (soleus muscle). ACh-induced dilation was diminished by 2 wk of hindlimb unloading in soleus 1A arterioles, but not in gastrocnemius 1A arterioles. These results indicate that structural remodeling and functional adaptations of the arterial microvasculature occur in skeletal muscles of the HU rat; the data suggest that these alterations may be induced by reductions in transmural pressure (gastrocnemius muscle) and wall shear stress (soleus muscle).
acetylcholine; arteriole; endothelium; shear stress; smooth muscle
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE HUMAN BODY is exquisitely adapted for maintaining an upright posture on Earth. However, when the force of gravity is removed during spaceflight, there is a cephalic fluid shift and an elimination of the head-to-foot hydrostatic pressure gradient (34, 36). This change in the fluid pressure distribution has been hypothesized to trigger adaptations within the cardiovascular system that are subsequently rendered inappropriate on return to the Earth's gravitational environment (36). These microgravity-induced alterations of the cardiovascular system are primarily manifested as a diminished aerobic capacity (30, 36) and orthostatic intolerance (36). Although several factors clearly contribute to the postflight orthostatic intolerance (36), one of the most prominent is orthostatic hypotension and a corresponding inability to elevate peripheral vascular resistance (2, 22). Whether this compromised ability to raise peripheral vascular resistance results from alterations in neurally mediated vascular tone, a diminished ability of resistance arteries to constrict, or a combination of the two remains to be determined.
To study these phenomena on Earth, the tail-suspended hindlimb-unloaded (HU) rat has been used to simulate the effects of microgravity. This model induces the cephalic fluid shift (10, 19, 28) and postural muscle unloading (24) that occur in microgravity. Additionally, the HU animals manifest many of the adaptations that are characteristic of exposure to microgravity, including postural muscle atrophy (24), hypovolemia (23, 32), a diminished capacity to elevate vascular resistance (20, 26, 38), orthostatic hypotension (18), and a reduced aerobic capacity (7, 27). Previous work with conduit arteries (5, 29) and skeletal muscle arterioles (4) from HU rats indicates that at least part of the inability to elevate vascular resistance results from a blunting of myogenic autoregulation and a diminished responsiveness to vasoconstrictor stimuli. The attenuated vasoconstrictor responsiveness was not due to alterations in the receptor-second messenger signal transduction mechanism but was hypothesized to result from smooth muscle atrophy or hypoplasia and the corresponding loss of contractile proteins (4, 5). In addition, reductions in myogenic and vasoconstrictor reactivity did not occur in arterioles isolated from postural muscles of the hindlimb, such as the soleus muscle, indicating that several factors may be involved in initiating adaptations in the skeletal muscle vasculature (4). Therefore, the purpose of the present study was to test the hypothesis that alterations in the mechanical environment of arterial microvessels, i.e., reduced fluid pressure and blood flow, induce a structural remodeling of the resistance vasculature in hindlimb skeletal muscles from HU rats and correspondingly alter the endothelium-dependent dilatory properties of these vessels.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. All procedures performed in this study were approved by the Texas A&M University Institutional Animal Care and Use Committee and conform to the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals [DHHS Publication No. (NIH) 85-23, Revised 1985, Office of Science and Health Reports, Bethesda, MD 20892].
