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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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The sleep apnea/hypopnea syndrome (SAHS) affects 1-4% of the middle-aged population and is
caused by repeated occlusion of the upper airway mainly at the retropalatal level. It is unclear why
SAHS patients obstruct their upper airways during sleep while others do not. We hypothesized that
upper airway dilator muscle function may be impaired in SAHS patients and that chronic CPAP therapy may enhance upper airway function. We, therefore, examined the effects of upper airway negative pressure on reflex palatal muscle activity in 16 normal nonsnoring awake male subjects and 16 awake SAHS patients using electromyography. The application of negative upper airway pressure (0 to 
12.5 cm H2O) caused increases in levator palatini (LP, p < 0.001) and palatoglossus (PG, p < 0.001) activity, 100 msec after pressure stimulus in normal subjects. Application of upper airway negative pressure in SAHS patients caused an increase in LP activity (p < 0.05) but not in PG activity. Reflex electromyographic response to negative pressure was reduced in SAHS patients compared to
normal subjects for both muscles (p < 0.001). When the seven thinnest SAHS patients were compared with seven normal subjects matched for BMI and age, the SAHS patients still demonstrated impaired responses to negative pressure for both muscles (p < 0.001). A further eight SAHS patients
were studied either while concurrently taking nightly CPAP therapy and also off CPAP (at least 3 nights). Chronic nightly CPAP therapy improved the reflex response of both LP (p < 0.001) and PG
(p = 0.003) to nasal negative pressure application. Thus, untreated SAHS patients have impaired
electromyographic responses to negative upper airway pressure suggesting impaired defence of the
upper airway, which is improved by nightly CPAP therapy.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The sleep apnea/hypopnea syndrome (SAHS) causes daytime sleepiness and impaired cognitive function in 1-4% of the middle aged population (1) and is associated with increased frequency of road traffic accidents (4), myocardial infarction, and stroke (5). The syndrome results from repeated occlusion of the upper airway during sleep (6) but it is unclear what determines whether an individual's airway will obstruct during sleep (7). Recent attention has focused on the importance of anatomical factors, with some (8, 9) but not all (10, 11) studies showing narrower upper airways in awake SAHS patients compared with normal subjects. However, even the studies showing a difference (8, 9) demonstrate considerable overlap in airway calibre between normal subjects and SAHS patients. An alternative hypothesis, which has received little attention, is that SAHS patients exhibit differences in the neuromuscular control of their upper airways (12, 13).
The retropalatal airway is the primary site of airway occlusion in the vast majority of SAHS patients (14). We have recently shown that palatal muscles reflexly increase their activity in response to negative pressure in normal subjects (15), which suggests that these muscles may play a role in protecting the upper airway against inspiratory collapse. We have, therefore, compared the responses of the palatal muscles to negative pressure using electromyography in SAHS patients and normal subjects to test the hypothesis that differences in reflex activity of upper airway muscles could contribute to the pathogenesis of SAHS. We have examined the EMG response of the muscles to negative pressure realizing that this approach has limitations and that the EMG response may not always parallel force generation. We have also examined the effects of chronic CPAP therapy on reflex palatal muscle electromyographic activity in SAHS patients to try to clarify whether any defect in upper airway muscle function is primary or could result from repeated upper airway obstruction during sleep.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
All subjects and patients gave informed consent to participate in the study, which had the approval of the local ethical advisory committee. Subjects took no medication or alcohol on the day of study.
SAHS patients/controls comparison. Sixteen nonsnoring healthy male subjects (mean age 33 SD 8 yr, mean body mass index 24 SD 2 kg/m2; Epworth Sleepiness Score [16] mean 5 SD 2) and 16 male SAHS patients (mean age 44 SD 11 yr, mean body mass index 32 SD 7 kg/m2; Epworth Sleepiness Score mean 10 SD 4) were recruited. SAHS patients either did not use CPAP therapy for three nights prior to the study or had not started therapy.
Effects of chronic CPAP therapy on EMG activity. Eight male
SAHS patients (apnea/hypopnea index 49 SD 17 hr
1, age 43 SD 8 yr;
body mass index 33 SD 6 kg/m2; CPAP compliance 6 SD 1 hr/night)
were studied both while on chronic nightly CPAP therapy (at least 2 mo) and when not taking CPAP therapy; either 3 nights off therapy
(n = 4) or prior to starting regular nightly CPAP (n = 4). The order of
the studies on or off CPAP therapy was determined using a randomized balanced design. All measurements were made during wakefulness without simultaneous CPAP. There was no significant change in
the patients' weight between the two limbs of the study.
