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Institute of Physiology, University of Hohenheim, Stuttgart, Germany
| ABSTRACT |
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KEY WORDS: enteral nutrition sodium osmolality miniature pigs water secretion
| INTRODUCTION |
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In contrast to the application of rehydration solutions, the aim of
enteral feeding is to administer the daily energy supply without a
surplus of water. Therefore, enteral diets are characterized by complex
and concentrated substrates, resulting in a high energy density. The
luminal degradation of carbohydrates and proteins by pancreatic enzymes
is associated with a marked increase in osmolality (Ehrlein and Haas-Deppe 1998
). Even with iso-osmotic enteral diets comprised
of polymeric macronutrients, osmolality rapidly increases in the
intestinal lumen because of the pancreatic degradation of the
substrates (Ehrlein and Haas-Deppe 1998
). Therefore, the
conditions of enteral feeding are completely different from those of
rehydration solutions.
The effect on the absorption of water, sodium and macronutrients obtained with iso-osmotic glucose-electrolyte solutions cannot be applied to enteral diets. The sodium content of enteral diets may differ depending on patients' needs. First, sodium content must meet daily requirements. However, there is a wide range between the minimal (~40 mmol/d) and maximal requirement (~140 mmol/d) of sodium. With most enteral diets, the sodium concentration varies from 40 to 70 mmol sodium/L, providing a sufficient daily supply of sodium by the infusion of a 2-L solution.
Second, sodium concentration might influence the transepithelial net
flux of sodium and water. A previous study in humans (Spiller et al. 1987
) showed that sodium absorption is directly
proportional to the sodium concentrations of enteral diets.
Concentrations <90 mmol sodium/L resulted in a net sodium and water
secretion. Due to this result, the authors (Spiller et al. 1987
) recommended enteral diets containing a high sodium
concentration of
90 mmol/L, especially in patients with massive
intestinal resection where sodium and water losses may be life
threatening. However, that study was performed with diluted, isotonic
diets. With diets of high energy density, the increasing osmolality in
the intestinal lumen because of the rapid degradation of the
macronutrients will modulate the net flux of both sodium and water
(Ehrlein and Stockmann 1998
). In response to a
hypertonic meal, monosaccharides and amino acids induce net sodium,
chloride and water secretion (Chang and Rao 1994
).
Therefore, the experimental procedure of Spiller et al. (1987)
did not
correspond to that of regular enteral feeding.
Third, the sodium content of the diet may also influence the absorption
of glucose, amino acids and peptides. The uptake of glucose from gut
lumen into enterocytes is driven by the sodium electrochemical
potential gradient across the brush border membrane (Wright et al. 1994
). The kinetics of the SGLT-1 transporter clearly
illustrate the sodium dependence of the glucose transport
(Wright et al. 1994
). Additionally, several in vivo
studies (Annegers 1964
, Csáky 1963
, Csáky and Zollicofer 1960
, Ortiz et al. 1979
, Schultz and Curran 1970
) showed that removal
of sodium from the lumen by substituting sodium with lithium,
potassium, mannitol or Tris markedly reduced or completely inhibited
active sugar and amino acid absorption.
In contrast, some studies in humans (Fleshler et al. 1966,
Olsen and Ingelfinger 1968,
Saltzman et al. 1972
) found the sodium concentration of
solutions had only small effects on the absorption of glucose and amino
acids. A reduction of intraluminal sodium concentration from 140 to 2.5
mmol/L diminished glucose absorption by <20% (Saltzman et al. 1972
). The authors supposed that the perfusion of a short
segment (30 cm) with high perfusion rates (16 mL/min) might cause poor
mixing and allow a microclimate of high sodium concentrations adjacent
to the brush border membrane, even when luminal sodium concentration
was small (Saltzman et al. 1972
). In all previous
studies, isotonic nutrient-electrolyte solutions were used. It remains
to be determined whether the sodium concentration of enteral diets
characterized by high energy density and consequently high osmolality
influences absorption of glucose, amino acids and peptides. An increase
in sodium concentration of enteral formulas inevitably
increases the osmolality of the diet.
