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Thermoregulation Laboratory, Legacy Holladay Park Medical Center, Portland, Oregon 97208-3950
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ABSTRACT |
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Abstract
Introduction
Methods
Results
Discussion
References
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This study explains why the recently described triphasic lipopolysaccharide (LPS) fevers have been repeatedly mistaken for biphasic fevers. Experiments were performed in loosely restrained male Wistar rats with a catheter implanted into the right jugular vein. Each animal was injected with Escherichia coli LPS, and its colonic (Tc) and tail skin temperatures were monitored. The results are presented as time graphs and phase-plane plots; in the latter case the rate of change of Tc is plotted against Tc. At an ambient temperature (Ta) of 30.0°C, the response to the 10 µg/kg dose of LPS was triphasic, as is obvious from time graphs of Tc (3 peaks), time graphs of effector activity (3 waves of tail skin vasoconstriction), and phase-plane plots (3 complete loops). When the Ta was below neutral (22.0°C) or the LPS dose was higher (100 or 1,000 µg/kg), the time graph of Tc did not allow for the reliable detection of all three febrile phases, but the phase-plane plot and time graph of effector activity clearly revealed the triphasic pattern. In a separate experiment, LPS (10 µg/kg) or saline was injected via one of two different procedures: in the first group the injection was performed through the jugular catheter, from outside the experimental chamber; in the second group the same nonstressing injection was combined with opening the chamber and pricking the animal in its lower abdomen with a needle. In the first group the febrile response was obviously triphasic, and none of the phases was due to the procedure of injection per se (injection of saline did not affect Tc). In the second group the fever similarly consisted of three Tc rises, but it might have been readily mistaken for biphasic because the first rise was indistinguishable from stress hyperthermia occurring in the saline-injected (and needle-pricked) controls. We conclude that several methodological factors (dose of LPS, procedure of its injection, and Ta) have contributed, although each in a different way, to the common misbelief that there are only two febrile phases.
thermoregulation; lipopolysaccharides; skin vasoconstriction; stress hyperthermia; ambient temperature; restraint; body temperature oscillations; nonlinear dynamics; rats
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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IN A RECENT STUDY INVOLVING several different rat strains and several different lipopolysaccharide (LPS) preparations, we showed that the febrile response of the rat to a typical biphasic fever-inducing dose of LPS (10 µg/kg) consists of not two, but at least three, separate phases (16). The triphasic (or polyphasic, a more general term) pattern of experimental fevers was mentioned in the old literature (6) and occasionally noticed by colleagues in the field (J. M. Krueger, personal communication). Yet the recent physiological literature, although replete with examples of biphasic fevers, does not mention polyphasic febrile responses. What is the reason for this omission? The general goal of the present study is to analyze this question for the case of LPS fever in the rat. We propose that several methodological factors can modify the fever course and mask one or more febrile phases (rises in body temperature, Tb), thus changing the "correct" phase count.
The ambient temperature (Ta) is likely to be an important factor. It is well known that, at a Ta within or slightly above the thermoneutral zone, rats respond to LPS with a fever and that a hypothermic component appears in the response to LPS at Ta below thermoneutrality (17, 22). Our working hypothesis was that this hypothermic component can overlap one of the febrile phases, mask it, and thus interfere with the phase count. Experiment 1 addresses this hypothesis.
Another obvious factor to consider is the dose of LPS. It is clear that
the febrile response is monophasic if the LPS dose is small (just above
apyrogenic); it is also clear that if the dose is slightly higher than
one inducing a monophasic fever, the response is biphasic (11, 14, 22).
It is not clear, however, why the polyphasic febrile responses to
higher doses of LPS, i.e., 
10 times greater than the monophasic
fever-inducing dose (for a description of such responses, see Ref. 16),
have been repeatedly assumed to consist of only two febrile phases (14,
15, 17). Could it be that, even within the range of doses causing a
polyphasic response, there is a subrange in which a certain febrile
phase becomes much less prominent than the others? If this is true, the
less expressed phase can be easily overlooked. In
experiment 2 we investigate the effect
of the dose of LPS on the pattern of the febrile response.