Electrodes
The electrodes were made of sterile silver wire (A 5766-36; Cooner Wire Company, Chatsworth, CA) with an uncoated diameter of 0.125 mm and a teflon coated diameter of 0.175 mm. The last 2-3 mm of the wire was bared and lightly chlorided. The wires were threaded through 23 swg needles and the tip bent over bevel of the needle to make hooked intramuscular wire electrodes (17). Electrodes were then sterilized in ethylene oxide for 5 d.
Electrode Placement
After spraying the pharynx with topical lidocaine (40 mg), two needles containing electrodes were inserted perorally into the palatoglossus muscle which forms the anterior palatal arch of the pharyangeal fauces and acts to pull the soft palate downwards and forwards. The electrodes were inserted on the same side, parallel to the plane of the hard palate, 10 mm apart and 5 mm deep. Levator palatini inserts onto the posterosuperior aspect of the soft palate and its action is therefore to elevate the soft palate. Levator palatini electrodes were placed by inserting the electrodes through the inferior surface of the soft palate into the levator dimple which can be seen inferiorly when subjects say "aah," a sound which requires elevation of the soft palate, as previously described (18). The actions of upper airway dilator muscles are shown in Figure 1.
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Electromyogram Recording
A grounding electrode was placed on the subject's clavicle. The electromyogram (EMG) signals were processed by a unity gain bipolar 4-channel AC preamplifier close to the electrodes (Neurolog NL 824; Digitimer Ltd, Welwyn Garden City, Herts, UK) and then further amplified by Isolator NL 820 to give an amplification of between 0.1-50k. After filtering between 10 Hz and 2 kHz (NL 125), the signals were rectified and integrated with a time constant of 100 ms (NL703). The raw and integrated EMGs were displayed on an oscilloscope monitor (Multichannel large screen display SG 4100; Knott Elektronik, Germany) and recorded on video tape (JVC HR-D725EK) through an A/ D VCR adapter (model PCM 4/8; Medical Systems Corp., Greenvale, NY). The videotape was subsequently played back through the same VCR adapter and the output printed on a paper printer (Mark 10-1 Thermal Array Corder; Western Graphtec Inc., Japan). A recording was also made of the output from the amplifier system with the input electrodes shorted to obtain a zero reference signal.
Respiration Monitoring
Chest wall movements were measured by inductance bands placed at the level of the nipples and umbilicus and displayed on the monitor as well as recorded on video tape.
Application of Negative Pressure Stimuli
The system of Horner and coworkers (19) was modified so that subjects breathed either via a nose mask with an expiratory valve to minimize dead space (approximately 100 ml) or via a mouth piece (dead
space 100 ml) attached to a circuit open to atmosphere such that inspiration occured through a solenoid actuated spring return valve (Martonair/Beech, B/6S5P/122/M, Lichfield, UK). At end expiration (functional residual capacity) the solenoid valve was activated to rapidly
change (10 ms) the breathing circuit from atmosphere to a 50 liter reservoir evacuated to an excess negative pressure of 100 cm H2O.
Spring loaded valves (Medic Aid, Pagham, UK) vented excess negative pressure to atmosphere so that subjects were exposed to a square
wave of negative pressure for approximately 400 msec. Negative pressures of 2.5, 5, 7.5, 10, 12.5 cm H2O were compared with a "dummy
stimulus" of 0 cm H2O. Integrated EMG amplitudes were measured
100 msec after the start of negative pressure application in order to
avoid voluntary muscle effects, which have been demonstrated to occur only after 150 msec (19).
Negative pressures were monitored at the nose mask and mouth piece using a Micromanometer (Furness Controls Ltd, Bexhil, UK) connected via 136 cm of tubing which introduced a delay of 2 ms; 0-90% response time was 10 msec. Retropalatal and oropharyngeal pressures were monitored using a catheter tip transducer (Gaeltec Ltd, S8b, Skye, Scotland) inserted via the nose with the tip positioned by visual per oral inspection 1 cm below the uvula, so that during mouth breathing the tip was below the soft palate and during nose breathing the tip was located behind the soft palate. This allowed both oropharyngeal (oral breathing) and nasopharyngeal (nose breathing) pressures to be measured. All pressure recordings were stored on video tape and transferred to paper for analysis as described above.
Protocol
After waiting 20 minutes to allow the effects of the lidocaine to wear off, by which time all subjects reported that sensation felt normal, maximum EMG amplitudes were recorded for levator palatini and palatoglossus by swallowing 5 times and also by breathing forcefully via the nose with the mouth open (palatoglossus), as described by Fritzell (20).
