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PubMed1975

A continuing common-source outbreak of botulism in a family.

In December, 1974, three cases of botulism occurred in a family; two were fatal. The first patient died after a 10-day illness without botulism being suspected. 4 days later, after a 2-day illness, the second patient was diagnosed as having botulism after a cardiorespiratory arrest; she died 3 days later. In the third patient, the only symptom was dysphagia. Clostridium botulinum type B was found in stool specimens from all three patients. Home-canned (bottled) mushrooms, which were found to contain C. botulinum type B and its toxin, were believed to be responsible for the outbreak; mushrooms were found at necropsy in the gastrointestinal tracts of both patients who died. Heat treatment of the mushrooms during canning had been inadequate.

Adult↗
PubMedDate not supplied

Development of vaccines for prevention of botulism.

Botulism is a potentially lethal disease caused by one of seven homologous neurotoxic proteins usually produced by the bacterium, Clostridium botulinum. This neuromuscular disorder occurs through an exquisite series of molecular events, ultimately ending with the arrest of acetylcholine release and hence, flaccid paralysis. The development of vaccines that protect against botulism dates back to the 1940s. Currently, a pentavalent vaccine that protects against BoNT serotypes A-E and a separate monovalent vaccine that protects against BoNT serotype F are available as Investigational New Drugs. However, due to the numerous shortcomings associated with the toxoid vaccines, several groups have efforts towards developing next-generation vaccines. Identifying a synthetic peptide that harbors a neutralizing epitope is one approach to a BoNT vaccine, while another employs the use of a Venezuelan equine encephalitis virus replicon vector to produce protective antigens in vivo against BoNT. The strategy used in our laboratory is to design synthetic genes encoding non-toxic, carboxy-terminal fragments of the C. botulinum neurotoxins (rBoNT(H(C))). The gene products are expressed in the yeast, Pichia pastoris, and purified to greater than 98% with yields typically ranging from 200-500 mg per kg of wet cells. Protective immunity to the purified products against high-level challenges of neurotoxin is elicited in mice and in non-human primates. A pre-Investigational New Drug meeting was held with the Food and Drug Administration, and the next milestone for the vaccine candidates will be clinical trials.

Animals↗
PubMed2002

[Botulism: the agent, mode of action of the botulinum neurotoxins, forms of acquisition, treatment and prevention].

The botulinum neurotoxins are produced by anaerobic, spore-forming bacteria belonging to the Clostridium genus. They are synthesised as a single chain protein (150 kDa), which is not or weakly active. The active form results from a proteolysis cleaving the precursor in a light chain (about 50 kDa) and a heavy chain (about 100 kDa), which are linked by a disulfide bridge. The heavy chain is involved in the recognition of a specific neuronal surface receptor and mediates the internalization of the light chain into the cytosol. The light chain is responsible for the intracellular activity. It catalyses the proteolysis of SNARE proteins, which are involved in the exocytosis of synaptic vesicles containing acetylcholine. Hence, the release of acetylcholine at the neuromuscular junction is blocked, leading to a flaccid paralysis. Human botulism, usually type A, B or E, is associated with intoxination, ingestion of preformed toxin in food, with digestive toxi-infection, mainly in newborns (infant botulism), or with wound contamination (wound botulism). The treatment of botulism is usually symptomatic. The specific treatment is based on the serotherapy or on the use of purified specific antibodies. The vaccination against botulism is efficient. However, since the botulinum neurotoxins are widely used for the treatment of numerous dystonias, a generalised vaccination is not conceivable.

Bacterial Vaccines↗
PubMed2004

Uptake of botulinum neurotoxin into cultured neurons.

