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1 Department of Neurochemistry
and Neurotoxicology, The
interleukin-1 (IL-1) receptor antagonist (IL-1ra) is an endogenous
antagonist that blocks the effects of the proinflammatory cytokines
IL-1
glial fibrillary acidic protein promoter; lipopolysaccharide; interleukin-1; cytokine
THE PLEIOTROPIC CYTOKINE interleukin-1 (IL-1) plays a
central role in local inflammatory and systemic responses after
infection. IL-1 activates a variety of cell types such as leukocytes,
fibroblasts, and endothelial cells, resulting in increased expression
of acute-phase proteins, adhesion molecules, chemokines, and other
inflammatory mediators, including prostaglandins (7). IL-1 is
biologically active at very low concentrations, and only a few IL-1
receptors on each cell need to be occupied to elicit the intracellular
signaling cascade (8). Hence, a strict regulation of IL-1's biologic activity is necessary; this is achieved by several mechanisms, including the existence of an endogenous antagonist. More explicitly, the IL-1 family of proteins consists of at least three different gene
products: the agonists IL-1 Cells in the central nervous system (CNS) have been shown to express
IL-1 receptors (11, 33), and IL-1 To study the role of IL-1 binding to central IL-1 receptors in
different experimental paradigms, we have produced a transgenic model
with overexpression of the secreted isoform of IL-1ra (sIL-1ra) in the
brain. It was reasoned that a persistent overexpression of an
extracellular IL-1ra (ecIL-1ra) in the brain would block the access of
IL-1 agonists to central IL-1 receptors. In this report we describe the
generation of two strains of transgenic mice (GILRA2 and GILRA4) with
astrocytic expression of the human secreted form of IL-1ra (hsIL-1ra)
under the control of the glial fibrillary acidic protein (GFAP)
promoter (27). The evidence of transgenic hsIL-1ra expression and
initial studies on its effect on the acute-phase response to central
IL-1 Materials
ABSTRACT
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
and IL-1
by occupying the type I IL-1 receptor. Here we
describe transgenic mice with astrocyte-directed overexpression of the
human secreted IL-1ra (hsIL-1ra) under the control of the murine glial
fibrillary acidic protein (GFAP) promoter. Two GFAP-hsIL-1ra strains
have been generated and characterized further: GILRA2 and GILRA4. These
strains show a brain-specific expression of the hsIL-1ra at the mRNA
and protein levels. The hsIL-1ra protein was approximated to ~50
ng/brain in cytosolic fractions of whole brain homogenates, with no
differences between male and female mice or between the two strains.
Furthermore, the protein is secreted, inasmuch as the concentration of
hsIL-1ra in the cerebrospinal fluid was 13 (GILRA2) to 28 (GILRA4)
times higher in the transgenic mice than in the control animals. To
characterize the transgenic phenotype, GILRA mice and nontransgenic
controls were injected with recombinant human IL-1 (central
injection) or lipopolysaccharide (LPS, peripheral injection). The
febrile response elicited by IL-1 (50 ng/mouse icv) was abolished in
hsIL-1ra-overexpressing animals, suggesting that the central IL-1
receptors were occupied by antagonist. The peripheral LPS injection (25 µg/kg ip) triggered a fever in overexpressing and control animals.
Moreover, no differences were found in LPS-induced (100 and 1,000 µg/kg ip; 1 and 6 h after injection) IL-1 and IL-6 serum levels
between GILRA and wild-type mice. On the basis of these results, we
suggest that binding of central IL-1 to central IL-1 receptors is not
important in LPS-induced fever or LPS-induced IL-1 and IL-6 plasma levels.
INTRODUCTION
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
and IL-1 and the IL-1 receptor antagonist (IL-1ra) (2, 10, 22). The IL-1ra, with the unique property
of being an endogenously produced antagonist, exists in three molecular
forms: one secreted and two intracellular forms (sIL-1ra and icIL-1ra
types I and II), all of which are encoded by a single gene and
generated by alternative splicing at the first exon (10, 15, 29). The
secreted form acts as an endogenous antagonist by binding to the
signaling type I IL-1 receptor without eliciting receptor activation,
whereas the function of the two intracellular forms remains unknown. It
has been suggested that icIL-1ra constitutes intracellular stores of
the protein that become secreted and available to extracellular domains
of receptors after cell death or that they affect the half-life of
IL-1-induced transcripts (29, 38). Similar to the IL-1ra, the type II
IL-1 receptor is believed to function as a negative regulator of
IL-1 and IL-1 activity, since it binds IL-1 and IL-1 with
higher affinity than it binds IL-1ra, but without triggering signal
transduction (24).
