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production contributes to
the attenuation of LPS-induced hypophagia by
pentoxifylline
Institute of Animal Sciences, Swiss Federal Institute of Technology, 8092 Zurich, Switzerland
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Cytokines such as
tumor necrosis factor-
(TNF-) and interleukin-1
(IL-1) are
assumed to mediate anorexia during bacterial infections. To improve our
understanding of the role that these two cytokines serve in mediating
infection during anorexia, we investigated the ability of
pentoxifylline (PTX), a potent inhibitor of TNF- production, to
block the anorectic effects of the bacterial products
lipopolysaccharide (LPS) and muramyl dipeptide (MDP) in rats.
Intraperitoneally injected PTX (100 mg/kg body wt) completely eliminated the anorectic effect of intraperitoneally injected LPS (100 µg/kg body wt) and attenuated the anorectic effect of a higher dose
of intraperitoneally injected LPS (250 µg/kg body wt). Concurrently,
PTX pretreatment suppressed low-dose LPS-induced TNF- production by
more than 95% and IL-1 production 39%, as measured by ELISA.
Similarly, high-dose LPS-induced TNF- production was reduced by
~90%. PTX administration also attenuated the tolerance that is
normally observed with a second injection of LPS. In addition, PTX
pretreatment attenuated the hypophagic effect of intraperitoneally injected MDP (2 mg/kg body wt) but had no effect on the anorectic response to intraperitoneally injected recombinant human TNF- (150 ug/kg body wt). The results suggest that suppression of TNF- production is sufficient to attenuate LPS- and MDP-induced anorexia. This is consistent with the hypothesis that TNF- plays a major role
in the anorexia associated with bacterial infection.
lipopolysaccharide; muramyl dipeptide; interleukin-1; cytokines; tolerance; food intake
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ACUTE
BACTERIAL INFECTIONS and other pathophysiological processes are
associated with anorexia. Anorexia is also observed after parenteral
administration of lipopolysaccharides (LPS), which are the major
constituents of the outer cell wall of gram-negative bacteria, and
muramyl dipeptide (MDP), which is the minimal immunologically active
structure of gram-positive bacterial cell walls. Administration of
either LPS or MDP results in the expression of cytokines such as tumor
necrosis factor- (TNF-) and interleukin-1 (IL-1) (28,
39). These cytokines act at central (and perhaps peripheral) target sites to reduce food intake through complex mechanisms (16, 21, 30) and are believed to mediate LPS- and
MDP-induced anorexia. Cytokine interaction in anorexia during bacterial
infections is supported by the observation that TNF- and IL-1
have a synergistic effect in inducing anorexia (36, 37).
Several studies have used cytokine-receptor antagonists and transgenic
animals to examine the role of cytokines in infection-induced anorexia
(e.g., 5, 14, 15, 24) with inconclusive results.
Another way of studying cytokine mediation of LPS- and MDP-induced
anorexia is to inhibit the endogenous synthesis of TNF- or IL-1
in LPS- and MDP-treated animals. The nonspecific phosphodiesterase (PDE) inhibitor pentoxifylline (PTX) is known to inhibit TNF- production after LPS stimulation both in vivo and in vitro (3, 9,
35). In the present study, we examined the ability of PTX to
inhibit the anorexia associated with the intraperitoneal injection of
LPS in rats. In addition, the production of TNF- and IL-1 was
quantified after LPS administration under the same conditions in
PTX-pretreated rats to determine if there was any relationship between
the suppressive effects of PTX on cytokine production and a possible
attenuation of LPS-induced hypophagia. The possibility that PTX
inhibition of cytokine synthesis might alter the development of
tolerance to LPS-induced hypophagia was also investigated. In a second
experiment, the ability of PTX to attenuate the anorexia in response to
MDP administration was evaluated. Finally, we studied the ability of
PTX to inhibit the hypophagia associated with exogenously administered
TNF- to provide evidence that blockade of TNF- synthesis is the
critical mechanism in a possible effect of PTX on LPS-induced anorexia.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Animals and housing conditions. Adult male, Sprague-Dawley rats (Charles River Laboratories, Sulzfeld, Germany) were used. They were individually housed in temperature-controlled (22 ± 0.5°C) colony rooms in stainless steel wire-bottom drawer cages. The rats were kept on an artificial 12:12-h light-dark cycle with the lights on from 2200 to 1000 and fed a ground rat chow diet (Nafag, Gossau, Switzerland).