Thirty-seven male Sprague-Dawley rats weighing ~350 g were randomly assigned to either HU or cage control groups. The HU animals were placed in a head-down position by elevating the hindlimbs to an approximate spinal angle of 40-45° from horizontal. This was done with a harness attached to the tail as previously described (4, 5). Briefly, a harness consisting of curved, molded plastic cast (X-Lite splint material; AOA/Kirschner) was placed around the wrapped (Co-Flex bandage, Andover) proximal two-thirds of the animal's tail. Moleskin adhesive material was placed as contact points between the tail skin and the cast to allow for adequate blood flow. Two hooks attached to opposite ends of the cast were connected by a small chain to a swivel apparatus fixed at the top of the cage. The length of the chain was adjusted to prevent the hindlimbs of the animal from touching any supportive surfaces while the forelimbs maintained contact with the cage floor. This allowed the animal free range of movement about the cage. Control animals were individually housed and maintained in a normal cage environment. Both groups were kept in their respective condition for 2 wk. This time period has been shown to be sufficient to induce cephalic fluid shifts (10, 19, 28) and produce cardiovascular alterations in HU animals (4, 7, 18, 20, 23, 26, 27, 38). After the experimental period, HU and control animals were weighed and injected with pentobarbital sodium (30 mg/kg ip) to induce deep anesthesia without allowing the hindlimbs of HU rats to become weight bearing. The animals were then decapitated, and the gastrocnemius-plantaris-soleus and triceps brachii muscle groups were carefully dissected free and placed in a 4°C filtered physiological saline solution (PSS) buffer (in mM: 145 NaCl, 4.7 KCl, 1.2 NaH2PO4, 1.17 MgSO4, 2.0 CaCl2, 5.0 glucose, 2.0 pyruvate, 0.02 EDTA, and 3.0 MOPS; pH 7.4).Microvessel preparation. Using a stereomicroscope, we identified and isolated the feed arteries leading to the forelimb triceps brachii muscle and the hindlimb superficial portion of gastrocnemius and soleus muscles. At the point where a branch from the hindlimb feed arteries entered the muscle, muscle fibers surrounding the branch were carefully dissected away and a first-order (1A) arteriole was isolated. Isolated feed arteries and 1A arterioles were transferred to a Lucite vessel chamber containing PSS. One end of the resistance artery was cannulated with a glass micropipette filled with filtered PSS-albumin solution (1 g of BSA per 100 ml) and tied securely to the pipette with 11-0 ophthalmic suture. The other end of each vessel was cannulated with a second micropipette and secured with suture.
Histomorphometry.
In the first set of animals (HU, n = 8; control, n = 8), intraluminal pressure in the isolated feed arteries and 1A
arterioles was set at 60 cmH2O, and
10
4 M sodium nitroprusside was added to
the vessel chamber. The addition of nitroprusside was used as a
precautionary measure to ensure that these vessels did not develop
spontaneous tone. In our experience, isolated skeletal muscle
arterioles do not develop spontaneous tone unless they are warmed to
37°C for 30-60 min. Thus the resistance arteries used for
histomorphometric analysis were considered maximally dilated. After a
15-min equilibration period with 104 M
nitroprusside at room temperature, the vessels were fixed with paraformaldehyde, stained with eosin, and embedded in paraffin.
Shear stress determination.
The internal radius (r, considered to be maximum or
rmax) of the feed arteries was calculated from the
media inner perimeter measurement. Wall shear stress (
) was then
calculated for three conditions (standing and after 10 min and 2 wk of
hindlimb unloading) using Eq. 1
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(1) |
is the blood viscosity (0.035 Poise) (17) and 
is the blood flow rate through the vessel. during
the three conditions was derived by dividing previously published (20) total blood flow (ml/min) to gastrocnemius (summed flows to red, white,
and mixed portions) and soleus muscles by the number of feed arteries
leading to the muscles (2 feed arteries to gastrocnemius muscle and
3-5 feed arteries to soleus muscle in control and HU rats). To
calculate shear stress in each of the three conditions, it was
necessary to consider the relative state of the artery in vivo during
standing and after 10 min and 2 wk of hindlimb unloading. The r
for soleus feed artery during standing was considered to be equivalent
to rmax because the soleus muscle is actively recruited in maintaining posture and, correspondingly, the soleus muscle vascular conductance can approach near maximal levels during standing (16). However, because the soleus muscle is quiescent during
the two unloaded conditions, and the superficial and middle portions of
the gastrocnemius muscle are inactive during each of the three
conditions (13, 16, 24), r was adjusted to reflect the amount
of intrinsic tone these vessels develop in vitro (Ref. 4 and present
study). Soleus feed artery r was estimated to be 70% of
rmax with 10 min of hindlimb unloading because
control soleus vessels develop ~30% spontaneous tone (Ref. 4 and
present study). Soleus feed artery r after 2 wk of hindlimb unloading was assumed to be 65% of rmax because
soleus vessels from 2-wk HU rats develop ~35% spontaneous tone. The
r for the superficial gastrocnemius feed arteries during
standing and 10 min of hindlimb unloading was estimated to be ~65%
of rmax, and after 2 wk of hindlimb unloading, it
was assumed to be ~80% of rmax.
In vitro studies.
