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AMER. ZOOL..1 9:295-304 (1979). Fever in Ectotherms: Evolutionary Implications MATTHEW J. KLUGER Department of Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109 SYNOPSIS Fever, an elevated thermoregulatory "set-point," occurs in vertebrates from fishes through mammals in response to infection with appropriate pathogens. The long phylogenetic history of fever supports the hypothesis that fever has an adaptive or beneficial role (i.e., fever is a component of the host's immunological defenses). Besides providing insight into determining the role of fever in disease, ectothermic vertebrates have also served as excellent animal models to specifically answer many questions relating to fever and disease. For example, survival studies using goldfishes, lizards, and newborn mammals (which are also virtually ectothermic) have shown that an elevated body temperature increases the survival rate of the infected organism. Furthermore, by using ectotherms it has been possible to demonstrate that the reduction in serum iron which accompanies most infections is not directly attributable to an elevation in body temperature. Nevertheless, a rise in body temperature, coupled with a fall in serum iron, appears to constitute a coordinated host defense mechanism in response to at least some bacterial infections in reptiles and mammals, and perhaps other groups of vertebrates. INTRODUCTION There is, occasionally, some misunderstanding concerning fever and hyperFever results when the thermoregulais not equivalent to hyperthermia. Fever tory "set-point" becomes elevated. While thermia. During hyperthermia, the ormany of the details of the pathways leading ganism's body temperature is raised above to a raised thermoregulatory "set-point" the thermoregulatory "set-point." This are still unknown, it is currently believed the result of exercise (particularly might be that in response to some activator or stimulating agent (bacteria, viruses, etc.) the on a warm day), or in response to some host organism produces pyrogenic pro- drug, or could be induced by some other teins collectively known as endogenous disturbance. The hyperthermic organism pyrogens (see review in Dinarello and actively attempts to return its body tempWolff, 1978). These proteins, by some erature toward the thermoregulatory poorly-defined mechanism, raise the ther- "set-point." In a human being, this is acmoregulatory "set-point" resulting in the complished by reducing metabolic heat initiation of both physiological and be- production, increasing skin blood How, havioral responses which lead to a rise in sweating, increasing the exposed surface body temperature. In a mammal such as a area (stretching out, removing clothing, human being this is accomplished by in- etc.), drinking cool liquids, and by other creasing metabolic heat production, de- physiological and behavioral means. creasing skin blood flow, decreasing the Clearly the effector responses during fever exposed surface area (huddling, adding and hyperthermia are diametrically oppoextra blankets, etc.), drinking warm liquids site. This distinction between fever and hyand by other physiological and behavioral perthermia is most striking when one means. studies fevers in ectotherms. This is because any substantial elevation in body Supported by NIH Al 13878. I thank W. W. temperature in an ectothermic organism Reynolds for organizing, and inviting me to, this (which is permitted to select its "preferred" symposium. Page charges for publication of this paper were supported by NSF Grant PCM78-05691 body temperature) must be caused by some change in its thermoregulatory "setto W. W. Reynolds. 295 296 MATTHEW J. KLUGER point." For example, if one places a lizard or a fish in a warm (above their thermal preference) environment, the ectotherm soon attempts to move to a cooler microclimate. In contrast, following an injection of some fever-inducing (pyrogenic) agent, these ectotherms will actively seek out this warm environment, and as a result their body temperature will rise. Within the last few years research from many laboratories has shown that both endotherms and ectotherms develop fevers in response to infection. The work on fever in ectotherms began when Vaughn et at. (1974) demonstrated that the desert Based on the many similarities between mammalian and non-mammalian fever, it is likely that fever in the vertebrates had a common origin. In other words, it is probable that the ability to increase the thermoregulatory "set-point" in response to some pyrogenic stimulus has existed in the vertebrate central nervous system for hundreds of millions of years. This is not particularly surprising since the area generally thought to be largely responsible for integrating thermal