However, the interrelationships between the sodium concentration of the diet, the absorption of macronutrients and net fluxes of sodium and water are complex. An increase in sodium concentrations may influence the absorption of carbohydrates and proteins. The absorption of these macronutrients is associated with a reduction in intraluminal osmolality. There are further bidirectional fluxes of sodium and water depending on both osmotic forces and sero-mucosal differences in sodium concentrations. Due to these multifactorial interactions, the effects of increasing sodium concentration cannot be predicted by theoretical considerations, but have to be evaluated experimentally.
Therefore, the aim of the present study was to clarify the effects of the sodium concentration of enteral diets on the absorption of macronutrients and the net fluxes of sodium and water. These parameters were measured by perfusing a 150-cm jejunal segment with enteral diets of various sodium concentrations in unanesthetized miniature pigs. Because we expected that changes in sodium concentration would influence osmolality and that the major effect of sodium concentrations might be caused by osmotic effects, we used three nutrient solutions that differed in the degree of hydrolysis of the macronutrients and, consequently, in osmolality. The sodium concentration of the solutions was varied between 30 and 150 mmol/L.
| MATERIALS AND METHODS |
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Surgical procedures.
The procedures used in this study were approved by the Animal Care Committee of the Regierungspräsidium, Stuttgart, Germany. Surgical procedures were performed under general anesthesia. After intramuscular application of 5 mg tiletamine and zolazepam/kg (1:1) (TILEST, Parke-Davis, Berlin, Germany), anesthesia was maintained by halothane on O2-N2O. Three cannulas made of silicone rubber (Elastosil R401/70E, Wacker, Munich, Germany) were implanted into the proximal jejunum 100, 200 and 365 cm distal to the ligament of Treitz (Fig. 1). The cannulas were exteriorized through the right abdominal wall. The intraluminal base of the cannulas were positioned at the abdominal wall in a ventrodorsal direction.
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The jejunal segment located between the middle and the distal cannulas
was perfused with enteral diets. The residues of the infused enteral
diets were drained by the distal cannula, whereas the chyme emptying
from the stomach, bile and pancreatic secretion were drained by the
proximal cannula. Absorption of macronutrients and transepithelial net
flux of sodium and water were measured by the differences between
infused and recovered macronutrients or water according to the equation
described by Modigliani et al. (1973)
:
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All diets were supplemented with the non-absorbable marker
cobalt-EDTA (50 mg/L) (Udén et al. 1980
).
Enteral diets.
Three enteral diets were used: a commercial oligopeptide diet, an oligomeric diet, and a polymeric diet5. The commercial diet Peptisorb(Pfrimmer, Erlangen, Germany) contained 75% of energy as carbohydrates 15% as proteins and 10% as fat (Table 1).We prepared the oligomeric and polymeric diets ourselves. The ratio of carbohydrates, protein and fat was adapted to that of the commercial diet Peptisorb. The commercial diet originally had an energy density of 4.2 MJ/L (1 Mcal/L). The energy density was reduced to 3.4 MJ/L to allow us to add sodium and a solution of cobalt-EDTA as a nonabsorbable marker. The energy density of the oligomeric and polymeric diets was also adjusted to 3.4 MJ/L (0.8 Mcal/L) so that all three diets had the same energy density. The commercial oligopeptide diet was infused into the jejunal segment without pancreatic enzymes because carbohydrates and proteins the substrates responsible for osmolality, were already hydrolyzed. The compositions of macronutrients and of electrolytes are summarized in Table 1 .
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NaCl was to the oligomeric diet added to achieve concentrations of 30, 60, 90, 120 and 150 mmol sodium/L. A concentration of 30 mmol sodium/L could not be prepared for the polymeric and the oligopeptide diets because the sodium content of the polymeric substrates and of the commercial diet was too large. Therefore, the sodium concentrations of the polymeric diet and the oligopeptide diet was adjusted to 60, 90, 120 and 150 mmol/L. The concentrations of the other electrolytes are summarized in Table 1 .
