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1 First Department of Medicine, Asahikawa Medical College, Asahikawa, 078-8510, Japan; and 2 Department of Physical Therapy, Exercise and Nutrition Sciences, and Center for Sleep Disorders Research, University at Buffalo, State University of New York, Buffalo, New York 14214-3079
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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To
investigate the hypothesis that the impaired respiratory drive noted in
morbid obesity was attributable to altered dopaminergic mechanisms
acting on peripheral and/or central chemoreflex sensitivity, seven
obese and seven lean Zucker rats were studied at 11 wk of age.
Ventilation (
E) was measured by the barometric
technique during hyperoxic (100% O2), normoxic (21%
O2), hypoxic (10% O2), and hypercapnic (7%
CO2) exposures after the administration of vehicle
(control), haloperidol [Hal, 1 mg/kg, a central and peripheral dopamine (Da) receptor antagonist], or domperidone (Dom, 0.5 mg/kg, a
peripheral Da receptor antagonist). In both lean and obese rats, Hal
increased tidal volume and decreased respiratory frequency during
hyperoxia or normoxia, resulting in an unchanged E.
In contrast, Dom did not affect tidal volume, frequency, or
E during hyperoxia or normoxia. During hypoxia,
however, E significantly increased from 1,132 ± 136 to 1,348 ± 98 ml · kg
1 · min1
(P < 0.01) after the administration of Dom in obese
rats, whereas no change was observed in lean rats. Hal significantly
decreased E during hypoxia compared with control in
lean but not obese rats. In both lean and obese rats, Hal decreased
E in response to hypercapnia, whereas Dom had no
effect. Our major findings suggest that peripheral chemosensitivity to
hypoxia in obese Zucker rats is reduced as a result of an increased
dopaminergic receptor modulation in the carotid body.
haloperidol; domperidone; peripheral chemosensitivity; hypoxia
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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MORBID OBESITY IS OFTEN ASSOCIATED with respiratory deficits, including alveolar hypoventilation. It has been demonstrated that severely obese patients with obesity hypoventilation syndrome exhibit blunted ventilatory responses to hypoxia and/or hypercapnia (21, 39), suggesting that the pathogenesis in the alveolar hypoventilation may be linked to altered chemoreflex mechanisms (39).
The control of breathing is modified by inputs that originate from
central and peripheral chemoreceptors. Dopamine (Da), a monoamine
neurotransmitter, is the most abundant catecholamine in the brain and
in carotid body (6). Although Da is known to inhibit the
afferent neuronal activity from the carotid bodies (6,
14), it stimulates neuronal activity involved in central respiratory regulation (13). Thus Da appears to exert
contrasting effects of ventilatory regulation: a depressive modulation
of E on peripheral chemoreflex drive, and a
stimulatory modulation of E on the central nervous
system (2, 13, 38).
The obese Zucker (Z) rat, a genetic model of morbid obesity with a
leptin receptor mutation (27), presents many of the same abnormalities as observed in obese humans, including a depressed respiratory drive (11, 17, 19, 23, 30) and increased serum
leptin levels (4). In obese Z rats, a deficit in leptin access into the brain has been known to account for their overeating and the development of their obesity. Moreover, leptin can stimulate E either directly by acting on respiratory control
centers or indirectly through other pathways (24). On the
other hand, Da metabolite content in the brain is reduced in obese Z
rats compared with lean rats (26), and it has been
demonstrated that eating behavior and food intake are associated with
Da levels in the hypothalamus (12). Moreover, Da is
required for feeding in mice with leptin deficiencies
(33). It has been recently demonstrated that leptin
inhibits Da release from perfused hypothalamic neuronal endings
(synaptosomes) in vitro (3). We speculate, therefore, that
the role of Da in mediating the control of breathing is altered in obesity.