and IL-1 affect neuroendocrine
activity (37), behavior (5), slow-wave sleep (35), and appetite (28)
and induce fever (18). Furthermore, IL-1 and IL-1 have been
implicated in several CNS disorders such as stroke, Alzheimer's
disease, and multiple sclerosis (25, 32, 39).
stimuli and peripheral lipopolysaccharide (LPS) are described.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
-35S]dATP were
purchased from Amersham. All reagents used for cell culturing were
obtained from GIBCO. Cell culture dishes were purchased from Nunc.
Centricon-10 columns were obtained from Amicon. The human IL-1ra
(hIL-1ra) and the murine IL-6 and IL-1 ELISA kits were obtained from
R & D systems. Ketamine (Ketalar) was purchased from Parke-Davis, and
xylazine (Rompun) was obtained from Bayer. LPS (055:B5) was purchased
from Sigma Chemical, human recombinant IL-1 was a kind gift of
Sclavo, and the telemetry equipment for the fever measurements was
purchased from MiniMitter (Sunriver, OR).
Methods
Development of GILRA mice.
The murine GFAP promoter, encompassing the region 
2570 to +93
(relative to the transcriptional start site), with a deletion between
+6 and +87 that contains the two ATGs of the GFAP gene, was provided in
the Hind
III-EcoR I site of the pUC18 plasmid. The 570-bp hsIL-1ra cDNA sequence, containing the whole coding region
including the ATG translational start site and the TAG stop codon, was
located at the Hind III site of the
pRcCMV expression vector.
Identification of GILRA founders. The DNA from tail biopsies of 3-wk-old mice was isolated according to Laird and colleagues (19). One-four hundredth of each purified DNA sample was then subjected to PCR by using hIL-1ra-specific primers (see below), and the PCR products were analyzed by electrophoresis in ethidium bromide-stained, Tris acetate-EDTA-buffered 1% (wt/vol) agarose gels.
RT-PCR.
Tissues from mice decapitated at 6 wk of age were rapidly dissected and
stored in liquid nitrogen. Total RNA was purified using the Ultraspec
method. In the RT reaction, 0.2 µg of total RNA was mixed with 50 pmol of oligo(dT)12-18, 0.5 mM dNTP, 17 U RNAguard, and 100 U Maloney's murine leukemia virus
reverse transcriptase in a 20-µl reaction volume containing 50 mM
Tris · HCl, pH 8.3, 75 mM KCl, 3 mM
MgCl2, and 10 mM dithiothreitol. The reaction was performed at 37°C for 1 h, then the sample was heated to 95°C for 5 min to inactivate the enzyme. Five percent of
each cDNA preparation was subjected to PCR analysis by using primer at
0.3 µM each, as well as 100 µM dNTP, 10 mM
Tris · HCl, pH 8.3, 1.5 mM
MgCl2, 50 mM KCl, and 0.5 U
Taq DNA polymerase in a final volume
of 20 µl, and cycled [30 times for -actin and hIL-1ra and 36 times for murine IL-1ra (mIL-1ra)] through the following
temperature profile: 95°C for 20 s, 51°C for 20 s, and 72°C
for 20 s. The PCR products were analyzed by electrophoresis in Tris
acetate-EDTA-buffered, ethidium bromide-stained 1% (wt/vol) agarose gels. The sequences of the primers were as follows: hIL-1ra, 5'-CGACCCTCTGGGAGAAAATC-3' (sense) and
5'-CTCATCACCAGACTTGACAC-3' (antisense); mIL-1ra,
5'-GACCCTGCAAGATGCAAGCC-3' (sense) and
5'-CAGGACGGTCAGCCTCTAGT-3' (antisense); murine
-actin, 5'-AGGGAAATCGTGCGTGACAT-3' (sense) and
5'-CATCTGCTGGAAGGTGGACA-3' (antisense).
Preparation of cytosolic fractions.
