1 Department of Cellular and Molecular Physiology and 2 Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, Massachusetts 01655-0127
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ABSTRACT |
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Initial studies on the
digestive hormone neurotensin (NT) showing that intestinal NT mRNA
expression and blood levels were altered in rats fed chow containing
bile acid (BA) and the BA chelator cholestyramine led us to investigate
the role of NT in the enterohepatic circulation of BA. In fasted,
anesthetized rats with common bile ducts cannulated for bile
collection, intravenous NT infusion (10 pmol · kg1 · min
1) enhanced
BA output relative to control over 3 h in animals administered donor bile into the duodenum (30 µl/min). This suggested that the
effect of NT was on the return of BA from the intestine to the liver,
which is rate determining in the normal process. In rats prepared as
described above and administered [3H]taurocholate
([3H]TC; 5 mM, 1 ml) duodenally, NT infusion (3-10
pmol · kg
1 · min
1)
increased the [3H]TC recovery rate in bile approximately
twofold, whereas sulfated CCK-8 (12-50
pmol · kg
1 · min
1) had no
effect. To investigate the roles of endogenous NT and CCK, we
administered [3H]TC into the rat duodenum or lower
jejunum and tested the effect of the NT antagonist SR-48692 (2 nmol · kg
1 · min
1) or CCK-A
antagonist lorglumide (100 nmol · kg
1 · min
1).
SR-48692 reduced the [3H]TC recovery rate by
50% and
24% in the duodenum and jejunum, respectively, whereas lorglumide
had no effect. These results suggest that NT or a similar peptide is an
endogenous regulator of enterohepatic BA cycling, which acts by
enhancing BA uptake in the intestine.
cholecystokinin; intestinal absorption
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INTRODUCTION |
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THE ENTEROHEPATIC CIRCULATION (EHC) of bile acids (BA), an efficient and dynamic process of hepatic BA excretion and intestinal BA uptake, plays central roles in the digestion and absorption of lipids and in cholesterol metabolism (32, 33, 51). In animals and humans, the EHC recycles conjugated BA 5-15 times per day, depending on the fat content of the meal (32). Thus it seems reasonable to propose that some intestinal factors, released during fat ingestion, are important regulators of this complex process. Given that the long-term mechanisms are already defined through which BA directly regulates its synthesis in liver and uptake in intestine by feedback effects on gene expression via the farnesoid nuclear receptor (42), we have focused our attention on short-term regulation (i.e., that occurring during a single meal). In regard to short-term effects, it is already well established that a number of enteroendocrine peptides contribute to BA cycling by acutely enhancing the delivery of bile constituents in response to a fat stimulus (32, 51). For example, CCK, by promoting gallbladder contraction, initiates BA delivery to the intestine (52), and secretin, by stimulating ductal secretion of bicarbonate and water, increases bile flow (39). Although numerous studies have examined the effects of these and other hormones on bile and BA delivery (48), there is a paucity of work on the short-term regulation of intestinal BA uptake (32). Given that the rate-determining or regulatory step in BA cycling is intestinal uptake (32) and that the intestinal BA uptake rate increases with eating and declines with fasting (12, 35, 38, 44), the mechanisms involved in regulating BA return from intestine to liver appear to warrant further investigation.
Neurotensin (NT), a tridecapeptide existing predominantly in the small intestine, is closely associated with fat intake and utilization. Ingestion of fat is the strongest stimulus for NT release in animals and humans (15, 16, 19, 27, 43, 47, 49), and circulating NT stimulates pancreatic secretion (7, 18, 34), slows intestinal transit (29), and promotes intestinal absorption of fatty acid (5). However, the possible effects of NT on BA cycling have not received much attention, except for the stimulatory action of NT on gallbladder contraction in some species (20, 26, 56). Because many of the effects of NT in the gastrointestinal tract compliment those of CCK (14), we hypothesized that NT might stimulate the EHC by enhancing intestinal BA uptake, and we (24) recently demonstrated a stimulatory effect of exogenously infused NT on the absorption of [3H]taurocholate ([3H]TC) from the intestinal lumen of biliary fistula rats.