Food intake was measured by manually weighing (±0.1 g) the feeding cups at 2, 4, 6, 8, 10, 12, and 24 h after injections. Spillage, collected on paper spread beneath the cages, was also measured. Food and tap water were available ad libitum. Before experiments, the rats were adapted to diet and experimental conditions for at least 2 wk. Each experiment was performed with a different group of rats. All procedures and protocols were approved by the Kanton of Zurich's Animal Use and Care Committee.Test procedures. On test days, groups of rats were matched for food intake and body weight during the preceding dark phase. In each study, all rats received a single intraperitoneal injection (pretreatment) of drug or corresponding vehicle solution followed 1 h later by another intraperitoneal injection (treatment) of drug or corresponding vehicle solution. Treatment injections were administered ~15 min before the onset of the dark cycle. Drug solutions were freshly prepared before injections.
For all feeding experiments, the pretreatment injections consisted of either 100 mg/kg body wt PTX (Sigma, dissolved in sterile isotonic saline) delivered in 0.1 ml/100 g rat or isotonic, pyrogen-free saline (NaCl). The treatment injection was either LPS (from Escheria coli serotype 0111:B4, Sigma L-2630, dissolved in sterile, isotonic saline), MDP (adjuvant peptide, Sigma, no. A-9519, dissolved in sterile, isotonic saline), or recombinant human TNF- (rhTNF-; Endotel, dissolved in a buffer consisting of sterile, filtered PBS
containing 0.1% pyrogen-free BSA). Control rats received an equivalent
volume of the appropriate vehicle. The dose of PTX was determined from
previous experiments examining its ability to attenuate TNF-
production in LPS-treated animals (3, 29). The doses of
LPS, MDP, and TNF- were selected on the basis of previous studies
comparing the effectiveness of these compounds to suppress food intake
in rats (17, 31).
Experiment 1. The effect of PTX pretreatment on the anorectic response to LPS (100 µg/kg body wt, delivered in 0.1 ml/100 g body wt) was tested in 28 rats (mean body wt 252 g) that were distributed into four groups (n = 7). The four groups were as follows: PTX pretreatment followed by LPS treatment (PTX-LPS), NaCl pretreatment followed by LPS treatment (NaCl-LPS), NaCl pretreatment followed by NaCl treatment (NaCl-NaCl), and PTX pretreatment followed by NaCl treatment (PTX-NaCl). Food intake was measured as previously described.
A previous study in this laboratory demonstrated that repeated exposure to LPS results in the rapid development of tolerance to the anorectic effect of LPS (31). Therefore, 24 h after the completion of the first study, the same rats as in the first trial received a second injection of LPS (100 µg/kg body wt) or vehicle to examine the effect of PTX on the induction of tolerance by LPS.Experiment 2. The effect of PTX pretreatment on the anorectic response to MDP (2 mg/kg body wt, delivered in 0.1 ml/100 g rat) was tested in 28 rats (mean body wt 288 g) that were distributed into four groups (n = 7) as explained in the first experiment, except that MDP was used instead of LPS. Food intake was then measured as previously described. A second injection of MDP was not given because MDP does not lose its anorectic effect with repetitive intraperitoneal injections (17).
Experiment 3.
The effect of PTX pretreatment on the feeding response to rhTNF-
(150 µg/kg body wt, delivered in 0.1 ml/100 g rat) was tested in 28 rats (mean body wt 280 g) that were distributed into four groups
[PTX-TNF, NaCl-TNF, NaCl-vehicle (Veh), PTX-Veh, n = 7 each] as described.
Experiment 4.
The rhTNF- (150 µg/kg body wt) administered in experiment
3 suppressed feeding more than the LPS (100 µg/kg body wt)
administered in experiment 1. Therefore, we performed a
fourth experiment to assess the ability of PTX (100 mg/kg body wt) to
inhibit the hypophagia in response to a higher dose of LPS (250 µg/kg
body wt) that would more closely resemble the hypophagia observed with
rhTNF-. The experiment was performed with 28 rats (mean body wt
252 g) in the same manner as experiment 1, except for
the higher dose of LPS used, and the second injection of LPS was not
administered to examine the effect on tolerance.
TNF- and IL-1 determination
after LPS administration.
Animals received either PTX- or NaCl-pretreatment injections followed
by either LPS- or NaCl-treatment injections as previously described.