information, the hypothalamus, is phylogenetically conservative. For example, studies involving vertebrates from fishes through mammals have shown that the hypothalamus is iguana (Dipsosaurus dorsalis) would select a warmer environmental temperature fol- thermally sensitive in all classes of vertelowing inoculation with the Gram-negative brates (see reviews in Bligh, 1973 and in bacteria Aeromonas hydrophila. This work Kluger, 1979). Since it is generally believed was followed by a series of studies from that pyrogens exert their effects largely at several laboratories which showed that the level of the hypothalamus (Cooper et many non-mammalian vertebrates also ai, 1976) it seems reasonable to speculate developed fevers in response to various that the hypothalamic neurons capable of stimuli. In fact, it has recently been shown responding to pyrogens by changing their that even crayfish develop fevers in re- firing rate, patterns, etc., have had a long sponse to injection with bacteria (Casterlin phylogeny. and Reynolds, 1977a), and PGE, (prostaThe assumption of a common phyloglandin E,) (Casterlin and Reynolds, 1978). genetic origin for the febrile mechanism Much of the work on fevers in non- allows the investigator to utilize various mammalian vertebrates is summarized in species of ectotherms as animal models Table 1. (For more detail, see reviews in to study various characteristics of fever Kluger, 1978a,b). and disease. The ectotherm has at least one major advantage in studies concerning fever and disease: an easily manipulated EVOLUTIONARY IMPLICATIONS body temperature. It is virtually impossible to substantially alter the body temperature Origin ojjever of an adult mammal for any considerable There are many similarities between the length of time; however, the body temperfebrile responses in mammals and in other ature of the temperature-labile ectotherm vertebrates. Table 1 summarizes the ex- can be raised oi lowered simply by placing periments which have shown that non- the ectotherm in a constant-temperature mammalian vertebrates respond to various chambei or bath set at a warm oi cool stimuli by developing fevers. These are temperature. The manipulation of the precisely the kind of stimuli which induce bod) temperature of the ectotherm allows fevers in mammals. Another similarity the investigator to determine whether the concerns the effects of antipyretic drug response under stud)' is attributable to therapy. Many drugs, such as sodium temperature or to some other factor. Foi salicylate and acetaminophen, are known example, during infection it is known that to reduce or attenuate fevers in mammals. serum iron levels fall in human beings and These drugs are also effective antipyretics other mammals (see review in W'einberg. 1974). It has recentl\ been shown that this in non-mammalian sei lebiates (D'Alccv and Kluger, 1975; Bernheim and Klugei, fall in serum iron is induced In a piotein bc'!ie\t'(l to be endogenous pyrogen (\Iei /; Reynolds, 1977). 297 FEVER AND DISEASE TABLE 1. Febrile responses of the non-mammalian vertebrates. Species Callus domesticus Gallus domesticus E. coli endotoxin (iv) Salmonella abortus equi Investigators van Miert and Frens (1968) Pittman <•< a/. (1976) Gallus domesticus endotoxin (ant. hypolhal.) Prostaglandin E, (ant. hypothal.) Pittman etal. (1976) Columba hvia Pasteurella multocida (iv, ip) D'Alecyand Kluger(1975) Dipsosaurus dorsalis Aeromonas hydrophila Vaughn rt al. (1974) 2 UJ -J Activator of fever* (intracardiac, [ic]) Dipsosaurus dorsalis Dipsosaurus dorsalis Dipsosaurus dorsalis Pasteurella haemolytica (ic) Citrobacter diversus (ic) Iguana iguana Aeromonas hydrophila (ic) Kluger(1978a) Aeromonas hydrophila (sc) Aeromonas hydrophila (ip) Aeromonas hydrophila (ip) Mycobacterium sp. (ip) i Hyla cmerea Rana pipiens Rana catesbeiana Rana esculenta Rana esculenta Kluger (1977) Casterlin and Reynolds (19776) Casterlin and Reynolds (19776) Myhreetal. (1977) Myhreetal. (1977) i < Rana esculenta I Micropterus salmoides Lepomis macrochirus Lepomis macrochinus Lepomis macrochirus Carassius auratus Carassius auratus u a. oi If) z< 3 r vi u> lizard or rabbit-derived endogenous pyrogen (ic) frog-derived endogenous pyrogen (ip) Prostaglandin E, (diencephalon) Aeromonas hydrophila (ip) Aeromonas hydrophila (ip) E. coli endotoxin (ip) Staphylococcus aureus (ip) Aeromonas hydrophila (ip) E. coli endotoxin (ip) Kluger (1978a) Kluger (19786) Bernheim and Kluger (1977) Myhre et al. (1977) Reynolds et al. (1976) Reynolds et al. (1976) Reynolds etal. (1978a) Reynolds et al. (1978a) Reynolds and Covert (1977) Reynolds et al. (19786) Stimulus used by investigators to induce fever. \\m<xn etal., 1977). Is this fall in serum iron induced by the elevation in body temperature, or is the endogenous pyrogen independently