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Thermoregulation Laboratory, Legacy Research, Legacy Portland Hospitals, Portland, Oregon 97227; and Institute of Physiology, Belarusian Academy of Sciences, Minsk 220725, Belarus
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Romanovsky, Andrej A., and Yelena K. Karman.
Posthemorrhagic antipyresis: what stage of fever genesis is
affected? J. Appl. Physiol. 83(2):
359-365, 1997.
It has been shown that hemorrhage leads to a
decreased thermal responsiveness to lipopolysaccharide (LPS). The aim
of this study was to clarify what stage of fever genesis
[production of endogenous pyrogens such as interleukin-1 (IL-1),
increase of the prostaglandin E2
(PGE2) concentration in brain
tissue, activation of cold-defense effectors] is deficient in
posthemorrhagic antipyresis. In adult rabbits, we evaluated the effect
of acute hemorrhage (15 ml/kg) on the rectal temperature (Tre) responses to LPS from
Salmonella typhi (200 ng/kg iv),
ethanol-purified preparation of homologous IL-1 (1 ml from 3.5 × 107 cells, 1.5 ml/kg iv), and
PGE2 (1 µg,
intracisternal injection). The effect of hemorrhage on
Tre was also studied in afebrile
rabbits, both at thermoneutrality (23°C) and during ramp cooling
(to 7°C). The hemorrhage strongly attenuated the biphasic
LPS-induced fever (a Tre rise of
0.4 ± 0.1 instead of 1.2 ± 0.2°C at the time of the second
peak), the monophasic Tre response
to IL-1 (by ~0.5°C for over 1-5 h postinjection), and the
PGE2-induced hyperthermia (0.4 ± 0.1 vs. 0.9 ± 0.1°C, maxima). In afebrile
animals, the hemorrhage neither affected
Tre at thermoneutrality nor
changed the Tre response to cold
exposure. The data suggest that neither insufficiency of cold-defense
effectors nor lack of endogenous mediators of fever (IL-1,
PGE2) can be the only or even
the major cause of posthemorrhagic antipyresis. We
speculate that fever genesis is altered at a stage occurring after the
intrabrain PGE2 level is increased
but before thermoeffectors are activated.
hemorrhage; temperature regulation; febrile response; cold
exposure; endotoxins; interleukin-1; prostaglandins; rabbits
INTRODUCTION DESPITE THE FACT that both fever and hemorrhage are
common signs of disease, their potential interactions are still poorly understood. One aspect of the problem, i.e., how the
pathophysiology of hemorrhage changes under febrile conditions, will
not be addressed in this paper. We studied the other aspect, i.e., how
hemorrhage modifies the thermoregulatory response to systemic
inflammation.
There is anecdotal evidence that physicians have been familiar with an
antipyretic effect of bloodletting for a long time. In the early 1800s,
the English surgeon Lionel Wafer wrote: "I bound up her arm ... and
with my lancet breathed a vein ... and I drew off about 12 ounces ... and desired she might rest till the next day; by which means the fever
abated and she had not another fit" (cited from Ref. 10). Yet,
experimentally, the posthemorrhagic attenuation of the febrile response
was rediscovered only recently. In 1980, Kasting and colleagues (8)
observed such an attenuation in acutely hemorrhaged sheep administered an exogenous pyrogen. This first communication was followed by a
detailed report (9) and, in a few years, by another study by Kasting
(7) showing that the hemorrhage-induced attenuation of
lipopolysaccharide (LPS)-induced fever similarly occurs in the
rat. A decade later, we reproduced the same phenomenon in yet another species, the rabbit, as described in a preliminary report
of the present work (17). We termed the observed phenomenon posthemorrhagic antipyresis.
The mechanisms of the posthemorrhagic antipyresis remain speculative.
Although it is conjectured that it occurs because of a release of
arginine vasopressin (AVP) in the brain and an action of the peptide on
central febrile pathways (7, 9), the proposed mechanism has never been
elucidated in direct experiments. Nor has any alternative mechanism
[e.g., blockade of the synthesis and/or release of
pyrogenic cytokines such as interleukin (IL)-1, IL-6, tumor necrosis
factor (TNF), and interferons] been seriously considered or
convincingly ruled out. The aim of the present study is to
clarify what stage of fever genesis is affected by hemorrhage. In
particular, we tested whether posthemorrhagic antipyresis could be due
to any of the following factors: 1)
incapability of the hemorrhaged organism to achieve an effective blood
concentration of IL-1, 2) inability
to secure a sufficient rise in the cerebrospinal fluid concentration of
prostaglandin E2
(PGE2), and
3) obvious or hidden functional
incompetence of thermoregulatory effector mechanisms.