In the present study, we hypothesized that the impaired respiratory
drive noted in obese Z rats could be linked in part to altered
dopaminergic mechanisms acting on peripheral and/or central chemoreflex
sensitivity. To examine our hypothesis, we measured E during hyperoxia, normoxia, hypoxia, and
hypercapnia in obese Z rats after the systemic administration of either
domperidone (Dom), a peripheral Da receptor antagonist that cannot
cross the blood brain barrier (BBB), or haloperidol (Hal), a Da
receptor antagonist that can cross the BBB. A parallel study design was used with age-matched lean Z rats serving as nonobese controls.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals
Seven pairs of the lean (Fa/?) and obese (fa/fa) male Z rats were studied at ~11-12 wk of age. Animals were purchased at 4 wk of age from Vassar College, Poughkeepsie, NY. One lean and one obese rat were housed per cage. Ambient temperature was maintained at 24°C with a 12:12-h light-dark cycle. All animals were provided with standard laboratory chow (Purina) and water ad libitum. The Institutional Animal Care and Use Committee, University at Buffalo, approved all experimental protocols.Techniques and Measurements
Ventilation was measured by using the barometric technique, which has been previously described (17-19, 23). A cylindrical Plexiglas chamber with a volume of 4 liters was used for the measurements ofE. The rat was placed in the
chamber within a restrainer that did not permit backward rotation. The
animal chamber had an inlet tube that was connected to pressurized air
tanks (BOC Gases). Inlet flow was regulated at 2 l/min by a flowmeter
(Dwyer Instruments, Michigan City, IN). An Ametek S-3A/I O2
analyzer and an Ametek CD-3A CO2 analyzer measured the
concentrations of inflowing or outflowing O2 and
CO2, respectively. The calibrations of the gas analyzers
were checked routinely, using certified calibration gases (BOC Gases).
To measure E, the chamber was completely sealed
after momentary interruption of the flow through it, and the
oscillations in pressure caused by breathing were recorded by a
sensitive pressure transducer (Statham Laboratories, model 236). The
signal was received, amplified (Grass Instruments), and displayed on an
oscillographic strip chart recorder (Grass polygraph). An average of 50 breaths was recorded on paper at a speed of 10 mm/s. Injection and
withdrawal of 0.3 ml of air with a 1-ml syringe were performed several
times during the recording, for calibration purposes. Body temperature
(Tb) was measured continuously by a thermometer probe (Yellow Springs
Instruments) placed at least 5 cm into the rectum. The thermometer was
calibrated with a mercury thermometer over the range from 35 to 40°C
of temperature. Chamber temperature and relative humidity were
monitored by a flow-through probe (Fisher Scientific) mounted within
the chamber. Barometric pressure values to the nearest hour were
obtained from the Internet posting of the U. S. weather bureau
located at the Buffalo International Airport.
Respiratory frequency (f) was calculated directly from the
E-induced pressure swings. Tidal volume
(VT) was obtained as a function of the pressure change
inside the chamber. Pulmonary E was calculated
(E = VT × f) and expressed in either
absolute value (ml/min) or corrected value for body weight
(ml · kg1 · min1).
O2 consumption (O2) and
CO2 production (CO2) were
calculated from the inflow-outflow O2 and CO2
differences multiplied by the gas flow, neglecting the small error
introduced by a respiratory quotient less than unity. All
O2 and
CO2 values (presented at
STPD) are expressed either in raw data (ml/min) or per unit of effective body mass because lean and obese rats of the same size
have different body compositions (28). Effective body mass for lean and obese Z rats was calculated as 1.00 × M0.75 and 0.86 × M0.75, respectively,
where M is the body weight (kg) of the animal.
Experimental Protocol
To reduce the stress level during the experiment, all animals were habituated to an intraperitoneal injection of 0.4 ml of saline, the insertion of the thermoprobe, and the restraining device within the chamber for 60 min on 2 successive days before the first experimental study.Study 1.
To rule out the possible stress effects due to handling,
insertion of the thermoprobe, and restraint, a preliminary study was
performed in lean (n = 6) and obese
(n = 6) Z rats at 8 wk of age. After an
intraperitoneal injection of dimethyl sulfoxide (DMSO; 1 ml/kg) and the
insertion of a colonic thermoprobe, the rat was placed into the
barometric chamber within the restrainer, and it breathed room air for
60 min. Tb and E were measured at 5- and 10-min
intervals, respectively.
