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response
Section of Neonatology, Department of Pediatrics, Rush Children's Hospital, Rush Presbyterian St. Luke's Medical Center, Chicago, Illinois 60612
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ABSTRACT |
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 Top
 Abstract
 Introduction
Materials and methods
Results
Discussion
References
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Previous
investigators have demonstrated that the tumor necrosis factor-
(TNF-) response to endotoxin is inhibited by exogenous corticosterone or catecholamines both in vitro and in vivo, whereas others have reported that surgical and nonsurgical stress increase the
endogenous concentrations of these stress-induced hormones. We
hypothesized that elevated endogenous stress hormones resultant from
experimental protocols attenuated the endotoxin-induced TNF- response. We used a chronically catheterized rat model to demonstrate that the endotoxin-induced TNF- response is 10- to 50-fold greater in nonstressed (NS) rats compared with either surgical-stressed (SS,
laparotomy) or nonsurgical-stressed (NSS, tail vein injection) models.
Compared with the NS group, the SS and NSS groups demonstrated significantly lower mean peak TNF- responses at 2 mg/kg and 6 µg/kg endotoxin [NS 111.8 ± 6.5 ng/ml and 64.3 ± 5.9 ng/ml, respectively, vs. SS 3.9 ± 1.1 ng/ml
(P < 0.01) and 1.3 ± 0.5 ng/ml
(P < 0.01) or NSS 5.2 ± 3.2 ng/ml (P < 0.01) at 6 µg/kg]. Similarly, baseline concentrations of corticosterone
and catecholamines were significantly lower in the NSS group
[84.5 ± 16.5 ng/ml and 199.8 ± 26.2 pg/ml, respectively,
vs. SS group 257.2 ± 35.7 ng/ml (P < 0.01) and 467.5 ± 52.2 pg/ml
(P < 0.01) or NS group 168.6 ± 14.4 ng/ml (P < 0.01) and 1,109.9 ± 140.7 pg/ml (P < 0.01)].
These findings suggest that the surgical and nonsurgical stress
inherent in experimental protocols increases baseline stress hormones,
masking the endotoxin-induced TNF- response. Subsequent studies of
endotoxic shock should control for the effects of protocol-induced
stress and should measure and report baseline concentrations of
corticosterone and catecholamines.
catecholamines; corticosterone; stress; endogenous
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INTRODUCTION |
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Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
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A SERIES OF STUDIES has documented the complex
interaction of the neuroendocrine and immune systems, an important
consideration in research addressing septic shock (3, 21, 34). For both humans and animals, corticosterone and catecholamines have been shown
to modulate the immune response in vivo and in vitro (7, 26, 33).
Although these mechanisms are not completely defined, human data
suggest that pretreatment with exogenous cortisol or catecholamine
attenuates the endotoxin-induced tumor necrosis factor- (TNF-)
response (2, 28). However, little research has focused on the release
of endogenous corticosterone and catecholamines during experimental
protocols for the study of septic shock and whether these endogenous
hormones have the capacity to attenuate the TNF- response.
The purpose of this study was to test the hypothesis that elevated
baseline concentrations of endogenous corticosterone and catecholamines
result from surgical and/or nonsurgical stressors in
experimental protocols and that these elevated endogenous hormones attenuate the TNF- response. We speculated that animals studied under nonstressed experimental conditions with physiological baseline concentrations of corticosterone and catecholamine would exhibit a
significantly greater endotoxin-induced TNF- response and that this
response could be elicited with relatively low doses of endotoxin.
