Toxins persistency

G-protein a-subunits also possess specific residues that can be covalently modified by bacterial toxins. Cholera toxin catalyzes the transfer of ADP-ribose moiety of NAD to a specific arginine residue in certain a-subunits, whereas pertussis toxin ADP-ribosylates those a-subunits that contain a specific cysteine residue near the carboxy-terminus. Modification of the a-subunit by cholera toxin persistently activates these protein by inhibiting their GTPase activity, whereas pertussis toxin inactives Gia protein and thereby results in the uncoupling of receptor from the effector. G-protein a-subunits are regulated by covalent modifications by fatty acids myristate and palmate. These lipid modifications serve to anchor the subunits to the membrane and increase the interaction with other protein and also increase the affinity of the a-subunit for 3y. In this regard, the myristoylation of Gia is required for adenylyl cyclase inhibition in cell-free assay (Taussig et al. 1993). 

While scant literature is available on persistence and distribution after inhalation exposure, several studies have evaluated the systemic behavior of parenterally administered toxins. One group investigated toxin persistence in serum and tissue distribution in white mice following intravenous (IV) administration of 1,000 lethal doses of S-labeled type B toxin (Pak and Bulatova, 1962). Mice were sacrificed at 20, 60, and 150 min after toxin administration, and blood and tissues were harvested for toxin distribution analysis. These mice showed symptoms of severe intoxication, including atypical breathing patterns and paralysis, at 150 min post-exposure. Toxin levels (as determined by... 

Somewhat slower kinetics for toxin clearance from the circulation were observed in dogs following parenteral [IV, IP, or intramuscular (IM)] exposure to type A toxin (House et al, 1964). Serum toxin persistence was evaluated in mongrel dogs receiving 8,000 to 10,000 mouse units/kg of type A toxin. Peak serum toxin levels were detected 5 h after IP administration (13% of injected dose), 12 h after IM administration (9% of injected dose), and within only 3 min after IV administration (79% of injected dose) (House et al., 1964). The relative clearance kinetics were slower after IM and IP exposure than for IV administration, as serum toxin levels were identical 22 h after injection via all three rounds (approximately 6% of injected dose). Some serum toxin activity could be detected by the mouse lethality assay for 2 to 4 days after parenteral administration. Serum toxin patterns were also evaluated in rhesus monkeys following IV administration of type A toxin (Stookey et al., 1965). Serum toxin levels dropped by about 50% of maximum within 16 to 24 h after IV injection, and previous exposure did not affect toxin clearance rates after the administration of subsequent doses. 

Since 1996, mussels produced in Ireland have resulted in a number of AZP incidents. In 1997, cases of contamination recurred in the Arramnore Island region of Donegal, Northwest Ireland. Mussels harvested in Ireland have caused human intoxication in other European countries. Mussels originating from Arramnore Island caused AZP in an estimated 20-24 people in Arramnore, Ireland in September/October 1997. The symptoms included nausea, vomiting, and diarrhea. AZA-1, AZA-2, and AZA-3 were identified in samples. After the initial intoxication in Arramnore Island and Killary Harbor, the toxin persisted for a further 7-8 months. Mussels traced to Clewe Bay, Ireland, caused AZP in ten people in Ravenna, Italy in September 1998. About the same time, AZP occurred in France in 20-30 people, which was traced to scallops (Pecten maximus) from Bantry Bay, Ireland. The last recorded incident of AZP traced to Irish shellfish occurred in the United Kingdom in... 

This chapter is divided into seven main sections. The first of these sections is focused on technological contaminants, namely heterocyclic amines, acrylamide, furan, chloropropanok and their fatty acid esters, polycycKc aromatic hydrocarbons, monocyclic aromatic hydrocarbons, nitroso compounds, and ethyl carbamate. Other sections deal with microbial toxins (mycotoxins and bacterial toxins), persistent organohalogen contaminants (such as polychlorinated biphenyls, dibenzodioxins and dibenzofurans), chlorinated ahphatic hydrocarbons, pesticides (persistent chlorinated hydrocarbons and modem pesticides), veterinary medicines and contaminants from packaging materials. Presented for each of these contaminants are structures, properties, occurrence and the main sources of dietary intake, mechanisms of formation, possibilities of food contamination, prevention and mitigation and health and toxicological evaluations. 

Toxin Persistence in Circulation and Transit to Target Tissues... 

Somewhat slower kinetics for toxin clearance from the circulation were observed in dogs following parenteral [IV, i.p., or intramuscular (i.m.)] exposure to type A toxin (House et al., 1964). Serum toxin persistence was evaluated in mongrel dogs receiving 8,000-10,000 mouse units/kg of type A toxin. Peak serum... 

The plant s product was hexachlorophene, a bactericide, with trichlorophenol produced ns an intermediate. During normal operation, a very small amount of TCDD (2,3,7,8 telrachlomdib zoparadioxin) is produced in the reactor as an undesirable side product. TCDD is perhaps the most ]in(enl toxin known to man. Studies have shown TCDD to be fatal in doses as small as lE-9 times die body weight, it insolubility in water makes decontamination very difficult. Nonlethal doses of TCDD result in chloracne, an acne-like disea.se that can persist for several years. 