The effect of the method of LPS injection on the fever response may also be important. If the pyrogen is injected through a preimplanted catheter exteriorized from the experimental chamber (i.e., without disturbing the animal), the injection procedure per se does not induce any stress hyperthermia, as is obvious from the control experiments with saline injection (14-17, 22). If, however, the injection involves handling and pricking the animal with a needle, stress-associated hyperthermia readily occurs (9, 12, 18). This stress-associated (injection induced) hyperthermia may overlap the authentic febrile response to the injected pyrogen, mask some part(s) of this response, and thus artifactually change the total number of febrile phases detected. In addition, a needle prick by itself has been recently shown to prolong the febrile response to the intraperitoneal administration of a low dose of LPS and perhaps to transform a monophasic fever into a biphasic one (21). Experiment 3 is designed to test the hypothesis that the pyrogen administration technique may affect the investigator's judgment of the number of febrile phases observed.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Animals and Surgical Preparation
Forty-six adult male rats of the Wistar strain (B & K Universal, Kent, WA) were used. The animals were initially housed three per box; after surgery, they were caged singly. The room was on a 12:12-h light-dark cycle; Ta was maintained at 22°C. Food [Teklad Rodent Diet (W) 8604, Harlan Teklad, Madison, WI] and water were available ad libitum. The animals were handled and weighed regularly. They were also habituated (5 training sessions, 3-4 h each) to a cylindrical restrainer that restricted their back-and-forth movements and prevented them from turning around; the same restrainer was used later in the experiment. Three days before the experiment, a catheter was implanted into the right jugular vein of each animal, as described in detail previously (16). The free end of the catheter was rolled into a coil and placed into a hollow polypropylene pedestal affixed to the skull; the pedestal was protected with a screw-on cap. On the day after the surgery the catheter was flushed with heparinized pyrogen-free saline (PFS). To obviate the possible effects of circadian rhythms, all experiments were started at the same time of day (between 0800 and 0900). To avoid the development of LPS tolerance, each animal was injected with LPS only once. At the end of the study, the rats were killed with an injection of pentobarbital sodium (20 mg/kg iv). The protocols were approved by the Institutional Animal Care and Use Committee.Instrumentation
For an experiment, all animals were instrumented with homemade copper-constantan thermocouples for colonic (Tc; 9 cm from the anus) and tail skin (Tsk) temperature measurement. The thermocouples were connected to a data logger (model AI-24, Dianachart, Rockaway, NJ) and then to a personal computer. The animal was placed into its restrainer and transferred to a climatic chamber (Forma Scientific, Marietta, OH) set to a relative humidity of 50% and a Ta of 30.0°C (upper limit of the thermoneutral zone for rats) or 22.0°C (slightly cool environment). The exteriorized portion of the intravenous catheter was pulled through a wall port and connected to a syringe. After a 1-h stabilization period, the measurements were begun, and Tc, Tsk, and Ta were sampled every 2 min for 8 h.Experimental Protocols
Experiment 1. In experiment 1 we investigated how the Ta affects the febrile response to a 10 µg/kg dose of LPS. The animals were instrumented as described above, placed in the environmental chamber (set to a Ta of 22.0 or 30.0°C), and, 1 h after the recording was started, injected intravenously with the 10 µg/kg dose of LPS in PFS (1 ml/kg). The LPS used in all the experiments was from Escherichia coli 0111:B4, prepared by phenol extraction (lot no. 35H4086, Sigma Chemical, St. Louis, MO).
Experiment 2. Experiment 2 was designed to determine the effect of LPS dose on the shape of the Tc response. The Ta in the chamber was set at 30.0°C. The animals were injected with a 10, 100, or 1,000 µg/kg dose of LPS in PFS (1 ml/kg).
Experiment 3. In experiment 3 we investigated how stress-associated hyperthermia interferes with the normal febrile course. The control rats were injected intravenously (via the preimplanted jugular catheter exteriorized through a wall port) with LPS (10 µg/kg) or PFS (1 ml/kg). The experimental rats received the same injection, but immediately before the injection the chamber was quickly opened and the animals were pricked in the lower abdomen with a 23-gauge needle.