Cytosolic fractions of mouse whole brain (without the cerebellum),
cerebellum, hypothalamus, spleen, liver, and skeletal muscle from
wild-type and GFAP-hsIL-1ra mice were obtained by homogenizing the
tissues (10% wt/vol) in 0.05 M
KH2PO4
(pH 7.3)-buffered 0.25 M sucrose solution containing 0.1 mM
phenylmethylsulfonyl fluoride, 10 µg/ml leupeptin, and 10 µg/ml
pepstatin. The homogenates were centrifuged for 10 min at 1,030 g at 4°C. The supernatants (S1) were collected and subjected to another centrifugation at 11,400 g for 1 h at 4°C. Finally, the
supernatants (S2) containing the cytosolic fraction were aliquoted and
stored at 85°C. The protein content of each sample was
determined using the "mini-Peterson" method (31).
Collection of serum. Blood from decapitated mice was collected in Eppendorf tubes. The blood was allowed to coagulate for 30 min at room temperature, and serum was obtained by centrifugation of the samples for 10 min at room temperature (1,000 rpm) followed by recovery of the supernatants. Neither EDTA nor anticoagulant was added to the sera.
Isolation of cerebrospinal fluid. Mice, 10-13 wk of age, were anesthetized with chloral hydrate (350 mg/kg). Skin and muscles were carefully removed from the neck, and a glass capillary was used to penetrate the tissue between the highest neck vertebra and the skull bone. Four to 8 µl of cerebrospinal fluid (CSF) were recovered from each animal.
Primary cell cultures. The brain (except the cerebellum) was dissected from mice that were <24 h old. Primary astrocyte cultures were prepared as described earlier (12). Briefly, the brain tissue was passed through an 8-µm nylon net, and the isolated cells from each mouse were seeded into ten 40-mm-diameter poly-L-lysine-coated cell culture dishes. The cells were grown in 4 ml of DMEM supplemented with 10% (vol/vol) fetal bovine serum, 100 µg/ml penicillin, and 100 µg/ml streptomycin at 37°C in an atmosphere containing 5% CO2. Cell culture supernatants were collected every time the medium was changed (twice a week). The supernatants were subsequently concentrated, and the buffer was changed to PBS by using Centriprep-10 spin columns. In addition, half-confluent astrocytes were harvested, and cytosolic fractions were prepared as described in Preparation of cytosolic fractions.
hIL-1ra ELISA. Four different preparations were analyzed for the presence of hsIL-1ra: cytosolic fractions from mouse tissues, cultured astrocytes, CSF, and medium from astrocyte cultures. Two hundred microliters of diluted (1:10) cytosolic fractions derived from different central and peripheral tissues of hsIL-1ra-overexpressing and wild-type mice were analyzed. The CSF samples (4-8 µl) were diluted to 200 µl with ELISA dilution buffer (supplemented with the R & D ELISA kit) and investigated for the presence of hsIL-1ra. Samples (200 µl) of concentrated (10 times) cell culture supernatants derived from the cultured astrocytes (wild-type as well as hsIL-1ra-overexpressing mice) and cytosolic proteins from the astrocyte culture cells were also analyzed for astrocyte-directed expression of hsIL-1ra.
IL-1 and mIL-6 ELISA.
Female mice, 6 wk of age, were injected intraperitoneally with 0.9%
NaCl or LPS. Two different doses of LPS were used (100 and 1,000 µg/kg), and the animals were decapitated 1 or 6 h after injection.
Blood samples were collected from the mice, and serum was prepared as
described above. Fifty microliters of each serum sample were used to
measure the IL-1 and IL-6 protein levels by ELISA. All assays were
performed according to the manufacturer's instructions.
Fever measurements.
The method used for fever measurements has been described earlier (1,
4, 6). Briefly, male mice, housed one per cage, were kept in a room
with controlled humidity (~80%) and at an ambient temperature of 30 ± 1°C. Sterile, wax-encapsulated MiniMitter transmitters were
implanted into the peritoneal cavity of mice anesthetized with ketamine
(50 mg/kg) and xylazine (10 mg/kg). At 5 days after surgery the animals
were injected intracerebroventricularly with 0.9% NaCl (saline) or
IL-1 (50 ng/mouse) or intraperitoneally with 0.9% NaCl (saline) or
LPS (25 µg/kg). The body temperature of each animal was measured by
receivers located beneath each cage. The recordings were started on the
day before injection and continued for 72 h.