inducing both a fever and a fall in serum iron? We have been able to answer this question using the lizard Dipsosaurus dorsalis (Grieger and Kluger, 1978). Elevating the body temperature of the uninfected lizards led to no changes in serum iron concentrations. However, in response to infection, serum iron levels fell regardless of whether body temperature was elevated to the febrile level or maintained at the afebrile level. Clearly, the fall in serum iron is the result of the inducer protein, and not of the rise in body temperature. Function oj fever For thousands of years, the question of whether fever is beneficial or harmful has been debated. According to the humoral theory of disease, a person became ill when one of the bodily "humors" was produced in excess (Yost, 1950). The response of the infected organism to this imbalance was first to "cook" the "raw" humor (i.e., develop a fever) and then to evacuate the cooked humor by sweating, vomiting, or defecating. This view of fever as a host defense mechanism was espoused by Hippocrates and other ancient physicians, and persisted until the latter part of the 19th century (Kluger, 1979). For some reason (perhaps related to the advent of antipyretic drugs), the view of fever as an adaptive response changed, so that it is now fairly common for physicians or laymen to prescribe antipyretic drugs, such as aspirin, for any febrile episode. In 1960 Bennett and Xicastri reviewed 298 MATTHEW J. KLUGER the experimental evidence concerning the function of fever and, based on the information available to them, were unable to conclude whether fever was beneficial or harmful. It has been very difficult to resolve the question of fever's function in mammals. Consequently, the simplest experiment would involve infecting a group of mammals with live bacteria or viruses, and then allowing some to develop the elevated body temperature and preventing others from developing an elevated temperature. Differences in survival rate could then be compared between the two groups. The problem with this experimental design is that, in order to manipulate the body temperature of most adult mammals (particularly those commonly used in laboratory investigations), one has to use fairly drastic procedures. These could entail infusing drugs, subjecting the animals to extremely high or low environmental temperatures, heating or cooling their hypothalami, etc. All of these experimental manipulations would make the interpretation of the survival data difficult. I believe that the results of the investigations on the evolution of fever have helped to resolve the question of fever's function. This is because fever is energetically very expensive. Whether an organism is an endotherm or an ectotherm, a rise in body temperature results in substantial increases in metabolic heat production and therefore energy expenditure. For example, assuming a Q10 of 2.5 for most biochemical reactions, a rise in body temperature of 2 or 3°C will result in an increase in energy expenditure of approximately 25%. While it is possible that fever arose dp novn as a harmful trait, linked genetically to some beneficial immunological effect, the widespread nature of the phenomenon, and the substantial metabolic costs of small elevations in body temperature argue against this. There is obviously no selective pressure for maladaptations. Since fever has apparently existed for millions of years in numerous vertebrate orders and classes without diminishing in magnitude, the comparative or phylogenetic approach argues strongly for fever being adaptive; that is, fe\er is likely a component of the host organism's immunological defense repertoire. ECTOTHERMS AS ANIMAL MODELS TO STUDY FEVER AND DISEASE As described above, ectotherms provide excellent animals to investigate various questions concerning fever and disease. One of the areas in which ectotherms have been used extensively has been to resolve the question of fever's adaptive value. Fever and survival We have used the lizard (D. dorsalis) to resolve the question of fever's adaptive value. Lizards were infected with live A. hydrophila and placed in constant-temperature chambers set at 34, 36, 38, 40, or 42°C. (Kluger e< ai, 1975). These represented temperatures ranging from afebrile (34-38°C) to febrile (40-42°C). The results of this study are shown in Figure 1. Lizards maintained at a febrile temperature had a higher percent survival than those maintained at the normal afebrile temperature of 38°C, or at temperatures below (36 or 34°C) their preferred body temperature. To determine whether this increased survival at febrile temperatures was related specifically to decreased bacterial growth, bacteria were grown in vitro at temperatures ranging from 34 to 42°C. We found no relationship between temperature