1. FeverFever

2. Regulation mode of normal body temperature Preoptic anterior hypothalamus, POAH hypothalamus, POAH Set-point ， 37 ℃ Thermal receptor Heat productionHeat dissipation

3. Elevation of body temperature physiological elevationphysiological elevation Pathophysiological elevationPathophysiological elevation fever fever hyperthermia hyperthermia

4. An elevation of body temperature that exceeds the normal daily variation and occurs in conjunction with an increase in the hypothalamic set point----fever Fever and hyperthermia Fever due to a disturbance of thermal regulatory control----hyperthermia For example: ● ● excessive heat production (vigorous exercise, reaction to some anesthetics) ● ● decreased dissipation (dehydration) ● loss of regulation (hypothalmic injury) ● ● excessive heat production (vigorous exercise, reaction to some anesthetics) ● ● decreased dissipation (dehydration) ● loss of regulation (hypothalmic injury)

5. Etiology and Mechanism of Fever

6. Development of fever Macrophage, monocyte, lymphocyte, etc. Endogenous pyrogen Thermoregulatory Centre fever Mediators in regulation of body temperature Rise in set point Pyrogenic activator

7. Pyrogenic activator 1 ． Exogenous pyrogen 1 ． Exogenous pyrogen bacteria bacteria virus virus other microorganism other microorganism 2. internal metabolic product 2. internal metabolic product antigen-antibody complex antigen-antibody complex steroid steroid inflammatory substance inflammatory substance A substance that can manufacture and release endogeneous pyrogen which produces a fever.

8. Exogenous pyrogen 1. Gram-negative bacterium 1. Gram-negative bacterium Lipoplysaccharide,LPS Lipoplysaccharide,LPS Endotoxin,ET Endotoxin,ET structure of ET structure of ET pyrogenic and toxic substance----lipid A pyrogenic and toxic substance----lipid A 。 LPS---strong heat resistance which allows bacteria to endure 160 ℃ dry heat for about 2 hours heat for about 2 hours。

9. 2. gram-positive bacterium engulfed by macrophages ； engulfed by macrophages ； exogenous toxin （ enterotoxin 、 erythogenic toxin, diphthera toxin ） exogenous toxin （ enterotoxin 、 erythogenic toxin, diphthera toxin ） peptide polysaccharide peptide polysaccharide Exogenous pyrogen 3. Virus and other microorganism 1. pyrogen of virus related with lipoprotein, hemagglutinin within the envelope ； 1. pyrogen of virus related with lipoprotein, hemagglutinin within the envelope ； 2. pyrogens of fungus 、 Spirochaeta 、 Chlamydia 、 plasmodium may be considered to be LPS 2. pyrogens of fungus 、 Spirochaeta 、 Chlamydia 、 plasmodium may be considered to be LPS

10. Pyrogenic activator — internal metabolic product 1. Ag-Ab complex activation of pyrogenic cells 。 activation of pyrogenic cells 。 2. Steroid and inflammatory Testosterone’s metabolic intermediate （ etiocholanolone ） Testosterone’s metabolic intermediate （ etiocholanolone ） Uric Acid Crystals Uric Acid Crystals

11. Development of fever endogenous pyrogenic cells Endogenous pyrogen Nerve center fever Mediators in regulation of body temperature Rise in set point Pyrogenic activator

12. Endogenous Pyrogen Source of EP monocytes and macrophages ： blood mononuclear cell 、 hepatic stellate cells 、 pulmonary alveolar macrophage 、 peritoneal macrophage monocytes and macrophages ： blood mononuclear cell 、 hepatic stellate cells 、 pulmonary alveolar macrophage 、 peritoneal macrophage Cancer cell ： hodgkin cancer cell 、 leukemia cell 、 renal carcinoma cell Cancer cell ： hodgkin cancer cell 、 leukemia cell 、 renal carcinoma cell other cells ： lymphocytes 、 fibroblast 、 endothelial cells other cells ： lymphocytes 、 fibroblast 、 endothelial cells Endogenous pyrogenic cells A fever-inducing substance (protein) produced by cells of the host body, such as leukocytes and macrophages

13. Types of EP （ 1 ） IL-1 (Interleukin-1) mainly from monocytes and macrophages mainly from monocytes and macrophages （ 2 ） IL-6 (Interleukin-6) mainly from monocytes fibroblasts and TB lymphocytes mainly from monocytes fibroblasts and TB lymphocytes （ 3 ） TNF (Tumor necrosis factor) TNF-  、 TNF-  TNF-  、 TNF-  rTNF used for treatment during the stage I of tumor, rTNF used for treatment during the stage I of tumor, however with side effect “ fever ” to the patients however with side effect “ fever ” to the patients （ 4 ） IFN (Interferon) IFN-  with strong pathogenicity IFN-  with strong pathogenicity （ 5 ） Macrophage inflammatory protein-1 （ MIP-1 ） （ 5 ） Macrophage inflammatory protein -1 （ MIP-1 ）

