Department of Molecular Physiology and Biophysics and Diabetes Research and Training Center, Vanderbilt University, Nashville, Tennessee 37232-0615
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ABSTRACT |
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Prior exercise stimulates muscle and liver
glucose uptake. A negative arterial-portal venous glucose gradient
(a-pv grad) stimulates resting net hepatic glucose uptake (NHGU) but
reduces muscle glucose uptake. This study investigates the effects of a
negative a-pv grad during glucose administration after exercise in
dogs. Experimental protocol: exercise (180 to
30 min),
transition (
30 to
20 min), basal period (
20 to 0 min), and experimental period (0 to 100 min). In the experimental
period, 130 mg/dl arterial hyperglycemia was induced via vena cava (Pe,
n = 6) or portal vein (Po,
n = 6) glucose infusions. Insulin and
glucagon were replaced at fourfold basal and basal rates. During the
experimental period, the a-pv grad (mg/dl) was 3 ± 1 in Pe and
10 ± 2 in Po. Arterial insulin and glucagon were similar in
the two groups. In Pe, net hepatic glucose balance
(mg · kg
1 · min
1,
negative = uptake) was 4.2 ± 0.3 (basal period) and
1.2 ± 0.3 (glucose infusion); in Po it was 4.1 ± 0.5 and
3.2 ± 0.4, respectively (P < 0.005 vs.
Pe). Total glucose infusion
(mg · kg
1 · min
1)
was 11 ± 1 in Po and 8 ± 1 in Pe
(P < 0.05). Net hindlimb and whole
body nonhepatic glucose uptakes were similar. Conclusions: the portal
signal independently stimulates NHGU after exercise. Conversely, prior
exercise eliminates the inhibitory effect of the portal signal on
glucose uptake by nonhepatic tissues. The portal signal therefore
increases whole body glucose disposal after exercise by an amount equal
to the increase in NHGU.
glucose uptake; liver; arterial-portal vein gradient; muscle
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INTRODUCTION |
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PHYSICAL EXERCISE depletes glycogen stores in the liver (26) and skeletal muscle (3, 10). If glucose is administered after the cessation of exercise, whole body glucose utilization is markedly enhanced compared with sedentary controls that are administered a similar amount of glucose (11, 24). This excess whole body glucose uptake measured during a glucose load after exercise has for many years been ascribed solely to increased skeletal muscle glucose disposal (12). Recent evidence from studies performed in rabbits (15) and dogs (5) indicates that the liver may also increase its uptake of glucose after exercise, contributing significantly to the increased whole body glucose disposal observed in the postexercise state.
In resting conditions, net hepatic glucose uptake (NHGU) is greater if glucose is administered intraportally than if it is given via a peripheral infusion when other determinants of liver glucose uptake are controlled (2, 6, 21, 23). The intraportal infusion of glucose generates a negative arterial-portal venous (a-pv) glucose gradient such as in the case with normal glucose feeding. This condition is believed to create a "portal signal" capable of activating NHGU over a broad range of physiological insulin (22) and glucose (4, 21) concentrations. In a recent study (6), it was shown that the portal signal can also inhibit net glucose uptake by rested skeletal muscle. The portal signal is believed to act on hepatic and extrahepatic tissues via a complex network of afferent and efferent sympathetic and parasympatheic nerve fibers (18).
The aim of the present study was therefore to ascertain whether an intraportal glucose load given after exercise would result in higher whole body glucose uptake than a similar glucose load administered after exercise into a peripheral vein. Higher whole body glucose uptake could be due to the combination of a greater activation of NHGU by the portal signal after exercise and the loss of the inhibitory effect of the portal signal on muscle glucose uptake after exercise. To address these aims, chronically catheterized, conscious dogs were administered glucose either in a peripheral vein or in the portal vein after a 150-min bout of moderate treadmill exercise. Arterial glucose, insulin, glucagon, and the hepatic glucose load were maintained at similar values in the two groups of animals.