Study 2. Each animal was tested at 3-day intervals after an intraperitoneal injection of equal volumes of vehicle (DMSO, 1 ml/kg), Hal (1 mg/kg, central and peripheral Da receptor antagonist), or Dom (0.5 mg/kg, peripheral Da receptor antagonist). The solutions were prepared daily and placed in vials labeled as I, II, or III. The three agents were given in a randomized design on days 1, 4, and 7. The investigator involved in the actual testing remained blinded to the contents of the vials until the entire study was completed and analyzed. To minimize any potential differences due to circadian rhythms, experiments were begun in each animal at the exact same time between 0800 and 1500.
After the administration of the agent, the rat was placed into the barometric chamber within the restrainer and exposed to normoxia (21% O2, balance N2) for 30 min followed by hyperoxia (100% O2) for 3 min, normoxia for 10 min, and hypoxia (10% O2, balance N2) for 3 min. Thereafter, the rat was exposed to hyperoxia (100% O2) for 5 min again followed by hypercapnia (7% CO2, balance O2) for 5 min. Ventilatory data were collected during the last minute of each gas exposure. The total experimental period was 60 min.Statistical Analysis
Body weights of individual rats were averaged over the experimental period, and differences between lean and obese rats were tested by unpaired Student's t-test. In study 1, analysis of variance (ANOVA) with repeated measure was used. In study 2, the differences inE responses
to hyperoxia/hypoxia or hypercapnia between lean and obese Z rats were
analyzed by factorial ANOVA concerning phenotype and gas exposure. The
differences between data among the responses after each agent
administration within a single group were analyzed by one-way ANOVA.
When significance was indicated (P < 0.05), a
Bonferroni's correction for multiple comparisons was used. A P value of <0.05 was considered statistically significant.
All data presented in the text, tables, and figures are means ± SD.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Study 1
As shown in Fig. 1, the mean Tb at 5 min after DMSO injection was 38.1 ± 0.1°C in lean and 37.9 ± 0.1°C in obese Z rats, respectively, and these values did not change significantly during the entire 60-min observation period. AlthoughE was increased at 10 min after DMSO
injection in the two groups, no difference in E was detected from 20 to 60 min after injection (Fig. 1).
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Study 2
Comparisons between control lean and obese rats.
The obese Z rats weighed more than age-matched lean animals (438 ± 42 vs. 283 ± 18 g, P < 0.01). Obese Z rats
adopted a breathing strategy with a higher f and a lower VT
(ml/kg) than lean rats during room air breathing (Table
1). Resting
O2 and
CO2 during room air were not different
between lean and obese rats. Figure 2
illustrates different ventilatory responses to hypoxia (Fig. 2A) and hypercapnia (Fig. 2B) between lean and
obese Z rats. Although E values during hyperoxia
(100% O2) and normoxia (21% O2) breathing were not different between lean and obese rats, ventilatory response to
3-min hypoxia (10% O2) was significantly reduced in obese
rats compared with lean rats (P < 0.01). In addition,
ventilatory response to 5-min hypercapnia (7% CO2) was
also significantly reduced in obese rats compared with lean rats
(P < 0.01).
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Normoxia.
As shown in Table 1, in both lean and obese Z rats, neither Hal nor Dom
administration changed Tb, O2, and
CO2 during room air breathing. However,
Hal significantly decreased f and increased VT, resulting
in no changes in E compared with the vehicle control
in both lean and obese Z rats. On the other hand, Dom had no effects on
f, VT, and E in both lean and obese Z rats during normoxic breathing (Table 1).
Hyperoxia and hypoxia.
The changes in E, f, and VT during
hyperoxia, normoxia, and hypoxia exposure after vehicle or Hal
injection are summarized in Fig. 3. In
lean Z rats during hyperoxia as well as normoxia, the administration of
Hal did not change E, although f decreased and
VT increased. During hypoxic exposure, the administration of Hal in lean rats elicited a significant depression in
E (P < 0.05) due to a decrease
in f and little change in VT. In contrast to lean
rats, obese rats displayed no change in E in
response to Hal during hypoxia, because of a decrease in f and an
increase in VT (6.31 ± 0.85 to 7.28 ± 0.61 ml/kg, P < 0.05).