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MATERIALS AND METHODS |
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Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
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Animals
A total of 91 adult male Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA) weighing 200-250 g were used in this study. Rats were housed singly in standard cages and were fed chow and water ad libitum. The environment was temperature- and humidity-controlled, with lights on and off at 0630 and 1630, respectively.Operative Procedures
Operative procedures were performed as previously described for our chronically catheterized rat model (17, 27). Briefly, the animals were anesthetized with intramuscular injections of 60 mg/kg ketamine and 5 mg/kg xylazine. Under an aseptic technique a 5-cm vertical midline abdominal skin incision was made from the subxiphoid process of the sternum to the suprapubic region and a 0.25-cm skin incision was made over the cervical vertebrae. Infusion sets (no. 4871, Abbott Laboratories, North Chicago, IL) were flushed with 0.9% saline solution containing 10 units of heparin/ml and were pulled through the skin opening over the vertebrae and into the abdominal incision. Then a 4.5-cm vertical midline incision was made through the abdominal wall. The infusion set tubes were introduced into the abdominal cavity through small punctures in the right abdominal wall.To prepare the abdominal aorta for catheterization, the gut was retracted onto sterile, saline-soaked gauze. The aortic catheter, consisting of an Insyte catheter tip (Becton Dickenson, Sandy, UT), Silastic tubing, and PE-60 tubing, in sequence, was introduced into the abdominal aorta over a 22-gauge Insyte needle. The Insyte tip of the catheter was advanced 0.5 cm into the aorta and secured with one drop of cyanoacrylate glue. The distal PE-60 tubing was inserted into its infusion tubing, and the line was flushed. This procedure was repeated for the inferior vena cava (IVC). The abdominal wall and skin were closed with 4-0 silk suture. The infusion sets exiting the cervical incision were sutured securely to the back of the rat with 2-0 silk suture and were glued postoperatively with silicon to form a single unit. Ampicillin (30 mg/kg) was injected into the IVC and aortic catheters. Catheters were flushed daily with saline.
Reagents
Endotoxin (Escherichia coli 0127:B8; Sigma Chemical, St. Louis, MO) was prepared in sterile saline, aliquoted, and stored at
80°C.
Experimental Design
Rats were given varying doses of endotoxin under three different experimental conditions: 1) nonstressed (NS), 2) surgical stressed (SS), and 3) nonsurgical stressed (NSS). This design allowed the identification of dose- and time-dependent responses, while controlling for the effects of protocol-induced stressors on outcome measures. For each group, experiments were performed between 0900 and 1000 to control for circadian variation (10).NS group. This group of chronically catheterized rats experienced the operative procedures described and thereafter were maintained under nonstressed experimental conditions. These animals were considered nonstressed from an experimental perspective in that the environment was manipulated to ensure that animals were not subjected to further protocol-induced surgery, restraint, or pain. These 60 animals were assigned to one of four experimental groups, according to the endotoxin dose to be administered: 1) 2 mg/kg (n = 7), 2) 6 µg/kg (n = 37), 3) 10 ng/kg (n = 8), or 4) control (saline diluent only, n = 8). At a median of 7 days postsurgery (range 3-14 days), endotoxin doses were diluted in 0.5 ml of saline and infused through the IVC for 0.5 min. Then the IVC was flushed with 1 ml saline.
SS group. The effect of surgical stress on outcome measures was studied for 16 rats who were injected with endotoxin immediately on completion of the described surgical procedures. The animals were assigned to receive one of three endotoxin doses: 1) 2 mg/kg (n = 5), 2) 6 µg/kg (n = 6), or 3) control (saline diluent only, n = 5). Endotoxin was diluted and infused into the IVC as described for the NS group.
NSS group. The effect of nonsurgical stress, including restraint, handling, and pain that are inherent in many other experimental protocols was studied for 15 rats on the 7th day after operative procedures were performed. These chronically catheterized rats received infusions into the tail vein of either 6 µg/kg of endotoxin (n = 9) or saline (controls, n = 6) using the following procedure. Each rat was secured in an individual restraining cage to allow tail access. The area of injection was swabbed with 70% ethanol and allowed to dry. A 25-g butterfly (no. 4573, Abbott Laboratories) was inserted into the tail vein, with placement confirmed by blood flow into the butterfly. Then blood samples were obtained from the aortic catheter. Endotoxin was infused into the tail vein, and the line was flushed with 1 ml of saline. The rat was removed from the restraining cage and placed into an individual cage for the duration of the experiment.
Measures
Mediators.
The following mediators were measured by aortic blood sampling at
baseline (0), and 30, 60, 90, 120, 180, and 240 min after endotoxin
infusion: TNF- (ng/ml), catecholamines (pg/ml), and corticosterone
(ng/ml). TNF- was measured by ELISA (Genzyme, Cambridge, MA).
Catecholamines, a combination of epinephrine and norepinephrine, were
measured by radioenzymatic assay (Amersham, Arlington Heights, IL) from
plasma collected with EGTA (90 mg/ml) and glutathione (60 mg/ml).