METHODS Animals
Experimental Protocols
Six experiments were conducted. Five of them (experiments 1-5) were designed to compare thermal responses to various stimuli between the two groups of rabbits, i.e., hemorrhaged (immediately before the stimulus application) and intact. In experiment 1, the stimulus was an intravenous injection of LPS; in experiment 2, the stimulus was represented by an intravenous administration of homologous IL-1; in experiment 3, the thermal response was induced by an intracisternal injection of PGE2; in experiment 4, no stimulus (other than an exposure to the experimental conditions) was applied; and in experiment 5, the thermal response to a cold exposure was studied. For experiments 1-4, no animal instrumentation or restraint was required, and the rabbits were kept in open plastic boxes [approximate dimensions are 100 cm (length) × 50 cm (width) × 30 cm (height)]. Their rectal temperature (Tre) was taken with an electronic thermometer at 10- to 30-min intervals. Ta was maintained at 23°C. In experiment 5, the rabbits were instrumented with thermocouple probes and lightly restrained with homemade conventional-type stocks that prevented the animals from turning around and restricted their back-and-forth movements but did not affect their normal posture. Tre was continuously monitored. Immediately after blood was withdrawn, these rabbits (in their stocks) were transferred into a temperature-controlled chamber (model Prima, Levin Workshop, Minsk, Belarus), and its air temperature was decreased by ramp cooling from 23 to 7°C; to maximize the effect of cooling, no dehumidification was used, and the air inside the chamber was vigorously mixed with a fan. A separate experiment (experiment 6) was conducted to assess the effect of acute hemorrhage on the plasma AVP level and thus to verify the effectiveness of this degree of blood loss to induce hormonal changes. For this experiment, the same protocol as in experiment 4 was followed, but no thermometry was performed. Instead, 2-ml samples of blood (to be analyzed for AVP later) were taken from a marginal ear vein, one 30 min before and the other 10 min after the hemorrhage.Hemorrhage
The caudal margin of the right ear pinna was gently compressed over the most proximal portion of the marginal vein, and a 2- to 3-mm incision of skin together with a wall of the underlying vein was made 1.5-2.5 cm distal to the place of compression. Before the procedure, the skin was shaved, disinfected with ethyl alcohol, and treated with xylene to induce local vasodilation. Blood (15 ml/kg; equivalent to 20% of the blood volume) was then gathered in a collection vessel, and a miniature hemostatic clip was placed over the incision thereafter. During the procedure, the animal remained in its plastic box and was gently restrained by hand to prevent accidental movements. Because rabbits tolerate this short-lasting (4- to 7-min) manipulation without any apparent autonomic or behavioral reactions, no anesthesia was used. The 15 ml/kg amount of blood withdrawn was chosen because such a hemorrhage does not cause macrohemodynamic alterations (for an extensive review, see Ref. 23) yet results in obvious changes of the hormonal status (for details, see DISCUSSION), including a dramatic increase in AVP secretion (9).Drugs and Drug Administration
Drugs injected intravenously. A commercially available LPS from Salmonella typhi (series 306-3; N. F. Gamaleya Institute of Epidemiology and Microbiology, Moscow, Russia) and rabbit IL-1 (ethanol purified; 1 ml from 3.5 × 107 cells of peritoneal exudate; Institute of Experimental Medicine, St. Petersburg, Russia) were injected intravenously (in a marginal ear vein) in a dose of 200 ng/kg and 1.5 ml/kg, respectively. The IL-1 preparation used was endotoxin-free and possessed high thymocyte-proliferating and pyrogenic activities. LPS was suspended in saline and stored at 4°C. IL-1 was aliquoted, frozen, and kept at
20°C; no sample of IL-1 was
frozen and thawed more than twice.
Drugs injected intracisternally.
