Flaccid paralysis in an infant associated with a dirty wound and application of honey.

An infant, who was born preterm at 36 weeks, presented with fever and ulcer at umbilical region which progressed to necrotising fasciitis of anterior abdominal wall. He was treated with intravenous penicillin, intravenous cloxacillin and local application of medicated honey. Subsequently, he required wound debridement. Postoperatively, he required prolonged invasive ventilation due to poor respiratory effort which was associated with hypotonia and areflexia. Nerve conduction study revealed absent responses. The diagnosis of infant botulism was made based on the clinical presentation, nerve conduction study and his clinical progress. Botulinum immunoglobulin was not available. He was treated with intravenous immunoglobulin and oral pyridostigmine. He was successfully extubated after 37 days, and currently the patient is doing well.

Small-molecule quinolinol inhibitor identified provides protection against BoNT/A in mice.

Botulinum neurotoxins (BoNTs), etiological agents of the life threatening neuroparalytic disease botulism, are the most toxic substances currently known. The potential for the use as bioweapon makes the development of small-molecule inhibitor against these deadly toxins is a top priority. Currently, there are no approved pharmacological treatments for BoNT intoxication. Although an effective vaccine/immunotherapy is available for immuno-prophylaxis but this cannot reverse the effects of toxin inside neurons. A small-molecule pharmacological intervention, especially one that would be effective against the light chain protease, would be highly desirable. Similarity search was carried out from ChemBridge and NSC libraries to the hit (7-(phenyl(8-quinolinylamino)methyl)-8-quinolinol; NSC 84096) to mine its analogs. Several hits obtained were screened for in silico inhibition using AutoDock 4.1 and 19 new molecules selected based on binding energy and Ki. Among these, eleven quinolinol derivatives potently inhibited in vitro endopeptidase activity of botulinum neurotoxin type A light chain (rBoNT/A-LC) on synaptosomes isolated from rat brain which simulate the in vivo system. Five of these inhibitor molecules exhibited IC(50) values ranging from 3.0 nM to 10.0 µM. NSC 84087 is the most potent inhibitor reported so far, found to be a promising lead for therapeutic development, as it exhibits no toxicity, and is able to protect animals from pre and post challenge of botulinum neurotoxin type A (BoNT/A).

Infant botulism following honey ingestion.

An apparently well baby girl born at term was presented with signs and symptoms suggestive of acute onset of generalised floppiness at the age of 3 months. Clinically, the baby had lower motor neuron type of muscle weakness; detailed investigation lead to the diagnosis of neuromuscular junction disorder secondary to botulism toxicity. Further tests confirmed the botulism toxicity secondary to honey ingestion. The baby was treated with specific anticlostridium antibodies; she recovered remarkably, now growing and developing normally.

Notes from the field: Botulism caused by consumption of commercially produced potato soups stored improperly--Ohio and Georgia, 2011.

In January and April 2011, CDC provided antitoxin for treatment of two persons with toxin type A botulism associated with consumption of potato soup produced by two companies. On January 28, 2011, an Ohio resident, aged 29 years, was hospitalized after 5 days of progressive dizziness, blurred vision, dysphagia, and difficulty breathing. The patient required mechanical ventilation and botulism antitoxin. On January 18, he had tasted potato soup from a bulging plastic container, noted a bad taste, and discarded the remainder. The soup had been purchased on December 7, 2010, from the refrigerated section of a local grocer, but it had been kept unrefrigerated for 42 days. He was hospitalized for 57 days and then was transferred with residual weakness to a rehabilitation facility.

The anti-botulism triterpenoid toosendanin elicits calcium increase and exocytosis in rat sensory neurons.

Toosendanin, a triterpenoid from Melia toosendan Sieb et Zucc, has been found before to be an effective anti-botulism agent, with a bi-phasic effect at both motor nerve endings and central synapse: an initial facilitation followed by prolonged depression. Initial facilitation may be due to activation of voltage-dependent calcium channels plus inhibition of potassium channels, but the depression is not fully understood. Toosendanin has no effect on intracellular calcium or secretion in the non-excitable pancreatic acinar cells, ruling out general toosendanin inhibition of exocytosis. In this study, toosendanin effects on sensory neurons isolated from rat nodose ganglia were investigated. It was found that toosendanin stimulated increases in cytosolic calcium and neuronal exocytosis dose dependently. Experiments with membrane potential indicator bis-(1,3-dibutylbarbituric acid)trimethine oxonol found that toosendanin hyperpolarized capsaicin-insensitive but depolarized capsaicin-sensitive neurons; high potassium-induced calcium increase was much smaller in hyperpolarizing neurons than in depolarizing neurons, whereas no difference was found for potassium-induced depolarization in these two types of neurons. In neurons showing spontaneous calcium oscillations, toosendanin increased the oscillatory amplitude but not frequency. Toosendanin-induced calcium increase was decreased in calcium-free buffer, by nifedipine, and by transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine. Simultaneous measurements of cytosolic and endoplasmic reticulum (ER) calcium showed an increase in cytosolic but a decrease in ER calcium, indicating that toosendanin triggered ER calcium release. These data together indicate that toosendanin modulates sensory neurons, but had opposite effects on membrane potential depending on the presence or absence of capsaicin receptor/TRPV 1 channel.