Botulinum neurotoxins (BoNTs) act within the synaptic terminal to block neurotransmitter release. The toxin enters the neuron by binding to neuronal membrane receptor(s), being taken up into an endosome-like compartment, and penetrating the endosome membrane via a pH-dependent translocation process. Once within the synaptic cytoplasm, BoNT serotypes A and E cleave separate sites on the C-terminus of the neuronal protein SNAP-25, one of the SNARE proteins required for synaptic vesicle fusion. In this study, we measured the effect of brief toxin exposure on SNAP-25 proteolysis in neuronal cell cultures as an indicator of toxin translocation. The results indicate that (1) uptake of both BoNT-A and -E is enhanced with synaptic activity induced by K+ depolarization in the presence of Ca2+ and (2) translocation of BoNT-A from the acidic endosomal compartment is slow relative to that of BoNT-E. Polyclonal antisera against each toxin protect cells when applied with the toxin during stimulation but has no effect when added immediately after toxin exposure, indicating that toxin endocytosis occurs with synaptic activity. Both serotypes cleave SNAP-25 at concentrations between 50 pM and 4 nM. IC50 values for SNAP-25 cleavage are approximately 0.5 nM for both serotypes. Inhibition of the pH-dependent translocation process by pretreating cultures with concanamycin A (Con A) prevents cleavage of SNAP-25 with IC50 values of approximately 25 nM. Addition of Con A at times up to 15 min after toxin exposure abrogated BoNT-A action; however, addition of Con A after 40 min was no longer protective. In contrast, Con A inhibited, but did not prevent, translocation of BoNT-E even when added immediately after toxin exposure, indicating that pH-dependent translocation of BoNT-E is rapid relative to that of BoNT-A. This study demonstrates that uptake of both BoNT-A and -E is enhanced with synaptic activity and that translocation of the toxin catalytic moiety into the cytosol occurs at different rates for these two serotypes.

Animals↗
PubMed2000

An outbreak in Italy of botulism associated with a dessert made with mascarpone cream cheese.

In the late 1996, an outbreak of botulism affected eight young people (age of patients ranged from 6 to 23 years) in Italy. The onset of the illness was the same for all of these patients: gastrointestinal symptoms (nausea and vomiting) followed by neurologic symptoms. The most common neurologic symptoms were dysphagia, respiratory failure (100%), diplopia (87%), dysarthria, ptosis (75%) and mydriasis (50%). All patients required mechanical ventilation. Botulinum toxin was detected from two of respectively five sera and six stool samples analysed, while spores of Clostridium botulinum type A were recovered from all patient' faeces. The epidemiological investigation led to suspect a commercial cream cheese ('mascarpone') as a source of botulinum toxin: indeed, it had been eaten by all the patients before onset of the symptoms, either alone or as the (uncooked) ingredient of a dessert, 'tiramisù'. Botulinum toxin type A was found in the 'tiramisù' leftover consumed by two patients and in some mascarpone cheese samples collected from the same retail stores where the other patients had previously bought their cheeses. A break in the cold-chain at the retail has likely caused germination of C. botulinum spores contaminating the products, with subsequent production of the toxin. One of the patients died, while the others recovered very slowly. Prompt international alerting and recall of the mascarpone cheese prevented the spread of the outbreak due to the wide range of distribution, demonstrating the importance of a rapid surveillance system. None of the people complaining of symptoms after the public alert resulted positive for botulinum spores and toxin.

Adolescent↗
PubMed1998

The detection of a deletion in the type B neurotoxin gene of Clostridium botulinum A(B) strains by a two-step PCR.

Differences between the type B neurotoxin gene sequence of Clostridium botulinum type A(B) and Cl. botulinum type B, including a six nucleotide deletion, were recently proposed as a cause of the lack of expression of this gene in the type A toxigenic strains. A polymerase chain reaction (PCR) based on two sets of primers was designed to investigate the absence of the 6-nucleotide sequence in the apparently unexpressed type B toxin gene of 42 strains of Cl. botulinum type A(B). Thirty-five strains were shown to exhibit a deletion in their type B toxin gene; two strains did not have the deletion and actually produced small amounts of type B toxin when tested by the mouse bioassay. This two-step PCR might be useful for the rapid determination of the presence of the six nucleotide deletion and consequently, whether the type B toxin is likely to be produced.