Subject position was standardized by seating subjects erect and asking them to look straight ahead. Negative pressure was applied at least 10 times at each negative pressure level. The order of application of the different levels of negative pressure were chosen for each subject using a randomized balanced design. Negative pressure applications were not applied until the EMG had returned to baseline tonic activity following a previous stimulus. Maximal maneuvers were repeated at the end of the experiment.
Analysis of Results
All integrated EMGs were expressed as a percentage of the maximum (17, 21) to allow intra- and intersubject comparison. The average integrated EMG for a minimum of 10 technically acceptable negative pressure applications at each level was used for statistical analysis. Technically acceptable applications were defined as stimulus application at FRC, the oro/nasal pressure approximated the applied pressure, baseline EMG activity was the same, and there was no EMG artifact. Repeat electromyography in individual patients/subjects was performed by placing the electrodes in the same position and depth on each occasion with reference to anatomical land marks previously described.
The effects of negative pressure on EMG activity were analyzed using one-way analysis of variance and t tests with Bonferroni corrections where appropriate (SPSS package, Microsoft Corp.). Nasopharyngeal and oropharyngeal pressures were measured in each subject with a catheter tip pressure transducer 100 msec after negative pressure application and compared by paired t tests. Two-way analysis of variance was used to compare catheter tip pressure stimulus in SAHS patients and normal subjects.
On average, SAHS patients were heavier and older than the normal subjects. To try to identify whether weight and age contributed to any observed differences between the groups, a further analysis was performed comparing results in the seven thinnest SAHS patients matched with seven of the normal subjects for body mass index (SAHS 27 SD 2, normals 26 SD 2 kg/m2; p > 0.3) and age (37 SD 11, 35 SD 8 yr; p > 0.5).
Two-way analysis of variance was used to compare reflex EMG activity in eight SAHS patients on and off CPAP therapy and also to compare SAHS patients on CPAP therapy with eight of the normal control subjects matched as closely as possible for age and body mass index.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Figure 2 shows the responses of levator palatini and palatoglossus to negative pressure application.
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Negative Pressure Application in Normal Subjects
In the normal subjects, reflex activity of levator palatini was significantly increased by application of increasing levels of negative pressure (Figure 3) via the nose (p < 0.001) and mouth (p < 0.001). Palatoglossus reflex activity was also increased significantly by negative pressure application via nose (p < 0.001) and mouth (p < 0.001).
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Negative Pressure Application in SAHS Patients
In the SAHS patients, reflex levator palatini activity was significantly increased by negative pressure applied via the mouth (p = 0.04) and via the nose (p = 0.006), Figure 4. Palatoglossus activity tended to increase with increasing negative pressure, but this was not statistically significant either via the mouth (p = 0.18) or nose (p = 0.17).
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Comparison of Negative Pressure Application in Normal Subjects and SAHS Patients
Comparison of the reflex EMG response in SAHS and normal subjects showed that there was a significantly greater levator palatini response in normal subjects when negative pressure was applied via mouth (p < 0.001) and nose (p < 0.001). Similar differences were demonstrated for palatoglossus, mouth (p < 0.001), and nose (p < 0.001). There was no significant difference in EMG response during dummy stimulus (0 cm H2O) application between the SAHS patients and normal subjects (p = 0.2). There was no significant difference in maximal EMG activity (measured in volts) for SAHS patients and controls for both levator palatini (p = 0.6) and palatoglossus (p = 0.8). There was also no difference in maximal EMG activity (p = 0.6) for both levator palatini and palatoglossus measured at the beginning and at the end of the experimental protocol.
Analysis of Age and Weight Matched Groups
The seven normal subjects demonstrated significantly greater EMG responses to negative upper airway pressure both for levator palatini (p < 0.001) and palatoglossus (p < 0.001) than age and weight matched SAHS patients irrespective of route (mouth p < 0.001; nose p < 0.001). There was no significant difference between the SAHS patients and normal subjects in the baseline EMG activity during dummy stimuli. The EMG responses for nasal negative pressure application in SAHS patients and normal subjects are shown in Figure 5.
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Nasopharyngeal and Oropharyngeal Negative Pressures
There were no significant differences in the negative pressure stimuli applied to the pharynx, via the nasal or oral route for either SAHS patients or normal subjects (Table 1). Comparison between normal subjects and SAHS patients showed no significant difference in the pressure applied to the pharynx via the nose (p = 0.6) or mouth (p = 0.6).