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RESULTS |
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Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
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Development of hsIL-1ra-Overexpressing Mice
To produce transgenic mice with brain-directed overexpression of hsIL-1ra, a DNA construct consisting of the murine GFAP promoter, the hsIL-1ra cDNA, and a splice site from the small t intron of SV40 was generated and microinjected into fertilized mouse eggs (Fig. 1). Sixteen of 67 mice (~24%) of the F0 generation carried the transgene construct, as determined by PCR analysis of tail DNA with use of primers specific for the transgene cDNA sequence (data not shown). The male transgenic mice were then bred with wild-type female mice to establish heterozygotic, GFAP-hsIL-1ra (GILRA) transgenic strains. The nontransgenic littermates of the transgenic offspring were used as control animals.
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Analysis of Transgene Expression
hIL-1ra mRNA expression.
RT-PCR analysis of DNase-treated total RNA from total brain
homogenates showed that six different heterozygotic GILRA mouse strains
expressed hIL-1ra mRNA. Mice from GILRA2 and GILRA4 had a significantly
higher expression of hsIL-1ra mRNA than the other four GILRA lines
(data not shown) and were therefore chosen for further
characterization. The hsIL-1ra mRNA was expressed in the CNS, but not
in the liver, of the GILRA4 transgenic line (Fig. 2), whereas no hsIL-1ra mRNA could be
detected in the nontransgenic siblings of the GILRA4 mice. Neither
GILRA4 nor wild-type mice showed endogenous mIL-1ra mRNA expression in
the different brain areas under normal conditions (36 PCR cycles; data
not shown). Similar results, with exclusively central expression of
hIL-1ra mRNA, were obtained from the GILRA2 line (data not shown). The fidelity of each cDNA sample was checked by concomitant RT-PCR analysis
by using murine -actin primers (data not shown).
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hIL-1ra protein expression.
Cytosolic fractions of different mouse brain regions and peripheral
tissues were prepared from 6-wk-old mice to study the expression of
hsIL-1ra at the protein level. The hsIL-1ra could be detected in the
brain tissues of the GILRA2 and GILRA4 strains (~2.5 ng/ml cytosolic
protein, total amount of hsIL-1ra ~50 ng/brain), whereas no hsIL-1ra
immunoreactivity could be detected in the different peripheral tissues
studied (Fig.
3A). No
major difference in hsIL-1ra expression could be seen between the two
GILRA strains or between the cerebral hemisphere and cerebellum of the
respective transgene strains (Fig.
3A). A similar degree of hsIL-1ra
expression was detected in 11-wk-old mice (data not shown). In the
hypothalamus the hsIL-1ra expression was 4.9 ± 0.9 ng hsIL-1ra/mg
cytosolic protein [pooled: GILRA2
(n = 3), GILRA4
(n = 1)]. The hsIL-1ra was
expressed at a high level in the CSF of 5- to 8.5-wk-old GILRA2 mice
(1.06 ± 0.4 nM) and 9- to 12-wk-old GILRA4 mice (2.37 ± 1.46 nM; Fig. 3B). The
hsIL-1ra could also be detected in cells and cell culture supernatants
(~50 pg/ml and ~3 nM, respectively) of primary astrocyte cultures
derived from the GILRA4 strain. Primary astrocyte cultures were not
prepared from GILRA2 mice.
|
Fever Measurements
A central IL-1 challenge (50 ng of intracerebroventricularly
injected human recombinant IL-1) in wild-type mice produced a
monophasic fever (Fig.
4A).
When the same stimulus was given to GILRA2 and GILRA4 transgenic
animals, however, no febrile response was triggered (Fig.
4A).
|
The transgenic mice were then further investigated for their ability to mount a fever response to a peripheral LPS stimulus. In initial experiments, wild-type mice were injected with different doses of LPS to establish a dose-response curve of the fever response (data not shown). An LPS challenge of 25 µg/kg ip was chosen, inasmuch as it gave a clear reproducible fever response. This dose of LPS induced a slightly biphasic fever in wild-type and GILRA mice; because there was no apparent difference between the GILRA2 and GILRA4 strains, the data are reported in a pooled form as "GILRA+" animals. The fever amplitude was slightly higher in the GILRA+ than in wild-type animals, although this did not reach statistical significance (Fig. 4B).