In this study, we extend our (24) previous work by comparing the effects of NT and sulfated CCK-8 (sCCK-8) on hepatic BA output and intestinal [3H]TC uptake in biliary fistula rats. In addition, we investigate the role(s) of the endogenous hormones by examining the effects of the NT antagonist SR-48692 (25) and the CCK-A antagonist lorglumide (33).
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MATERIALS AND METHODS |
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Materials
NT, sCCK-8, and TC (sodium taurocholate) were from Sigma (St. Louis, MO), and [3H(G)]TC was from New England Nuclear (Boston, MA). Sanofi Recherche (Montpellier, France) supplied the NT antagonist SR-48692. Stocks of NT (1 mM), sCCK-8 (1 mM), and SR-48692 (1 mM, DMSO) were atAnimals and Surgery
Male Sprague-Dawley rats (225-300 g, Taconic Farms, Germantown, NY) were housed in the University of Massachusetts Medical School Animal Facility and given rat chow and water ad libitum. All protocols were approved by the institutional animal care and use committee. Rats used for bile flow study were fasted for 24 h and anesthetized with ketamine-xylazine (80:10, mg/kg ip; 20:2, mg · kgInfusion of NT
The doses of NT (3-10 pmol · kgProtocols
Feeding experiments.
Adult rats were fasted for 48 h and given 5 g of powdered rat
chow (Purina), some of which contained 5% (wt/wt) cholestyramine or
2% (wt/wt) TC and 0.5% (wt/wt) sodium cholate. After 4 h, when all food was consumed, rats were anesthetized, hepatic portal blood was
collected into EDTA, and plasma was isolated and stored at 20°C.
Plasma was extracted with acid-acetone before RIA for NT using
antiserum HC8, which displayed a coefficient of variation of 7.7%
(8, 9). To complement this short-term feeding experiment, a second study was performed in which rats were given the same formulated chow (15 g/day) for 5 days. In a third study, fasted rats
were given the formulated foods overnight, and tissues were harvested
16 h later for measurement of NT mRNA in 20-cm segments of small
intestine. Total RNA was prepared using the guanidinium isothiocyanate
extraction method, and NT mRNA was quantitated as described previously
(6, 54). Briefly, RNA (20 µg) from either the proximal
or distal small intestine of individual rats was mixed with rat
32P-labeled NT and glyceraldehyde-3-phosphate dehydrogenase
(GAPDH) antisense probes (3 × 105 cpm of each probe),
ethanol precipitated, dried, dissolved in 30 µl hybridization buffer,
and incubated at 42°C for 24 h. The samples were subsequently
digested with nucleases P1 (20 µg/ml) and T1 (1 µg/ml), digested
with proteinase K, phenol extracted, ethanol precipitated, dried, and
analyzed on sequencing gels. Autoradiographs were scanned and
protection products were quantitated using a Bio-Rad Fluor-S
MultiImager and MultiAnalyst software. Sense NT mRNA was transcribed
from pGEM4-rbNT (2), linearized with BamH I
using SP6 RNA polymerase, and analyzed as described above to generate
standard curves. Rat 32P-labeled NT antisense probe was
transcribed from EcoR I-linearized prNT4 (2)
using T7 RNA polymerase. A rat GAPDH cDNA fragment (nt 882-1016)
was amplified by RT-PCR from total rat brain RNA using the following
primers: 5'-TTTTGAATTCAACAGCAACTCCCATTCCT-3' and
5'-TTTTGGATCCATGTAGGCCATGAGGTCCAC-3'. The PCR fragment was digested with EcoR I and BamH I and subcloned
into pBluescript KS(+) (Stratagene) digested with the same enzymes to
create prGAPDH. The plasmid was linearized with EcoR I and
transcribed with T7 RNA polymerase to generate 32P-labeled
antisense probe.