Data Processing and Analysis
To evaluate the thermal response, the absolute value of Tc and its deviation from the mean Tc at the time of the injection (
Tc) were used. To evaluate
the thermoeffector response of tail skin vasculature, the heat loss
index (HLI) was calculated: HLI = (Tsk 
Ta)/(Tc Ta); the HLI changes
between 0 (maximal heat conservation due to skin vasoconstriction) and
1 (maximal heat loss due to skin vasodilation). To compare the
responses between the groups, we performed a two-way ANOVA (repeated
measures) followed by Scheffé's post hoc test. To determine the
number of febrile phases, the data were plotted in the phase-plane
format [rate of change of displacement vs. displacement; in our
particular case,
T'c(t)
vs. Tc], and the number of
loops (cycles) was then counted (16).
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Experiment 1
At thermoneutrality the 10 µg/kg dose of LPS caused a Tc rise of 1.0-1.5°C in conscious, unstressed rats. The phase-plane plot clearly demonstrates the polyphasic (triphasic) pattern of this fever (Fig. 1). In a cool environment the same dose of LPS induced a different (P < 0.003) response, which was characterized by a smaller rise in Tc and a different Tc dynamic. The phase-plane plot showed, however, that the latter response was also triphasic (Fig. 2). The major difference between the two responses (i.e., at 30 and 22°C) was in the Tc dynamics during phase I. In thermoneutrality (Fig. 1), phase I resulted in an overall 0.4°C rise in Tc [on a phase plane, compare the abscissa at the start of phase I (20 min) with that at its end (74 min postinjection)]; T'c(t) was positive most of the time (the ordinate above 0). In contrast, the injection of LPS in a cool environment (Fig. 2) resulted in an overall Tc fall during phase I [compare the abscissa at the start of phase I (24 min) with that at its end (76 min postinjection)]; the T'c(t) after a transient rise became negative and remained below 0 for most of phase I.
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Experiment 2
The increase in the dose of LPS changed the febrile response; the analysis of variance rejected the null hypothesis of the responses to 10, 100, and 1,000 µg/kg doses being the same (P < 0.018). The phase-plane presentation (compare Figs. 1, 3, and 4) allows for the visualization of the effect of the increase in LPS dose on each febrile phase. Phase I changed most drastically: at 100 µg/kg, its maximal Tc and T'c(t) decreased two to three times (Fig. 3) compared with the response to 10 µg/kg (Fig. 1); as the dose was increased to 1,000 µg/kg (Fig. 4), phase I not only further decreased in magnitude but also resulted in a slight drop in Tc, rather than a rise. In contrast to phase I, phase II became more prominent as the dose increased: compare the distances between the starting point and the ending point of the second loop on Fig. 1 (~0.4°C), Fig. 3 (~0.9°C), and Fig. 4 (~1.1°C). Phase III did not change much with the increase of the dose from 10 to 100 µg/kg but became somewhat less pronounced at 1,000 µg/kg. Time graphs of an effector response (HLI) exhibit more obvious triphasic patterns than time plots of Tc (Figs. 1, 3, and 4) orTc (Fig.
5), especially for the case of higher LPS doses.
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Experiment 3
Figure 6 shows how the febrile response of the rats to the 10 µg/kg dose of LPS depends on the injection method, i.e., with and without a needle prick. Without a needle prick, the response to LPS was triphasic, and none of these phases was due to the injection procedure per se (Fig. 6A). The Tc curve of the response to LPS of the needle-pricked rats was also triphasic and appeared similar to that of nonpricked animals (P = 0.983); however, phase I of this response was indistinguishable from the stress hyperthermia induced by the injection procedure per se (Fig. 6B). Therefore, in the case of the injection with a needle prick, it could have been easily concluded that the response to LPS was biphasic, occurring after the initial stress-associated (injection induced) hyperthermia.