PGE2 (Sigma Chemical, St. Louis,
MO) was dissolved in a 5% ethanol solution, aliquoted, frozen, and
stored at 20°C; each aliquot was thawed only once. The drug
was administered intracisternally, at a dose of 1 µg, in a 100-µl
volume. For an injection, the rabbit was taken out of the box and, with
the help of a specially designed stock, fixed lying on its belly, with
the maximal possible flexion in the atlanto-occipital joint. The skin
of the occiput and nape (that had been shaved previously) was
disinfected. Soft tissues over and caudal to the external occipital
protuberance were infiltrated with a local anesthetic (Novocain, 1%,
0.5 ml). Thereafter, the atlanto-occipital membrane (together with its
overlaying tissues) was punctured with the help of a short-bevel
18-gauge injection needle (with a mandrel inserted in the needle).
After the mandrel was removed and the correct position of the needle
verified by the appearance of a drop of the cerebrospinal fluid, the
needle was connected to a microsyringe and an injection into the
cisterna magna was made. Thereafter, the rabbit was released from the
stock and returned to its box. The experimenters underwent special
training to perform the intracisternal puncture; the entire procedure
never lasted >2 min.
Thermometry
In experiments 1-4, Tre was measured with an electronic thermometer (Institute of Experimental Medicine); the probe length was 5 cm. In experiment 5, Tre was measured with a copper-constantan thermocouple inserted 7 cm beyond the anus. The reference junction of the thermocouple was kept at 37.0°C; the signal from a thermocouple was fed to a direct-current amplifier (model F116/2, KINAP, St. Petersburg, Russia) and sent to a recorder (model KSP-4; Institute of Experimental Medicine).AVP Assay
Blood (2 ml) was collected into chilled plastic tubes each containing 200 µl of saturated Trilon B solution and immediately centrifuged (5,000 m/s2, 10 min). Plasma was transferred to new tubes, frozen, and stored at20°C until
the analysis. AVP concentration (±1 pg/ml) was determined with the
help of a radioimmunoassay kit (antidiuretic hormone; Bühlmann
Laboratories, Basel, Switzerland); for plasma samples, the analysis was
preceded by ethanol extraction of protein according to the kit manual.
Data Analysis
Data (means ± SE) are presented in the form of either the absolute value or the deviation (
) of a parameter from its preinjection level
(averaged over 60 min). To compare two
Tre curves, we integrated the
Tre functions over the entire
length of the experiment and treated the obtained integrals by using
the unpaired Student's t-test. To
compare the blood levels of AVP before and after hemorrhage (experiment 6), the paired
Student's t-test was used.
RESULTS
In all the experiments, the initial values of
Tre were similar, with the mean
for the whole study being 39.2 ± 0.1°C. In
experiment 1, control animals
responded to LPS with a typical biphasic fever; this response was
greatly attenuated (P < 0.027) and
became monophasic under the conditions of hemorrhage
(Fig. 1). At the time of the second phase
(4 h postinjection), Tre was
only 0.4 ± 0.1 compared with 1.2 ± 0.2°C in the
nonhemorrhaged controls. In experiment 2, IL-1 caused a monophasic fever, which did not change
its shape but was substantially (by ~0.5°C) and significantly
(P < 0.005) attenuated in
hemorrhaged animals throughout the period of observation (Fig.
2). In experiment
3, PGE2 caused a
typical (rapid and short-lasting) rise in
Tre of the controls; in the
hemorrhaged rabbits, this thermal response was both delayed and
attenuated (P < 0.048; Fig. 3). The attenuation persisted over the
first 2 h postinjection, reaching its maximum at 45 min when
Tre was 0.9 ± 0.1°C in
the controls but only 0.4 ± 0.1°C in the hemorrhaged rabbits.
By itself, the hemorrhage neither induced any hypothermia under
thermoneutral conditions (experiment 4 and Fig. 4) nor influenced the rabbits' thermal responses to an external cooling
(experiment 5 and Fig. 5). Although the chosen volume of blood
loss (15 ml/kg) was subthreshold for affecting the thermal balance in
afebrile animals, it was sufficient to cause a >14-fold rise (from 5 ± 3 to 71 ± 15 pg/ml; P < 0.003) in the plasma AVP concentration in experiment
6 (Fig. 6).