Research in this area advanced in the 1970 s as several groups reported the isolation of potent toxins from P. brevis cell cultures (2-7). To date, the structures of at least eight active neurotoxins have been elucidated (PbTx-1 through PbTx-8) (8). Early studies of toxic fractions indicated diverse pathophysiological effects in vivo as well as in a number of nerve and muscle tissue preparations (reviewed in 9-11). The site of action of two major brevetoxins, PbTx-2 and PbTx-3, has been shown to be the voltage-sensitive sodium channel (8,12). These compounds bind to a specific receptor site on the channel complex where they cause persistent activation, increased Na flux, and subsequent depolarization of excitable cells at resting... 

The lipid-soluble toxins (veratridine, batrachotoxin, aconitine, grayanotoxins). These toxins cause persistent activation of Na channels, i.e., their permanent opening and hence membrane depolarization 56-58). 

Denileukin diftitox is a combination of the active sections of interleukin 2 and diphtheria toxin. It binds to high-affinity interleukin 2 receptors on the cancer cell (and other cells), and the toxin portion of the molecule inhibits protein synthesis to result in cell death. The pharmacokinetics of denileukin diftitox are best described by a two-compartment model, with an a half-life of 2 to 5 minutes and a terminal half-life of 70 to 80 minutes. Denileukin diftitox is used for the treatment of persistent or recurrent cutaneous T-cell lymphoma whose cells express the CD25 receptor. Side effects include vascular leak syndrome, fevers/chills, hypersensitivity reactions, hypotension, anorexia, diarrhea, and nausea and vomiting. 

EAggEC children in the developing world 20-48 h persistent FliC - inflammation EAST-1 - guanylate cyclase -t secretion heat-labile toxin Ca2+-dependent actin phosphorylation cytoskeletal damage Pet - histopathologic effects on human intestinal mucosa... 

Toxins have also been micropulverized and microencapsulated to facilitate their dispersal and increase their persistency. Color and other physical properties of the toxin may be affected by these modifications. 

Polyclonal antibody preparations have been used for several decades to induce passive immunization against infectious diseases and other harmful agents, particularly toxins. The antibody preparations are usually administered by direct i.v. injection. While this affords immediate immunological protection, its effect is transitory, usually persisting for only 2-3 weeks (i.e. until the antibodies are excreted). Passive immunization can be used prophylactically (i.e. to prevent a future medical episode) or therapeutically (i.e. to treat a medical condition that is already established). An example of the former would be prior administration of a specific anti-snake toxin antibody preparation to an individual before they travel to a world region in which these snakes are commonly found. An example of the latter would be administration of the anti-venom antibody immediately after the individual has experienced a snake bite. 

The ultimate localization of LC depends on toxin type, with, for example, type A residing near the plasma membrane and type E remaining in the cytosol, a phenomenon that may explain the differential stability of the toxin isoforms and the persistence of their action. Nevertheless, the LC fragment is always effectively sequestered from the degradative cycle of the terminal. Tyrosines in both LC and HC may be phosphorylated by Src (see Ch. 24), enhancing the stability and proteolytic activity of LC. 

Signs and Symptoms From three to six hours after aerosol exposure, sudden onset of chills, fever, headache, pain in one of more muscles, and nonproductive cough. Some patients may develop shortness of breath and retrostenal (situated or occurring behind the sternum) chest pain. Fever may last two to five days, and cough may persist for up to four weeks. Patients may also experience nausea, vomiting, and diarrhea if they swallow toxin. Higher exposure levels can lead to septic shock and death. 

Defensive Measures Good personal hygiene, physical conditioning, wearing protective mask, and practicing good sanitation. Mycotoxin-induced disease is not contagious, but the stability of this toxin in the environment is quite persistent. 

Infection 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body s defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]... 

Proleukin is a recombinant form of IL-2. It is approved for the treatment of malignant melanoma and renal cell cancer. Ontak (denileukin diftitox) is a fusion protein for the treatment of persistent or recurrent T-cell lymphoma. Activated T cells express lL-2 receptors. Ontak has a fragment that binds to the IL-2 receptor while the other part presents a diphtheria toxin to kill the activated T cell. 

Red tides (and some with other colors as well) occur with some regularity in certain coastal waters of New England, Alaska, California, and several other areas. If it is the type of tide that can produce PSP or other toxins, public health officials typically quarantine affected areas to prevent harvesting of shellfish. In some areas of the Gulf of Alaska, large reservoirs of shellfish cannot be used as food because of a persistent PSP problem. 

Substitution, rather than risk management is therefore essential. Chemicals identified as of very high concern, e.g. carcinogens, reproductive toxins, those that persist and bioaccumulate in the environment and affect the hormone system, should be targeted for substitution based on their intrinsic hazards. 

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