Effect of NT on bile flow and BA output.
Bile was collected every 10 min for 150 min in biliary fistula rats
receiving saline or NT (10 pmol · kg1 · min
1) by
intravenous infusion in the jugular vein. The effects of NT on bile
flow and BA output were measured in rats in which bile was not returned
to the intestine and in rats in which donor bile was administered into
the duodenum at the basal excretion rate (30 µl/min).
Effects of NT and sCCK on [3H]TC uptake.
One milliliter of 5 mM TC containing [3H]TC (1 µCi)
was infused (1.57 ml/min) into the duodenum (2 cm distal to pylorus) of biliary fistula rats. The rate of intestinal uptake of
[3H]TC was measured by monitoring the appearance of
radioactivity (%dose) in bile during intravenous infusion of NT
(3-10
pmol · kg
1 · min
1), sCCK
(12-50
pmol · kg
1 · min
1), or NT
plus sCCK. Biliary concentration and output of total BA were also
measured in some animals.
Effect of NT on hepatobiliary transport of [3H]TC
from blood.
One milliliter of [3H]TC (1 µCi, 5 mM) was
infused (1.57 ml/min) into the jugular vein of biliary fistula rats.
The rates of hepatic uptake and transport of [3H]TC into
bile were measured during infusion of saline or NT (10 pmol · kg1 · min
1).
Effect of NT antagonist and CCK antagonist on
[3H]TC uptake.
Biliary fistula rats were infused via the jugular vein with SR-48692 (2 nmol · kg1 · min
1),
lorglumide (100 nmol · kg
1 · min
1), or
vehicle. After 10 min, 1 ml [3H]TC (5 mM, 5 µCi) was
injected into the duodenum or lower jejunum (25 cm distal to Treitz's
ligament), and [3H]TC uptake into bile was measured.
Effect of NT antagonist on uptake of [3H]TC
administered with lipid into intestine.
Biliary fistula rats were infused with SR-48692 (2 nmol · kg1 · min
1) or
vehicle. After 10 min, a mixture of 3 ml 20% Intralipid and 1 ml
[3H]TC (5 mM, 5 µCi) was administered by bolus
injection into the duodenum (1.57 ml/min). The appearance of
[3H]TC in bile was monitored.
Effect of NT antagonist on BA uptake from bile infused with lipid
into intestine.
Biliary fistula rats were infused with SR-48692 (2 nmol · kg1 · min
1) or
vehicle. After 10 min, a mixture of rat bile (6 ml) with 20%
Intralipid (9 ml) was infused into the duodenum (75 µl/min) while
bile flow and BA output were measured.
Simultaneous measurement of intestinal transit and
[3H]TC uptake.
Intestinal transit was measured by adding [51Cr]sodium
chromate (0.5 µCi) to the [3H]TC solution administered
into the duodenum in rats infused with saline or NT (10 pmol · kg1 · min
1). Uptake
of [3H]TC into bile was measured as described above for
100 min. Rats were then killed, and the small intestine was cut into 10 equal segments. The radioactivity of 51Cr was measured in
each segment with its contents using a gamma counter. The percentage of
radioactivity in each segment was calculated, and the geometric center
of 51Cr distribution was determined (46).
Analyses and Statistics
Bile volume was measured gravimetrically, and BA concentration was measured using the 3- ![]() |
RESULTS |
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BA Decreased and BA Chelator Increased NT Blood Levels
When adult rats were fed for 4 h or 5 days with chow containing BA (TC and cholate), blood levels of NT were decreased by
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BA Decreased Intestinal NT mRNA Expression
To complement these findings, a third experiment was performed in which rats were fed overnight, and 16 h later, blood was taken to measure NT and intestines were processed to measure NT mRNA. Blood levels of NT were decreased in rats fed BA chow (70 ± 13% of control, P < 0.05) and increased in rats fed cholestyramine chow (164 ± 26% of control, P < 0.05). Similar results were obtained for NT mRNA expression (Fig. 2A) quantitated in proximal and distal intestine (Fig. 2B). In the distal intestine, where most NT-containing cells exist, NT mRNA expression was decreased in rats fed BA chow (57% of control, P < 0.01) but not significantly affected in rats fed cholestyramine chow. Similar results were obtained in the proximal intestine (Fig. 2B; BA chow = 51% of control).