Serum IL-6 and IL-1 Levels
|
In addition, LPS-induced (100 and 1,000 µg/kg ip) IL-1 serum
levels were measured by ELISA 1 and 6 h after injection. LPS stimulated
the induction of IL-1 5- to 18-fold in serum collected 1 h after LPS
injection (31-53 pg IL-1/ml plasma) and 18- to 64-fold in serum
collected 6 h after LPS administration (110-280 pg IL-1/ml
plasma; Table 1). There was, however, no difference in the LPS
inducibility of serum IL-1 levels between the GILRA strains and
wild-type animals (Table 1).
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DISCUSSION |
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Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
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The objective of the present study was to produce an animal model for studying the contribution of brain IL-1 receptors in IL-1- and LPS-induced biologic activities. It has become evident that IL-1 plays an important role in modulating CNS-mediated physiological responses (34). IL-1 effects such as fever induction, decrease in social behavior, and hypothalamus-pituitary-adrenal axis activation have been considered as centrally mediated activities, because an intracerebroventricular injection requires a 100- to 1,000-fold lower dose of IL-1 than the peripheral injection to elicit the same responses (17). However, IL-1 receptors are widely expressed throughout the body, and the target of IL-1 activity along the neuroimmune axis in different IL-1-mediated effects is still poorly understood. New biologic tools, such as tissue-specific overexpression or deficiency of the IL-1ra gene, would be valuable in this research.
Here we describe the generation of transgenic mice with
astrocyte-directed expression of hsIL-1ra under the control of the GFAP
promoter. The antagonist property of IL-1ra has been exploited in
studies on effects exerted by IL-1 agonists at IL-1 receptors. The
human form of the IL-1ra binds to mIL-1Rs with high affinity and has
commonly been used to block IL-1- and IL-1-induced responses in
rodents (9, 23). A large molar excess of the IL-1ra is required to
block the IL-1- and IL-1-mediated biologic activities (8), since
the affinities of the agonist and antagonist are not significantly
different and since a very low degree of receptor occupancy with the
agonist is sufficient to evoke an IL-1 response. Given the widespread
distribution of IL-1 receptors in the brain (6, 11, 33, 34) and the
large excess of IL-1ra required to block IL-1- and IL-1-induced
biologic responses (23), we decided to use the GFAP promoter to drive a
strong and constitutive expression of the hsIL-1ra (3, 13, 27, 36). We
have characterized two GFAP-hsIL-1ra (GILRA) lines: GILRA2 and GILRA4.
The expression of hsIL-1ra was exclusively limited to the CNS in both
lines, as investigated by RT-PCR and ELISA. The total amount of
hsIL-1ra in cytosolic fractions prepared from whole brain homogenates
was 50 ng/brain, which would correspond to ~2.5 nM hsIL-1ra, with the
assumption of a mouse brain volume of 1 ml and an even distribution of
the hsIL-1ra throughout the brain. In the hypothalamus, however, a
brain structure believed to elicit IL-1-induced biologic activities such as the fever response, the expression of hsIL-1ra was about twice
as high as in the whole brain. Unfortunately, we were not successful in
our attempts to determine the cellular distribution of the hsIL-1ra by
immunohistochemistry or in situ hybridization studies. However, cell
extracts of primary astrocyte cultures derived from newborn transgenic
mice were shown to contain hsIL-1ra, indicating an astrocyte-driven
expression of hsIL-1ra. The presence of hsIL-1ra in astrocyte culture
medium suggested that the hsIL-1ra was secreted, and this was further
suggested by the occurrence of hsIL-1ra in CSF samples from the
transgenic mice. The concentration of hsIL-1ra in the CSF samples was
1-2.5 nM, in close agreement with the estimated concentration of
the hsIL-1ra in the total brain homogenates (~2.5 nM). In view of the
suggested affinity constant for the sIL-1ra-type I IL-1 receptor
interaction (0.15 nM) (9), an extracellular concentration of
1.0-2.5 nM of hsIL-1ra would indicate that most brain IL-1
receptors are occupied by the hsIL-1ra. However, this would rely on the
assumption that hsIL-1ra is evenly distributed.