Animals↗
PubMed1989

Foodborne botulism: an international outbreak.

We report an outbreak of fishborne botulism caused by type E Clostridium botulinum. The eight cases, six in Israel and two in New York City, resulted from the consumption of ribbetz or kapchunka, a freshwater whitefish soaked in brine and air-dried, that was processed commercially in New York. Half the cases were males; the age range was 9 to 77 years. Five of the victims were hospitalized; the oldest died, and two others required ventilatory assistance. Laboratory confirmation of botulism was obtained in three cases. Prolonged lack of refrigeration during transatlantic flight and packaging contributing to an anaerobic environment were felt to be contributing environmental factors in the Israeli cases. Rapid communication and full cooperation between Israeli and US health authorities limited the extent of the outbreak. Despite adequate understanding of how foodborne botulism may be avoided, outbreaks still occur, particularly among people consuming certain high-risk or ethnic foods.

Adolescent↗
PubMed1997

Preventing ptosis after botulinum treatment.

In a series of 33 blepharospasm patients who had the side effect of ptosis following therapeutic botulinum toxin type A (Botox: Allergan, Inc., Irvine, CA, U.S.A.) injection, we administered 41 injections of human botulinum immune globulin (IG) following injections of the toxin to test the dosage and timing of IG injection and its effectiveness in limiting or avoiding ptosis. An IG dose of 3.2 x 10(-3) international units (IU) per unit of Botox was effective in blocking toxin effect when injected into the same tissue site within 4 hours. An IG dose of 1.6 x 10(-2) to 3.2 x 10(-2) into the levator of the eye having more frequent ptosis in 19 patients reduced the incidence of ptosis to 11%. The fellow (control) eye had a ptosis incidence of 37%. No orbital hemorrhage or other adverse effect occurred from the IG or its injection.

Animals↗
PubMed1994

Retrospective study of 108 cases of botulism in Poitiers, France.

Botulism, a food-borne toxin-mediated disease caused by Clostridium botulinum is still a common disease, which is most frequent in the rural environment; 108 cases, 66 males and 42 females, average age 32 years, were recorded from 1965 to 1990 in the infectious disease department of the University Hospital of Poitiers (France). In 83% of patients, the food responsible was home-cured ham. Mean incubation time was 3.4 days; digestive symptoms were observed in 93% of cases, ocular symptoms in 92% and urinary tract dysfunction in 22%. A scale of severity was used to classify the patients into those suffering from severe (6), intermediate (50) and mild (52) forms of the disease. Botulinum toxin type B was found in 36 (52%) of 69 blood samples and in 41 (51%) of 81 samples of the suspected food. From 1965 to 1976, 44 patients were treated with both toxoid and heterologous equine serotherapy. Since 1976, 29 patients have been treated with guanidine hydrochloride (35 mg/kg daily) and 35 patients with guanidine hydrochloride plus heterologous serotherapy. All 108 patients recovered without any sequelae.

Adolescent↗
PubMed1991

Infant botulism with Down syndrome.

A 4-month-old boy with Down syndrome and infant botulism is reported. He was admitted to our hospital with stridor and developed respiratory failure and generalized paralysis. Laboratory examination revealed botulinal toxin type A in his blood and feces. Clostridium botulinum organisms were found in the feces and in the honey which he had been fed. Anti-botulinal toxin was administered on the 10th day of illness. Artificial ventilation was given for 87 days and he survived. This is the 11th known case of infant botulism in Japan. It is possible that other cases remain undiagnosed.

Botulinum Antitoxin↗
PubMed1977

Cultural and physiological characteristics of Clostridium botulinum type G and the susceptibility of certain animals to its toxin.