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E. However, the remaining three lean
rats exhibited no changes in VT, f, and
E during hypoxia. Dom did not significantly change f, VT, and E during hypoxia compared
with vehicle control in lean rats as a group (Fig.
4). In contrast, all obese rats increased VT during hypoxia after administration of Dom compared with
vehicle control (7.57 ± 0.88 vs. 6.31 ± 0.85 ml/kg,
P < 0.01) without changes in f, resulting in a
pronounced rise in E compared with control
(1,348 ± 98 vs. 1,132 ± 136 ml · kg1 · min1,
P < 0.01). On the other hand, Dom did not change any
parameters during hyperoxia in both lean and obese rats (Fig. 4).
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Hypercapnia.
In both lean and obese rats, Hal decreased E
responses to hypercapnia mainly because of a decreased response in
VT (Fig. 5). The patterns of
alterations in E, f, and VT with Hal
were not different between lean and obese rats. On the other hand, Dom
did not affect E, f, or VT in response
to hypercapnia compared with control in both lean and obese rats (data
are not shown).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Critique of Experimental Design
Before discussing our results, we need to address several limitations of the experimental design. First, restraint may have influencedE, and our vehicle, DMSO, may have
stimulated E (8) and depressed body
temperature (25). However, as demonstrated in study
1, E and Tb were constant (Fig. 1) at least
during the experimental period tested in study 2, and
therefore we do not believe that either restraint or DMSO affected our
findings. In addition, a potential neurotoxicity has been
reported when DMSO is administered daily for 10 successive days
(5). However, because we injected each animal with DMSO at
3-day intervals and only on three occasions, it is unlikely that
neurophysiological alterations would have resulted.
Second, although we did not examine dose-response relationship and time
course of drug activity, the doses of Hal and Dom selected in the
present study and the timing of the ventilatory parameters after drug
administration were determined carefully according to previous reports.
Hal, a neuroleptic agent that crosses the BBB, has been widely used in
conscious rats ranging in doses up to 2 mg/kg (ip) to examine its
effect on seizures and behavior (22, 29). Hal is known to
progressively increase E at low doses (0.1-100
µg/kg) and to decrease E at intermediate doses (1 mg/kg) (6). This dual action of Hal on
E is considered to reflect either peripheral
chemoreceptor stimulation or central dopaminergic neuron inhibition.
Thus, to block both peripheral and central Da receptors, we chose an
intermediate dose (1 mg/kg) of Hal to investigate the difference in
ventilatory response to chemical stimuli between lean and obese Z rats.
On the other hand, Dom, which does not readily cross the BBB, has been
used safely up to a dose of 10 mg/kg in conscious rats to protect from
gastrointestinal disorders (20). With regard to
ventilatory effects of Dom, it has been demonstrated that 0.1 mg/kg of
Dom increased ventilatory response to hypoxia in rats
(36), and the E or carotid sinus nerve
response to hypoxia is significantly enhanced by the administration of
0.7 mg/kg of Dom in cats (14, 35). Therefore, to achieve a
sufficient inhibition of peripheral Da receptors, we selected 0.5 mg/kg
of Dom in the present study. In all rats tested, behavioral effects
such as hypoactivity or sedation were never observed after the
administration of either agent.
Two major families of Da receptors, referred to as D1 and D2, have been identified (10). Because two selective D2 antagonists, Hal and Dom, have been widely utilized for the investigation of dopaminergic mechanism, we selected them to examine our hypothesis in the present experimental design. Any effects we observed should be ascribed predominantly to D2 receptors because we limited the scope of our study to the effects of Da acting on central and/or peripheral D2 receptors. Because Hal and Dom were injected systemically to produce a widespread antagonistic action, we have to add a cautionary note that any effects we observed cannot be isolated either to any specific system or to any neural structure. Nevertheless, the goal of the present study was to differentiate the ventilatory effects of endogenous Da acting on central and/or peripheral D2 receptors and potential difference in ventilatory response between lean and obese Z rats.
Normoxia and Hyperoxia
Da is widely accepted as an inhibitory neurotransmitter in the carotid body (2). In mammals, Da and Da receptor agonists injected into the central nervous system consistently produced ventilatory augmentation during either normoxia or hypoxia (13), whereas peripheral Da receptor antagonism consistently enhancedE and carotid chemoreceptor
discharge (2). Thus Da appears to exert a dual effect on
respiratory modulation: central ventilatory stimulation and peripheral
ventilatory depression.