and the growth rate of these bacteria from 34-40°C; however, at 42°C the bacteria grew more slowly. The fact that moderate fevers (40°C) did not diminish the growth of these bacteria has been confirmed in a later study by Bernheim et ai (1978). To determine whether drug-induced antipyresis would adversely affect the survival rate of these lizards, we infected additional lizards with live bacteria, as well as with a non-toxic dose of sodium salicylate. The dose of salicylate used was selected because an earlier study (Bernheim and Kluger, 1976«) had shown that this dose of antipyretic led to an attenuation of the fever in some, but not all lizards. It was found that in those lizards in which the fever failed to develop, the mortality rate 299 FEVER AND DISEASE 100 m *% ^^ "• — ^ ^ * 80 - * • ^k^ ^ "-vx ^ • • 40<'0(12) -h 60 oc z> CO A \ - \\ 20 \\ 38C '0(36) 40 - 1 K 1 3 6 C > r* /JO] 34 £ > Q(\O) 1 1 1 1 0 TIME (days) FIG. 1. Percentage survival of D. dorsalis injected 34° to 42°C. The number of lizards in each group is with A. hydrophila and maintained at temperatures of given in parenthesis, (from Kluger et al., 1975) was 100%, while in those lizards in which enced no mortality (Fig. 2). The goldfish the sodium salicylate failed to attenuate or maintained at 30.5°C had a survival rate of reduce the fever, their survival rate was 84%, while those at 28°C had a survival 100% (Bernheim and Kluger, 1976ft). rate of 64%, and those at 25.5°C had a surThese studies demonstrated that prevent- vival rate of only 24% (Fig. 2). Overall, the studies using ectothermic ing the development of an elevated body temperature by physical means (Kluger et vertebrates to determine fever's function al., 1975) or by pharmacological means indicate that the prevention of an elevated (Bernheim and Kluger, 1976ft) was harm- temperature during bacterial infection is harmful. Whether this is a general pheful to the infected animals. Covert and Reynolds (1977) have found nomenon throughout the vertebrates is as that fever also has survival value in fishes. yet unknown; however, similar studies They infected goldfish (Carassim auratus) resulting in virtually the same conclusion with live bacteria (A. hydrophila) and main- have been performed using newborn tained these animals at either afebrile mammals infected with viruses. Newborn temperatures (25-28°C) or at the moder- mammals tend to be fairly thermolabile ate febrile temperature of 30.5°C. In addi- (Pembrey, 1895), and as a result one can tion, ten goldfish were allowed to thermo- manipulate their body temperatures in regulate behaviorally following infection much the way that one can manipulate the with live bacteria; these fish selected a mean body temperature of ectotherms. In one body temperature of 32.7°C, and experi- study, newborn mice were infected with 300 MATTHEW J. KLUGER 100 *32.7°c no; 80 *30.5°C (25) 60 *28.0° C (25) 40 20 0 25.5° C (25? i i i 4 8 12 24 48 72 Time (hours) FIG. 2. Percent survival of goldfish infected with A. hydrophila and maintained at temperatures of 25.5°C, 28.0°C, and 30.5°C; 10 goldfish were allowed to behaviorally thermoregulate and selected a mean body temperature of 32.7°C. The numbers of fishes in each group is given in parenthesis. (From Covert and Reynolds, 1977) Coxsacki B, virus (Teisner and Haahr, 1974). One group was held at 34°C, and as a result had a mean body temperature close to 36°C (some 2 to 3°C higher than control mice held at normal room temperature), similar to the body temperature of adult mice. The mice held at 34°C had a lower mortality rate than did the control mice. Similar results were found by Carmichael et al. (1969) for 2-5-day-old dog pups which were inoculated with canine herpesvirus. Based on these results, Haahr and Mogensen (1977) suggested that one of the reasons that generalized herpes infections are greatly over-represented in premature babies might be attributable to their restricted temperature regulation and poor febrile responses. and indirect effects. There are many examples of the direct effects of temperature on both viral and bacterial growth. One such example is the effects of temperature on the growth of poliomyelitis virus (Lwoff, 1969). The yield of these viruses when grown at 37°C was 250 times greater than when grown at 40°C. The mechanism behind the inhibitory effects of temperature on the growth of viruses is not known. The effect of temperature on bacterial growth is illustrated by the adverse effects of temperatures as low as 40—41°C on the gonorrhea gonococci (Carpenter et al., 1933). Neurosyphilis spirochetes are also killed by temperature elevations (Bruetsch, 1949), and it is this effect of elevated temperature which has provided the rationale for fever therapy, a practice dating back thousands of years (Kluger, 