Ditch the Reliever, Bring on the Fever Duration of sickness behaviour will  be significantly different with no aspirin tre...
Outline <ul><li>Introduction </li></ul><ul><ul><li>What’s the deal with fever and sickness behaviour? </li></ul></ul><ul><...
 
What’s the deal with fever and sickness behaviour? <ul><li>Fever </li></ul><ul><ul><li>Elevated temperature above the norm...
 
Julius Wagner-Jauregg
Transformation <ul><li>“ Fever Phobia” </li></ul><ul><ul><li>“ Fever had become a harmful by-product of infection rather t...
Sickness Behaviour <ul><li>Sickness Behaviour </li></ul><ul><ul><li>Fatigue </li></ul></ul><ul><ul><li>Loss of appetite  <...
What has been done so far… <ul><li>Quantitative relationship between cytokine levels of  non-specific sickness behaviour s...
We hypothesize… <ul><li>Alternative Hypothesis (H 1 ): </li></ul><ul><li>There will be a significant difference  in durati...
Method
Albino Wistar Rats <ul><li>60 Adult male albino rats </li></ul><ul><li>200-250 g </li></ul><ul><li>Decreased appetite </li...
Groups
Experimental Phases
Phase 1 Weeks 1 and 2 <ul><li>Temperature Telemetry Transmitter (TTT)  transplant </li></ul><ul><li>Recovery (week 1)  </l...
Phase 2 Week 3 <ul><li>Measure baselines: </li></ul><ul><ul><li>Temperature </li></ul></ul><ul><ul><li>Food Consumption </...
Phase 3 Experimental Day – Induce Fever <ul><li>Inject Lipopolysaccharide (LPS) for both  Aspirin  and  Non-Aspirin  group...
Phase 4 Experimental Day – Induce Treatment <ul><li>Aspirin group  </li></ul><ul><ul><li>Inject Aspirin at 6-hour peak of ...
Phase 5 Experimental Day – Data collection <ul><li>Temperatures </li></ul><ul><li>Feeding behaviour  (How much food eaten?...
Food Consumption <ul><li>At 24 hr intervals </li></ul><ul><li>Remaining food measured on triple beam balance </li></ul>
Food Consumption <ul><li>EXPECTED RESULTS: </li></ul><ul><ul><li>After fever induction, initial decrease in appetite for b...
Motor Activity <ul><li>Open Field Test </li></ul><ul><li>Field is separated into 16 boxes, marked by horizontal and vertic...
Motor Activity <ul><li>EXPECTED RESULTS: </li></ul><ul><ul><li>The Non-aspirin group will resume activity sooner over the ...
Sleeping Behaviour <ul><li>Measure duration of sleep in percentage </li></ul><ul><li>Measure by camera recording </li></ul>
Sleeping Behaviour <ul><li>EXPECTED RESULTS: </li></ul><ul><ul><li>Compared with baseline: An increase in sleep duration a...
Data Analysis <ul><li>Dependent Paired T-test </li></ul><ul><li>Independent variables: Rats with Aspirin vs. Rats with tra...
Discussion
Limitations <ul><li>Administration of LPS will always induce fever </li></ul>
Future implications and  potential applications
But remember… <ul><li>Take with a grain of salt </li></ul><ul><li>Fever can be fatal </li></ul><ul><ul><li>Too high </li><...
Thank you! Dr. Faure, Brandon & class!
Questions?
References <ul><li>Brown, R, E., Gunn, R, K., Schellinck, H, M., Wong, A, A., & O’Leary, T, P. (2004) Anxiety, exploratory...
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Fever - ACES

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Ditch the Reliever, Bring on the Fever

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  • As students with busy lifestyles…we can’t afford to get sick. At the first sensations of symptoms: fever, fatigue, sore throat, dizziness—an overall feeling of anguish and discontent we run to our medicine cabinets or mommies and pop two aspirins. But fever is one of the oldest medical symptoms and has persisted throughout the animal kingdom for hundreds of millions of years. If it’s so bad…why is it still here plaguing us? So…because of this persistence and prevalence we decided to delve deeper into this phenomenon, with the idea that there “must be some sort of purpose as to why this mechanism has evolved” However, we are also taking a different approach; not only focusing on fever but also the sickness behaviour that accompanies it—which I will be elaborating on further in a little bit.