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METHODS |
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Animals and surgical procedures. Twelve mongrel dogs of either gender (mean weight 24 ± 2 kg) were studied. Animals were housed in a facility that met American Association for the Accreditation of Laboratory Animals Care guidelines, and they were fed a standard diet of meat and chow (34% protein, 14.5% fat, 46% carbohydrate, and 5.5% fiber based on dry weight). Experimental protocols were approved by the Vanderbilt University School of Medicine Animal Care and Use Committee. At least 16 days before each experiment, a laparotomy was performed while the dogs were under general anesthesia. Silastic catheters (0.03 ID) were inserted in the inferior vena cava for tracer and indocyanine green (ICG) infusion. Silastic catheters (0.04 ID) were also inserted in the portal vein and left common hepatic vein for blood sampling. Incisions were made in the neck region and the inguinal region for the insertion of Silastic sampling catheters (0.04 ID) in the carotid artery (advanced so that its tip rested in the aortic arch) and in a lateral circumflex vein (advanced so that its tip was in the common iliac vein). After insertion, the catheters were filled with saline containing heparin, and their free ends were knotted.
Doppler flow probes (Transonic Systems, Ithaca, NY) were used to measure portal vein, hepatic artery, and external iliac artery blood flows. A small section of the portal vein, upstream from its junction with the gastroduodenal vein, was cleared of tissue, and a 6.0-mm-ID flow cuff was placed around the vessel and secured. The gastroduodenal vein was isolated and ligated proximal to its coalescence with the portal vein. A section of the main hepatic artery proximal to the portal vein was isolated, and a 3.0-mm-ID flow cuff was placed around the vessel and secured. The external iliac artery was accessed from the abdominal incision, dissected free of surrounding tissue, and fitted with a 4.0-mm-ID flow probe cuff that was then secured around the vessel. The flow probe leads and the knotted free catheter ends, with the exception of the carotid artery and the common iliac vein catheters, were stored in subcutaneous pockets in the abdominal region so that complete closure of the skin incision was possible. The carotid artery and common iliac vein catheters were stored in subcutaneous pockets in the neck and inguinal regions, respectively. Starting 1 wk after surgery, dogs underwent three to four practice sessions of progressively longer duration on a motorized treadmill, so that by the date of the experiment they would be familiar with treadmill running. Dogs were not exercised during the 48 h preceding an experiment. Only animals that had 1) a leukocyte count <18,000/mm3, 2) a hematocrit >36%, 3) normal stools, and 4) a good appetite (consuming all of the daily ration) were used. Studies were conducted after a 42-h fast. The 42-h fast produces a metabolic state more comparable to that in overnight-fasted humans than to an 18-h fast in the dog (9). On the day of the experiment, the subcutaneous ends of the catheters were freed through small skin incisions made under local anesthesia (2% lidocaine; Astra Pharmaceutical Products, Worcester, MA) in the abdominal, inguinal, and neck regions. The contents of each catheter were aspirated, and catheters were flushed with saline. Silastic tubing was connected to the exposed catheters and brought to the back of the dog, where they were secured with quick-drying glue. Saline was infused in the arterial catheters throughout experiments (0.1 ml/min).Experimental procedures.
The exercise and treatment protocols are shown in Fig.
1. Animals were exercised at a moderate
intensity (100 m/min, 12% grade) on a motorized treadmill from
t = 180 to
30 min. The
exercise duration and intensity used in these experiments have been
shown previously to result in a twofold increase in heart rate (25) and
an increase in O2 uptake to 50%
of maximum (20). A period of exercise recovery or continued rest
followed (
30 to 100 min). At t =
100 min, a constant venous infusion of ICG (0.1 mg · m
2 · min
1)
was started that continued for the duration of the study. ICG was used
as a backup for the Doppler method. Basal samples were drawn from
t
20 to 0 min. From
t = 0 to 100 min (experimental period), a glucose infusion was performed in all dogs. In one group of
dogs (Pe, n = 6), glucose
was given into the inferior vena cava via a variable infusion adjusted
to clamp the arterial blood glucose at 130 mg/dl. In the remaining six
animals (Po), glucose was given via a constant intraportal infusion
(3.5 k/min) and by a variable infusion into the inferior vena cava
adjusted to clamp the arterial blood glucose at 130 mg/dl. The data
from the Po group, with the exception of alanine, glycerol, and free fatty acid (FFA), appeared in a previous publication by our laboratory (5), in which they were compared with a sedentary control group of
animals receiving intraportal glucose infusion. During the experimental
period, endogenous pancreatic hormone secretion was suppressed via a
continuous somatostatin infusion in the inferior vena cava (0.8 µg · kg
1 · min
1).