Corticosterone was measured by radioimmunoassay kit (ICN Biomedicals,
Costa Mesa, CA).
were measured daily between 0900 and 1000. Blood samples were cultured on tryptic soy, MacConkey's, and
blood agar plates. The measures of these 14 rats document that the NS
group was studied under conditions of no or minimal stress, and no
day-to-day variability existed in these measures over the 14-day study period.
Statistical analysis. All results are expressed as means ± SE. For kinetic studies, differences were compared by both one-way and repeated-measures ANOVA. Peak responses were compared with Student's t-test or with post hoc comparison as appropriate. Type 1 error was set at 0.05.
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RESULTS |
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Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
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Experimental Conditions of NS Group
Our data document that animals in the NS group were studied under conditions of no or minimal stress. At day 1 postsurgery these animals exhibited a 5.3 ± 1.5% weight loss, but preoperative weight was reestablished by day 3. Mean daily weight gain for days 2-14 was comparable to that of control animals (7.2 ± 2.8 vs. 7.8 ± 1.2 g, P = 0.98). An initial corticosterone surge (278 ± 51 ng/ml) was noted in response to surgery, but mean daily corticosterone concentration for days 2-14 was 57 ± 5 ng/ml (Fig. 1). A repeated-measures ANOVA demonstrated that mean corticosterone did not vary significantly from 2 to 14 days (P < 0.57). The rats were not bacteremic, and neither endotoxin nor TNF- was noted in the daily
blood and serum analyses (data not shown).
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Endotoxin-Induced TNF-, Catecholamine, and
Corticosterone Responses in NS Group
, catecholamines, and
corticosterone revealed significant dose- and time-dependent effects in
response to endotoxin challenge (Fig. 2).
For TNF- a repeated-measures ANOVA revealed a significant effect for
dose (P < 0.001) and time (P < 0.001). Peak TNF-
concentrations were noted at 90 min postendotoxin challenge in response
to 2 mg/kg and 6 µg/kg, and at 60 min postendotoxin challenge in
response to 10 ng/kg. No TNF- was observed in the serum of NS rats
in the control group.
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Peak catecholamine and corticosterone responses occurred, respectively, at 60 and 120 min postendotoxin challenge (Fig. 2). The catecholamine and corticosterone responses to 2 mg/kg of endotoxin were of significantly greater amplitude and duration than for 6 µg/kg (P < 0.001 and P < 0.005, respectively) and 10 ng/kg of endotoxin challenge (P < 0.001 and P < 0.001, respectively). Furthermore, catecholamine and corticosterone responses to 2 mg/kg of endotoxin had not returned to baseline by 240 min. Control rats displayed no changes in catecholamine or corticosterone concentrations, and control values were not significantly different from values for those given 10 ng/kg of endotoxin (P < 0.24).
Endotoxin-Induced TNF- Response Over Time
response was not affected by the number of
days after surgery that experiments were conducted, we compared the
peak TNF- concentrations from 3 (61.0 ± 14.8 ng/ml) to 14 (54.2 ± 16.9 ng/ml) days postsurgery in 32 of the rats in the 6 µg/kg
endotoxin challenge group. The median day of experimentation was 7 days
(62.3 ± 17.8 ng/ml). A repeated- measures ANOVA revealed no
statistically significant time-dependent effect for peak TNF- over
this period (P < 0.65), indicating
that the timing of the experiment did not influence the TNF- response.
Relationship Between Endotoxin-Induced TNF- Response
and Baseline Corticosterone Concentration
response. To test the
hypothesis that elevated baseline corticosterone concentrations in
these animals had attenuated the TNF- response, we plotted baseline
corticosterone concentrations against peak serum TNF- concentrations
for the 37 NS rats (Fig. 3). The five rats
that did not produce TNF- in response to endotoxin challenge had
serum corticosterone concentrations >200 ng/ml (mean 358.8 ± 23.2 ng/ml), whereas their mean peak TNF- concentration was only 3.9 ± 2.8 ng/ml. In contrast, the remaining 32 rats demonstrated serum
concentrations of corticosterone <200 ng/ml (mean 84.5 ± 16.5 ng/ml) and a mean peak TNF- concentration of 63.6 ± 7.6 ng/ml.