  • So…first of all fever! What’s the deal with fever? Fever is generally known as a normal and expected physiological response to infection marked by an elevated temperature above the normal range. As mentioned earlier, it is exhibited by numerous species throughout the animal kingdom, even the ones that cannot generate fever. In one famous experiment by Matt Kluger, he found that infected cold-blooded desert lizar ds sought places warm enough to raise their body temperature up by two degrees. And lizards unable to do this were more likely to die. Baby rabbits, who are unable to generate fever, find warmer places to raise their body temperature when they are sick. Adult rabbits can have fever, but blocking it with fever lowering drugs results in a higher likelihood of death. The benefits of fever can also be found in humans through historical records. Before the widespread use of anti-pyretics (drugs that cause the hypothalamus to override an interleukin -induced increase in temperature) there were various forms of fever-therapy in which fever was used as a cure. [ show photo] and in the human nervous system follows a mechanic, physiological, biochemical response.
  • Take for example this 1950 machine called “The Hypertherm”. It is an insulated cabinet where temperature is raised and maintained by circulating hot moist air.
  • Another notable example is the work by Julius Wagner-Jauregg who noted that some syphilis patients improved after getting malaria (in which symptoms typically include fever) and he intentionally infected thousands of syphilis patients with malaria (very unethical!) and achieved a 30% remission rate in an era where fewer than 1 in a hundred syphilis patients recovered. Another example would be what the American Indians of the Northwest Tribe did to the sick…if you read our proposal…you know it would entail stuffing the patient in a freshly killed horse carcass…and fortunately, I have no pictures to show for that.
  • From these examples, it is clear that the benefits of fever were appreciated before the rise in Anti-pyretics. However, shortly after this anti-pyretic revolution “fever phobia” began to take hold and fever had been transformed into a harmful by-product of infection rather than a host-defense response, probably due to the misconstruction of the relief felt after the use of anti-pyretics, which are often analgesics as well.
  • Now, fever in the human nervous system follows a mechanic, physiological, biochemical response and this complex cascade also results in sickness behaviour which include: fatigue, loss of appetite, inability to concentrate, loss of interest in social activity… These changes in behaviour, like fever, can be considered to be an adaptive strategy that resets the organism’s priorities in order to promote resistance to pathogens and recovery from infection.
  • With this as our background, our rationale is to examine the effect of anytipyretics (particularly aspirin) in fever and sickness behaviour. Only a few human studies have tried to evaluate fever as an adaptation to combat infection and in terms of sickness behaviour. Most have been limited to the effectiveness of fever. For example, in one study, a group of volunteers got colds on purpose some then took aspirin and the others a sugar pill/placebo. Results show that individuals who took the placebo had a significantly higher antibody response and less nasal stuffiness. So from our knowledge, no studies have attempted to document the quantitative relationships between cytokine levels and non-specific sickness behaviour symptoms. Therefore we conclude that more research needs to be done in terms of the benefits of the sickness behaviour that accompanies fever, in humans and how anti-pyretics affect this. Using animal models we decided to explore the fever and sickness behaviour relationship. We hypothesize…
  • The main motivation for our study was to add to the evidence of fever and sickness behaviour as a beneficial mechanism during sickness and that We must re-evaluate the use of anti-pyretics in suppression of fever because of the negative consequences, particularly, in prolonging sickness and increasing the risk of a secondary infection. Additional research on fever may also provide another benefit by easing “fever phobia” seen especially in new parents. Further research can also fuel novel ideas and hypotheses regarding the adaptiveness of these mechanisms but also providing insight and possible applications in overlapping behaviour found in disorders or syndromes. For example, major clinical depression follows and involves very similar biochemical cascades in cytokine-induced sickness behaviour.
  • Another thing to remember is that you must take our presentation with a grain of salt. We are not advocating that people never take drugs to combat or reduce fever, merely bringing to light that fever is not a bad thing and has positive effects and a survival value. In fact, we all know that fever can be fatal when it is too high above the normal range and if it persists for more than 4 days. In this case, anti-pyretics, drugs and cooling techniques must be employed. Our study aims not only to add to the literature of fever and sickness behaviour as adaptive mechanisms with survival value but also provide further appreciation for these evolved physiological and psychological mechanisms which persist for a purpose.