DISCUSSION
Mechanisms of Posthemorrhagic Antipyresis
The results of experiment 1 showed that the febrile response to LPS, which is known to be attenuated by hemorrhage in sheep (9), rats (7), and presumably humans (10), is similarly affected in hemorrhaged rabbits. What stage of fever pathogenesis is influenced by hemorrhage? In this study, we have examined several possibilities. Posthemorrhagic antipyresis: is it due to a decreased production of endogenous pyrogens? Because hemorrhage results in the mechanical removal of a substantial number of blood cells (including leukocytes, which are producers of cytokines), it might be suggested that LPS-induced cytokine synthesis is abated in hemorrhaged animals. Yet, depletion of blood phagocytes is unlikely, by itself, to have any physiologically meaningful effect on the production of pyrogenic cytokines: first, it is well established that leukocytes from even minute quantities of blood are capable of producing a sufficient amount of endogenous pyrogens to cause substantial fevers (6); and, second, blood removal does not affect (at least directly) the number of residual, tissue producers of cytokines (Kupffer cells, microglia, etc.). Hemorrhage is also known to drastically alter the hormonal pattern of blood by activating the hypothalamic-pituitary-adrenal, renin-angiotensin-aldosterone, and several other components of the endocrine system (for an example of hormonal changes induced by a 15 ml/kg hemorrhage in the sheep, see Ref. 4). The list of affected hormones includes catecholamines, adrenocorticotropic hormone (ACTH), glucocorticoids, angiotensin II, enkephalins,
-endorphin,
insulin, vasoactive intestinal peptide, and others. In the present
work, the effectiveness of a 15 ml/kg hemorrhage to induce hormonal
changes was verified by a >14-fold increase in the plasma AVP
concentration (experiment 6), which
is consistent with the literature (9). The hemorrhage-associated shifts
in the blood hormonal pattern can readily affect various immunocyte functions, including the synthesis and release of pyrogenic cytokines (14). Yet, because of the multiplicity of the endocrine-immune interactions, it is difficult to predict the overall effect on cytokine
production. Attempts to address this issue in direct experiments led to
contradictory results. Thus there are some data showing that, in the
rat, a 30% hemorrhage attenuated the LPS-induced rise in the plasma
IL-6 concentration 24 h postbleeding (12). In accord with this,
LPS-induced surges in blood IL-6 and TNF-
were shown to be blocked
over the first several hours postbleeding in the rat model of a 20%
hemorrhage (D. Soszynski, personal communication). Yet,
several studies have shown that the processes of cytokine gene
transcription in a wide spectrum of peripheral tissues, the ability of
various cell types to produce pyrogenic cytokines, and the blood
level of several endogenous pyrogens are all increased during the first
several hours posthemorrhage, sometimes for as long as 24 h (5, 12,
21). Much work is still needed to convincingly answer the question of
whether hemorrhage attenuates the synthesis and/or release of
pyrogenic cytokines.
One of the questions we tried to answer in the present study is whether
the inability of the organism to synthesize sufficient amounts of
pyrogenic cytokines (or, in particular, IL-1) could be the major reason
for the development of the posthemorrhagic antipyresis. If it were,
fevers induced by exogenous pyrogens (those that require de novo
synthesis and release of pyrogenic cytokines) could be attenuated, but
febrile responses to endogenous pyrogens (those that do not require
cytokine synthesis) should not be compromised. This was not the case in
our experiment 2: the hemorrhaged
rabbits responded to IL-1 with a substantially attenuated fever
compared with the controls. We conclude, therefore, that bypassing the
stage of cytokine production and release (by administration of
already-synthesized IL-1 directly into the blood) does not obviate
posthemorrhagic antipyresis. In other words, the mechanisms of the
phenomenon would not seem to involve (at least as the major
and/or only contributor) the blockade of the production of
IL-1.
Can posthemorrhagic antipyresis be due to an insufficient rise in
brain prostaglandins?
If PGE2 plays a role in fever
genesis, hemorrhage could be thought to affect the febrile response by
inhibiting the rise in the brain
PGE2 concentration. It could then
be expected that fevers induced by either exogenous or endogenous
pyrogens might be attenuated by hemorrhage but that the thermal
response to exogenous PGE2 delivered into the brain directly should not be affected. This was not
the case in experiment 3, in which the
PGE2-induced
Tre rise was substantially
attenuated in hemorrhaged animals compared with the nonhemorrhaged
controls. This suggests that the posthemorrhagic antipyresis affects a
stage of fever downstream from a rise in PGE2 concentration in the brain
tissue.