In a second set of animals (HU, n = 8; control, n = 7),
isolated 1A arterioles from soleus and gastrocnemius muscles were transferred to a Lucite vessel chamber containing PSS and cannulated as
described in Microvessel preparation. After
cannulation, each isolated vessel in the tissue chamber was transferred
to the stage of an inverted microscope (Olympus IX70) coupled to a
video camera (Panasonic BP310), video micrometer (Microcirculation
Research Institute, Texas A&M University), video recorder (Panasonic
AG-1300), and data-acquisition system (Macintosh/MacLab). Intraluminal
pressure was set at 60 cmH2O, and the vessels were allowed
to equilibrate for 1 h at 37°C before endothelium-dependent
vasodilation was characterized; the bathing solution was replaced every
15 min during the equilibration period. Internal diameter was
continuously measured throughout the experiment with the use of
videomicroscopic techniques (4, 8). To assess endothelium-dependent
vasodilation, we determined concentration-response relationships to the
cumulative addition of ACh
(109-104 M).
9-104
M) manner.
Data analysis. Student's t-tests were used to determine the significance of differences in the morphological parameters of resistance arteries, body mass, soleus muscle mass, and the soleus muscle-to-body mass ratio between control and HU groups. A one-way ANOVA was used to compare wall shear stress during standing and after 10 min and 2 wk of hindlimb unloading. The Student-Newman-Keuls method was used as a post hoc test to determine the significance of differences among means. ACh concentration-response curves were evaluated using repeated-measures ANOVA with one within-treatment (ACh concentration) and one between-treatment (experimental groups) factor. Planned contrasts were conducted at each molar concentration level to determine whether differences existed among groups. All values are presented as means ± SE. A P < 0.05 was required for significance.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Body and soleus muscle mass. Body mass of control rats (436 ± 12 g) tended to be greater than that of 2-wk HU (407 ± 7 g) and 4-wk HU rats (418 ± 9 g) (P = 0.071). Hindlimb unloading reduced soleus muscle mass of HU rats (2-wk HU: 148 ± 7 mg; 4-wk HU: 127 ± 6 mg) relative to control soleus muscle mass (230 ± 9 mg). Similarly, the soleus-to-body mass ratio of 2-wk (0.362 ± 0.015 mg/g) and 4-wk HU rats (0.305 ± 0.007 mg/g) was lower than that of control rats (0.530 ± 0.023 mg/g). Soleus muscle atrophy, which is characteristic of reduced skeletal muscle weight-bearing activity, confirms the effectiveness of the hindlimb unloading intervention.
Vessel morphology.
Hindlimb unloading elicited structural adaptations in resistance
arteries that differed for each of the three skeletal muscles studied.
However, the pattern of adaptation induced in feed arteries and 1A
arterioles was similar within the same muscle (Figs.
1 and 2). In
the forelimb triceps muscle, unloading resulted in a tendency
(P = 0.064) for the media CSA of the feed artery to increase
(Fig. 3). This apparent increase in media
CSA resulted from a significant increase in vessel diameter (control:
140 ± 27 µm; HU: 212 ± 25 µm), no change in media wall
thickness (Fig. 4), and a
tendency for media outer perimeter (Fig.
5) to increase (P = 0.086). Hindlimb unloading did not induce a change in the number of nuclei in the media (control: 60 ± 4 nuclei; HU: 54 ± 6 nuclei) in the triceps muscle feed artery.
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Shear stress.
Acute (10 min) or chronic (2 wk) hindlimb unloading (Fig.
6) did not significantly alter calculated
wall shear stress in gastrocnemius muscle feed artery during standing.
However, in soleus muscle feed artery, acute unloading diminished shear
stress relative to that occurring during control standing. By 2 wk of
hindlimb unloading, shear stress returned to levels similar to that
during standing.
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ACh-induced dilation.