  • Fever - ACES

    1. 1. Ditch the Reliever, Bring on the Fever Duration of sickness behaviour will be significantly different with no aspirin treatment versus aspirin treatment in male rats Alisha Jiwani, Dorcas Kwan, Amanda Li, Joy Santiago
    2. 2. Outline <ul><li>Introduction </li></ul><ul><ul><li>What’s the deal with fever and sickness behaviour? </li></ul></ul><ul><li>Hypotheses </li></ul><ul><li>Method </li></ul><ul><ul><li>Experimental Phases </li></ul></ul><ul><ul><li>Data Analysis </li></ul></ul><ul><li>Limitations </li></ul><ul><li>Conclusion </li></ul><ul><ul><li>Implications </li></ul></ul><ul><ul><li>Applications </li></ul></ul>
    3. 4. What’s the deal with fever and sickness behaviour? <ul><li>Fever </li></ul><ul><ul><li>Elevated temperature above the normal range </li></ul></ul><ul><li>1800s </li></ul><ul><ul><li>Anti-pyretics </li></ul></ul><ul><li>Fever therapy </li></ul>
    4. 6. Julius Wagner-Jauregg
    5. 7. Transformation <ul><li>“ Fever Phobia” </li></ul><ul><ul><li>“ Fever had become a harmful by-product of infection rather than a host-defense response, probably due to the misconstruction of the relief felt after the use of anti-pyretics, which are often analgesics as well.” </li></ul></ul>
    6. 8. Sickness Behaviour <ul><li>Sickness Behaviour </li></ul><ul><ul><li>Fatigue </li></ul></ul><ul><ul><li>Loss of appetite </li></ul></ul><ul><ul><li>Inability to concentrate </li></ul></ul><ul><ul><li>Loss of interest in social activity </li></ul></ul><ul><li>Adaptive strategy </li></ul><ul><ul><li>Reset priorities </li></ul></ul>
    7. 9. What has been done so far… <ul><li>Quantitative relationship between cytokine levels of non-specific sickness behaviour symptoms </li></ul><ul><li>More research on sickness behaviour </li></ul><ul><li>Effect of anti-pyretics in duration of sickness behaviour </li></ul><ul><li>Is recovery faster when fever is not suppressed? </li></ul>
    8. 10. We hypothesize… <ul><li>Alternative Hypothesis (H 1 ): </li></ul><ul><li>There will be a significant difference in duration of sickness behaviour when antipyretics are administered. </li></ul><ul><li>Null Hypothesis (H 0 ): </li></ul><ul><li>There will be no significant difference in duration of sickness behaviour when antipyretics are administered. </li></ul>
    9. 11. Method
    10. 12. Albino Wistar Rats <ul><li>60 Adult male albino rats </li></ul><ul><li>200-250 g </li></ul><ul><li>Decreased appetite </li></ul><ul><li>Decreased activity levels </li></ul><ul><li>Increased sleeping time </li></ul>
    11. 13. Groups
    12. 14. Experimental Phases
    13. 15. Phase 1 Weeks 1 and 2 <ul><li>Temperature Telemetry Transmitter (TTT) transplant </li></ul><ul><li>Recovery (week 1) </li></ul><ul><li>Acclimation to device (week 2) </li></ul>
    14. 16. Phase 2 Week 3 <ul><li>Measure baselines: </li></ul><ul><ul><li>Temperature </li></ul></ul><ul><ul><li>Food Consumption </li></ul></ul><ul><ul><li>Motor Activity </li></ul></ul><ul><ul><li>Sleeping Behaviour </li></ul></ul>
    15. 17. Phase 3 Experimental Day – Induce Fever <ul><li>Inject Lipopolysaccharide (LPS) for both Aspirin and Non-Aspirin groups </li></ul>