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Effects of CPAP on Reflex EMG Activity
There was a significant increase in EMG activity in response to nasal negative pressure application when patients were on CPAP compared with off CPAP (levator palatini p < 0.001, palatoglossus p = 0.003, Figure 6). Comparison of dummy stimulus response on and off CPAP showed no significant difference in EMG activity (levator palatini p = 0.2, palatoglossus p = 0.8).
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Oral negative pressure application resulted in a greater reflex EMG response to negative pressure on CPAP compared with off CPAP for levator palatini (p = 0.03). There was a nonsignificant trend for palatoglossus to show increased activity on compared with off CPAP (p = 0.1). Comparison of dummy stimulus response on and off CPAP showed no significant difference in EMG activity (levator palatini p = 0.4, palatoglossus p = 0.9). Maximal EMG activity measured in volts was not significantly different whether patients were on or off CPAP; levator palatini (p = 0.5) and palatoglossus (p = 0.3).
Comparison of Negative Pressure Application on Reflex EMG Activity in 8 SAHS Patients on CPAP and 8 Normal Control Subjects
Comparison of negative pressure application in eight SAHS patients and eight normal control subjects using analysis of variance demonstrated that there was no significant difference in reflex EMG activity in response to nasal negative pressure application for both palatoglossus (p = 0.3) and levator palatini (p = 0.3). Oral negative pressure application was associated with greater palatoglossus activity in control subjects compared with SAHS patients on CPAP (p = 0.03); however, there was no difference in levator palatini EMG activity (p = 0.3). Comparison of EMG responses to individual negative pressures (0, 2.5, 5, 7.5, 10, and 12.5 cm H2O) between the two groups using t tests with multiple comparison corrections revealed no significant difference for both muscles and routes.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
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The present study has demonstrated that the levator palatini and palatoglossus muscles of SAHS patients have decreased electromyographic reflex responses to negative upper airway pressure compared with normal subjects and that in SAHS patients this attenuated reflex response may be significantly improved by chronic CPAP therapy. This suggests that there may be altered upper airway neuromuscular function in SAHS patients, which may play a significant role in the development of upper airway obstruction during sleep.
Both levator palatini and palatoglossus exhibit phasic inspiratory EMG activity in awake normal subjects (15), with
the level of activity varying according to the route of respiration. Palatoglossus is more active during nose breathing and is
presumably acting to pull the soft palate forwards. Levator palatini on the other hand is more active during mouth breathing
which will elevate the soft palate. These observations coupled
with reflex EMG activity in response to a negative pressure
stimulus (15) strongly suggest that these muscles are acting as
upper airway dilators. In the present study SAHS patients
show increased levator palatini activity with negative upper
airway pressure, but no statistically significant increase in
palatoglossus activity with negative upper airway pressure
and SAHS patients also show a reduced response to negative upper airway pressure compared with normal subjects. The
lack of a marked palatoglossal response to negative airway
pressure in SAHS patients would be expected to impair defence of the upper airway on inspiration, permitting the soft
palate to obstruct the upper airway during nasal breathing
the dominant route during sleep. The reduced activation of
both palatoglossus and levator palatini to negative airway
pressure in SAHS patients compared with normal subjects
would suggest a lack of palatal stiffening in response to negative pressure contributing to increased upper airway compliance and predisposing to upper airway occlusion. The suggestion that these muscles, which are traditionally believed to be
antagonists, in fact act together to stiffen the pharynx is compatible with the recent observation of a parallel reduction in
palatoglossus and levator palatini tone during obstructive apneas (22).
EMG activity was expressed as percentage maximum to allow intersubject comparison for both levator palatini and palatoglossus; the maneuver which elicited the greatest activity for both muscles was swallowing. This maneuver is highly reproducible, which is probably a reflection of the fact that swallowing is initiated voluntarily but, thereafter, is involuntary. The validity of this approach is strengthened by the finding that maximal activity in voltage units was the same for SAHS patients and normal control subjects and did not change during the course of the experiment.
Awake subjects were studied because it would be difficult to get normal control subjects to sleep with all the instrumentation required and this would compromise the validity of a comparison with SAHS patients. However, we believe that the differences in reflex activity may persist during sleep.