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Why Polyphasic Fevers Were Often Mistaken for Biphasic
The overall idea of the present study is that polyphasic fevers may easily be (and often are) mistaken for biphasic. Various factors can account for such a mistake, the most obvious of them being the length of the observation period. If, e.g., LPS fever is monitored in rats for 3 h postinjection only (19, 22), the response looks biphasic simply because no phase is recorded after phase II. This was the case in our recent study (17): biphasic fevers were reported (3 h postinjection), but the actual experimental records (when obtained for a longer time) revealed polyphasic patterns indistinguishable from those seen in the present experiments.Besides the observation time, other factors may interfere with the
phase count. One of these factors is the
Ta. The present study shows that
if the Ta is neutral (30°C),
the time plot of the LPS (10 µg/kg) fever demonstrates a clearly
triphasic pattern; if, however, Ta
is decreased to subneutral (22°C), the time plot becomes
"confusing" (Fig. 2). Not surprisingly, therefore, responses similar to those shown in Fig. 2 are often described as "a slight decrease in Tc ... followed by a
characteristic biphasic fever" (15). In the present work, by
comparing the febrile response in a cool environment with that in a
thermoneutral environment, we came to the conclusion that what
resembles phase I at a subneutral Ta corresponds to
phase II of fever at thermoneutrality
and that what appears to be phase II
is actually phase III. In other words, the pattern that is usually described as "hypothermia 
phase I phase II" is actually
"hypothermia overlapping phase I
phase II phase III."
The dependence of the pattern of the febrile response on the pyrogen dose also contributes to the difficulty of determining the "true" number of febrile phases. It has been emphasized (14, 17) that the higher the dose of LPS, the less pronounced phase I appears (although it starts earlier at higher doses) and the more prominent phase II becomes. The present study shows that at high doses febrile phase I almost completely vanishes and becomes practically unnoticeable in time plots (Fig. 5). Figure 5 also shows that the number of bursts of thermoeffector activity (waves of tail skin vasoconstriction, in our case) may be a more reliable indicator of the number of febrile phases than the Tb. Indeed, the Tb is more subject to inertia than thermoeffector activity: the activity of effectors directly changes the body's heat content and, therefore, is proportional to the rate of change of Tb, not to Tb per se. Then, if no thermoeffector is evaluated, a small Tb rise (resulting from a short-lasting burst of effector activity) is readily assumed to be statistically insignificant and disregarded as a febrile phase. Interestingly, the high "diagnostic value" of thermoeffector activity is compatible with the high diagnostic value of the phase plane, for which the rate of change of Tb [in our case, the T'c(t)] is one of the two dimensions.
Finally, the present study identifies one more factor that is extremely important for correctly counting the number of phases: the method of pyrogen administration. Apparently, the same febrile response may be considered biphasic or polyphasic, depending on whether the pyrogen is administered with or without a needle prick. Figure 6 shows that, when injected without any needle prick, LPS induces the triphasic rise in Tb. Because the injection of PFS (also without a needle prick) has no effect on Tb, all three LPS-induced Tb rises are thought to be attributed to the action of LPS (not to the injection procedure), and the febrile response is considered truly triphasic. When, however, the injection is associated with a needle prick, PFS induces a rise in Tb (stress hyperthermia), which closely resembles febrile phase I. In this case, although the response to LPS consists of three consecutive Tb rises, the first rise is thought to be due to stress hyperthermia (has nothing to do with LPS per se); only the two remaining rises are regarded as febrile, and the fever response is thought to be biphasic (7, 9, 12, 18). As a complex combination of psychological and physical factors, the stress hyperthermia is characterized by great variability; the simultaneous development of the low-magnitude febrile phase I and the high-variability stress hyperthermia does not allow for the reliable detection of fever. Interestingly, the stress hyperthermia (sometimes called emotional fever) has been pointed out (2, 8, 10) as a potential explanation of the reported failures to induce fever in several vertebrate species.