Plasma samples were taken 85 min after the completion of the treatment
injections, a time point at which both TNF- and IL-1 plasma
levels are elevated in response to LPS (1). Rats were
anesthetized by intraperitoneal injection (1.00 ml/kg body wt) of a
mixture of 80 mg/ml ketamine (Ketasol-100, Graub), 20 mg/ml xylazine
(Rompun, Bayer), and 0.05 mg/ml acepromazine (Sedaline, Chassot and
Cie). A cutaneous incision on the midline of the upper abdomen was made
that extended to the chest cavity, exposing the heart. Blood was
aspirated by heart puncture with a needle and syringe. Blood was then
placed in polypropylene test tubes treated with 40 µl EDTA solution
and stored on ice until the end of the collection procedure. Samples
were then centrifuged (1,500 g at 4°C for 10 min). Plasma
was placed in microcentrifuge tubes for storage at 
80 C° until
cytokine determination.
and IL-1 analyses were performed for experiment 1 (low dose LPS: 100 µg/kg body wt), whereas only TNF- was analyzed for experiment 4 (high dose LPS: 250 µg/kg body wt).
Biotrak cellular communication assays (Amersham Life Science) were used
for quantitative determination of rat TNF- and IL-1 in plasma.
These TNF- and IL-1 assays are based on a solid-phase ELISA that
uses an antibody for either rat TNF- or rat IL-1 bound to the
wells of a microtitre plate together with a biotinylated detection
antibody to either rat TNF- or rat IL-1 and streptavidin conjugated to horseradish peroxidase. Both assays are highly sensitive (TNF-: <10 pg/ml, IL-1: <8 pg/ml) and specific for either rat TNF- or IL-1.
Statistics. Differences between group means were tested using an analysis of variance appropriate for a 2 × 2 factorial arrangement of PTX and LPS followed by a modified t-test when appropriate. P values <0.05 were considered significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Pretreatment with PTX (as compared with NaCl pretreatment) clearly
attenuated the hypophagia after intraperitoneal injection of 100 µg
LPS/kg body wt (Fig. 1). At every time
point measured, food intake was significantly lower in NaCl-LPS rats
than in the rats of the other three groups. PTX pretreatment did not
affect the food intake of NaCl-treated animals.
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After the second injection of 100 µg LPS/kg body wt in PTX-pretreated
rats (administered 48 h after the first injection of LPS), food
intake started to decline compared with NaCl-LPS animals at 8 h.
This difference reached statistical significance at 24 h (Fig.
2).
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PTX pretreatment (when compared with NaCl) reduced LPS induction of
TNF- production by >95% (P < 0.001; Fig.
3). TNF- was virtually nondetectable
in the NaCl-treatment groups. In contrast, PTX pretreatment (juxtaposed
to NaCl) reduced LPS-induced IL-1 production by only 39%
(P < 0.01; Fig. 4).
IL-1 was significantly lower in both NaCl-treatment groups
(P < 0.001) compared with either LPS-treatment group.
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Similar to its abolition of LPS-induced hypophagia, PTX pretreatment
(as opposed to NaCl pretreatment) prevented the hypophagia induced by
intraperitoneal administration of 2 mg MDP/kg body wt (Fig.
5). Beginning at 4 h, the food
intake of NaCl-MDP animals was significantly lower than in the three
other groups. The food intake of NaCl-treated animals was similar
regardless of the pretreatment (either NaCl or PTX).
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The intraperitoneal injection of 150 µg rhTNF-/kg body wt
significantly suppressed feeding (compared with vehicle treatment), and
PTX did not alter this hypophagic effect (Fig.
6).
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PTX pretreatment (as compared with NaCl pretreatment) attenuated the
hypophagia after administration of a high dose (250 µg/kg body wt) of
LPS (Fig. 7). This increase was
statistically significant from 10 h until 24 h. However,
regardless of the pretreatment, LPS treatment (as compared with NaCl
treatment) resulted in statistically significant hypophagia at every
time point measured. Unlike experiment 1 (Fig. 1), PTX
pretreatment (compared with NaCl pretreatment) significantly altered
the food intake of NaCl-treated animals at 2, 6, 8, and 10 h.
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PTX pretreatment (when compared with NaCl pretreatment) again reduced
LPS induction (250 µg/kg body wt) of TNF- production significantly
(P < 0.05; Fig. 8).
TNF- levels were miniscule in the NaCl-treatment groups and
significantly lower than the TNF- levels in LPS-treated animals
(P < 0.05).