Posthemorrhagic antipyresis: a weakness of thermoeffectors?
In the present study, hemorrhage attenuated fevers induced by LPS and
IL-1 as well as hyperthermia induced by
PGE2. Could it be
possible that, in all three cases, the hemorrhaged animals did not
develop the same Tre rise as did
the naive controls because their thermoeffectors (heat production
and/or heat conservation) were affected? Hemorrhage, if severe
enough, could result in hemodynamic alterations (shock, in an extreme
case) and hypoxia; both hypoxia and compromised hemodynamics might
affect various peripheral functions. The volume of blood loss chosen
for our experiments (20%) was sufficient for inducing profound
hormonal changes, as judged from a dramatic rise in the blood AVP
(experiment 6). Yet, such a volume is known to be subthreshold for the development of any macrohemodynamic alterations: an acute loss of 25% of the blood volume is usually rapidly compensated for as a result of hemodilution, flow
redistribution, and other factors; clinical symptoms of blood loss
occur only if it reaches 25% or more of the initial volume; systemic
arterial pressure usually does not decrease after hemorrhage if the
blood loss is below 25-30%; and tachycardia does not usually
occur in surgical (heart) patients even in cases of 25-30% blood
loss (23).
We addressed the issue of possible posthemorrhagic thermoeffector
deficiency in experiments 4 and
5. The results indicate that, after a
15 ml/kg (20%) hemorrhage, afebrile (not injected with any pyrogen)
rabbits are capable of maintaining their
Tre at the same level as did the
controls in both thermoneutral (experiment 4) and cold (experiment
5) environments. In the latter case, cold exposure
should be regarded as severe for the rabbits maintained at (acclimated
to) 23°C: their Tre decreased
by >1°C, and the effective
Ta was probably much lower than
7°C because of high air humidity and velocity (see
Experimental Protocols). Our
observation of cold defense remaining competent in hemorrhaged rabbits
is in agreement with the literature: the same degree of blood loss (20%) resulted in no apparent thermoregulatory deficiency either in
rats exposed to a slightly cool environment, i.e., room temperature (Ref. 7; D. Soszynski, personal communication), or in sheep exposed to
a moderate (4°C) cold (9). Because effectors of cold defense (as
tested in 3 species with a minimal-to-severe cold exposure) seem to
work normally in animals with a 20% hemorrhage, the posthemorrhagic
antipyresis is unlikely to represent a result of thermoeffector
insufficiency.
What stage of the fever genesis is affected by hemorrhage?
The major question we tried to answer in the present work is not a
trivial one. Part of the problem is that the current ideas of the
pathomechanism of the febrile response are not very clear (for review
on controversial issues in the current concept of fever genesis, see
Refs. 3, 24). Are pyrogenic cytokines the first (earliest) endogenously
released mediators of fever (as it is generally believed), or,
alternatively, may anaphylatoxic complement components, C3a and C5a,
play this role? How does the pyrogenic signal reach the brain: is it
through a humoral pathway only (as it is commonly thought) or via a
neural path as well? Are prostaglandins involved in the pathogenesis of
fever at all, and, if they are, are they blood borne or of local
(cerebral) origin? Without the answers to such questions, it seems
difficult to specify, with a certain degree of confidence, the stage of fever affected by hemorrhage (or, to this end, any another
disturbance). Yet, the present work allows us to exclude several
potentially possible mechanisms.
The present experiments show that hemorrhage attenuates not only
LPS-induced fever but also the febrile response to an endogenous pyrogen (IL-1) and the
PGE2-induced hyperthermia. This
means that neither the synthesis of pyrogenic cytokines nor the
processes leading to the rise in the brain level of
PGE2 are likely to constitute the
only and/or main reason of the posthemorrhagic antipyresis. On
the other hand, hemorrhaged animals seem to be capable of mounting sufficient cold-defense responses; the thermoeffector insufficiency could, therefore, also be excluded as the important underlying mechanism. This would mean that hemorrhage affects fever genesis at a
stage after the release of IL-1 into the blood and the rise of the
intrabrain PGE2 concentration but
preceding the activation of heat-production and/or
heat-conservation effectors.