Although the numbers were small, a Student's
t-test demonstrated significantly
greater mean corticosterone (P < 0.001) and significantly lower mean peak TNF-
(P < 0.001) for these five animals
compared with the remaining 32 rats. Mean daily weight gain for these
five animals was not significantly different from the remaining 32 rats
(6.1 ± 3.6 vs. 7.2 ± 2.8 g).
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Endotoxin-Induced TNF-, Catecholamines, and
Corticosterone Responses in SS Group
responses for 2 mg/kg
(P < 0.01) and 6 µg/kg
(P < 0.03) groups (Fig.
4). Dose- and time-dependent responses were
noted for catecholamine but not for corticosterone in SS animals (Fig.
4). A striking difference in peak TNF- between NS and SS groups
(Figs. 2 and 4) was observed. For the NS group peak TNF-
concentrations of 111 ± 6.5 ng/ml and 64.3 ± 5.9 ng/ml, for 2 mg/kg and 6 µg/kg endotoxin doses, respectively, were significantly
higher (P < 0.001) than comparable values of 3.9 ± 1.1 ng/ml and 1.3 ± 0.5 ng/ml, respectively,
for the SS group.
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Endotoxin-Induced TNF-, Catecholamine, and
Corticosterone Responses in NSS Group
, corticosterone, and catecholamine responses for the NSS group
are depicted in Fig. 5, and compared with
those for the NS group (Fig. 2). A repeated- measures ANOVA confirmed
the difference in the TNF- response
(P < 0.001) for the NSS and NS
groups.
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Effect of Associated Stress Hormones on TNF-
Response
responses (NS, Lo-Cort; n = 32) and
2) those with baseline
corticosterone concentrations >200 ng/ml and low peak TNF-
responses (NS, Hi-Cort; n = 5). Then
we constructed two scatterplots (Fig. 6) to
depict the relationships between peak TNF- and baseline
concentrations of corticosterone and catecholamines for 50 animals
within the four subgroups: 1) NS,
Lo-Cort, n = 32;
2) NS, Hi-Cort,
n = 5;
3) SS,
n = 6;
4) NSS, n = 9. These data reveal visual
differences between the NS, Lo-Cort group and the remaining three
subgroups. To confirm these group-specific differences we performed
separate one-way ANOVA for TNF-, baseline corticosterone, and
baseline catecholamines, using the four subgroups as independent
variables.
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The ANOVA revealed statistically significant differences among the four
groups (P < 0.001). All pairwise
post hoc Scheffé's tests were significant between the NS,
Lo-Cort group and each of the three subgroups separately
(P < 0.001), with the exception of
baseline catecholamine for NS, Lo-Cort and NS, Hi-Cort. Using separate
post hoc Scheffé's comparisons, we tested the hypothesis that
the NS, Lo-Cort group was different from the remaining three groups
that were characterized by elevated stress hormones and lower TNF-.
Resulting mean values for the NS, Lo-Cort group were significantly
different from mean values for the combination of the three
"stressed" groups; peak TNF- (64.3 ± 5.9 vs. 4.0 ± 1.5 ng/ml, P < 0.001),
corticosterone (84.5 ± 16.5 vs. 254.6 ± 27.3 ng/ml,
P < 0.001), and catecholamine (198.8 ± 26.2 vs. 940.8 ± 290.9 pg/ml,
P < 0.001)(23).
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DISCUSSION |
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Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
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These data are the first to demonstrate that rats with low baseline
concentrations of corticosterone and catecholamine possess the ability
to mount a TNF- response to relatively low doses of endotoxin. The
peak TNF- concentrations for animals in the NS group were greater
than previously described at endotoxin doses equivalent to from 1 to
1/1 × 106 those used in previous studies (13, 15, 18, 22,
31). In contrast, rats that were studied under surgically or
nonsurgically induced stress demonstrated elevated baseline
corticosterone and catecholamine concentrations and diminished TNF-
responses for all doses examined. Although our findings confirm the
hypotheses of others that experimental conditions associated with
high-stress hormones affect physiological responses to endotoxin, our
study is the first to experimentally manipulate protocol-induced stress while examining the effect on baseline corticosterone, catecholamine, and peak TNF- (6, 8, 14, 32).