In the present study we did not try to differentiate between the direct effects of sodium and the effects of osmolality by means of control experiments with mannitol because such controls are problematic. The osmolality of the intestinal contents may be different when sodium or mannitol are used as osmotic substrates; sodium can be absorbed as well as secreted, and consequently osmolality and fluxes of water will depend on sodium fluxes. This does not occur with mannitol. Therefore, the osmotic effects of mannitol as control might be completely different from those of sodium and thus might be misleading.
Experimental procedure.
At the onset of each experiment, the cannulas were opened, and a balloon catheter was inserted into the middle cannula (Fig. 1) . The tip of the catheter was positioned 15 cm aboral of the cannula. Thus the length of the jejunal test segment was 150 cm. The balloon was continuously inflated with air by a pump at a constant pressure of 25 cm of water to occlude the intestinal lumen (Fig. 1) . The corresponding volume of the balloon varied between 5 and 15 mL, resulting in a balloon diameter between 10 and 20 mm. One of the enteral diets was infused into the jejunal segment via the balloon catheter over a period of 90 min. The residues of diets remaining unabsorbed were drained from the distal cannula. The ventro-dorsal direction of the cannulas and the upward flow of digesta facilitated the outflow of chyme and the residues of the diets through the opened cannulas (Fig. 1) .The initial 30 min of the 90-min perfusion period served as an equilibration period. During the subsequent 60-min test period, absorption rates of macronutrients and energy and transepithelial sodium and water fluxes were measured. The infusion rate of all diets into the jejunal segment was 2.5 mL/min, including infusion of pancreatic enzymes with the polymeric diet. The oligomeric diet and the commercial diet Peptisorb were infused without pancreatic enzymes, whereas the polymeric diet was supplemeted with pancreatic enzymes. Because the energy density was 3.4 MJ/L (0.8 Mcal/L), the energy supply was 8.4 kJ/min (2 kcal/min). This energy load corresponded to the postprandial energy flow in these miniature pigs. At the end of the test period, infusion of the diet was stopped, and saline was perfused over an additional 30 min for marker recovery. The mean recoveries of the cobalt marker during the 60-min test period and the complete experiment were 98.1 ± 5.9 % and 96.0 ± 5.8 %, respectively. At the middle of the test period, transit time was measured by injection of an 0.5-mL bolus (5 mg) chromium-EDTA into the jejunal segment. During the subsequent period, the effluent of the distal cannula was collected in intervals of 0.52 min for recovery of the transit marker.
At the onset of the test period, the animals were fed a test meal to induce postprandial conditions. The meal was eaten within 2 min. The energy of the meal (3485 kJ) met one-half of the daily requirement. The meal was drained by the proximal cannula as it emptied from the stomach. Consequently, bile and pancreatic juice did not enter the jejunal test segment during the experiment.
Analysis of macronutrients, energy, marker, sodium and water.
The concentrations of macronutrients (carbohydrates, proteins and fat),
sodium concentration, water content and the cobalt marker were
determined in the diets and the effluent of the distal cannula. The
methods of analysis have been previously described in detail
(Weber and Ehrlein 1998
).
The concentration of carbohydrates was determined enzymatically
(starch-test, Boehringer, Mannheim, Germany). The protein content was
determined by an automatic nitrogen analyser (Macro-N, Heraeus, Hanau,
Germany). The fat was extracted with petroleum ether and determined
gravimetrically as described previously (Ehrlein and Stockmann 1998
). The energy densities of the diets and of the intestinal
effluents were determined as the sum of the energy of each nutrient.
The energy values used to convert g macronutrients (kJ) are summarized
in (Table 3).
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Transit time and flow rate.
The mean transit time of a bolus was determined as the time interval
between the injection of the chromium-EDTA marker and the recovery of
50% of the marker in the effluent of the distal cannula. The flow rate
(mL/min) was defined as the volume of fluid passing the
jejunal segment per min. It was determined from the equation:
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where volume effluent is the volume/minrecovered at the distal cannula, marker infused and marker recovered are the amounts of marker that were infused and recovered, respectively, during the 60-min test period.