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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To our knowledge, this is the first study to demonstrate that the
PDE inhibitor PTX is able to attenuate the anorexia in response to
intraperitoneally administered LPS (100 µg/kg body wt; 250 µg/kg
body wt) and MDP (2 mg/kg body wt) but is unable to inhibit the
anorexia in response to intraperitoneal rhTNF- (150 µg/kg body
wt). PTX pretreatment also blocked TNF- production in response to
low (100 µg/kg body wt)- and high (250 µg/kg body wt)-dose LPS
stimulation. Together, these findings support the hypothesis that
endogenous TNF- plays a major role in LPS-induced hypophagia. This
interpretation is also consistent with a previous study from our
laboratory (31) that showed that tolerance to the
hypophagic effect of exogenous TNF- is sufficient to eliminate
LPS-induced hypophagia.
PTX pretreatment before low-dose LPS administration resulted in a
significantly greater (P = 0.0023) suppression of
TNF- production (>95%) compared with the inhibition of IL-1
production (39%). TNF- production in response to high-dose LPS
administration was also significantly reduced (90%) by PTX
pretreatment (IL-1 production was not measured in response to
high-dose LPS stimulation). The decrease in IL-1 levels may be a
direct result of TNF- inhibition, because TNF- stimulates IL-1
production (1). The literature is confusing concerning the
ability of PTX to inhibit IL-1 production in models of bacterial
infection. Depending on the experimental conditions, PTX has been shown
to upregulate, downregulate, or have no effect on IL-1 production
after administration of gram-negative or gram-positive bacterial
products (8, 34, 38). Nevertheless, the present data do
not allow for the exclusion of a role of IL-1 in LPS-induced
hypophagia. The results demonstrate, however, that without substantial
TNF- production, even high plasma levels of IL-1 (presumably 
the 61% of the NaCl-low-dose LPS group) are not sufficient to
inhibit feeding to the same extent as in the presence of TNF-. This
observation is in agreement with other data suggesting a limited role
for IL-1 alone in the anorexia of the LPS model of infection. For
example, intraperitoneal or intracerebroventricularly administered
IL-1-receptor antagonist (IL-1ra) does not inhibit LPS-induced
hypophagia (14). More recently, IL-1-converting
enzyme-deficient mice were shown to resist the anorectic effect of
intracerebroventricularly but not intraperitoneally administered LPS
(4). In addition, tolerance to the hypophagic effect of
LPS is accompanied by the absence of an increase in serum TNF- in
response to subsequent LPS stimulation, whereas IL-1 production is
not affected or even augmented (17, 33). Furthermore,
sensitization to the anorectic effect of IL-1 after repeated
administration does not alter the hypophagic effect of LPS on feeding
(22), as would be expected if endogenous IL-1 mediates
LPS-induced anorexia. The lack of IL-1 in transgenic mice also does
not prevent the anorexia induced by LPS or influenza virus
(15). It should be noted, however, that LPS also reduces food intake in TNF double-receptor knockout mice (24).
Thus IL-1 and, in particular, TNF- presumably play a substantial role in LPS-induced anorexia, which becomes evident when these cytokines or their actions are acutely antagonized. On the other hand,
IL-1 and TNF- are not necessary for LPS-induced hypophagia. Yet,
it is reasonable to assume that transgenic animals do not discretely
evaluate how the intact system works and are probably not the best
models to investigate LPS-induced hypophagia, because the knockout
strategy does not account for adaptive and compensatory mechanisms
during development that may modify the connection between hypophagia
and the knockout gene product (TNF- or IL-1).
PTX pretreatment also partially inhibited the development of tolerance
to low-dose LPS-induced hypophagia in the first experiment. This may be
the result of PTX's ability to block TNF- expression after LPS
stimulation. Studies indicate that LPS stimulation of cytokine
production initiates mechanisms that lead to tolerance (11,
26). Thus by drastically attenuating TNF- production after
LPS administration, PTX may interfere with the initiation of tolerance.
Infections caused by gram-positive organisms, which contain sparse LPS,
are also accompanied by elevated plasma levels of TNF- and IL-1
(39). In agreement with results from a previous study in
this laboratory (17), administration of 2 mg/kg body wt
MDP significantly inhibited food intake in the second experiment. The
novel finding in this study is that PTX pretreatment was sufficient to
completely attenuate MDP-induced hypophagia. From this observation, it
can be speculated that TNF- production plays a significant role in
MDP-induced hypophagia. Further studies are necessary to substantiate
this possibility.
PTX blocks TNF- production (in response to both gram-positive and
gram-negative bacteria) by inhibiting the synthesis of TNF- mRNA
(10, 13, 41). In the third experiment, PTX did not alter
the anorexia associated with administration of exogenous rhTNF-.