    16. 18. Phase 4 Experimental Day – Induce Treatment <ul><li>Aspirin group </li></ul><ul><ul><li>Inject Aspirin at 6-hour peak of LPS effect </li></ul></ul><ul><ul><li>Wait 2 hours for peak of Aspirin’s anti-pyretic effect </li></ul></ul><ul><li>Non-Aspirin group </li></ul><ul><ul><li>Inject tragacanth at 6-hour peak of LPS effect, </li></ul></ul><ul><ul><li>Wait 2 hours </li></ul></ul>
    17. 19. Phase 5 Experimental Day – Data collection <ul><li>Temperatures </li></ul><ul><li>Feeding behaviour (How much food eaten?) </li></ul><ul><li>Exploration behaviour (How much activity?) </li></ul><ul><li>Sleeping behaviour (How much sleep?) </li></ul><ul><li>** each experiment will span over 4 days </li></ul>
    18. 20. Food Consumption <ul><li>At 24 hr intervals </li></ul><ul><li>Remaining food measured on triple beam balance </li></ul>
    19. 21. Food Consumption <ul><li>EXPECTED RESULTS: </li></ul><ul><ul><li>After fever induction, initial decrease in appetite for both groups </li></ul></ul><ul><ul><li>Animals in Non-Aspirin group will have appetites restored sooner than animals in Aspirin group </li></ul></ul>
    20. 22. Motor Activity <ul><li>Open Field Test </li></ul><ul><li>Field is separated into 16 boxes, marked by horizontal and vertical blue lines </li></ul><ul><li>Camera-based computer tracking system and video camcorder </li></ul><ul><li>Total Motor Activity = Line Crossing + Rearing </li></ul>
    21. 23. Motor Activity <ul><li>EXPECTED RESULTS: </li></ul><ul><ul><li>The Non-aspirin group will resume activity sooner over the four days that the Aspirin group </li></ul></ul>
    22. 24. Sleeping Behaviour <ul><li>Measure duration of sleep in percentage </li></ul><ul><li>Measure by camera recording </li></ul>
    23. 25. Sleeping Behaviour <ul><li>EXPECTED RESULTS: </li></ul><ul><ul><li>Compared with baseline: An increase in sleep duration after the LPS injection </li></ul></ul><ul><ul><li>Duration of sickness behaviour: the rats with Aspirin injection will experience a longer duration of sickness behaviour </li></ul></ul>Aspirin Non-Aspirin
    24. 26. Data Analysis <ul><li>Dependent Paired T-test </li></ul><ul><li>Independent variables: Rats with Aspirin vs. Rats with tragacanth </li></ul><ul><li>Dependent variables for each experiment: </li></ul><ul><ul><li>Experiment 1 : Remaining food after 24 h (g) </li></ul></ul><ul><ul><li>Experiment 2 : Motor activity calculated </li></ul></ul><ul><ul><li>Experiment 3 : Sleep duration (%) </li></ul></ul><ul><li>For each experiment, the dependent variables will be:  </li></ul><ul><ul><li>i. Comparing the baseline level with the performance after LPS injection </li></ul></ul><ul><ul><li>ii. Comparing the difference between the 2 groups over the four-days </li></ul></ul>
    25. 27. Discussion
    26. 28. Limitations <ul><li>Administration of LPS will always induce fever </li></ul>
    27. 29. Future implications and potential applications
    28. 30. But remember… <ul><li>Take with a grain of salt </li></ul><ul><li>Fever can be fatal </li></ul><ul><ul><li>Too high </li></ul></ul><ul><ul><li>Fever persists </li></ul></ul><ul><li>Appreciation of evolved physiological and psychological mechanisms </li></ul>
    29. 31. Thank you! Dr. Faure, Brandon & class!
    30. 32. Questions?