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Biliary Fistula Increased and Bile Duct Ligation Decreased NT Release Response
To complement these findings, biliary fistula and bile duct ligation were employed to manipulate the BA pool and the effects on NT release were determined (Fig. 3). The increment in hepatic-portal NT blood level was measured 30 min after injection of an Intralipid-TC mixture into the duodenum of 1) rats treated for 6 h with biliary fistula (model for reduction of the BA pool); 2) rats treated for 6 h with common bile duct ligation (model for expansion of the BA pool); and 3) sham-operated rats (control group). In agreement with the results of the diet studies, NT release increased approximately twofold with the reduction of the BA pool and decreased approximately twofold with the expansion of the BA pool (Fig. 3).
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The fact that intestinal NT secretion and mRNA expression were altered by manipulations known to change intestinal BA concentration and total BA pool size suggested that NT, which is released during fat ingestion, might regulate BA secretion and/or enterohepatic BA cycling. To test this, we infused rats with a dose of NT shown by us (24) to mimic the two- to threefold increase in NT blood level seen after fat ingestion.
NT Enhanced Bile Flow and BA Output Only When EHC is Maintained
In fasted biliary fistula rats, in which bile bypassed the intestine (i.e., EHC was interrupted), NT infusion (10 pmol · kg
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NT but Not CCK-8 Enhanced Intestinal Absorption of [3H]TC
In biliary fistula rats, NT dose dependently enhanced (up to 5-fold; P
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NT Enhanced Intestinal but Not Hepatic Uptake of [3H]TC
The effect of NT was shown to be on the intestine and not on the liver, because NT did not alter the rate of transport of [3H]TC from blood into bile (Fig. 5D). Consistent with this, the basal hepatic uptake rate for [3H]TC from blood into bile (NT Enhanced BA Absorption From Bile Infused into Duodenum
When bile was administered into the duodenum of biliary fistula rats, total BA output was significantly elevated in NT-infused animals (Fig. 6B, P < 0.01) precisely during the time of enhanced intestinal [3H]TC uptake (Fig. 6A). These results indicated that the effect of NT was exerted not only on [3H]TC but also on a large portion of the intestinal pool of BA returning to the liver.
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NT but Not CCK Antagonist Reduced Absorption Rate for [3H]TC From Intestine
In biliary fistula rats, infusion of the NT antagonist SR-48692 (2 nmol · kg
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NT Enhanced [3H]TC Uptake in Presence of Lipid
Because BA uptake is known to be a function of lipid ingestion, we also tested the effect of SR-48692 in the presence of a lipid load. When 3 ml of Intralipid were given with 1 ml [3H]TC into the duodenum of biliary fistula rats, SR-48692 infusion reduced the rate of [3H]TC recovery by
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Enhanced Intestinal [3H]TC Uptake by NT Not Due to Altered Gut Transit
One conceivable mechanism by which NT might enhance [3H]TC uptake is through stimulating intestinal motility, thereby increasing the surface area exposed to the substrate. However, infusion of NT (10 pmol · kg
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DISCUSSION |
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In addition to showing that near-physiological levels of NT infused into fasted biliary fistula rats increased [3H]TC absorption from the intestine, resulting in enhanced hepatic BA output, the present studies demonstrate that the NT antagonist SR-48692 inhibited [3H]TC absorption from the intestine, diminishing hepatic BA output. Together, these results argue that NT or a similar peptide is an endogenous regulator of the EHC, which acts to enhance intestinal BA absorption. Also supporting this notion is the present finding that NT secretion into blood is acutely affected by altering intestinal BA concentration during feeding and by changing the distribution of the BA pool in models of cholestasis and biliary diversion. Although the importance of the EHC in the efficient use of BA to promote digestion and absorption is well recognized, a hormonal regulator of this process has not been identified (31, 32, 51). The fact that ingestion of fat, which can enhance jejunal uptake of BA and increase hepatic bile flow (35, 45, 53), is the strongest stimulus for NT release (15, 19, 27, 43, 47, 49) suggests that intestinal NT could play a role in this process. Established roles (14) for NT in fat digestion include effects on intestinal motility and pancreatic enzyme secretion. Here, we provide evidence that enhancement of enterohepatic BA cycling is yet another mechanism by which NT could facilitate the digestion and absorption of lipids.