Several methodological controls ensured that animals in our NS group
were maintained and studied under experimental conditions that were
free of surgically and nonsurgically induced stress. During the
3-14 days postsurgery when experiments were conducted, animals
demonstrated a mean daily weight gain comparable to control rats and
did not have bacterial infection or endotoxin in the blood. Similarly,
no difference over the 3-14 days was noted in the mean baseline
corticosterone or the peak TNF- response. In contrast, our SS and
NSS groups were studied under conditions of laboratory stress that are
standard in experimental protocols used by other investigators. Whereas
both the SS and NSS groups demonstrated an attenuated TNF- response
to endotoxin, baseline stress hormones differed for the two groups. Our
SS group displayed elevated baseline corticosterone, suggesting stress
from surgery, whereas the NSS group displayed elevated baseline
catecholamine suggesting stress from handling and pain.
We observed that five chronically catheterized rats (NS, Hi-Cort) demonstrated baseline serum corticosterone concentrations >200 ng/ml. These rats showed no overt signs of stress and demonstrated weight gain that was not statistically different from other rats in the NS group. Although the reasons for these elevated baseline corticosterone values are unknown, we suspect that these animals experienced nonbacterial surgical complications. The fact that these rats appeared to be NS, yet demonstrated elevated baseline corticosterone, underscores the importance of measuring and reporting stress hormones for all animals in studies of endotoxic shock.
Although experimental models with indwelling catheters for endotoxin
infusion and blood sampling have been reported, these protocols
incorporate significantly greater endotoxin doses to elicit the TNF-
response than doses required by animals in our NS group (11, 15, 18,
22, 31). Previous investigators administered 
1.0 mg/kg of endotoxin
to achieve a mean peak TNF- response that was only 
to
of values for our NS animals that received this endotoxin
dose. Our findings are the first to reveal a statistically significant TNF- response to 10 ng/kg of endotoxin. Feuerstein et al. (11) described a minor TNF- response to 100 ng/kg of endotoxin, and Givalois et al. (13) used 5 µg/kg of endotoxin administered intraarterially to achieve a mean peak TNF- concentration equivalent to one-half that reported in our NS animals. These
different findings can be explained by the fact that previous protocols
did not permit sufficient postsurgical recovery, with resultant
elevations in baseline stress hormones at the time of endotoxin
challenge. Indexes of stress, such as weight loss, baseline
corticosterone, and catecholamines were not reported in these studies.
Similarly, the fact that our experimental protocol permitted the
manipulation of NS, SS, and NSS conditions challenges previous hypotheses of a species-specific inconsistency in endotoxin doses for
eliciting the TNF- response. Whereas previous work has suggested that some animal models, such as rats, require larger (>1 mg/kg) doses than other models, such as humans (4 ng/kg), none of these protocols controlled for conditions of handling, restraint, pain, and
surgical stress. Our data reveal significantly different mean peak
TNF- for the NS, Lo-Cort group when compared with the combination of
the remaining three stressed groups, for the same endotoxin dosage.
This finding suggests a within-species variability in the TNF-
response, which is dependent on the concentrations of baseline stress hormones.
The hypothesis linking elevated endogenous baseline stress hormones to
the TNF- response is supported by findings that the study of rats in
stressed conditions, such as surgery and handling, influences
physiological responses. Brackett et al. (6) demonstrated that
anesthetizing rats induces norepinephrine, an inhibitor of the
endotoxin-induced TNF- response, whereas Zellweger et al. (32) have
shown significant impairment of cell-mediated immunity for at least 24 h postlaparotomy. Bagby et al. (1) demonstrated that exercise-induced
stress before endotoxin challenge suppresses the TNF- response.
Furthermore, several chronically catheterized rat models, similar to our NS animals, have been developed to examine the physiological and hormonal response to endotoxin and bacterial infections (8, 9, 12, 13, 16). These investigators have described significant biochemical and physiological differences between chronic and acute catheterization models and have emphasized that experimental protocols for the study of septic shock and hormone function should incorporate a conscious animal model and the avoidance of anesthesia. These experimental conditions are essential for maintaining physiological concentrations of corticosterone and catecholamines that characterized our NS group.
A related body of research has linked exogenous corticosterone and
catecholamines to suppression of the immune defense mechanisms (20,
26). In vitro, treatment with epinephrine or corticosterone inhibits
macrophage activation and the secretion of TNF- postendotoxin challenge (24). Exogenous epinephrine and corticosterone also inhibit
the in vivo TNF- response to endotoxin when given before or at the
time of endotoxin challenge in humans and rats (2, 29, 30). In one
study, TNF- for rats that had undergone adrenalectomy or
hypophysectomy remained elevated following endotoxin challenge (34).
