Vol. 279, Issue 3, H924-H931, September 2000
Chronic metabolic sequelae of traumatic brain
injury: prolonged suppression of somatosensory activation
M. J.
Passineau1,5,
W.
Zhao1,2,3,
R.
Busto1,2,3,
W. D.
Dietrich1,2,3,4,5,
O.
Alonso1,
J. Y.
Loor2,
H. M.
Bramlett1,4, and
M. D.
Ginsberg1,2,3,5
1 Neurotrauma Research Center, 2 Cerebral Vascular
Disease Research Center, Departments of 3 Neurology and
4 Neurological Surgery, and 5 Neuroscience Program,
University of Miami School of Medicine, Miami, Florida 33101
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ABSTRACT |
Injuries to the brain
acutely disrupt normal metabolic function and may deactivate functional
circuits. It is unknown whether these metabolic abnormalities improve
over time. We used 2-deoxyglucose (2-DG) autoradiographic
image-averaging to assess local cerebral glucose utilization
(lCMRGlc) of the rat brain 2 mo after moderate (1.7-2.1 atm) fluid-percussion traumatic brain injury (FPI). Four animal groups (n = 5 each) were studied: sham-injured
rats with and without stimulation of the vibrissae-barrel field
ipsilateral to injury; and animals with prior FPI, with or without this
stimulation. In sham-injured rats, resting lCMRGlc was
normal, and vibrissae stimulation produced right-sided metabolic
activation of the ventrolateral thalamic and somatosensory-cortical
projection areas. In rats with prior injury, lCMRGlc
contralateral to injury was normal, but lCMRGlc of the
ipsilateral forebrain was depressed by ~38-45% compared with
shams. Whisker stimulation in rats with prior trauma failed to induce
metabolic activation of either cortex or thalamus. Image-mapping of
histological material obtained in the same injury model was undertaken
to assess the possible influence of injury-induced regional brain
atrophy on computed lCMRGlc; an effect was found only in the lateral cortex at the trauma epicenter. Our results show
that, 2 mo after trauma, resting cerebral metabolic perturbations persist, and the whisker-barrel somatosensory circuit shows no signs of
functional recovery.
deoxyglucose; autoradiography; trauma; barrel circuit; vibrissae
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INTRODUCTION |
TRAUMATIC
BRAIN INJURY (TBI), in both humans (3) and animal
models (9, 15, 29), is followed
by alterations of local cerebral metabolism. In human brain injury,
alterations in local cerebral glucose utilization (lCMRGlc)
have been reported to coincide with significant mental disability
(3). Transiently elevated lCMRGlc has been
described in the first few hours after acute brain trauma in rats
(15, 20, 29), followed by
sustained hypometabolism (9, 20,
29). In patients, lCMRGlc elevations may
persist for several days after TBI (3).
Characterizing the chronic time course and extent of posttraumatic
brain hypometabolism takes on potential relevance in the context of
functional recovery. Although brain-injured patients typically undergo
at least partial recovery of functions lost as a result of TBI, little
is known about the physiology of the recovering brain. The acute
histopathological consequences of TBI do not always correlate with
chronic outcome, and a number of studies have highlighted the dynamic
nature of TBI and have shown that tissue loss may continue for weeks
and months following injury (4, 11,
16, 19).
In the present study, we examined the metabolic state of the
traumatically injured brain following chronic (2 mo) survival, using
2-deoxyglucose (2-DG) autoradiography combined with image-averaging methods (15, 32). To our knowledge, this is
the longest post-TBI time point yet examined in an experimental model
using this method. To understand better the physiology of the
chronically injured brain, it is also helpful to examine the
alterations that take place in specific functional circuits. The rat
whisker-barrel system, consisting of trigeminal-medullary and thalamic
relays that terminate in sharply defined cortical barrel fields
(2, 25, 26), provides an
excellent opportunity for such study (8, 28),
since this circuit can be easily and robustly activated by mechanical
stimulation of the facial vibrissae (14). Previous studies
showing that this circuit exhibits depressed metabolic responsiveness
immediately following TBI (9) and global and focal
ischemia (10, 13) have led us to ask whether
this circuit recovers its responsiveness in the chronic setting.
