1. The biologic effects of endotoxins in man.

The human being is the most sensitive animal to

bacterial endotoxins. The sensitivity of the various parameters measured revealed that granulocytosis induced by endotoxin is the most sensitive (i.e., requires the smallest dose), fever the next most sensitive, an increase in plasma cortisol the third most sensitive, and the induction of a reproducible growth hormone response the least sensitive. Although many of our studies are descriptive, it is hoped that they will lead to better understanding of some of the pathophysiologic events that accompany gram-negative bacterial infections in man. Finally, when appropriately used, bacterial endotoxins can be useful tools in the diagnosis and management of certain hematologic and endocrinologic disorders of man.

2. Pet Animal and Livestock Endotoxemias and Other Pathophysiological Entities with High
Probability of Being Prevented or Treated by Administration of Compounds Which Inhibit GTPase are the following: Mammalian Gastritis Digestive disorders of the rumen including-Bloat Simple indigestion Grain overload Abomasal disorders Displacement/torsion of the abomasum Impaction of the abomasum Edema disease of swine Colibacillosis of weaned pigs Enteritis of small and large animals Small intestinal obstruction Colon impaction of small animals Intussusceptions Intestinal torsion and volvulus Impaction of the large intestine Intestinal foreign bodies Intestinal incarceration Colitis Colic in horses Salmonellosis/typhoid fever Colibacillosis Diarrhea of newborn animals Chronic diarrhea Toxicosis of chemical and plant origins Gastrointestinal parasites including coccidiosis and sarcosporidiosis Malabosorbtion syndrome Hemorrhagic bowel syndrome

BIOLOGICAL EFFECTS OF SOME BACTERIAL EXOTOXINS WITH ENZYMATIC ACTIVITY

TOXIN (subunit arr)* ENZYMATIC ACTIVITY ADP ribosylates eucaryotic adenylate Cholera toxin (A-5B) cyclase Gs regulatory protein Diphtheria toxin (A/B) ADP ribosylates elongation factor 2

BIOLOGICAL EFFECTS Activates adenylate cyclase; increased level of intracellular cAMP promote secretion of fluid and electrolytes in intestinal epithelium leading to diarrhea Inhibits protein synthesis in animal cells resulting in death of the cells Blocks inhibition of adenylate cyclase; increased levels of cAMP affect hormone activity and reduce phagocytic activity Similar or identical to cholera toxin

ADP ribosylates Pertussis toxin (A-5B) adenylate cyclase Gi regulatory protein E. coli heat-labile toxin LT (A-5B) ADP ribosylates adenylate cyclase Gs regulatory protein

Inactivates the mammalian 60S Glycosidase cleavage of ribosomal subunit and leads to inhibition ribosomal RNA (cleaves Shiga toxin (A/5B of protein synthesis and death of the a single Adenine base susceptible cells; pathology is diarrhea, from the 28S rRNA) hemorrhagic colitis (HC) and/or hemolytic uremic syndrome (HUS) ADP ribosylates PseudomonasExotoxi elongation factor-2 Inhibits protein synthesis in susceptible n A (A/B) analogous to diphtheria cells, resulting in death of the cells toxin Zn++ dependent protease acts on Inhibits presynaptic acetylycholine Botulinum toxin (A/B) synaptobrevin at motor release from peripheral cholinergic neuron ganglioside neurons resulting in flaccid paralysis ++ Zn dependent protease acts on Inhibits neurotransmitter release from Tetanus toxin (A/B) synaptobrevin in central inhibitory neurons in the CNS resulting nervous system in spastic paralysis Metallo protease that cleaves MAPKK Anthrax toxin LF Combined with the B subunit (PA), LF (mitogen-activated (A2+B) induces cytokine release and death of protein kinase kinase) target cells or experimental animals enzymes Cleaves desmoglein 1, a cadherin found in Separation of the stratum granulosum of desmosomes in the the epidermis, between the living layers epidermis and the superficial dead layers. (also a superantigen)

Staphylococcus aureusExfoliatin B