Vasodilation induced by ACh was unaltered by HU in arterioles from the
gastrocnemius muscle (Fig. 7). In contrast,
2-wk HU, but not 4-wk HU, diminished ACh-induced dilation in soleus
muscle arterioles (Fig. 8).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The primary purpose of the present study was to determine whether the reduction of hydrostatic fluid pressure in the hindlimbs of tail-suspended rats and reductions in muscle blood flow would induce a structural remodeling of the resistance vasculature in skeletal muscle. The results demonstrate that the media CSA of feed arteries and 1A arterioles from both gastrocnemius and soleus muscles is diminished by hindlimb unloading (Figs. 1-3), whereas the media CSA of the feed artery from the forelimb triceps brachii muscle is unaltered (Fig. 3). The decrease in media CSA appears to be due to smooth muscle cell atrophy, as indicated by the decreased CSA without a change in the number of media nuclei. The reduction in media CSA of resistance arteries from gastrocnemius muscle resulted from a decrease in media thickness (Figs. 1 and 4), whereas the reduction in media CSA of resistance arteries from soleus muscle resulted from a decrease in the media outer perimeter (Figs. 2 and 5) and vessel diameter.
Two primary mechanical forces are thought to act on the vasculature to induce structural adaptations: 1) the shear stress that arises from the blood acting on endothelial cells, and 2) the stress and strains that cause deformations within the artery wall (13, 14). Calculated shear stress in the arteries from gastrocnemius muscle during both acute and chronic hindlimb unloading was not different from that during standing (Fig. 6). Thus it does not appear that changes in shear stress stimulate the media thinning that occurs in gastrocnemius resistance arteries with hindlimb unloading. However, elevation of the hindlimbs during the unloading procedure produces a reduction in transmural pressure within the hindlimb arterial vasculature by inducing a cephalic fluid shift and increasing diuresis (10, 19, 23, 28). In addition, increases in central blood volume engage cardiopulmonary receptors and elicit reflexive decreases in efferent sympathetic nerve activity (35). Thus the reduction in transmural pressure and a putative attenuation of sympathetic nerve activity may diminish both myogenic and sympathetically mediated smooth muscle contractile activity in resistance arteries from gastrocnemius muscle. The data suggest that the persistent decrease in vasomotor tone is an adequate stimulus to induce a structural remodeling of the feed artery and 1A arteriole. The remodeling does not involve a change in vessel diameter but rather consists of a decrease in media thickness that appears to occur as a result of radial atrophy of smooth muscle cells (i.e., a decrease in smooth muscle cell thickness). This type of vascular adaptation is in fact the inverse of that reported to occur with hypertension (9) and hindlimb unloading in cerebral (basilar) resistance arteries (37), where increases in transmural pressure elevate the circumferential stress within the arterial wall. The elevation of circumferential stress leads to radial hypertrophy of smooth muscle cells and increased media wall thickness (9, 11, 25, 37).
The same decrease in vasomotor tone may not occur in resistance
arteries from soleus muscle. For example, soleus muscle is actively
recruited in the conscious standing rat and receives a relatively
constant perfusion of 70-140
ml · min1 · 100 g1 (16, 20). When hindlimb unloading
eliminates the weight-bearing activity of soleus muscle, blood flow
immediately decreases to 
10
ml · min1 · 100 g1 (20). Although the diminished
intravascular fluid pressure resulting from the elevation of the
hindlimbs would tend to induce myogenic relaxation (4, 6, 21), this
effect is presumably offset in soleus muscle by a reduction in
vasodilatory metabolite release when the muscle becomes unloaded (6,
20). In other words, we speculate that the soleus muscle resistance
vasculature goes from a metabolite-induced relaxed state during
standing to a myogenic-induced relaxed state during unloading. Thus the
circumferential stress within the wall of soleus muscle resistance
arteries may not be greatly altered by hindlimb unloading and,
therefore, would not appear to be the stimulus for structural
adaptation in these vessels. Rather, it appears that the chronic
decrease in blood flow to soleus muscle may provide the stimulus for
adaptation. Acute unloading of the hindlimb reduces calculated shear
stress in the feed arteries from soleus muscle (Fig. 6). Although blood flow to soleus muscle remains low through 2 wk of unloading (20), the
estimated decrease in shear stress appears to be normalized to
presuspension levels by a structural reduction in vessel diameter. The
data suggest that this decrease in diameter is the result of
circumferential atrophy of smooth muscle cells (i.e., a decrease in
smooth muscle cell length), because the outer media perimeter is
decreased and media thickness is unaltered.