Effects of BA on NT mRNA Expression and Secretion
It is well established (15, 17) that lipids stimulate intestinal NT secretion. In this study, we show that postprandial blood levels of NT in rats are decreased by feeding chow containing TC and cholic acid, whereas they are increased by feeding chow containing the BA chelator cholestyramine. We obtained these results in both acute (for 4 to 16 h) and chronic feeding experiments (for 5 days). We supported these results by showing that intestinal NT mRNA expression was diminished in rats fed chow with BA. The fact that cholestyramine did not enhance NT mRNA expression suggests that feeding by itself maximizes this parameter. Overall, our findings indicate that meal-stimulated NT synthesis and secretion are subject to regulation by intestinal BA, and when combined with the finding that NT enhances enterohepatic BA cycling, they suggest that this represents a regulatory feedback loop. Thus NT release is enhanced in the face of falling intestinal BA concentration, and this serves to stimulate enterohepatic BA cycling until the BA concentration rises to a level that inhibits further NT synthesis and release. Consistent with this, Lillienau et al. (40) showed that the rate of ileal BA absorption in rodents was increased by feeding chow with cholestyramine and decreased by feeding TC-enriched chow.Our findings in biliary fistula and cholestatic rats are also in agreement with this idea. Here, we found that NT release in response to lipid was enhanced in BA-depleted biliary fistula rats, whereas it was diminished in BA-replete cholestatic rats. Although we do not know yet whether it is luminal BA concentration per se that regulates NT release or if it is the blood BA concentration that is sensed, the results in cholestatic rats, in which intestinal BA concentration is low and blood BA concentration is high, suggest that elevated blood BA concentration can inhibit NT release. Consistent with a possible role for NT in the regulation of BA uptake are observations by Sauer et al. (50) showing a reduction of active ileal uptake of [3H]TC and a downregulation of the ileal Na+-BA transporter in cholestatic rats. Sauer et al. (50) have also proposed that intestinal BA uptake is regulated by systemic BA concentration and that a protective feedback mechanism exists.
Our finding that elevation of the BA pool in rats inhibits postprandial NT release is in agreement with studies in dogs (21) showing that NT release in response to food is inhibited by concomitant administration of either TC or bile. Although bile and BA were found to increase NT release in perfused rat intestine (11), inhibition may not be possible in this system since BA does not accumulate in the vascular perfusate. Our finding that diminishing the BA pool in rats enhanced postprandial NT release is in accord with studies in dogs (21) showing that bile diversion increased NT release in response to triglyceride. A reasonable working hypothesis at this point is that the regulation of postprandial NT release by BA involves increased or decreased feedback inhibition imposed by BA present in hepatic portal blood.