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METHODS |
Fluid-percussion brain injury.
The experiments were conducted on 20 male Sprague-Dawley rats weighing
275-325 g. Studies were approved by the University of Miami Animal
Care and Use Committee, and the NIH "Guide for the Care and Use of
Laboratory Animals" (NIH Publication No. 86-23, Revised 1986)
was followed. Ten rats underwent TBI, and 10 others served as
sham-injured controls. Rats were initially anesthetized with Equitensin
(1.0 ml) and surgically prepared for fluid-percussion brain injury as
described previously (4, 12). Briefly, a parasagittal craniotomy (4.8 mm) was performed 3.8 mm posterior to
bregma and 2.5 mm lateral to the midline. A plastic injury tube was
placed over the exposed dura and bonded to the skull by adhesive.
Twenty-four hours later, animals were anesthetized with 3% halothane,
70% nitrous oxide, and a balance of oxygen, and a fluid-percussion injury device was connected to the injury tube. Moderate TBI was induced by conveying a pressure transient of 1.7 to 2.1 atm to the
right dorsolateral parietal cortex. Cranial temperature during this
procedure was monitored by a thermistor probe inserted into the left
temporalis muscle and held at 36.5°C by a warming lamp above the
head. Rectal temperature was monitored and maintained at 37.0°C
throughout the study. Sham animals received preparatory anesthesia and
placement of the injury tube but were not subjected to fluid-percussion injury.
After these procedures were performed, the injury tube was removed, and
the scalp was sutured shut. Animals were returned to their cages with
free access to food and water and normal exposure to light-dark cycles,
and they were allowed to recover for 2 mo. This survival duration was
chosen in that its histopathology has already been extensively
evaluated (4). During the first month postinjury, animals
underwent sensorimotor testing every third day. In addition, on
days 22-28, they underwent alternating days of hidden-
and visible-platform Morris water-maze testing; and an open-field
behavioral test was performed on day 31 (5); these results are not presented here.
Autoradiographic measurement of local cerebral glucose
utilization.
Following 2 mo of survival, animals with fluid-percussion injury
(n = 10) and with sham injury (n = 10)
were each randomly assigned to one of two study subgroups. Animals of
the "stimulated" subgroups (n = 5 each) underwent
unilateral stimulation of the left vibrissae during measurement of
lCMRGlc, whereas in animals of the "nonstimulated"
subgroups (n = 5 each), lCMRGlc was
measured in the awake, resting state.
In preparation for these studies, rats were briefly reanesthetized with
halothane for insertion of femoral arterial and venous catheters and a
rectal temperature probe, and they were placed in a loosely fitting
plaster body cast which was secured to a lead block. Animals were
placed in a dark, quiet room and allowed to recover for 1 h.
To activate the vibrissae-barrel somatosensory circuit projecting to
the side of prior TBI (right hemisphere), all the large whiskers on the
left side of the rat's face were cut to equal length and stroked
2-3 times per second with a soft hand-held brush for 5 min before
and 30 min following a pulse injection of ~20 µCi of
14C-labeled 2-DG
(2-[1-14C]deoxy-D-glucose, specific activity
45-55 mCi/mmol; New England Nuclear) dissolved in isotonic saline.
Arterial blood samples were withdrawn at frequent intervals over the
next 45 min, and plasma aliquots were assayed for their radioactive
contents by liquid scintillation counting and for their glucose content
by means of an automated glucose analyzer (Beckman), as previously described (15).
Autoradiographic studies were terminated by decapitation. Brains were
quickly removed and frozen over liquid nitrogen. There were
subsequently embedded and sectioned subserially in a cryostat (20-µm
thickness, 120-µm intervals) as previously described
(15). These sections, together with calibrated
[14C]methylmethacrylate standards, were exposed to
Amersham Hyperfilm Beta-max film for 10 days.
Autoradiographic image analysis.