Previous investigators have demonstrated that sustained reductions in
blood flow for 2 wk through large conduit arteries of rabbits (1, 14,
15) and dogs (12) reduce vessel diameter without altering media wall
thickness. This process was shown to be endothelium dependent and
serves to restore vessel wall shear stress (1, 12, 14, 15). The present
study demonstrates that a similar remodeling can also occur in the
arterial microvasculature to maintain relatively constant levels of
shear stress. In addition, data from the present study suggest that
reductions in shear stress precede the diminution of
endothelium-dependent dilation in skeletal muscle arterioles and that
the structural remodeling that occurs to normalize shear stress
precedes the normalization of endothelium-dependent dilation.
The functional consequences of changing the structure of resistance arteries are profound. For example, the thinning of the medial layer of resistance arteries from the superficial portion of the gastrocnemius muscle results in the blunting of myogenic autoregulation and a diminished responsiveness of these vessels to vasoconstrictor stimuli (4). These adaptations to hindlimb suspension undoubtedly contribute to the diminished ability to elevate vascular resistance in other hindlimb muscles that have activity levels or fiber composition similar to that of the superficial gastrocnemius muscle (20). Furthermore, the decrement in myogenic and vasoconstrictor responsiveness of resistance arteries and arterioles is consistent with the inability of HU rats to maintain arterial pressure during an acute orthostatic challenge (90° head-up tilt) (18).
Although the structural remodeling that occurs in soleus muscle resistance arteries does not affect vascular responsiveness to vasoconstrictor stimuli (4), the reduction in vessel diameter and endothelium-dependent vasodilation does appear to have important functional consequences. After a 2-wk period of unloading, blood flow to rat soleus muscle is reduced both at rest and during exercise (20, 38). This reduction in the blood flow capacity in soleus and other highly oxidative muscles presumably results, at least in part, from the reduction in intraluminal CSA of resistance arteries and perhaps the temporary decrease in endothelium-mediated dilation. Furthermore, the reduction in blood flow to highly oxidative muscles coupled with the elevation in perfusion of low oxidative skeletal muscles results in a less precise matching of oxygen delivery to muscle oxidative capacity (20). McDonald and colleagues (20) and others (27) have hypothesized that this alteration in blood flow distribution within the hindlimb musculature contributes to the reduced aerobic capacity of these animals. This hypothesis is consistent with alterations that occur following exercise training, where blood flow is elevated to highly oxidative muscles and reduced to low oxidative muscles, resulting in a more precise matching of oxygen delivery to oxidative capacity and a corresponding increase in maximal oxygen consumption (3).
In conclusion, the present study demonstrates that structural and functional remodeling of the arterial microvasculature occurs in skeletal muscles of the HU rat, apparently as a result of reductions in transmural pressure and wall shear stress. Reductions in transmural pressure appear to induce radial atrophy of smooth muscle cells that results in the thinning of the medial layer (Figs. 1 and 4) with no change in vessel diameter. Reductions in wall shear stress appear to induce 1) circumferential atrophy of smooth muscle cells, resulting in a reduction in vessel diameter with no change in media thickness (Figs. 2 and 4), and 2) reductions in endothelium-dependent dilation (Fig. 8). Furthermore, estimates of wall shear stress suggest that the reduction in vessel diameter serves to normalize intraluminal shear stress (Fig. 6) and subsequently restore endothelium-dependent dilation (Fig. 8). It is possible that the altered fluid pressure gradients and the unloading of postural muscles that occur in humans residing in space or during prolonged bed rest may also induce similar changes in the mechanical forces acting on the resistance arteries. If this does occur, then arterial vascular remodeling may underlie the compromised ability to elevate peripheral vascular resistance that leads to orthostatic hypotension (2, 22, 33) and the decrements in maximal aerobic power (30, 31) in humans.
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ACKNOWLEDGEMENTS |
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This study was supported by National Aeronautics and Space Administration (NASA) Grants NAGW-4842 and NAG5-3754 (to M. D. Delp), National Space and Biomedical Research Institute Grant NCC9-58-H (to M. D. Delp), and two NASA Space Physiology Research Grants awarded through the American College of Sports Medicine Foundation (to P. N. Colleran and M. K. Wilkerson).
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FOOTNOTES |
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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: M. D. Delp, College of Education, Dept. of Health and Kinesiology, Texas A&M University, College Station, TX 77845 (E-mail: mdd{at}hlkn.tamu.edu).
Received 11 August 1999; accepted in final form 7 December 1999.
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TOP
ABSTRACT
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METHODS
RESULTS
DISCUSSION
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