Insulin was replaced via an intraportal infusion of 1.2 mU · kg
1 · min
1
(fourfold basal), and glucagon was replaced via an intraportal infusion
of 0.5 ng · kg
1 · min
1
(basal). Arterial samples were drawn at 5-min intervals from t =
20 to 100 min. Portal,
hepatic, and common iliac venous samples were drawn at
t =
20,
10, 0, 60, 70, 80, 90, and 100 min. Portal vein, hepatic artery, and external iliac
artery blood flows were recorded continuously from the frequency shifts
of the pulse sound signal emitted from the Doppler flow probes (7, 8).
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Processing of blood samples.
Plasma and deproteinized blood samples that were not analyzed on the
day of the study were stored at 70°C after the completion of
the experiment. Plasma glucose levels were determined during experiments by the glucose oxidase method with a glucose analyzer (Beckman Instruments, Fullerton, CA). Whole blood (samples
deproteinized by 1:3 dilution in 4% percloric acid), lactate,
glycerol, alanine, glucose, and plasma FFA were measured by enzymatic
methods (14) on a Technicon Autoanalyzer (Tarrytown, NY) or on a
Monarch 2000 centrifugal analyzer (Instrumentation Laboratories,
Lexington, MA).
Calculations.
Net hepatic balances of lactate, glucose, alanine, FFA, and glycerol
were determined by the formula HAF × ([H] [A]) + PVF × ([H]
[P]), where [A], [P], and
[H] are the arterial, portal vein, and hepatic vein
substrate concentrations, and HAF and PVF are the hepatic artery and
portal vein blood flows determined by use of Doppler flow probes. With
this equation, a positive number indicates net hepatic output of a
substrate, and a negative number indicates net uptake. If no net
hepatic output of a substrate was measured throughout the study,
balance data will be presented as "uptake" data and will have a
positive sign. The load of a substrate reaching the liver was
calculated as [P] × PVF + [A] × HAF. Net hepatic substrate fractional extraction was calculated as the
ratio of net hepatic balance to hepatic load.
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Statistical analysis.
Data are expressed as means ± SE. Part of the data from the Po group
appeared in a previous publication by our laboratory (5). The
time-course curves of measured variables (three measurements for the
basal period, 20 to 0 min, plus five measurements for the
glucose infusion period, 60 to 100 min) were compared between groups
and over time by use of ANOVA (SuperAnova, Abacus Concepts, Berkeley,
CA) designed to account for repeated measures. Specific time points
were examined for significance by use of contrasts solved by univariate
repeated measures. Data from basal and glucose infusion periods were
pooled and compared using unpaired
t-tests. Levels of significance
detected in this manner were always in agreement with ANOVA results.
Statistics are reported in the corresponding table or figure legend for
each variable. Differences were considered significant when
P values were <0.05.
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RESULTS |
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Arterial plasma glucose, a-pv glucose gradient, pancreatic hormones,
and cortisol.
Arterial plasma glucose was similar in Pe and Po at baseline and rose
similarly by ~80% in both groups during the experimental period
(Fig.
2A). The
a-pv glucose gradient, positive in both groups at baseline, was
unchanged in Pe and became markedly negative in Po during the
experimental period (Fig.
2B).
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Hepatic glucose metabolism.