Autoradiographic film images from individual animals were digitized at
8-bit precision by means of a charge-coupled device (CCD)-based camera
(Xillix Technologies, Vancouver, Canada) equipped with a 55-mm
Micro-Nikkor lens (Nikon, Tokyo, Japan). The camera was interfaced to
an advanced image analysis system (MCID model M2; Imaging Research, St.
Catharines, Ontario, Canada); images were captured at 70 µm/pixel
resolution. [14C]methylmethacrylate standards placed on
the film were digitized in parallel, to permit conversion of optical
density values to activity units of nanocuries per gram of
tissue. The operational equation for the 2-DG method, modified
for variable plasma glucose, was then used to compute
lCMRGlc (21, 23). Normal values
for the kinetic constants and the lumped constant of the 2-DG model were assumed (23); to our knowledge, there has been no
published evaluation of these constants in rats surviving 2 mo
post-TBI.
Image files for each experimental group were then transferred to a DEC
Alpha Station (266 MHz, 128 MB RAM; Digital Equipment) for
three-dimensional registration and averaging of corresponding coronal
sections from individual animals.
Three-dimensional autoradiographic image registration was based upon
the image-alignment algorithm that we have previously published in
detail (32, 33) and have implemented in
previous studies of brain ischemia (1, 31)
and trauma (15, 30). In this method, a linear
affinity transformation was first used to register sequential coronal
sections of each brain, and transformation parameters were calculated
by point-to-point disparity analysis. Each coronal section was aligned
to its adjacent neighbor by applying a reverse transformation with the
estimated translation and rotation parameters. After alignment of
individual rats, corresponding coronal sections of all brains were
placed in register with one another at a common coronal reference level
(bregma +0.7 mm). We digitized a functional-anatomic atlas of the
coronally sectioned rat brain (34) at all corresponding
levels. The digitized brain atlas served as a template at each coronal
level of interest, and all other sections were mapped into its contours
at each level by means of an averaging procedure similar to that
employed for image alignment (32). These procedures
resulted in quantitative three-dimensional image data sets representing
mean values of lCMRGlc for each animal group, which could
be displayed in pseudo-color. The averaged data sets could also be used
for further arithmetical manipulations.
Autoradiographic region-of-interest (ROI) analysis was carried out at
five coronal levels (0.7, 1.3, 1.8, 3.8, and 5.8 mm posterior to
bregma). (At the first 3 of these levels, an averaged image data set
for each animal, consisting of 3-4 subserial sections spanning
these nominal levels, was used to represent each level, to decrease
intra-animal variability). At each level, a digitized wire-frame atlas
template was fitted to the image data by disparity analysis, and a
polygon tool was used to define standardized ROI values corresponding
to atlas-demarcated anatomic regions. These ROI values were then used
to obtain measurements from the individual lCMRGlc data
sets comprising each animal group, and group mean values were computed.
Statistical analysis.
Intergroup differences for lCMRGlc were assessed by
repeated-measures ANOVA followed by multiple-comparison procedures.
lCMRGlc image data sets from the various groups of this
study were compared with one another by applying the Mann-Whitney
U test on a pixel-by-pixel basis. P < 0.05 was regarded as statistically significant.
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RESULTS |
Physiological variables.
All animals exhibited normal physiological variables immediately prior
to the 2-DG study (Table 1). Rectal
temperature during the 2-DG study was maintained at 35.5-37.0°C.
Autoradiographic image analysis.
Sham nonstimulated rats showed a normal pattern of lCMRGlc,
with symmetrical levels of cortical and subcortical glucose utilization in the two hemispheres typical of the awake, resting state (Fig. 1). In sham rats with left vibrissal
stimulation, conspicuous zones of elevated lCMRGlc were
apparent in the dorsolateral cortex at bregma levels 
1.3 and 1.8 mm
(Fig. 1), corresponding to the primary somatosensory barrel-field
cortex (18, 34). More posteriorly (bregma
3.8 mm), metabolic activation of the right ventroposteromedial thalamus (the secondary relay station of the barrel-field circuit) was
also evident (Fig. 1). Pixel-based statistical image analysis confirmed
that these were zones of highly significant intergroup difference with
respect to sham, nonstimulated rats (Fig.
2).
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Fig. 1.