Neither developmental, physical, nor overt behavioral abnormalities were observed in the transgenic mice, suggesting that agonist occupancy of IL-1 receptors is not vitally important during development and that the primary role of IL-1ra is that of an anti-inflammatory cytokine during pathophysiological conditions. However, Hirsch and collaborators (16) recently reported that mice deficient in the IL-1ra gene lose weight from 6 wk of age, suggesting a physiological role of the IL-1ra in normal homeostasis. The same authors also produced mice with general overexpression of the IL-1ra gene. Those mice, in accordance with our central hsIL-1ra-overexpressing mice, did not show any weight abnormalities. This may suggest that IL-1ra occupancy of IL-1 receptors distinguishes the IL-1ra-deficient and IL-1ra-overexpressing mice in terms of body weight.
To analyze the hypothesis that central IL-1 receptors mediate
LPS-induced physiological responses, LPS was injected intraperitoneally into the transgenic mice and their siblings. First, the occupancy of
central IL-1 receptors by antagonist was assessed by means of an
intracerebroventricular injection of IL-1. Accordingly, a central
injection of IL-1 was unable to trigger a fever in GILRA+ mice,
suggesting that central IL-1 receptors were occupied by antagonist
(Fig. 4A). Subsequently, the febrile
response in GILRA mice after LPS challenge was studied (Fig.
4B); the GILRA mice were able to run
fevers, although their central IL-1 receptors were occupied, suggesting
that IL-1 binding to its receptors in the CNS is unimportant in
intraperitoneal LPS fever, at least in mice. In fact, the transgenic
mice exhibited a tendency toward a supersensitive fever in response to
LPS compared with the wild-type mice. Our finding partly contradicts a
previous study in the rat, where central injections of IL-1ra were able
to block peripherally induced endotoxin fever (21).
Next, plasma levels of IL-1 and IL-6 were measured, since LPS is
known to increase peripheral levels of cytokines (26). No difference in
serum levels of IL-6 or IL-1 could be detected between GILRA and
wild-type mice after a peripheral LPS challenge. These data are in line
with experiments performed in rats where peripheral LPS-induced serum
IL-6 levels were blocked with an intraperitoneal, but not an
intracerebroventricular, injection of hsIL-1ra (21) and suggest that
LPS triggers increases in plasma cytokines independent of central IL-1
receptor occupancy.
In summary, two transgenic mouse strains with CNS-specific expression
of the anti-inflammatory cytokine hsIL-1ra under the control of the
murine GFAP promoter were developed (GILRA2 and GILRA4). Central
injection of IL-1 did not cause fever in these mice, suggesting a
blockade of the central IL-1 receptors by hsIL-1ra. However,
intraperitoneal injection of LPS resulted in a febrile response in the
GILRA mice, suggesting that brain IL-1 receptors are not involved in
the cytokine cascade in LPS fever.
Perspectives
It is conceivable that the GILRA mice will be useful tools in examining the contribution of centrally expressed IL-1 receptors in different physiological or pathophysiological processes, such as investigating the role of IL-1 in different CNS-associated diseases. IL-1 has been suggested to be one of the major proinflammatory cytokines responsible for the induction of inflammatory events in the CNS during trauma, ischemia, stroke, and neurological disorders such as multiple sclerosis and Alzheimer's disease (25, 32, 39). Loddick and colleagues (20) recently presented evidence for a neuroprotective role of endogenously expressed IL-1ra. It will therefore be of value to study different disease models in the GILRA mice.| |
ACKNOWLEDGEMENTS |
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We are grateful to Prof. Urban Lendahl and Erik Nilsson, Marie-Louise Alun and colleagues, and Clas Johansson for generation of the transgenic strains, animal care, and isolation of CSF fluid, respectively.
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FOOTNOTES |
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This work was supported by the European Community Biomed II program CYBRAINET Grant CT97-2492, Swedish Medical Research Council, Loo and Hans Ostermans Foundation, Kapten Artur Erikssons Foundation and Stiftelsen Gamla Tjänarinnor.
J. Lundkvist and A. K. Sundgren-Andersson contributed equally to this work.
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 reprint requests to M. Schultzberg.
Received 26 May 1998; accepted in final form 19 October 1998.
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Abstract
Introduction
Materials and methods
Results
Discussion
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