The basal hepatic glucose load was 24 ± 2 mg · kg1 · min
1
in Pe and 2 5 ± 2 mg · kg
1 · min
1
in Po. It increased to 40 ± 1 mg · kg
1 · min
1
in Pe and to 40 ± 1 mg · kg
1 · min
1
in Po during the experimental period (Fig.
4A).
Both groups had similar net hepatic glucose output at baseline (4.2 ± 0.3 and 4.1 ± 0.5 mg · kg
1 · min
1).
Both Pe and Po shifted to net hepatic glucose uptake during the
experimental period, but values were significantly greater in Po than
in Pe (3.2 ± 0.4 vs. 1.2 ± 0.2 mg · kg
1 · min
1,
P < 0.005; Fig.
4C). The net hepatic fractional
extraction of glucose during the experimental period was proportionally
greater in Po than in Pe (0.08 ± 0.01 vs. 0.03 ± 0.01, P < 0.01; Fig. 4B).
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Hindlimb and whole body glucose metabolism.
Basal net hindlimb glucose uptake was 6 ± 1 mg/min in Pe and 8 ± 1 mg/min in Po. During the experimental period it rose to 30 ± 3 mg/min
in Pe and to 33 ± 3 mg/min in Po (not significant; Fig.
5A).
Basal net hindlimb glucose fractional extraction was similar in the two
groups (0.04 ± 0.01 in Pe and 0.05 ± 0.01 in Po; Fig.
5B). During the experimental period
this variable increased in both groups (0.10 ± 0.01 in Pe and 0.13 ± 0.01 in Po), the increase tending to be less
(P = 0.06) in Pe than in Po. The total glucose infusion, which in our experimental setting reflects whole body
glucose disposal, was greater in Po than in Pe (10.8 ± 1.5 vs. 8.1 ± 1.0 mg · kg1 · min
1,
P < 0.05). The whole body nonhepatic
glucose uptake, on the other hand, was similar at baseline (3.8 ± 0.4 mg · kg
1 · min
1
in Pe and 4.2 ± 0.3 mg · kg
1 · min
1
in Po) and rose similarly in the two groups during the experimental period (6.9 ± 0.8 mg · kg
1 · min
1
in Pe and 7.8 ± 1.4 mg · kg
1 · min
1
in Po). This indicates that the liver, and not the extrahepatic tissues, was responsible for the greater total glucose infusion in Po.
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Blood levels and net hepatic and hindlimb balances of lactate.
Arterial lactate concentrations were similar at baseline (850 ± 138 µM in Pe and 719 ± 92 µM in Po) and did not change significantly during the experimental period (838 ± 95 µM in Pe and 1,108 ± 122 µM in Po). Both groups displayed net hepatic lactate uptake at
baseline (14.6 ± 2.0 µmol · kg
1 · min
1
in Pe and
12.5 ± 1.4 µmol · kg
1 · min
1
in Po) and shifted to net hepatic lactate output during the
experimental period (2.0 ± 2.2 µmol · kg
1 · min
1
in Pe and 5.1 ± 1.2 µmol · kg
1 · min
1
in Po). There were no significant differences in Pe vs. Po. The basal
net hindlimb lactate output was similar in the two groups (16.5 ± 6.0 µmol/min in Pe and 21.8 ± 4.0 µmol/min in Po) and was almost
completely suppressed in all animals during the experimental period
(2.9 ± 4.6 µmol/min in Pe and 1.7 ± 2.7 µmol/min in Po).
Arterial levels, net hepatic uptake, and net hindlimb output of
alanine.
Arterial alanine concentrations were similar at baseline in Pe and Po,
and they increased similarly during the experimental period (Table
1). Net hepatic alanine uptake was constant
and similar between the two groups throughout the study. Net hindlimb alanine output was not significantly different in the two groups (data
not shown).
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Arterial levels, net hepatic uptake, and net hindlimb output of
glycerol and FFA.