Quantitative autoradiographic images of local cerebral
glucose utilization (lCMRGlc) at 4 coronal levels (with
reference to bregma) in the 4 experimental groups of this study. Each
image is the average of n = 5 brains. The right
hemisphere is shown on the right. In sham-injured brains,
stimulation-induced (Stim) increases in lCMRGlc are
apparent in somatosensory cortex (levels 1.3 and 1.8 mm) and in
ventrolateral thalamus (level 3.8 mm). TBI brains show depressed
lCMRGlc levels in the right hemisphere and nonresponsivity
to whisker stimulation. TBI, traumatic brain injury.
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Fig. 2.
Statistical maps generated by application of the
Mann-Whitney U test on a pixel-by-pixel basis to compare
autoradiographic data sets for the 4 groups and 4 levels shown in Fig.
1. The color bar displays 1 P, where P is the
level of statistical significance, thresholded from 0.95 to 1.00, so
that colored pixels represent areas of P < 0.05. Coherent loci of somatosensory activation are apparent in somatosensory
cortex and ventrolateral thalamus in the sham group but are absent in
the TBI groups. The right hemisphere of the TBI nonstimulated group
shows widespread areas of depressed lCMRGlc compared with
sham nonstimulated brains; these differences become more pronounced in
the comparison of the stimulated groups owing to failure of the TBI
brains to undergo functional activation.
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lCMRGlc in nonstimulated rats with prior right-hemisphere
trauma was moderately suppressed throughout the right hemisphere, with
the most severe depression occurring near the epicenter of prior injury
(bregma 3.8 mm, Fig. 1). Both cortical and subcortical structures
were affected. Statistical mapping confirmed significantly depressed
lCMRGlc throughout extensive regions of the right
hemisphere, compared with the nonstimulated sham group (Fig. 2).
Left vibrissae stimulation in rats with prior right-hemisphere trauma
failed to produce metabolic activation of the right hemisphere, either
within the barrel-field cortex or ventral posteromedial thalamus (Fig.
1). Statistical maps comparing stimulated sham rats vs. stimulated TBI
rats disclosed highly significant reductions in right-hemisphere
structures of the latter group (Fig. 2).
Atlas-based ROI analysis.
Table 2 presents atlas-based ROI
measurements of lCMRGlc in standardized brain regions of
the four groups of this series, at five coronal levels.
Repeated-measures ANOVA of left-hemisphere lCMRGlc data
disclosed no intergroup differences for any measured region
(F3,16 = 0.29, P = 0.83). By contrast,
repeated-measures ANOVA of right-hemisphere lCMRGlc data
revealed a highly significant between-groups effect
(F3,16 = 6.66, P = 0.004); and post
hoc Bonferroni tests demonstrated that lCMRGlc values in
nonstimulated rats with TBI were significantly (P < 0.05) below corresponding values in nonstimulated sham animals in
lateral and paramedian cortical zones near the trauma epicenter and
below values in stimulated sham animals in multiple forebrain regions
(Table 2).
A global intergroup comparison of right- vs. left-hemisphere
lCMRGlc values was then undertaken across all measured
forebrain regions listed in Table 2. These data, shown in Table
3, revealed left-right hemispheric
symmetry of lCMRGlc values in sham nonstimulated rats,
significant right-hemisphere elevations in sham rats with left
vibrissal stimulation, and highly significant right-hemisphere lCMRGlc depression in both stimulated and
nonstimulated rats with prior TBI, relative to left-hemisphere values.
Image-guided ROI analysis.
The pixel-based statistical maps comparing the lCMRGlc
image data sets of the sham stimulated vs. sham nonstimulated groups by
the Mann-Whitney U test (Fig. 2) allowed us to define the
precise locations of the metabolically activated barrel-field cortex
and thalamus in animals without TBI. Having defined these coherent loci
of statistically significant activation in sham brains, we then
interrogated the image data sets of stimulated and
nonstimulated TBI rats to derive lCMRGlc values within
those same cortical and thalamic loci. These data are shown in
Table 4. Stimulation in sham rats led to
mean lCMRGlc increases of 44% and 28% within these
cortical and thalamic loci, respectively. By contrast, rats with TBI
exhibited reduced lCMRGlc levels in each locus and failed to show stimulation-induced increases of lCMRGlc in either
the barrel-field cortex or ventrolateral thalamus (Table 4).