Bile Flow, BA Output, and Status of BA Cycling
The initial bile flow rate (220 µl/10 min) and BA output rate (2.8 µmol/10 min) in the rats in the current study are in good agreement with those measured in other studies (12, 30) in fasted adult biliary fistula rats. For 250-g rats, Higgins et al. (30) found bile flow to be 180 µl/10 min and BA output to be 2.7 µmol/10 min. Dumaswala et al. (12) found bile flow to be 196 µl/10 min and BA output to be 2 µmol/10 min. Because the total BA pool for a 250-g rat is ~50-60 µmol (41), the fistula rats in the current study excretedMagnitude of Responses to NT and SR-48692
Bile flow, hepatic BA output, and [3H]TC absorption from the intestine are all reduced ~50% in fasted rats compared with fed rats (12, 30, 45). In the present study, infusion of NT into fasted rats elevated bile flowRelationship of NT to CCK
Fat ingestion is a strong stimulus for the release of intestinal NT and CCK (15, 22, 27, 36, 37, 49), hormones that exhibit some similar biological effects when given peripherally (e.g., pancreatic secretion, gut motility pattern) and centrally (e.g., anorectic, neuroleptic). An established physiological function of CCK is to relax the sphincter of Oddi and to contract the gall bladder, thereby increasing the delivery of bile to the intestine and initiating the BA cycling process (31, 32, 51). In animals possessing a gallbladder, NT might be regarded as a backup for CCK since it contracts the gallbladder of mammals (20, 26, 56) and birds (Carraway, unpublished data). However, in animals lacking a gall bladder (e.g., rat), the effects of NT and CCK to mobilize the BA pool may be more subtle and complex. Our present finding that CCK and the CCK antagonist lorglumide, unlike NT and the NT antagonist SR-48692, had no effect on the rate of [3H]TC uptake from the rat intestine argues that the ability of NT to promote intestinal BA absorption is not shared with CCK. Thus this effect of NT in rats (to enhance BA return to liver) compliments that of CCK (to relax the sphincter of Oddi), with the result being a stimulation of enterohepatic BA cycling. If NT exhibits this effect in humans, where BAs are recycled 10-15 times per day and exert important effects on cholesterol handling, then NT could be a key contributor to the efficient digestion and absorption of fats and to human health.Site and Mechanism of Action
The effect of NT on [3H]TC recovery was more pronounced in the proximal gut (2.3-fold increase) than in the distal gut (1.3-fold increase), although a significant response was obtained at both sites (24). Thus the enhanced BA uptake is likely to involve passive mechanisms (which are known to predominate in proximal gut) rather than the active Na+-BA cotransporter (localized to distal gut). In addition to passive diffusion, carrier-mediated transport of [3H]TC occurs in the jejunum, as demonstrated originally by Amelsberg et al. (3, 4) and extended by Abe et al. (1) and Walters et al. (55), who identified the sodium-independent organic anion transporting polypeptide (OATP3) in apical brush-border membranes from rat and mouse jejunal enterocytes. Whether NT targets this transporter or other undefined transporters in the proximal intestine is an important question. This possibility is supported by our observation that NT also enhances carrier-mediated uptake of [3H]glucose and [3H]leucine (24). The mechanism is not yet defined, but the fact that NT does not significantly affect gut transit (present data) and does not alter the uptake of [3H]cholic acid and [3H]antipyrene (24) argues against the involvement of a nonselective action on peristalsis or villus motility. Although NT increases intestinal blood flow and vascular permeability (28), such changes are also not likely to selectively affect the uptake of conjugated BA. Because NT receptors are abundant in the myenteric plexus of the gut, it seems reasonable to suggest that the absorptive effects of NT may involve release of mediators from enteric neurons. The finding by Grune et al. (23) that cAMP enhances BA transport in hepatocytes suggests that it may be fruitful to investigate cAMP formation in intestinal epithelial cells. ![]() |
ACKNOWLEDGEMENTS |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant 5R01DK-28565, although the opinions expressed are not necessarily those of the National Institutes of Health.
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FOOTNOTES |
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Address for reprint requests and other correspondence: R. E. Carraway, Dept. of Physiology, Univ. of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655-0127 (E-mail: Robert.Carraway{at}umassmed.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 21 December 2000; accepted in final form 8 August 2001.
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