14. Site affected by EP ： Advanced thermoregulator centre- Preoptic anterior hypothalamus （POAH） Lower thermoregulator centre- Lower thermoregulator centre- Medulla oblongata、pons、 mesencephalon、spinal cord Pyrogenic activator Macrophage, monocyte, lymphocyte, etc. Endogenous pyrogen Thermoregulatory Centre fever Mediators in regulation of body temperature Rise in set point

15. EP ’ s ways of affecting nervous system （ 1 ） blood-brain barrier IL-1, IL-6, TNF through saturable transport system IL-1, IL-6, TNF through saturable transport system infilterating to the brain from choroid plexus infilterating to the brain from choroid plexus （ 2 ） organum vasculosum laminae terminalis (OVLT) OVLT: the blood-brain barrier’s weakest site comprising OVLT: the blood-brain barrier’s weakest site comprising fenestrated capillary with high permeability fenestrated capillary with high permeability （ 3 ） indirect regulation through vagus nerve EP conduct impulse to the brain by stimulating vagus nerve. EP conduct impulse to the brain by stimulating vagus nerve.

16. Mediators of positive regulation 3. CRH （ Corticotrophin releasing hormone ） 3. CRH （ Corticotrophin releasing hormone ） 2. cAMP （ Cyclin adenosine monophosphate ） 2. cAMP （ Cyclin adenosine monophosphate ） cAMP, second messager cells ， regultion of cellular function and synaptic transmission in POAH neurons ， positive regulation of body temperature 。 cAMP, second messager cells ， regultion of cellular function and synaptic transmission in POAH neurons ， positive regulation of body temperature 。 1. PGE

17. 4. Na + /Ca 2+ ratio 4. Na + /Ca 2+ ratio ＊ Na + /Ca 2+ ratio ↑ elevated thermoregulation ＊ Na + /Ca 2+ ratio ↑ elevated thermoregulation ＊ ventricle[Ca 2+ ] ↑ limit EP and cAMP in cerebrospinal fluid ↑ ＊ ventricle[Ca 2+ ] ↑ limit EP and cAMP in cerebrospinal fluid ↑ EP PGE 2 ↑ Na + /Ca 2+ ratio ↑ cAMP ↑ elevated thermoregulation ↑ EP PGE 2 ↑ Na + /Ca 2+ ratio ↑ cAMP ↑ elevated thermoregulation ↑ 5. NO 5. NO ＊ new type of neurotransmitter ＊ new type of neurotransmitter ＊ mechanism ① act on POAH 、 OVLT ＊ mechanism ① act on POAH 、 OVLT ② stimulate metabolism of brown fat to produce heat ② stimulate metabolism of brown fat to produce heat ③ inhibit negative regulation ③ inhibit negative regulation Mediators of positive regulation

18. 3. A1(annexin A1) the working together of positive and negative regulation to produce heat rise in the course of fever the working together of positive and negative regulation to produce heat rise in the course of fever 2. α-melanocyte stimulating hormone,α-MSH decomposition product of adrenocorticotropic hormone ， highly effective in reducing temperature Mediators of negative regulation 1. Arginine vasopressin, AVP AVP ↑ VSA 、 MAN EP ↓ PO/AH temperature ↓ EP ↓ PO/AH temperature ↓ OVLT cap permeability ↓

19. Action mode of EP EP Positive regulation center POAH Negative regulation center VSA,MAN Elevated set point CRH↑ cAMP↑ PGE2↑ Ca2+↓ ↑AVP ↑α-MSH ↑Ca2+ Ventral Septal Area Medical Amygdaloid Neuleus

20. The phase of fever Ⅰ.feverscence period Ⅱ.fastigium Ⅲ.defeverscene period ⅠⅡⅢ

21. phasecharacteristics Clinical manifestations Onset of fever Set point core temperature lower than the set point Dissipation < production Pale skin ， chilly ， shiver Persistent of fever Core temeprature meets set point Dissipation = production rubefaction ， dry skin ， hot Subsidence of fever Set point normal set point Dissipation > production Heavy perspiration 1.Metabolic features and clinical manifestations

22. ■ cardiovascular ： heartbeat, blood pressure ■ respiratory: fever, blood temperature, metabolism, acid production, metabolism, acid production, respiration frequency respiration frequency ■ digestive ： appetite ， digestion ■ CNS: headache, illusion, febrile convulsion 2.Changes in physiological functions

23.  Anti-infection inactivation of some heat-sensitive pathogenic microorganism like streptococcus, enhancement of the ability of some immune cells like human lymphocytes, while reduced function of some immune cells like NK cells  Cancer cells. to some extent, EP could inhibit cancer cells growth.  Acute phase response definition ： a series of reactions against injury caused by bacteria infection and tissue damages, including increased acute phase proteins and changes in microelements of blood plasma and white cells 3.Changes in immune systems

24. Prevention and treatment 1. Primary affection 2. Basic treatment of fever 3. Cases in need of treatment in time 1. high fever (> 40 ℃ ) 1. high fever (> 40 ℃ ) 2. patients with heart disease 2. patients with heart disease 3. pregnant women 3. pregnant women 4. headache, disturbance of consciousness, infantile convulsion 4. headache, disturbance of consciousness, infantile convulsion Cases need emergency treatment

25. drugs Chemicals like salicylic acid Treament Physical measures Herbal drugs Steroids like glucocorticoids