Because Hal crosses the BBB, it produces effects that are a combination
of peripheral chemoreceptor stimulation and central dopaminergic neuron
inhibition. In the present study, both lean and obese Hal-treated rats
decreased f and increased VT, resulting in an unchanged
E during hyperoxic and normoxic breathing. These results are in agreement with a previous study in rats showing that the
intracerebroventricular injection of Hal elicited a depression in f and
an increase in VT, suggesting a tonic influence on Da receptors involved in central respiratory regulation (13).
Dom, on the other hand, does not cross the BBB; thus its effects are limited to peripheral chemoreceptors. Because Dom administration did
not affect f, VT, and E in both lean and
obese Z rats during hyperoxic and normoxic breathing, endogenous Da
acting on D2 receptors does not modulate
E under these conditions without hypoxia. Our
findings are consistent with a report in healthy humans reporting that
Dom administration produced no significant change in
E during normoxic breathing (9).
Hypoxia
As stated earlier, Hal crossing the BBB antagonizes both central and peripheral D2 receptors, which consists of reversing Da-mediated peripheral ventilatory stimulation and central ventilatory depression. Indeed, it has been demonstrated that Hal greatly attenuates the ventilatory response to hypoxia despite an increase in carotid chemoreceptor activity, suggesting that Da acts as an excitatory neurotransmitter in the integrating centers projecting from peripheral chemoreceptor activity (31). In lean Z rats, Hal did not change VT, but f declined during hypoxia, resulting in a significant decrease inE compared
with vehicle control, suggesting that the role of central
D2 modulation of E outweigh the role of
peripheral D2 receptors in lean Z rats. In contrast, the
administration of Hal in obese Z rats significantly increased VT with a concomitant decline in f during hypoxia,
resulting in no (minimal) overall effect on E.
Although the central inhibitory effects by Hal are superimposed on the
ventilatory output in obese Z rats, the augmented VT
response to hypoxia by Hal seems to be due to an increased
D2 contribution to the peripheral chemoreceptors in obese Z
rats. However, from our results with Hal, we cannot exclude a
possibility that central D2-mediated hypoxic ventilatory stimulation may be blunted in obese Z rats.
It is known that the peripheral Da receptor antagonist Dom stimulates
E and carotid body chemoreceptor afferent neural
activity (16, 38). Moreover, in normal awake cats and
goats, Dom increases E in response to hypoxia by
removing tonic inhibition from endogenous carotid body Da receptors
(16, 35). We noted that, in lean Z rats,
E in response to acute hypoxia did not significantly increase after treatment with Dom (Fig. 4), suggesting no tonic peripheral inhibitory ventilatory modulation by Da in lean rats. Walsh
et al. (37) showed that, in humans, half of the population did not augment their hypoxic ventilatory response when pretreated with
Dom, suggesting a wide variability in individual hypoxic sensitivities
in response to Dom. Tatsumi et al. (35) also demonstrated in cats that peripheral chemoreceptor responsiveness to hypoxia was
highly variable among individual cats as well as the ventilatory response to Dom. In the present study, four of the seven lean (Fa/Fa or Fa/fa) rats, but all the obese
(fa/fa) rats, exhibited increased VT
and E responses to hypoxia after the administration of Dom, indicating that a genetic factor may account for the variable responsiveness to Dom during hypoxia. Nevertheless, in comparison between the two groups, we found that the administration of Dom in
obese Z rats restored the ventilatory response to hypoxia compared with
vehicle control, such that it became indistinguishable from that of
control lean rats (Fig. 4). These results suggest that in the carotid
body Da could have a pivotal role in modulating the depressed
ventilatory responses to hypoxia observed in obese Z rats compared with
lean Z rats.
Our findings from both the Hal and Dom studies suggest that the sensitivity to hypoxia in the peripheral chemoreceptors in obese Z rats may be blunted as a result of an abnormality originating from dopaminergic mechanisms. Further studies, including measurements of the carotid sinus nerve activity, however, will be necessary to substantiate our perspectives.