Corrections for brain atrophy.
The present image-based analysis is predicated upon comapping brains of
all animal groups into a common template derived from an atlas of the
normal brain. It is possible, however, that TBI with chronic survival
may have induced brain atrophy. If so, this would have led to an
under-representation of atrophic brain areas within standardized ROIs
as defined by normal atlas templates and, hence, to an underestimation
of lCMRGlc values in chronically injured brain areas. To
assess this potential source of error, we made use of histological
material derived from a previous study of TBI with 2-mo survival in an
identical injury model (4). Paraffin-embedded,
hematoxylin- and eosin-stained coronal sections were available from
seven sham-injured rats and six rats with TBI and 2-mo survival. At
four of the coronal levels used for lCMRGlc analysis in the
present study (bregma 1.3, 1.8, 3.8, and 5.8 mm) (Table 2), we
traced histological section outlines and right lateral-ventricle areas.
These data were then computer-mapped into the respective atlas
templates; frequency maps were generated of right lateral ventricle
areas of the TBI and sham groups; and pixel-based Fisher exact tests
were used to identify intergroup differences.
At three of the four coronal levels analyzed (bregma 1.3, 1.8, and
5.8 mm), ventricular contours were narrow in both TBI and sham
groups, and intergroup differences were unimportant. However, at
coronal level 3.8 mm, corresponding to the epicenter of TBI, a
significant intergroup difference in ventricular size was apparent
(TBI > sham; Fig. 3). In TBI rats,
there was significant intrusion of the enlarged ventricle into the ROIs
used for lCMRGlc analysis at this level (Fig. 3). By
assuming lCMRGlc of the ventricle to be 0, we computed that
mean right-sided lCMRGlc values computed at coronal level
3.8 mm (see Table 2) were underestimated by 1.7% in right
dorsolateral cortex and by 18.4% in right lateral cortex.
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Fig. 3.
Statistical map at coronal level of 3.8 mm with respect to
bregma, based upon brains studied at 2-mo post-TBI by
perfusion-fixation and hematoxylin-eosin histopathology
(4). (The right hemisphere is shown on the
left.) The map, which was generated by application of the
Fisher exact test on a pixel-by-pixel basis, compares right lateral
ventricle size in sham and TBI rats; the significance level (1 P) is thresholded at 0.95 (i.e., P < 0.05).
The subcortical zone shown in red depicts a region in which a highly
significant enlargement in ventricular size was noted in TBI brains
compared with shams. Shown in white are the outlines of the 2 regions
of interest (ROI) from which lCMRGlc measurements were made
in the corresponding brains of the present series (see Fig. 1, Table
2). The dorsolateral cortical ROI contains only a trivial zone of
ventricular-size difference, whereas the lateral cortical ROI contains
a more substantial zone in which an enlarged lateral ventricle has
intruded into the ROI of the TBI group. (See text for details of
correction procedure.)
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DISCUSSION |
In animals surviving for 2 mo following moderate fluid-percussion
brain injury, our study disclosed a widespread depression of
lCMRGlc in forebrain regions ipsilateral to the prior
injury; global intergroup comparisons confirmed highly significant
ipsilateral depressions of lCMRGlc relative to
corresponding values of the left (nontraumatized) hemisphere (Table 3).
lCMRGlc was most severely depressed near the
injury-epicenter, and both cortical and subcortical structures were
involved (Figs. 1 and 2).
A major goal of this study was to assess whether brains with prior
moderate TBI were metabolically responsive to activation of the
vibrissae-barrel-field circuit projecting to the previously traumatized
hemisphere. The application of image-averaging methods allowed us to
localize the precise sites of thalamic and somatosensory-cortical activation in sham-injured animals (Figs. 1 and 2). These activation maps permitted us to define coherent loci of expected activation, which
could then be interrogated at the corresponding pixel locations in
brains with prior TBI. This image-guided ROI analysis (Table 4)
substantiated a significant stimulation-induced activation of
barrel-field cortex and ventrolateral thalamus in sham rats, but
nonsignificant increases in rats with prior TBI. The effect of prior
trauma was to reduce local glucose utilization of both cortical and
thalamic sites by ~38-45% in both nonstimulated and stimulated groups.