We speculate that this stage might be the action of
PGE2 (and other propyretic
mediators) on neurons (perhaps warm sensitive) "wired" to
thermoeffectors. In nonhemorrhaged animals, fever mediators modify the
activity of these neurons and thus trigger the appropriate thermoeffector responses. Under the conditions of hemorrhage, a
centrally released substance or, even more likely, substances (endogenous antipyretics) modify the chemoresponsiveness of these neurons; this is why the thermal responses to LPS, IL-1, and
PGE2 were all blocked in the
hemorrhaged rabbits. Yet endogenous antipyretics do not affect the
responsiveness of the same neurons to other (nonfebrile) stimuli such
as temperature per se; this is why the thermal responses to cold are
apparently not affected by hemorrhage. This hypothesis does not
contradict the original explanation by Kasting and colleagues (7, 9),
who speculated that the posthemorrhagic antipyresis occurs as a result
of endogenous AVP released in the brain and affecting the central
febrile pathways. We might add, however, that not only AVP but also
other neuropeptides with putative antipyretic activity (ACTH,
angiotensin II, -melanotropin, etc.) are likely to contribute to the
development of the posthemorrhagic antipyresis. The detailed
characterization of the mechanisms of this phenomenon, including
localizing of the responsible neurons in the brain and drawing their
functional portraits, awaits further investigation.
Posthemorrhagic Antipyresis: Biological and Clinical Significance
Under natural conditions, hemorrhage is usually associated with trauma, the consequent disintegration of the barrier between the internal and external environments, and, potentially, infection. It is clear that hemorrhage, if severe enough, can readily impair various functions of the organism, including its defense against infection (5). Yet, the repeated occurrence of the association hemorrhage
infection
and the vital importance of its outcome could have resulted in the
evolutionary development of some adaptive interactions between
hemorrhage, on the one hand, and various mechanisms and manifestations
of the infectious process, on the other hand. The relationship between
fever and hemorrhage described in this paper could represent an example
of such adaptive interactions. If so, what is the biological
significance of the phenomenon of posthemorrhagic antipyresis? Let us
try to answer this question from the position of the dual
thermoregulatory strategy of adaptation to systemic inflammation (for
details, see Refs. 18, 20).
We have hypothesized that fever and hypothermia represent two adaptive responses, each developed under certain conditions and each beneficial under these conditions. The antimicrobial and immunostimulating benefits of a high body temperature (for review, see Ref. 11) could be easily offset by its high energy cost; fever, therefore, is protective only when there is no immediate threat of a substantial energy deficit. Hypothermia, on the other hand, constitutes a response aimed at energy conservation and, as such, is beneficial exactly under the conditions of a substantial energy deficit: whether it is septic (1), endotoxin (19) or hemorrhagic (2, 15) shock, hypothermia seems to possess a recuperative value. Whenever the conditions are unfavorable (stress, cold exposure, hypoxemic hypoxia, etc.) or the organism is particularly vulnerable (pregnancy, neonatal period, hemorrhage, etc.) and the threat of energy deficiency becomes real, a decrease in body temperature (hypothermia and antipyresis) becomes beneficial. It is not by chance, therefore, that antipyresis can be induced by such heterogeneous stimuli and conditions as hemorrhage (7, 9), malnutrition (22), a severe osmotic load (7, 16), and restraint (13), as well as many others. An understanding of the adaptive value of such a phenomenon could change our approach to several clinical situations, including those that involve a substantial blood loss.
ACKNOWLEDGEMENTS
We thank Drs. E. G. Rybakina, I. A. Kozinets, the late A. V. Sorokin, and H. (E.) A. Korneva for their generous gift of IL-1. The expert help of the late Dr. V. P. Zhukov with radioimmunoassays is gratefully acknowledged. Advice on a first draft of the paper by Dr. M. Székely and statistical consultations by Dr. L. D. Homer are sincerely appreciated. We also thank L. S. Pavlov for technical help, C. T. Simons for graphic assistance, and R. S. Hunter and J. Emerson-Cobb for editing the manuscript.
FOOTNOTES
Address for reprint requests: A. A. Romanovsky, Thermoregulation Laboratory, Legacy Research, Legacy Portland Hospitals, 2801 N. Gantenbein Ave., Portland, OR 97227 (E-mail: romanovs{at}ohsu.edu).
Received 27 January 1997; accepted in final form 28 March 1997.
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