In vitro hydrolysis of the polymeric diets.
The polymeric diets were concomitantly infused with pancreatic enzymes to induce hydrolysis of the macronutrients in the jejunal segment. The degradation of carbohydrates and proteins increases the osmolality. To estimate the increase in osmolality occurring in the gut, the polymeric diets were hydrolyzed in vitro by pancreatic enzymes. As in the in vivo experiments, 5 mL of a 3.33% Pancreatin solution was added to 20 mL of the diets. The solution was kept at 37oC. Over a 30-min period samples were taken in 1-min intervals, and the osmolality was immediately measured by an osmometer (OM 801, Vogel, Giessen, Germany). Osmolality rapidly increased within a few minutes. After this initial period, osmolality increased only slightly approaching plateau values. The osmolality occurring in the gut because of the hydrolysis might depend on the transit time. Therefore, the osmolality of the in vitro hydrolysis was evaluated after a period corresponding to the mean transit time (5.6 min) of the polymeric diets (Table 2) . These values might resemble the osmolalities occurring in the jejunal segment after hydrolysis of the polymeric macronutrients.
Statistics.
With each diet and each sodium concentration two experiments were performed in each pig, i.e., with each pig 26 experiments were carried out. One experiment was performed per day. The sequence of the diets was randomly selected. Data from the five pigs are presented as grand means ± SD calculated from the mean values of the two experiments in each pig. Relationships between sodium concentrations and absorption of macronutrients and energy, fluxes of water and sodium, sodium concentration of chyme, flow rate and transit time were tested with linear regression analysis. When no linear regression existed, differences of the parameters among the diets were tested using ANOVA and the Student-Newman-Keul's test. A probability value P < 0.05 was considered significant.
| RESULTS |
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With all three enteral diets, increasing concentrations of sodium did not significantly influence absorption rates of the three macronutrients and of energy (Fig. 2).Regression analysis showed no linear relationships between sodium concentrations and the absorption rates of carbohydrates, proteins, fat or total energy. Variance analysis also showed no significant differences of the absorption rates among the different sodium concentrations. Therefore, the mean absorption rates of carbohydrates, proteins, fat and total energy were determined for each diet (Table 4) .The mean absorption rates for energy and protein were significantly smaller with the oligopeptide diet Peptisorb when compared to the oligomeric diet (Table 4) , whereas the mean absorption rates of the three macronutrients and total energy were not significantly different between the oligomeric and polymeric diets and between the polymeric diet and the oligopeptide diet Peptisorb.
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The perfusion of all three diets was associated with net secretion of water caused by the high osmolality of the solutions. With increasing sodium concentrations, net secretion of water increased linearly with all three diets (Fig. 3 , top paneland Table 5 ). With the oligomeric, polymeric and oligopeptide diets, an increase in sodium concentration by 30 mmol/L enhanced the net secretion of water by 0.37, 0.26 and 0.32 mL/min, respectively (Table 5) .Both the differences in water secretion among the three diets and the linear increase in water secretion with increasing sodium concentration were caused by the osmolality of the solutions (Fig. 4, top panel).The osmolality of Peptisorb was less than that of the oligomeric diet and the polymeric diet after hydrolysis by pancreatic enzymes. With the oligomeric, polymeric and oligopeptide diets, an increase in osmolality by 100 mosmol/kg enhanced net secretion of water by 0.6, 0.5 and 0.6 mL/min, respectively (Table 5) .
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Net flux of sodium and intestinal sodium concentrations.
With the three diets and with all sodium concentrations varying between 30 and 150 mmol/L, a net flux of sodium into the intestinal lumen occurred. We had expected that, with increasing sodium concentrations of the diets, the secretion of sodium would be diminished because of the reduced gradient between plasma and the intestinal lumen. However, although a slight reduction in sodium secretion with increasing concentration occurred, there was no significant correlation between the sodium concentration and the sodium secretion. With the oligomeric diet, sodium secretion was significantly greater (P < 0.05) than the polymeric diet and the oligopeptide diet Peptisorb (Fig. 6, left panel).There was a positive, linear relationship between secretion of water and secretion of sodium (Fig. 7). This indicated that net secretion of sodium was influenced by secretion of water.