Hypercapnia
In contrast to the role of Da on ventilatory sensitivity to hypoxia, controversy remains over its role in mediating the response to hypercapnia. In the present study, Hal decreased ventilatory response to hypercapnia mainly as a result a decreased response in VT, whereas Dom had no the effect on them in both lean and obese rats. These results are consistent with the findings of Berkenbosch et al. (1), who reported that Hal diminished both the peripheral and central ventilatory sensitivity to CO2 whereas Dom had no effect on peripheral CO2 sensitivity in anesthetized cats. Donnelly et al. (7) further demonstrated that Hal had no effect on carotid sinus nerve discharge in response to hypercapnia in cats. From our results, we suggest that D2 receptors in the central pathways play an important role in ventilatory response to hypercapnia in both lean and obese Z rats. In contrast to the above findings, it has been reported that Dom enhanced the ventilatory response to hypercapnia via an effect on the carotid bodies in awake goats (16), and also Dom augments that peripheral chemosensory discharge in response to hypercapnia in anesthetized cats (14). These conflicting findings could be ascribed, at least in part, to species differences, to the state of consciousness, or to differences in dosages of drugs or levels of hypercapnia.In comparison with lean rats, obese Z rats did not differ in the effects of both Hal and Dom on their hypercapnic ventilatory response, suggesting that the dopaminergic mechanisms for CO2 sensitivity in the brain stem integrating centers or the peripheral chemoreceptors may not be different between obese and lean Z rats. We, therefore, suggest that the mechanism underlying the decreased hypercapnic ventilatory response in obese Z rats may not be dopaminergic D2 modulation in origin.
Obesity and Hypoxic Chemosensitivity
Previous studies have shown that severely obese subjects with alveolar hypoventilation have depressed ventilatory responses to hypoxia (21, 39). In the present study, obese Z rats were much heavier than lean rats and displayed blunted ventilatory response to hypoxia. In our previous studies, we have suggested that several neuromodulators including the opioids, GABA, nitric oxide, and glutamate may partially account for the depressed ventilatory response in obese Z rats (17-19, 23). The novel finding reported herein is that the blunted ventilatory response to hypoxia could be linked to a depression of the peripheral chemoreflex response of dopaminergic origin. The genetically obese Z rat has a mutation in the gene expressing leptin receptors (27), which have been found to be widely distributed in many organs. Leptin is known to inhibit Da release from neuronal endings of hypothalamic synaptosomes (3). Thus, in obese Z rats, abnormal leptin receptors lead to a disrupted leptin transport into the carotid body, resulting in an enhancement of Da release, which may be contributing to the blunted ventilatory response to hypoxia. Although little is known about whether obesity per se affects the peripheral dopaminergic metabolism, we suggest that an inhibitory action of Da in the carotid body may in part contribute to the development of obesity hypoventilation. Future studies evaluating the effects of Da receptor antagonists on obese Z rats of various ages may be used to test this hypothesis.In conclusion, the present results suggest that peripheral chemosensitivity to hypoxia in obese Z rats may be blunted as a result of altered dopaminergic mechanisms. Recent evidences, however, support a genetic predisposition for a reduced ventilatory response to hypoxia (32, 34). Thus, beside a mutation in leptin receptor, the altered dopaminergic modulation observed in obese Z rats may be genetic in origin. Furthermore, either synergistic or additive interaction of obesity with a preexisting genetic predisposition may exacerbate the blunted ventilatory response to hypoxia in obese Z rats. Further studies are needed to investigate the interactions between genetic and environmental factors on the drive to breathe in obesity.
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ACKNOWLEDGEMENTS |
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This research was supported by grants from the National Institute on Aging (AG-16048) and American Lung Association.
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FOOTNOTES |
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Address for reprint requests and other correspondence: G. A. Farkas, Dept. of Physical Therapy, Exercise and Nutrition Sciences, 405 Kimball Tower, Univ. at Buffalo, 3435 Main St., Buffalo, NY 14214-3079 (E-mail: farkas{at}acsu.buffalo.edu).
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. Section 1734 solely to indicate this fact.
Received 3 April 2001; accepted in final form 26 July 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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