Basal arterial glycerol and net hepatic glycerol uptake were similar in
Pe and Po, and they decreased similarly during the experimental period
(Table 2). Basal arterial FFA levels and net hepatic FFA uptake were similar in the two groups at baseline, and
they decreased similarly during the experimental period (Table 2). Net
hindlimb glycerol and FFA outputs were not significantly different, Pe
vs. Po, throughout the study (data not shown).
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Blood flows.
The external iliac artery blood flow was similar between groups
throughout the study (Table 3). The basal
hepatic artery blood flow was higher in Po than in Pe
(P < 0.05). Portal blood flow was
similar between the two groups throughout the study. Because total
hepatic blood flow is comprised mainly of flow from the portal vein,
this variable was also similar between groups throughout the study.
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DISCUSSION |
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The effect of prior exercise and the portal signal on the net uptake of
an intraportal venous glucose load was studied in conscious dogs in
which arterial glucose, insulin, glucagon, and hepatic glucose load
were controlled. After 150 min of moderate exercise, the intraportal
infusion of glucose resulted in a 2.0 mg · kg1 · min
1
greater NHGU than during the infusion of glucose in a peripheral vein.
Net hepatic glucose fractional extraction was also proportionally higher in animals in which glucose was infused intraportally than in
those that were infused peripherally. The magnitude of the difference
in NHGU between intraportal and peripheral glucose infusions is
consistent with previous observations made in the presence of different
degrees of hyperglycemia and hyperinsulinemia (6, 21-23).
Galassetti et al. (6), for instance, reported that NHGU was increased
by ~2
mg · kg
1 · min
1
in the presence of ~165 mg/dl arterial blood glucose. Although the
absolute values of NHGU were higher in this study, because of the
difference in glucose levels, the increase in NHGU induced by the
portal signal was identical to that observed in the present study. Our
data therefore support the hypothesis that the route of glucose
infusion is just as important in activating NHGU in the postexercise
state as in resting conditions. Interestingly, also, the magnitude of
the increase in NHGU induced by the portal signal is similar to the
increase in NHGU induced by exercise, when exercised and sedentary
dogs, both receiving glucose intraportally, are compared (5).
One issue to be taken into consideration in all studies using the peripheral vs. intraportal glucose infusion model is how glucose infusion affects the glucose load reaching the liver. Differences in glucose load may complicate the interpretation of the NHGU data, as this parameter is directly influenced by the hepatic glucose load. If the portal glucose levels are higher in the group receiving the intraportal infusion, and all other determinants of the hepatic glucose load are identical, the glucose load itself must be greater in the intraportal than in the peripheral group of subjects. This is in apparent contrast with what was observed in the present study, in which hepatic glucose loads were identical. Portal glucose was slightly higher (<10%) in Po. Although not significantly different between groups, the hepatic blood flow was also ~10% lower in Po than in Pe. As a consequence, hepatic glucose load was similar in the two groups.
The hepatic balances of the gluconeogenic precursors alanine and glycerol were not different with the two routes of glucose delivery. Rates of net hepatic lactate output were also unaffected by the route of glucose delivery. Net hepatic FFA uptake was also similar in the two groups. Similar rates of net hepatic uptake of gluconeogenic precursors suggest that gluconegenesis was probably not inhibited in Po compared with Pe. This is consistent with previous reports (23) indicating that the greater NHGU observed in the presence of the portal signal is the result of a stimulation of unidirectional glucose uptake, whereas glucose production is not altered. In resting conditions, the great majority of the extra glucose taken up by the liver in response to the portal signal is stored as glycogen, and a smaller fraction is released as lactate. Intracellular glucose oxidation, the pentose phosphate cycle, and conversion to lipids all appear to play minor roles (23). The intrahepatic fate of the glucose that was taken up by the liver was not directly assessed in this study. Nevertheless, similarities in the circulating levels and hepatic balance data of glucose, lactate, and other metabolites suggest that a pattern of intracellular events similar to those observed in rested conditions likely occurred.