An Important Corollary
In the recent literature on fever, the pyrogen is usually injected in one of two ways: intravenously (through a preimplanted catheter) or intraperitoneally (with the injection procedure involving animal handling and needle pricking). The two methods produce very different results: the febrile response of rats to the intravenous LPS (10-1,000 µg/kg; present paper) is characterized by a short latency (~10 min) followed by three Tb rises (peaks at ~1, 2.5, and 5 h postinjection), whereas the response to the intraperitoneal LPS (within the same dose range) (7, 9, 18) involves an ~90-min-long latent period (during which stress hyperthermia occurs; Tb peak at ~1 h) followed by two febrile phases (peaks at ~2.5 and 5 h). The difference between the two fevers is usually explained by the route of LPS administration (intravenous vs. intraperitoneal). The present results suggest that there may be another explanation. We hypothesize that the time course of the fever response is similar for the two routes but that the stress hyperthermia readily masks febrile phase I if the injection procedure per se involves a needle prick and animal handling. If this hypothesis is correct, results that are currently thought to be incomparable (obtained by different techniques) become highly comparable, but certain changes in our interpretation of the results are required. Our hypothesis could be tested directly: if, at thermoneutrality, a relatively low dose of LPS is injected intraperitoneally through a preimplanted catheter (in a way that the injection of the vehicle only produces no stress hyperthermia), the response should be similar in its dynamic to fevers described here and elsewhere (16, 17). Interestingly, in a recent study by Carlson (3), when a pyrogen was injected into freely moving rats intravenously or intraperitoneally (in both cases, through a preimplanted catheter), the responses of plasma hormones (ACTH and corticosterone) showed the same dynamics, regardless of the route of administration.Concluding Remarks
Two live as one One live as two Two live as three Under the bam Under the boo Under the bamboo tree. (T. S. Eliot "Sweeney Agonistes")The febrile response (at least the response of the rat to LPS)
can have a triphasic (polyphasic) pattern. This pattern could be easily
revealed if several methodological conditions are satisfied: the dose
of LPS is not too high; the method of LPS administration does not
involve stressing (handling and needle pricking) the animal; the
experiments are run at thermoneutrality;
Tb and thermoeffector activity are
recorded; and the time of observation is 5-6 h postinjection. If
any of these conditions is not satisfied, the number of phases can
easily be miscounted due to one of the following reasons. If
phase I is low in magnitude (the dose
is too high and no effector activity is recorded) and/or if it
is masked by the subsequent hypothermia
(Ta below thermoneutrality), it
can be easily overlooked; then, phase
II is mistaken for phase
I, phase III is
mistaken for phase II, and the
polyphasic pattern is mistakenly called biphasic. If
phase III is missing because of
insufficient observation time or simply is not obvious (too high a
dose; no record of effector response), the response is described as
biphasic. If all three phases are recorded, but phase
I is assumed to be stress associated (handling and
needle pricking during pyrogen administration), it is disregarded as a
febrile phase; therefore, phase II
becomes phase I,
phase III becomes
phase II, and the triphasic pattern becomes biphasic. Finally, in those early studies where several conditions identified here were not in effect simultaneously (e.g., Ta was low, the dose of LPS was
high, administration of LPS was stressful, time of observation was
short, and no effector activity was recorded), all phases of the
febrile response were missed and conclusions such as "rats do not
respond with fever to a single dose of ... endotoxin" (20) were
typical. Thus the present study highlights once again that the outcome
of a thermophysiological experiment strongly depends on its methodology
(1).
Perspectives
Over the last decades, a great deal of research effort in the physiology of fever has been concentrated around the question of the differential triggering of the two febrile phases. Although this enormous effort has hardly resulted in any consensus (for review see Ref. 13), the two febrile phases are often viewed as two separate events, each having its own mediatory system. The present study, as well as our previous one (16), has shown that there are more than two febrile phases; does it mean that there are more than two systems mediating the febrile response? It may be so. Yet it is definitely plausible to suggest that a single trigger (whether represented by a single mediator or by a cascade of mediators) causes a febrile shift in Tb, which then oscillates at a new, elevated level (febrile phases II, III, and beyond), and that the development of these oscillations does not require the introduction of additional fever mediators. Although the literature contains some attempts to analyze oscillatory processes in the thermoregulatory system (4, 5), there is only one work directly aimed at testing the intriguing hypothesis of a single trigger for more than one febrile phase (13). That work, however, failed to demonstrate the oscillatory nature of febrile phase II, and additional research is required for more definite conclusions. Future studies on this topic may also include an analysis in the phase plane: although we have used the phase plane as a technique of topographic presentation of thermophysiological data (16), a formal analysis in the phase plane has yet to be performed.| |
ACKNOWLEDGEMENTS |
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Discussions on oscillations in physiological systems with Dr. L. D. Partridge and statistical consultations with Dr. L. D. Homer are gratefully acknowledged. Dr. J. M. Macpherson kindly reviewed an early draft of the manuscript and provided important feedback. The authors also thank N. V. Romanovsky for indispensable help with the animal care and J. Emerson-Cobb for excellent editorial assistance.