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| DISCUSSION |
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The results on the relationships between sodium concentrations of
enteral diets and net secretion of sodium and water differed markedly
from that of a previous study (Spiller et al. 1987
).
Spiller et al. (1987)
observed a significant linear decrease in net
secretion of sodium and water as sodium concentration of the diets
increased, whereas in our study the net secretion of sodium was
independent of the initial sodium concentration of the diets, and the
net secretion of water increased linearly with increasing sodium
concentrations. The differences are obviously caused by the different
experimental designs. In Spiller's study (1987), the enteral diets were
diluted to obtain isotonic solutions. However, in enteral nutrition,
diets of high energy density are required to meet the daily energy
supply without surplus of water. The energy density of commercial
enteral diets varies between 4.184 and 5.23 MJ/L (1000 and 1250 kcal/L)
(Gottschlich et al. 1997
). The initial osmolality of
enteral diets depends on the degradation of carbohydrates and proteins.
Polymeric diets are iso-osmotic, whereas oligomeric diets are
hyperosmotic. The commercial enteral diets usually represent a
compromise between the degree of degradation of carbohydrates and
proteins and the increase in osmolality. Thus, the commercial diet
Peptisorb was only slightly hyperosmotic. However, the consequence of
the incomplete degradation of carbohydrates and proteins is that,
without further hydrolysis by pancreatic enzymes, the absorption of the
macronutrients is limited. In the present study, significantly less
total energy was absorbed from the commercial diet Peptisorb than from
the oligomeric diet. On the other hand, the low initial osmolality of
oligopeptide or polymeric diets is only an apparent advantage. The
present results showed that, in the small intestine, the polymeric
macronutrients were rapidly hydrolyzed by pancreatic enzymes providing
absorption rates similar to those with oligomeric macronutrients, but
osmolality increased rapidly reaching values comparable with those of
the oligomeric diet. Consequently, enteric application of diets with
high energy density is inevitably associated with a pronounced increase
in osmolality. This effect markedly influences water and sodium fluxes.
Therefore, results obtained with diluted enteral diets or nutrient
solutions of low energy density are not representative for enteric
feeding. In the present study, the net secretion of water was the most
pronounced phenomenon. Because of the increasing osmolality of the
diets with increasing sodium concentrations, the net secretion of water
increased linearly. There is evidence that luminal macronutrients and
hypertonic chyme modulate the paracellular permeability. Changes in
cytoskeletal arrangement of the perijunctional actomyosin ring can
increase the permeability of the tight junctions (Blada 1991,
Chang and Rao 1994,
Madara and Trier 1994
). This effect of macronutrients and osmolality may
not only enhance absorption of water parallel with the absorption of
macronutrients, but may also enhance serosal-mucosal fluxes of sodium
and water. In the present study, net secretion of water increased the
luminal volume and flow rate and diluted the chyme. The linear
relationship between net water and net sodium fluxes indicated that the
reduction in sodium concentration by dilution obviously increased the
sodium gradient between the plasma and intestinal contents and enhanced
sodium secretion. Consequently, the net secretion of sodium was not
diminished as the sodium concentration of the diet increased. For
enteral nutrition, our recommendations, derived from the present
findings, are contrary to that of Spiller et al. (1987)
. According to
our results the sodium concentration of enteral diets should be as low
as possible and only just meet the patient's minimal daily requirement
of sodium. The lower the sodium concentration the lower the osmolality
and consequently net secretion of water and sodium. In contrast,
Spiller et al. (1987)
recommended a high sodium concentration of
90
mmol/L, especially in jejunostomy patients with massive resection of
the distal small intestine where losses of sodium and water may be life
threatening. However, in such patients enteral diets might be infused
into the stomach rather than into the small intestine because of the
osmotic problems.