Under NS, physiological conditions in animals and humans,
endotoxin-induced TNF-, corticosterone, and catecholamines have been
shown to reach peak concentrations in a predictable pattern (7). This
pattern, in which glucocorticoids peak immediately after TNF-, but
catecholamines peak before TNF-, is similar to the time- and
dose-pattern for these hormones in our NS group. In contrast, the
animals with elevated baseline corticosterone (NS, Hi-Cort; SS; NSS
groups) demonstrated no time-dependent corticosterone responses. Our
findings explain those of previous investigators who suggested that
corticosterone and catecholamines may be involved in the
counterregulation of the TNF- response under both stressed and
normal, NS conditions.
Our finding that corticosterone inhibits the TNF- response is
supported by related studies of septic shock in both humans and
animals. Several investigators have reported that exogenous glucocorticoids are efficacious during the early phases of septic shock
but that they do not increase survival in humans when administered during severe late septic shock (5, 19, 25). These therapeutic attempts
most likely failed because of the transient nature of the rise in serum
TNF-. TNF- orchestrates the immunological response following its
very early appearance after endotoxin challenge. Removal of TNF-
from experimental models of septic shock minimizes the shock response
(4). However, in patients presenting with septic shock, the acute phase
of the disease has passed and the majority of patients do not possess
detectable serum concentrations of TNF- (5). The data from our study
are consistent with those of previous researchers in suggesting that
glucocorticoid concentration at the time of endotoxin challenge
regulates the TNF- response. These findings imply that therapeutic
attempts to limit septic shock with glucocorticoids must concentrate on
the early stages of the disease process.
Catecholamines may also regulate the TNF- response since our SS and
NSS animals demonstrated a dose- and time-dependent catecholamine response. However, the response for these groups was slower and reflected a lower catecholamine concentration compared with the NS
group. Furthermore, the NSS group had a significantly higher (P < 0.05) peak TNF- response to
6 µg/kg of endotoxin compared with the SS group. This time-dependent
response occurred in the NSS group despite the markedly elevated
increases in baseline catecholamine. The observed differences in
catecholamine concentrations for the three groups suggest that in
addition to the baseline concentration subsequent increases in
catecholamines further attenuate the TNF- response to endotoxin.
Previous studies have raised the possibility that prior exposure to
exogenous stress hormones may enhance the observed TNF- response to
endotoxin. Barber et al. (2) showed that, in humans, antecedent
treatment of cortisol enhanced the endotoxin-induced (4 ng/kg) TNF-
response from 12 to 144 h postadministration but inhibited the response
at 6 h postadministration. Van der Poll and Lowry (29) reported similar
results with epinephrine. We controlled for this possibility in the
current study by examining the TNF- response to 6 µg/kg for
3-14 days postsurgery during the time that all experiments were
conducted. Although our data confirm that the NS group was not affected
by surgery-induced stress during this time, we did not examine rats 1 or 2 days postsurgery because they had not returned to preoperative
weight and because we have previously reported intestinal blood flow
and metabolism during this time (27). The possibility exists in our NS
group that the enhanced TNF- response to endotoxin persists beyond 14 days, but the inability to maintain consistently low corticosterone concentrations has limited our investigation of this hypothesis.
In summary, we believe that this is the first study to demonstrate the
relationship between baseline stress hormones and the endotoxin-induced
TNF- response when the conditions of NS, SS, and NSS are manipulated
experimentally within the same animal model. Our findings underscore
the importance of measuring and reporting baseline concentrations of
corticosterone and catecholamines in subsequent studies of endotoxin shock.
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ACKNOWLEDGEMENTS |
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We gratefully acknowledge Drs. Michael Uhing, Luven Tujero, and Yong Chen for assistance in surgery, experiments, and assays. We also extend gratitude to Paula P. Meier, for a critical review of the manuscript.
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FOOTNOTES |
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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 reprint requests: D. W. A. Beno, Section of Neonatology, Dept. of Pediatrics, MU 622, Rush Children's Hospital, Rush Presbyterian St. Luke's Medical Center, 1653 W. Congress, Chicago, IL 60612.
Received 30 March 1998; accepted in final form 21 October 1998.
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REFERENCES |
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Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
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