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FOOTNOTES |
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V. A. Kulchitsky was on leave from the Institute of Physiology, Minsk 220072, Belarus. N. Sugimoto was on leave from the University of Kanazawa Medical School, Kanazawa 920, Japan.
This study was made possible by intramural support and a research grant-in-aid from Legacy Health System (Portland, OR).
Address for reprint requests: A. A. Romanovsky, Thermoregulation Laboratory, Legacy Holladay Park Medical Center, PO Box 3950, Portland, OR 97208-3950.
Received 14 July 1997; accepted in final form 18 March 1998.
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Abstract
Introduction
Methods
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Discussion
References
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T. Hubschle, J. Mutze, P. F. Muhlradt, S. Korte, R. Gerstberger, and J. Roth Pyrexia, anorexia, adipsia, and depressed motor activity in rats during systemic inflammation induced by the Toll-like receptors-2 and -6 agonists MALP-2 and FSL-1 Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R180 - R187. [Abstract] [Full Text] [PDF]
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J. A. DiMicco and D. V. Zaretsky The mysterious role of prostaglandin E2 in the medullary raphe: a hot topic or not? Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1589 - R1591. [Full Text] [PDF]
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A. Y. Rudaya, A. A. Steiner, J. R. Robbins, A. S. Dragic, and A. A. Romanovsky Thermoregulatory responses to lipopolysaccharide in the mouse: dependence on the dose and ambient temperature Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2005; 289(5): R1244 - R1252. [Abstract] [Full Text] [PDF]
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A. A. Steiner, S. Chakravarty, J. R. Robbins, A. S. Dragic, J. Pan, M. Herkenham, and A. A. Romanovsky Thermoregulatory responses of rats to conventional preparations of lipopolysaccharide are caused by lipopolysaccharide per se-- not by lipoprotein contaminants Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2005; 289(2): R348 - R352. [Abstract] [Full Text] [PDF]
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S. Saha, L. Engstrom, L. Mackerlova, P.-J. Jakobsson, and A. Blomqvist Impaired febrile responses to immune challenge in mice deficient in microsomal prostaglandin E synthase-1 Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2005; 288(5): R1100 - R1107. [Abstract] [Full Text] [PDF]
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A. I. Ivanov, A. A. Steiner, S. Patel, A. Y. Rudaya, and A. A. Romanovsky Albumin is not an irreplaceable carrier for amphipathic mediators of thermoregulatory responses to LPS: compensatory role of {alpha}1-acid glycoprotein Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2005; 288(4): R872 - R878. [Abstract] [Full Text] [PDF]
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A. A. Romanovsky Do fever and anapyrexia exist? Analysis of set point-based definitions Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2004; 287(4): R992 - R995. [Abstract] [Full Text] [PDF]
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J. B. Buchanan, E. Peloso, and E. Satinoff Thermoregulatory and metabolic changes during fever in young and old rats Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2003; 285(5): R1165 - R1169. [Abstract] [Full Text] [PDF]
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A. I. Ivanov, A. C. Scheck, and A. A. Romanovsky Expression of genes controlling transport and catabolism of prostaglandin E2 in lipopolysaccharide fever Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2003; 284(3): R698 - R706. [Abstract] [Full Text] [PDF]
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A. I. Ivanov, R. S. Pero, A. C. Scheck, and A. A. Romanovsky Prostaglandin E2-synthesizing enzymes in fever: differential transcriptional regulation Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2002; 283(5): R1104 - R1117. [Abstract] [Full Text] [PDF]
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A. A. Romanovsky, C. T. Simons, and V. A. Kulchitsky "Biphasic" fevers often consist of more than two phases Am J Physiol Regulatory Integrative Comp Physiol, July 1, 1998; 275(1): R323 - R331. [Abstract] [Full Text] [PDF]
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; number near each data point
corresponds to time elapsed after injection, in minutes. Three phases
can be determined as 3 loops of curve (cycles): cycle
I (green), from 1st circle (20 min
postinjection) to 2nd circle (74 min); cycle
II (red), from 2nd circle to 3rd circle (196 min);
cycle III (blue), from 3rd circle to
end of plot (
, 330 min postinjection). For clarity, data points are
plotted in phase plane at a 10-min interval, and dynamics of
Tc during latent period of fever
and during very end of experiment are not shown.