    31. 33. References <ul><li>Brown, R, E., Gunn, R, K., Schellinck, H, M., Wong, A, A., & O’Leary, T, P. (2004) Anxiety, exploratory behaviour, and motor activity in 13 strains of mice. MPD:94. Mouse Phenome Database website, The Jackson Laboratory, Bar Harbour, Maine USA. http://www.jax.org/phenome . Available March 2008 </li></ul><ul><li>Camus, P., Lombard, J., Perrichon, M., Piard, F., Gutrin, J. Thivolet, F. B., Jeannin, L. (1989). Bronchiolitis obliterans organising pneumonia in patients taking acebutolol or amiodarone. Thorax, 44, 711-715. </li></ul><ul><li>Clement, J. G., Mills, P., Brockway, B. (1989). Use of telemetry to record body temperature and activity in mice. Journal of Pharmacological Methods Viewpoint, 21, 129-140. </li></ul><ul><li>Ennaceur, A., Michalikova, S., & Chazot, P, L. (2006). Models of anxiety: Responses of rats to novelty in an open space and an enclosed space. Behavioural Brain Research, 171, 26-49. </li></ul><ul><li>Johnnson, R. W. (2002). The concept of sickness behaviour: a brief chronological account of four key discoveries. Veterinary Immunology and Immunopathology, 87, 443-450. </li></ul><ul><li>Kelley, K. W., Bluthe, R., Dantzer, R., Zhou, J., Shen, W., Johnson, R. W., Broussarda, S. R. (2003). Cytokine-induced sickness behavior. Brain, Behaviour and Immunity, 17, 112-118. </li></ul><ul><li>Kent, S., Buth, R., Kelley, K., Dantzer, R. (1992). Sickness behavior as a new target for drug development. Viewpoint, 13, 24-28. </li></ul><ul><li>Kluger, M., Kozak, W., Corm, C., Leon, L. R., Soszynski, D. (1996). The Adaptive Value of Fever. Infectious Disease Clinics of North America, 10 (1), 1-20. </li></ul><ul><li>Kozak, W., Conn, C.A., & Kluger, M.J. (1994). Lipopolysaccharide induces fever and depresses </li></ul><ul><li>locomotor activity in unrestrained mice. American Journal of Physiology, 266 (1), R125-135. </li></ul><ul><li>Loux, J.J., DePalma, P.D., & Yankell, S.,L. (1971). Antipyretic testing of aspirin in rats. </li></ul><ul><li>Toxicology & Applied Pharmacology, 22 (4), 672-675. </li></ul><ul><li>Mackowiak, P. A. (2000). Brief History of Antipyretic Therapy. Clinical Infectious Diseases, 31, 154-156. </li></ul><ul><li>Makela, M. J., Puhakka, T., Ruuskanen, O., Leinonen, M., Saikku, P., Kimpima, M., Blomqvist, S., Hyppia, T., Arstila, P. (1998). Viruses and Bacteria in the Etiology of the Common Cold. Journal of Clinical Microbiology, 36, 539-542. </li></ul><ul><li>Moran, M, M., Roy, R, R., Wade, C, E., Corbin, B, J., & Grindeland, R, E. (1998). Size constraints of telemeters in rats. J Appl Physiol, 85, 1564-1571. </li></ul><ul><li>Oka, T., Oka, K. Scammell, T.E., Lee, C., Kelly, J.F., Nantel, F., Elmquist, J.K., & Saper, C.B. (2000). Relationship of EP1-4 Prostaglandin Recpetors With Rat Hypothalamic Cell Groups Involved in Lipopolysaccharide Fever Responses. The Journal of Comparative Neurology, 428 , 20-32. </li></ul><ul><li>Roth, J., McClellan, J.L., Kluger, M.J., & Zeisberger, E. (1994). Attenuation of fever and release of cytokines after repeated injections of lipopolysaccharide in guinea-pigs. Journal of Phsyiology, 477 (1), 177-185 </li></ul><ul><li>Tomazetti, J., Silva Avila, D., Ferreira, A.P.O., Martins, J.S., Souza, F.R., Royer, C., Rubin, </li></ul><ul><li>M.A., Oliveira, M.R., Bonacorso, H.G., Martins, M.A.P., Zanatta, N., & Mello, C.F. (2005). Baker yeast-induced fever in young rats: Characterization and validation of an animal model for antipyretics screening. Journal of Neuroscience Methods, 147 (1), 29-35. </li></ul><ul><li>Walsh, R.N., & Cummins, R.A. (1976). The open field test: A critical review. Psychological Bulletin, 83 (3), 482-504 </li></ul><ul><li>Williams, G. C., & Nesse, R. (1991). The Dawn of Darwinian Medicine. The Quarterly Review of Biology, 66 (1), 1-22. </li></ul><ul><li>Zhang, Y.H., Lu, J., Elmquist, J.K., & Saper, C.B. (2003). Specific Roles of Cyclooxygenase-1         and Cyclooxygenase-2 in Lipopolysaccharide-Induced Fever and Fos Expression </li></ul><ul><li>in Rat Brain. The Journal of Comparative Neurology , 463, 3-12. </li></ul>

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