1979). One component of the immune response which is thought to be increased by temperature elevation is leucocyte function. There is considerable evidence that the leucocyte mobility increases with temperature (Bryant et al., 1966; Phelps and Stanislaw, 1969; Xahas rt al., 1971; Bern- Mechanisms behind the function of fever An elevation in body temperature might enhance the survival of an infected organism directly by an effect of temperature on the pathogen, indirectly by an effect of temperature on the host's defense mechanisms, or by a combination of both direct FEVER AND DISEASE heim et al., 1978). Several investigators have also reported that the bactericidal activity of leucocytes is also increased with elevations in temperature. For example, Sebag et al. (1977) noted that elevations in temperature led to increased killing of some species of bacteria, but had little effect on others. In another study, it was reported that the percentage of ingested Staphylococcus bacteria killed increased as temperature was raised from 26 to 36°C (Craig and Sutter, 1966). As a result of this study, it was suggested that fever could not increase the intracellular killing power of leucocytes, since most fevers in human beings are in the range of perhaps 38 to 40°C. This is not technically correct. While it is true that the average rectal temperature of a febrile individual might be 38 to 40°C during a fever, the average body temperature will be considerably less, perhaps only 36 or 37°C. This is because the average body temperature incorporates the warmer tissues in the deep body areas, for example the abdomen, chest cavity, etc., along with the cooler peripheral areas, the skin, respiratory tract, limbs, etc. Since many infections actually reside in the cooler areas of the body, an increase in the bactericidal activity of the white blood cells at a temperature as low as 36°C might still represent a beneficial effect of fever. Another area of leucocyte function which might be enhanced by small elevations in temperature is lymphocyte transformation. It is well known that lymphocytes undergo proliferation and transformation in response to various stimulants. These activated or "transformed" lymphocytes are then capable of participating in various aspects of the immune response. Studies by Roberts and Steibigel (1977), and by Ashman and Nahmias (1977), have shown that in vitro temperatures approximating moderate fevers in human beings (38.5 to 39.0°C) result in enhancement and acceleration of lymphocyte transformation in response to various antigens. Other components of the immune response are also thought to be enhanced by small elevations in temperature. Among these are increased lysosome activity (l.woff, 1969; Overgaard, 1977) and increased produc- 301 tion of interferon (Ho, 1970). Space does not allow a detailed discussion of these immunological processes. Another way in which fever might be beneficial is by a combination of direct and indirect effects. For example, it is known that during infections the levels of serum iron fall in both reptiles and mammals. This appears to be a response of the host to some substance released by white blood cells and currently thought to be endogenous pyrogen (Merriman et al., 1977). The iron is stored in various sites such as the liver and spleen and remains there until the infection is over. Garibaldi (1972), Weinberg (1974) and others have suggested that the growth potential of pathogenic bacteria might be related to the availability of iron or some other nutrient. The reduction of some specific vital nutrient by the host organism might be a defense mechanism, a process Kochan (1973) termed "nutritional immunity." Bacteria are usually able to obtain adequate amounts of iron from their growth medium, whether this be a broth solution or a person's plasma, by producing iron chelating substances known as siderophores. This capacity for producing these iron chelators by various species of bacteria has been shown by Garibaldi (1972) to decrease with increasing temperature in the range of normal to febrile body temperature in mammals. Garibaldi (1972) suggested that fever might thereby decrease growth rates of microorganisms which are already in an iron-poor environment. We have tested this "nutritional immunity" theory using lizards (Grieger and Kluger, 1978). First, uninfected D. dorsalis were subjected to afebrile and febrile temperatures. This led to no change in serum iron levels. Following infection with A. hydrophila, serum iron levels fell irrespective of whether the lizards were maintained at afebrile or febrile temperatures. We concluded that the fall in serum iron during infections is not temperature dependent, and that the protein (endogenous pyrogen?) responsible for inducing the fever and reducing