Botulism was described much later than tetanus (Kerner 1817; Midura and Arnon 1976; Pickett et al. 1976), and this delayed recognition is due to its much less evident symptoms, which include a generalized muscular weakness with diplopia, ptosis, dysphagia, facial paralysis, and reduced salivation and lacrimation. The paralysis then progressively descends to affect the muscles of the trunk, including respiratory and visceral muscles. All the symptoms of botulism can be ascribed to the blockade of skeletal and autonomic peripheral cholinergic nerve terminals (Tacket and Rogawski 1989).
The gravity of the illness depends on the amount and type of BoNT, which is usually acquired via the oral route. Death follows the blockade of respiratory muscles, but if ventilated mechanically, the patient will eventually recover completely. In general terms, botulism is much less dangerous than tetanus also because, in most cases, the amount of toxin that reaches the general circulation is not sufficient to block respiration. BoNT/A, /B and /E account for most cases of human botulism, and the disease caused by BoNT/A is more dangerous with symptoms persisting much longer.
The incidence and the types of botulism depend on the occurrence of toxigenic strains of Clostridium botulinum, C. barati, and C. butyrricum in the environment and subsequently in foods, and on the cooking practices. The geographical distribution of the different types of botulism corresponds to the distribution of the different toxinotypes of Clostridium in the environment. Consequently, type E botulism is mainly found in the colder regions of the northern hemisphere, and aquatic animals are usually involved (Hauschild 1993), while types A and B botulism generally occur in the temperate countries. Most of botulism outbreaks are caused by home-prepared or - stored/fermented food contaminated by spores of BoNT producing strains of Clostridium and kept under anaerobic conditions which permit bacterial germination and production of the poison; contamination of foods prepared by food industries is very rare (Hauschild 1993).
A less common form of the disease is that of infant botulism, which follows the ingestion of spores of neurotoxigenic Clostridium that germinate and multiply within the intestinal tract. Rather than a primary intoxication, this disease is an intoxication following a previous infection of the infant's intestinal tract, which lacks the protective bacterial flora of the adult, allowing colonization by Clostridium. It has been estimated that fewer than 100 spores are sufficient to cause such disease (Arnon 1980). The affected infants present constipation, weak sucking, hypotonia, and ptosis. In the more severe cases, the patient becomes lethargic and loses head posture control. The disease progresses to a flaccid paralysis which may extend to respiratory muscles with arrest. Type A toxin is usually associated with more severe diseases and a higher mortality rate than type B or E toxin, and the recovery time is accordingly longer (Arnon 1980). "Wound botulism" following spore contamination of wounds is very rare. On the contrary, animal botulism is rather common, and it can also be caused by BoNT/C and /D.
As a consequence of the fact that a single protein is responsible for all the clinical symptoms of tetanus and botulism, these diseases can be completely prevented by anti-toxin specific antibodies (Galazka and Gasse 1995; Middlebrook and Brown 1995). Toxin neutralizing antibodies can be acquired passively by injection of im-munoglobulins isolated from immunized donors or, actively, as a result of vaccination with toxoids, obtained by treating TeNT or BoNT with formaldehyde (Ramon and Descombey 1925; Galazka and Gasse 1995). Tetanus toxoid is very immuno-genic, and it is used as a standard immunogen in a variety of immunological studies (Corradin and Watts 1995). Antitetanus and antibotulism vaccines based on the recombinant binding domain (Hc) of TeNT and BoNT have been recently developed based on the observation that the majority of protecting antibodies are directed against this part of the molecule (Byrne and Smith 2000).
3.3 Features of Envenoming from Bites of Snakes Producing Venoms Containing Large Amounts ofPLA2 Presynaptic Neurotoxins
At variance from most neurotoxigenic Clostridia, which release only BoNT or TeNT, snake venoms contain a multitude of pharmacologically active molecular components. In general, they can be divided into three classes based on their physiological targets: (1) the neuromuscular system, similarly to BoNTs, (2) the blood coagulation system, and (3) the control of blood pressure (Gutierrez et al. 2006). In the case of many highly poisonous snakes of Asiatic and Australian origin, the major role in envenomation is played by presynaptic neurotoxins endowed with PLA2 activity (SPAN) (Connolly et al. 1995; Prasarnpun et al. 2005). SPANs cause a persistent blockade of neurotransmitter release from peripheral nerve terminals with no evidence of central activities, though they bind to and act on neurons isolated from brain and spinal cord (Kini 1997; Lambeau and Lazdunski 1999; Othman et al. 1982; Rehm and Betz 1982; Rigoni et al. 2004, 2005; Rossetto et al. 2006; Rugolo et al. 1986). Venoms from Elapidae and Hydrophiidae snakes also contain paralytic a-toxins, which act postsynaptically by binding and inhibiting the acetylcholine receptors. In fact, independently on the anatomical site of biting, patients develops symptoms comparable to those of botulism. They are reported to have ptosis, diplopia, ophthalmoplegia, difficulty in swallowing, respiratory paralysis, abdominal pain, and autonomic symptoms. Mechanical ventilation is often required, but most patients recover within days/weeks (Connolly et al. 1995; Kularatne 2002; Prasarnpun et al. 2005; Theakston et al. 1990; Trevett et al. 1995; Warrell et al. 1983).
There is no accurate estimation of the incidence and number of deaths caused by snake bites in the world. It is possible that tens of thousands of individuals die each year following snake envenomation in Asia, which is the most affected area (Gutierrez et al. 2006). The death rate has strongly decreased in Australia following the introduction of first-aid procedures and of anti-venoms animal antisera (Hodgson and Wickramaratna 2002, 2006).
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