Possible methodological explanations for the differences between the normal subjects and SAHS patients need to be examined. Differences in obesity do not explain the disparity as the subgroup of patients who were not different in body mass from the subgroup of normal subjects still showed highly significant differences in upper airway responses to negative pressure and further, there was no correlation between body mass and upper airway response to negative pressure in either group. Similarly, we do not believe that age is a factor as differences in upper airway response to negative pressure between SAHS patients and normal subjects were highly significant in the age matched group and again there was no correlation between age and upper airway response to negative pressure in either group. Differences in upper airway anatomy do not provide an explanation as there is considerable overlap between upper airway size in normal subjects and SAHS patients (8, 23) and head position was standardized. Differences in facial bone structure and muscle length may play a role in some SAHS patients (24) but are unlikely to be major factors in this relatively obese group (25). The EMG response measured 100 ms after negative pressure application is a reflex and not a voluntary response (19). The pressure applied to the upper airway was identical in the two groups. Genioglossus has been shown to be a heterogeneous muscle with different responses at different sites (26). If this also applied to palatal muscles, it would increase data scatter, but such dispersion would be random tending to obscure differences, and thus would not account for the observed differences between the groups. Thus, we believe that there is a genuine difference in the EMG response to negative upper airway pressure between SAHS patients and normal subjects.
The only upper airway dilator muscle in which force genration can be tested in vivo is the genioglossus. We have found no difference in the maximal genioglossus protrusion force or fatiguability when comparing SAHS patients and control subjects matched for fat free mass (an index of total body muscle) and age (27) and also no difference in the EMG activity/force relationship for genioglossus when comparing SAHS patients and control subjects (28). If these results are applicable to the palatal muscles (at present we know of no way to assess this in vivo), this would suggest impaired force generation in response to negative upper airway pressures in SAHS patients. This would be compatible with the observation that upper airway obstruction can be more readily induced by negative upper airway pressure in SAHS patients than control subjects (29). We cannot be certain that EMG activity correlates with force for palatal muscles, it may also reflect muscle stiffening without generation of force which could also serve to maintain upper airway patency. Therefore, maintenance of upper airway patency could have two mechanisms (force generation or intrinsic muscle stiffening) and EMG activity could be a surrogate marker for both.
After CPAP therapy the upper airway response to negative pressure increased in SAHS patients such that there was no significant difference in palatal muscle reflex EMG response to negative pressure between SAHS patients and control subjects for three of four analysis of variance comparisons; palatoglossal activity was still impaired in response to oral negative pressure. However, a post hoc comparison of the EMG responses to individual pressures revealed no difference between SAHS patients and control subjects. These results support the hypothesis that there is no inherent primary differences between SAHS patients and normal subjects, but rather the observed difference in untreated SAHS patients is a reversible consequence of SAHS. The underlying mechanisms causing the observed difference could include upper airway edema (30, 31) resulting from repetitive upper airway trauma associated with snoring decreasing the sensitivity of pressure receptors, sleep fragmentation altering upper airway control (32), altered length/tension relationships or increased upper airway muscle strength requiring a lower EMG increase to produce a similar force generation (33). However, it must be recognized that the SAHS patients on CPAP were not ideally matched to the original control group and were more obese (BMI 32.3 SD 6/24 SD 2 Kg/m2) and older (age 43 SD 9/37 SD 3 yr) and the numbers studied were small. Thus, although the data that CPAP increases the upper airway EMG response to negative pressure is firm, further studies would be required to determine whether total normalization of the response to negative pressure results from chronic CPAP therapy. However, CPAP compliance is not perfect (34) and, therefore, even a larger and better matched study might not give a categorical answer to that question.
SAHS patients are reported to have increased resting (tonic) genioglossal EMG activity compared with normal subjects (21) and this has been interpreted as showing that they have greater defence of their upper airways. We have previously been unable to confirm this observation (17). The current study showed no difference in baseline (tonic) palatal muscle EMG activity between SAHS patients and normal subjects, the difference being in their response to negative pressure. Palatal muscles tense on inspiration and in response to negative pressure (15) and impairment of this response is, therefore, likely to predispose to upper airway narrowing and occlusion characteristic of the SAHS syndrome. The differences demonstrated may, therefore, significantly contribute to the pathogenesis of upper airway occlusion in the sleep apnea/hypopnea syndrome. The improved reflex response following chronic CPAP therapy may help to explain the observations of Kribbs and coworkers (35) of a reduction in apnea/hypopnea index during a first night off chronic CPAP therapy.
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Footnotes |
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This study was funded by The Wellcome Trust.
Correspondence and requests for reprints should be addressed to Professor Neil J. Douglas, Respiratory Medicine Unit, Department of Medicine, Royal Infirmary, Edinburgh, EH3 9YW, Scotland, UK. E-mail N.J.Douglas{at}ed.ac.uk
(Received in original form August 6, 1996 and in revised form April 7, 1997).
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References |
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
REFERENCES
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