A previous histological analysis of brains of rats surviving for 2 mo
after a similar fluid-percussion brain injury has documented tissue
damage and gliosis involving the ipsilateral lateral neocortex, thalamus, and hippocampus, together with lateral-ventricle enlargement (4). The image-averaging methods used in the present study allowed us to assess whether brain atrophy, as evidenced by
compensatory ventricular enlargement, might have influenced the
lCMRGlc values computed by standardized ROI analysis. This
proved to be the case, however, for only a single measured region near
the epicenter of prior trauma (right lateral cortex at bregma level
3.8 mm; Fig. 3). The enlargement of the ipsilateral lateral ventricle is the composite reflection of all atrophy within the region. As others
have shown (4, 19), atrophy (at 2 mo) is more
pronounced in ipsilateral thalamus and hippocampus than in cerebral
cortex. Despite reorganization of cell layers, however, ROIs remain
morphologically distinct and, hence, definable according to a
predefined atlas template. A thorough study of white matter atrophy in
the chronic phase of TBI has not been published, but unpublished data
from our laboratory suggest that white matter atrophy may be more
significant than gray, and thus ventricular enlargement may be due in
large part to the loss of periventricular white matter, which would not
affect the integrity of our analysis.
Depressed lCMRGlc in the chronically injured brain may
reflect the disproportionate loss of metabolically active structural components and, in particular, synapses. In brains followed up to 1 yr
post-TBI, structures that are metabolically perturbed in this study,
such as the cerebral cortex, have been shown to become progressively
atrophic (11, 19, 22). These
results, taken in the context of the present study, suggest that
metabolic dysfunction of injured tissue may precede neurodegeneration
in areas destined to die following brain injury. If such a mechanism were operative, then therapeutic approaches to reverse metabolic dysfunction might possibly be effective in retarding the
neurodegenerative process. Alternatively, however, it is possible that
depressed CMRglu at 2 mo post-TBI represents a homeostatic response of
the injured brain and that interfering with this process might prove maladaptive.
Many injury mechanisms that participate in the acute phase of traumatic
injury, e.g., excitotoxicity, protease activation, ischemia, free
radical formation, and vascular perturbations (see Ref. 17 for review),
are not thought to remain operative at the 2-mo time point. It is
possible, however, that the widespread axonal injury seen after TBI
(6) leads to a progressive deafferentation in the chronic
phase, with loss of synaptic connections and secondary death of neurons
that depend upon transsynaptic or paracrine supply of trophic
factors. Apoptotic mechanisms, which can be activated by trophic factor
deprivation, have been identified in the early postinjury setting and
may contribute to progressive neuronal death (7,
24, 27). Slow axonal degeneration spreading
outward from the injury epicenter over weeks has been reported
(6, 19).
In summary, our results corroborate an enduring depression of cerebral
metabolic activity 2 mo after moderate brain injury, together with a
resistance of the chronically injured brain to functional activation.
As the present study did not directly measure the cellular responses of
barrel-field neurons to vibrissal stimulation, however, we cannot
comment upon the electrophysiological function of this circuit. Further
studies of the survival mechanisms upon which neurons depend are needed
to clarify the significance of this metabolic depression in terms of
chronic neurodegenerative processes.
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ACKNOWLEDGEMENTS |
This work was supported by National Institutes of Health Grants
NS-30291 and NS-05820.
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FOOTNOTES |
Address for reprint requests and other correspondence: M. D. Ginsberg, Cerebral Vascular Disease Research Center, Dept. of Neurology (D4-5), Univ. of Miami School of Medicine, PO Box
016960, Miami, FL 33101 (E-mail:
mdginsberg{at}stroke.med.miami.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 1 December 1999; accepted in final form 25 February 2000.
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