1. Chapter 5 Fever Pain of China in 2003, difficulty to forget forever Zhao Mingyao zzu

2. Child's temperature depends on where it is measured. Method Temperature equal or higher than Armpit37.3° C Oral37.5° C Ear (tympanic)38.0° C Rectal38.0° C

3. fever means enhance of body temperature?

4. Physiological ~ Pathological ~ Hyperthermia Fever Body T↑ Enhance of body temperature 3 types 36 ℃ 40 ℃

5. Hyperthermia due to a disturbance of thermal regulatory control excessive heat production decreased dissipation loss of regulation

6. Fever Definition a regulatory body temperature elevation response to the pyrogen, it is induced by an upward shift of the set-point in thermoregulatory center

7. 37 ℃ Set point BT normal Pyrogen affected body Fever happened Fever

8. Hyperthermia Fever 1. Cause body or environment changes pyrogens 2. Set-point unchanged or damaged, up regulating or effector or gains fails 3. Body T very high level higher level 4. Treatment water-alcohol bathing antipyretics and eliminate the cause The Comparison between Hyperthermia and Fever

9. Section 1 Regulation of normal body temperature

10. hypothalamus Set point 37 ℃ effectors Heat production Heat loss Regulation of body T WSN CSN Heat ++++ cold ++++ Body T 37 ℃

11. Section 2 Etiology Infectious factors Noninfectious factors

12. Infective fever Metabolites( pyrogens) from microorganism Most common causes (50%~60%) Bacteria : (43%) Viral pyrogens: (6%)

13. Non-infective fever Absorption of necrotic substances: cell necrosis Allergy ： Antibiotics (Ag + Ab + C)

14. Section 3 Pathogenesis of fever Pyrogens: Substances that can cause fever Either exogenous ~ or endogenous ~(EP)

15. 1. Exogenous Pyrogens (1)From outside the host Majority are microorganism G - : endotoxin (LPS) G + : lipoteichoic acid peptidoglycan

16. Exogenous Pyrogens (2)Others (endogenous products) complement products steroid hormone metablites ( mesostate) --- --- etiocholanolone Ag + Ab + C

17. (3) Features of Exogenous Pyrogens Most ： with high molecule weight Could not penetrate blood-brain barrier

18. 2. Endogenous Pyrogen (1)Features of EP In response to invasive stimuli: Produced by the host, cells of immune system Designated “cytokines”

19. MW: small, less than 20 000 peptide sensitive to heat, 56 ~ 70 ℃, 30 min, deactivation sensitive to enzyme acting site in brain Features of EP

20. monocyte macrophage lymphocyte endothelium starlike cell neutrophil tumor cell glial mesenchymal cells (2) EP producing cells

21. Production of EP

22. Determined: IL-1 TNF IFN IL-6 MIP-1 ( macrophage inflammatory protein-1 ) Related: ciliary neurotrophic factor, endothelin, IL-8, IL-2(?) (3)Kinds of EP

23. Bacteria provoke release of IL-1 Viral proteins stimulate IFN Total tendency

24. (4) LPS trigger EP-releasing from cell Activator + receptor （ /Toll-like receptor ， TLR ）  signal transduction system  nuclear transcription(NF-κB)  expression of cytokine gene  EP ↑

25. Section 4 Thermoregulation of fever 1. Thermoregulation center Positive~: preoptic anterior hypothalamus (POAH); organum vasculosum laminae terminalis ( OVLT) Negative~ : ventral septal area (VSA) medial amydaloid nucleus(MAN)

26. 2.Routes of peripheral signals into thermoregulation center

27. (1) chiasma of optic nerve OVLT area EP MΦ POAH neuron EP Supraoptic recess third ventricle of brain Indirective action of EP OVLT neuron

28. Directive action of EP(2) OVLT area EP chiasma of optic nerve POAH neuron EP EP EPEP Supraoptic recess third ventricle of brain

29. Kuffer cell Vagal nerve brain ipIL-1 ivLPS fever IL-R rich Liver If cut off (3) EP stimulating Hepatic Vagal Nerve

30. 3. Central mediators of fever (1) the positive ~ (2) the negative ~ hyperthermic ceiling

31. Regulatory mediators Positive : PGE, CRH, NO, cAMP, Na + /Ca 2+ ect Negative : AVP,α-MSH, lipocortin-I ect

32. CRH  EP   PGE   Hypothalamus Na + /Ca 2+  cAMP  NO  Febrile centric regulatory mediators

33. Infection noninfection Exogenous pyrogens EP-produced Cells (MO/MΦ etc.. ) EP (Pyrogenic cytokines) Circumventricular organs (OVLT) POAH VSA(MAN) Central Chemical Febrile Mediators +? ﹣ ? Elevated set-point Heat loss↓ Heat Conservation↑ Fever Steps in pathogenesis of fever

34. Section 5 Effect of fever on body

35. 1. Pathogenesis of sign and symptom during fever Base on: Directive heat stimulation Sympathetic nerve system +++ Metabolism: synthesize↓ decompose↑ ， but katolysis Cytokines:

36. Heat production/conservation shivering dermal vasoconstriction goose skin Heat loss sweating dermal vasodilation Heat metabolism in fever

37. Goose Skin Goose skin

38. 2. Periods of fever (1)fervescence ~ (2)persistent febrile ~ (3)defervescence ~

40. Clinical manifestation The grade of fever Low grade fever: 37.3~38 o C Moderate fever: 38~39 o C High fever: 39.1~41 o C Hyperthermia fever: >41 o C

41. (3)The biological roles of fever beneficial harmful

42. Benefits of Fever kills and limits microorganisms decrease [iron, zinc, and copper] s lysosomal breakdown and autodestruction of cells increases lymphocytic transformation and motility of phagocytes

43. Harmfulness of Fever Metabolism: Function: Structure:

44. Section 6 Prevention and treatment

45. How to treat fever 1. Remove causes 2. Under the status of heart disease, >40C, CNS symptom 3. Antipyretics: aspirin---PGE GC----NF-κB, stabilize phagocyte membrane 4. Physical method: ice water or alcohol sponging

46. 36 ℃ 40 ℃ Thanks !