This indicates that PTX does not act downstream of TNF- production
and is therefore consistent with the hypothesis that PTX blocks LPS-
and MDP-induced hypophagia by inhibiting the synthesis of endogenous
TNF-. The failure of PTX to attenuate the anorectic effect of
TNF- was not due to the magnitude of TNF-'s effect, because PTX
attenuated the even stronger anorexia induced by the high LPS dose in
experiment 4.
Substances other than PTX also inhibit TNF- production and attenuate
LPS-induced hypophagia. For example, pretreatment with the
calcium-channel blocker verapamil inhibits the hypophagic effect of LPS
(20), suggesting a calcium-sensitive mechanism is
involved. Similar to PTX, verapamil also suppresses both LPS-induced TNF- and IL-1 increases in plasma (12) but does not
attenuate the hypophagic effect of exogenously administered TNF-
(18).
Glucocorticoids also inhibit LPS- and MDP-induced hypophagia
(16). Similar to PTX and verapamil, dexamethasone blocks
TNF- production (10, 13). Therefore, glucocorticoid
treatment for the anorexia of acute bacterial infections may be
beneficial. However, many of the side effects of glucocorticoids
preclude their sustained administration (2).
Eicosanoids are also implicated in the anorexia associated with the
administration of bacterial products, because LPS and MDP hypophagia is
inhibited by the antipyretic drug indomethacin (19, 20).
It is unlikely that indomethacin inhibits LPS- and MDP-induced anorexia
through the same mechanism as PTX, because indomethacin actually
increases rather than suppresses LPS-stimulated TNF- production
(27) under most circumstances.
The molecular mechanisms by which PTX and other compounds inhibit
TNF- synthesis remain unclear. PTX prevents the degradation of cAMP,
leading to an increase in the intracellular concentration of cAMP,
which suppresses TNF- production (9, 13, 35, 41).
Increased cAMP activates protein kinase A (PKA), which catalyzes the
phosphorylation of proteins, altering their conformation and activity.
The modes of action by which activation of the cAMP/PKA cascade affects
molecular mechanisms responsible for TNF- production (and, to a
lesser extent, IL-1 production) remain unclear but are the focus of
ongoing research (40). Perhaps increased PKA activity
alters factors such as activation of phospholipase C, ceramide-activated protein kinase, protein kinase C, and protein tyrosine kinase, which are known to play a role in LPS induction of
cytokine synthesis (32).
In conclusion, our results suggest that PTX, mainly through its ability
to drastically inhibit TNF- production, can either inhibit or
significantly attenuate the anorexia associated with LPS and MDP
administration. A role for IL-1 in LPS-induced hypophagia cannot be
excluded due to the pleiotropic actions of cytokines. However, the data
do indicate that without substantial TNF- production, even IL-1
plasma levels at 61% (PTX-LPS) of control (NaCl-LPS) have absolutely
no effect on feeding. This observation corresponds with other data that
indicate that IL-1 is not necessary for LPS-induced hypophagia
(14, 15, 22). On the contrary, our results suggest that
inhibition of TNF- by PTX is crucial for the elimination of
LPS-induced anorexia. In addition, suppression of TNF- production
also appears capable of antagonizing MDP-induced hypophagia, despite
evidence that these compounds (LPS and MDP) do not inhibit feeding
through the same mechanisms (17).
Perspectives
PTX alone, or in combination with other agents, may prove beneficial in treating anorexia during acute and chronic disease. PTX is an established drug with no severe side effects (41) and may improve therapeutic strategies in a variety of clinical situations that involve TNF-. Several disease models and clinical studies suggest a beneficial effect of TNF- blockade by PTX
administration. PTX was found to prevent mortality during endotoxic
shock and to inhibit the inflammatory action of TNF- on neutrophil
function (29). In rheumatoid arthritis, PTX treatment
resulted in a significant improvement in 50% of patients
(25). PTX decreases TNF- mRNA accumulation and TNF-
production in human immunodeficiency virus (HIV)-infected patients
(6) and decreases HIV replication (7). PTX is
also beneficial in the treatment of premature infants with sepsis
complicated by shock (23). Further studies are necessary to determine whether PTX administration can be beneficial in
attenuating the anorexia associated with acute and chronic
pathophysiological processes in humans.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. H. Porter, Veterans Administration Medical Center, Rm. 5A 170, Clinical Addition, 1670 Clairmont Road, Decatur, GA 30033 (E-mail: mhporter{at}yahoo.com).
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 May 2000; accepted in final form 3 Aug 2000.
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TOP
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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