serum iron works independently. When we injected infected 302 MATTHEW J. KLUGER lizards with excess iron, their mortality rate rose significantly, suggesting that the fall in serum iron was a host defense response. The synergistic nature of fever and the reduction in serum iron was demonstrated by the results of our bacterial growth experiments. Pathogenic bacteria were grown at afebrile (38°C) and febrile (41°C) bath temperatures. The growth of the bacteria in a broth containing the normal non-infected levels of iron was virtually identical at 38 and 41°C. However, when the iron levels in the broth were either reduced or made less available to the bacteria by adding an iron chelator, this led to marked reductions in the growth of the bacteria at the febrile, but not the afebrile, temperature. Based on these results, we concluded that a reduction in serum iron and the development of a fever constitute a coordinated host defense response which leads to a decrease in the growth potential of pathogenic bacteria. Further support for this theory has resulted from our investigations on fever as a defense mechanism in rabbits. New Zea- of the bath was raised to a febrile temperature (41°C), the growth of the bacteria was inhibited by the low, but not the high, iron concentrations. When the bacteria were grown at a subphysiological level of iron (19 pig Fe/100 ml growth medium), there was no growth at febrile or at afebrile temperatures. Furthermore, addition of deferoxamine mesylate (an iron chelator) to the growth medium slightly inhibited the growth of the bacteria at 39 and 40°C, severely attenuated the growth at 41°C, and completely prevented the growth at 42 and 43°C. These data support the hypothesis that one of the mechanisms behind the adaptive role of fever is the reduced ability of pathogenic bacteria to grow well at elevated temperatures in an iron-poor medium. IMPLICATIONS Based on the data presented above, which suggest that fever has had a long phylogeny, along with the specific experiland rabbits (Oryctolagus cuniculus) were in- ments which have demonstrated a survival fected with live Pasteurella multocida (a value for fever, it is likely that any process common rabbit pathogen), and their resul- which lowers the temperature of a febrile tant fevers were correlated with their sur- subject (unless the fever is extremely high) vival rates (Kluger and Vaughn, 1978). is harmful to the infected host. In addition, The results demonstrated that there was a based on the results concerning iron and positive correlation between the fever and infection, it appears that any process which survival rates for fevers up to 2.25°C (a raises plasma or serum iron (e.g., eating body temperature rise from about 39.50°C excessive amounts of iron) could be harmto 41.75°C). In a subsequent study we ful to the infected host. found that during infection with P. mulThe converse of the above statements tocida, plasma iron of rabbits fell from an might also be true; that is, elevating body average of 261 pig Fe/100 ml plasma to 118 temperature above the normal febrile pig Fe/100 ml plasma by 4 hours post- level, or reducing the iron concentration injection, and to 66 pig Fe/100 ml plasma or accessibility (by adding iron chelators) by 24 hours post-injection (Kluger and could have therapeutic value during infecRothenburg, 1978, 1979). To determine tion with certain species of pathogens. whether the rise in body temperature It is also known that other mineral con(fever) and the fall in plasma iron was a centrations change during infection. For coordinated host defense response, P. example, serum zinc levels fall and copper multocida were grown in vitro at various levels rise. It is not yet known, however, temperatures and iron levels. At afebrile whether these changes along with the contemperatures (39 and 40°C) the bacteria comitant rise in body temperature congrew equally well at low (79 or 139 pig Fe/ stitute an immunological defense mecha100 ml growth medium) or high (266 pig nism. Clearly, the relationship between Fe/100 ml growth medium) iron concen- fever and changes in trace elements is an trations. However, when the temperature area which deser\es further study. FEVER AND DISEASE REFERENCES 303 Garibaldi, J. A. 1972. Influence of temperature on the biosynthesis of iron transport compounds by Salmonella typhtmurium. J. Bact. 110:262-265. Ashman, R. B. and A. J. Nahmias. 1977. EnhanceGrieger, T. A. and M. \. Kluger. 1978. Fever and ment of human lymphocyte responses to phytosurvival: The role on serum iron. J. Physiol. (Lond.) mitogens in vitro by incubation at elevated tempera279:187-196. tures. Clin. Exp Immunol. 29:464-467. Haahr, S. and S. Mogensen. 1977. Function of fever. Bennett, I. L. and A. 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