The sodium concentration of the effluent did not increase with
increasing sodium concentrations of the diets. With the oligomeric and
polymeric diets the sodium concentrations of the jejunal contents was
~100 mmol/l, whereas the oligopeptide diet Peptisorb was 125 mmol/l.
In the present study we did not determine bidirectional fluxes of
sodium and water, but measured only their net fluxes. It is likely that
under the present experimental conditions both serosal-mucosal
(secretion) and mucosal-serosal (absorption) fluxes of water and sodium
occurred. Secretion of water was primarily caused by osmolality and
secretion of sodium by the sodium gradient. On the other hand, the
absorption of glucose, amino acids and peptides is associated with the
osmotic absorption of water. Additionally, the co-transport of sodium
with glucose and amino acids and the Na+/H+exchange transport in association with the absorption of amino
acids and peptides (Chang and Rao 1994,
Gerson. 1971,
Loike et al. 1996,
Loo et al. 1996
) may have produced absorption of sodium and water.
Therefore, the sodium concentration of the chyme was the result of the
bidirectional fluxes of both sodium and water. Because the absorption
of macronutrients was significantly smaller with the commercial diet
Peptisorb compared to the oligomeric diet, the absorption of sodium and
water might also have been smaller. This effect might have contributed
to the higher sodium concentration of the jejunal contents with
Peptisorb.
Discrepancies exist in the literature about the effects of the sodium
concentration of solutions on absorption of glucose, amino acids and
peptides. In vitro studies clearly showed that the
absorption of glucose, amino acids, and peptides depends on the sodium
concentration of the solution (Holtug and Skadhauge 1991,
Schultz and Curran 1970
). Under in vitro
conditions, the sodium concentration can be exactly defined on both
sites of the epithelium, and undesirable serosal-mucosal fluxes can be
eliminated. In contrast, during in vivo perfusion of an
intestinal segment with electrolyte-glucose or amino acid solutions,
sodium may enter the gut lumen across paracellular pathways. In the
proximal small intestine, permeability of the paracellular junctions is
larger than in the distal small intestine (Chadwick et al. 1977,
Loehry et al. 1973,
Madara and Trier 1994,
Madara et al. 1980
). Therefore, with
in vivo studies the sodium effects may be different between specific
regions of the gut. Sodium fluxes may further depend on a variety of
experimental conditions, such as concentrations of macronutrients
influencing paracellular permeability (Chang and Rao 1994,
Madara and Trier 1994
) or concentrations
of sodium being responsible for the gradient between plasma and luminal
contents. In all previous studies on interactions between sodium
concentrations and solute absorption isotonic solutions were used. The
present study is the first that investigated the effects of the sodium
concentrations of diets with high energy density and, consequently,
high osmolality on the absorption of macronutrients and energy. With
all three diets and all sodium concentrations a net secretion of sodium
occurred. Therefore, in all cases the sodium concentrations were
sufficient to provide optimal absorption rates of macronutrients, even
with initial low sodium concentrations of the diets. The increase in
sodium concentration had no stimulatory effect on solute absorption.
These findings indicate that, under the conditions of enteric feeding,
absorption of macronutrients is independent of the sodium concentration
of the diet. Therefore, sodium concentrations of diets can be minimized
without negative effects on nutrient absorption.
| ACKNOWLEDGMENTS |
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| FOOTNOTES |
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1 Supported by the Deutsche
Forschungsgemeinschaft, grant EH 64/64. ![]()
2 The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked ''advertisement'' in accordance with 18 USC section 1734 solely to indicate this fact. ![]()
3 Abbreviation used: SGLT, Sodium dependent
glucose transporter ![]()
4 Terminology used: The polymeric dietcontained the three macronutrients in large molecular form.The
hyperosmotic oligomeric diet contained the three
macronutrients as hydrolyzed substrates not requiring further
pancreatic degradation. The commercial formula containing oligopeptides
and oligosaccharides was defined as oligopeptide diet. ![]()
Manuscript received June 16, 1998. Initial review completed August 18, 1998. Revision accepted November 4, 1998.
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