In several previous studies, the observation was made that NHGU was
greater during intraportal glucose infusion, compared with peripheral
glucose infusion, but that glucose uptake by nonhepatic tissues was
also proportionally reduced (1, 6, 21). The consequence of this was
that whole body glucose uptake was similar with the two routes of
glucose infusion (1, 6, 23). In the present study, the whole body
glucose uptake was 2.7 mg · kg1 · min
1
(33%) greater when part of the glucose infusion was performed intraportally than during peripheral glucose infusion only (10.8 ± 1.5 vs. 8.1 ± 1.0 mg · kg
1 · min
1).
Of the 8.1 mg · kg
1 · min
1
of whole body glucose uptake in Pe, 1.2 mg · kg
1 · min
1
(15%) was accounted for by NHGU and the remaining 6.9 mg · kg
1 · min
1
(85%) by glucose uptake by nonhepatic tissues. Of the 10.8 mg · kg
1 · min
1
of whole body glucose uptake measured in Po, 3.2 mg · kg
1 · min
1
(30%) could be accounted for by NHGU and the remaining 7.6 mg · kg
1 · min
1
(70%) by glucose uptake by nonhepatic tissues. Therefore, the greater
NHGU observed during intraportal glucose infusion was not paralleled by
a simultaneous reduction in glucose uptake by nonhepatic tissues. This
led to higher values of whole body glucose uptake during intraportal
infusion. These findings indicate that the integrated whole body
response to a change in the route of glucose administration is
different under basal conditions compared with the postexercise state.
The mechanisms and pathways through which the portal signal exerts its metabolic effects are now partly understood. The sensing of high glucose concentration in the portal vein leads to the generation of afferent impulses leaving the liver through the hepatic branch of the vagus nerve. This information is processed in the central nervous system, compared with a reference arterial site, and is relayed by efferent sympathetic and parasympathetic impulses to the pancreas, liver, and skeletal muscle. Control of NHGU by the portal signal is believed to occur indirectly (via modulation of pancreatic hormone secretion) and directly (by altering the balance of sympathetic inhibitory and parasympathetic stimulatory impulses to the liver). In the present study, the indirect effects of the portal signal on NHGU could not be assessed. The direct mechanisms, on the other hand, appear to be maintained in the postexercise state. The observations that skeletal muscle glucose uptake can be inhibited by sympathetic stimulation (16) and epinephrine (13), on the other hand, support the possibility that the effects of the portal signal on skeletal muscle are also mediated by efferent neural pathways leaving the brain in response to afferent hepatic impulses (18). Unfortunately, circulating levels of catecholamines could not be determined in the present study. In the postexercise state, insulin-independent glucose uptake is increased and insulin sensitivity is enhanced. It may be that one or both of these effects make the formerly working muscle refractory to the peripheral effects of the portal signal.
In summary, when in the postexercise state other factors that regulate
NHGU (levels of glucose and pancreatic hormones, hepatic glucose load)
are controlled, the administration of a glucose load results in ~2.0
mg · kg1 · min
1
greater NHGU (2.7-fold) if part of the glucose is infused
intraportally, compared with glucose infusion in a peripheral vein
only. Glucose uptake by nonhepatic tissues, on the other hand, is
unaffected by the route of glucose delivery. Our data support the
hypothesis that the portal signal is still able to exert its
stimulatory effect on NHGU in the postexercise state. The ability of
the portal signal to also modulate muscle glucose uptake, on the other
hand, is overridden by the stimulatory effect of prior exercise. The result is that the portal signal increases the rate of whole body glucose disposal by an amount equal to the increase in the rate of NHGU.
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ACKNOWLEDGEMENTS |
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We thankfully acknowledge Wanda Snead, Pam Venson, and Brittina Murphy for excellent technical assistance.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-50277. P. Galassetti was supported by National Institute of Health Training Grant DK-07061.
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. §1734 solely to indicate this fact.
Address for correspondence and reprint requests: P. Galassetti, Room 754, MRB-I, Vanderbilt Univ. Medical Center, Nashville, TN 37232-0615 (E-mail: pietro.galassetti{at}vanderbilt.edu).
Received 21 January 1999; accepted in final form 12 July 1999.
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