Strain 89 of Clostridium botulinum type G, isolated by Gimenez and Ciccarelli in 1969, was characterized culturally, biochemically, and toxigenically. It was motile, hemolytic asaccharolytic, weakly proteolytic, lipase and lecithinase negative, and it produced acetic, isobutyric, butyric, and isovaleric acids in peptone-yeast extract-glucose broth. No spores were seen in smears from solid or liquid media. Very low levels of toxin were produced in regular broth cultures, but dialysis cultures yielded 30,000 mouse 50% mean lethal doses (LD50 per kg, orally and subcutaneously, respectively; and for guinea pigs, 10,000 to 20,000 and 100 mouse LD50 per kig, intragastrically and intraperitoneally, respectively.

Animals↗
PubMed1972

Activation of a toxic component of Clostridium botulinum types C and D by trypsin.

When the Stockholm and 468C strains of type C and the 1873 strain of type D Clostridium botulinum are "cured" of their prophages, they simultaneously discontinue the production of their dominant toxins (C(1) and D), but they continue to produce a second antigenically monospecific toxin (C(2)). These "cured" strains of types C and D therefore become indistinguishable with respect to the toxin produced. Fifteen type C cultures received from other laboratories discontinued to produce the dominant toxin when subcultured in broth. The C(2) toxin, however, was produced by eight of these cultures. The C(2) toxin is produced by these cultures as a protoxin that requires treatment with trypsin before its toxicity can be demonstrated. Of the 21 type C cultures that produce the C(1) toxin, 20 were shown to produce the C(2) toxin. The filtrates of 14 of these cultures required trypsin treatment before the C(2) toxicity could be demonstrated. Low levels of toxicity could be demonstrated in the six remaining culture fluids without trypsin; toxicity, however, was increased with trypsin.

Ammonium Sulfate↗
PubMed1972

Clostridium botulinum type F: isolation from venison jerky.

A Clostridium botulinum type F was isolated from the venison jerky responsible for the only type F botulism outbreak reported in the United States. The isolate differed from the prototype Langeland type F strain in being nonproteolytic.

Anaerobiosis↗
PubMed1976

Phage conversion to hemagglutinin production in Clostridium botulinum types C and D.

Five toxigenic strains of Clostridium botulinum types C and D were incubated at 37 degrees C for 7 days in 15 ml of the following media: LYG medium, cooked-meat medium, egg meat medium, and N-Z-amine medium. The supernatants of these cultures were tested for hemagglutinin production with 1% erythrocytes obtained from mice, guinea pigs, chickens, sheep, monkeys, and humans. Four toxigenic strains produced hemagglutinin. The highest hemagglutinin titer was obtained with a combination of human erythrocytes and cultures incubated in LYG medium. When the same experiment was carried out with many nontoxigenic strains, hemagglutination was observed in only one strain, C-N71. Strains producing hemagglutinin also produced phages. The phages obtained from toxin- and hemagglutinin-producing strains converted nontoxigenic indicator strains to produce both toxin and hemagglutinin. The phage obtained from a toxin-positive hemagglutinin-negative strain could only induce cultures to produce toxin, and the phage from a toxin-negative hemagglutinin-positive strain could only induce production of hemagglutinin. These studies suggest that the production of hemagglutinin by C. botulinum types C and D is governed by bacteriophages and that hemagglutinin production can be transmitted separately or concomitantly with toxin production.

Bacteriophages↗
PubMed1985

Purification and characterization of neurotoxin produced by Clostridium botulinum type C 6813.

The toxin produced by Clostridium botulinum type C 6813 (C-6813) was purified 1,009-fold from the culture supernatant in an overall yield of 30%. The specific toxicity was 1.1 X 10(7) mouse minimum lethal doses per mg of protein. The toxin had a molecular weight of 144,000, composed of the light and heavy chains with molecular weights of 52,000 and 92,000, respectively, linked by one or two disulfide bond(s). The purified C-6813 toxin heavy and light chains reacted strongly with anti-type D heavy chain immunoglobulin G and anti-type C1 light chain immunoglobulin G, respectively. The amino acid compositions of C-6813 toxin heavy and light chains were more similar to those of type D heavy chain and type C1 light chain than to those of type C1 heavy chain and type D light chain, respectively. These results suggest that in the toxin produced by the type C strain at least two subtypes exist.

Amino Acids↗