The role of a poison control center in identifying and limiting an outbreak of foodborne botulism.

Many poison control centers partner with public health agencies to handle weekend and after-hours consultations and emergencies. This event describes the effective use of poison control center capabilities in identifying and limiting an outbreak of foodborne botulism. On September 8, 2006, the poison control center received a call regarding a man aged 77 years admitted to a hospital neurology service with dysarthria, dysphagia, and weakness. The poison control center was contacted regarding a concern for botulism. Further information revealed that the patient's wife and a friend had similar symptoms and had eaten together on the previous night. All three sought treatment at different hospitals. The poison control center successfully located the other two patients and provided information regarding the treatment of botulism. In addition, the poison control center notified the on-call local public health official and the CDC for the release of botulinum antitoxin. Public health officials were informed of our concerns for a foodborne outbreak given the common meal. Their investigation determined that the source of botulism was carrot juice.

Toosendanin: synthesis of the AB-ring and investigations of its anti-botulinum properties (Part II).

Botulinum neurotoxins (BoNTs) are the etiological agents responsible for botulism, a disease characterized by peripheral neuromuscular blockade and a characteristic flaccid paralysis of humans. The natural product toosendanin, a limonoid, is a traditional Chinese medicine that has reported anti-botulinum properties in animal models. Toosendanin effectively inhibits the biological activity of BoNT/A in neuronal cells at concentrations of 200 nM, and partial inhibition can be observed with concentrations as low as 8 nM. Mechanistically, toosendanin's inhibition is due to prevention of transduction of the BoNT LC through the HC channel. Intriguing questions as to the molecular architecture of toosendanin as related to its anti-botulinum properties have focused our attention on a synthesis of toosendanin's unusual AB-ring, containing a unique bridged hemi-acetal. Within the current work, a synthetic strategy allowing access to the AB-fragment of toosendanin was achieved from a trans-decalin system. In addition, this fragment was examined for its modulation of BoNT/A intoxication in a rat spinal cord cellular assay.

Function-oriented synthesis applied to the anti-botulinum natural product toosendanin.

Botulinum neurotoxins (BoNTs) are the etiological agents responsible for botulism, a disease characterized by peripheral neuromuscular blockade and a characteristic flaccid paralysis of humans. The natural product toosendanin is a traditional Chinese medicine which has been reported to have anti-botulinum properties in animal models. To establish what chemical functionalities are necessary for the anti-botulinum properties found within toosendanin, a study was initiated with the goal of using function-oriented synthesis (FOS) as a strategy to begin to unravel toosendanin's powerful anti-botulinum properties. From these studies a new synthetic strategy is put forth allowing access to a 4-acetoxy CD fragment analogue (14) of toosendanin, which was achieved from mesityl oxide and acetylacetone in 14 steps. Animal studies on this fragment are also reported.

Biological effects of toosendanin, a triterpenoid extracted from Chinese traditional medicine.

Toosendanin (TSN) is a triterpenoid extracted from Melia toosendan Sieb et Zucc, which was used as a digestive tract-parasiticide and agricultural insecticide in ancient China. TSN was demonstrated to be a selective presynaptic blocker and an effective antibotulismic agent. By interfering with neurotransmitter release through an initial facilitation followed by a subsequent depression, TSN eventually blocks synaptic transmission at both the neuro-muscular junction and central synapses. Despite sharing some similar actions with botulinum neurotoxin (BoNT), TSN has a marked antibotulismic effect in vivo and in vitro. Studies suggest that the antibotulismic effect of TSN is achieved by preventing BoNT from approaching its enzymatic substrate, the SNARE protein. It is also found that TSN can induce differentiation and apoptosis in several cell lines, and suppress proliferation of various human cancer cells. TSN inhibits various K(+)-channels, selectively facilitates Ca(2+)-influx via L-type Ca(2+) channels and increases intracellular Ca(2+) concentration ([Ca(2+)](i)). The TSN-induced [Ca(2+)](i) increase and overload could be responsible for the TSN-induced biphasic effect on transmitter release, cell differentiation, apoptosis as well as the cytoxicity of TSN.

Cure of experimental botulism and antibotulismic effect of toosendanin.

Botulinum neurotoxins (BoNTs), a group of bacterial proteins that comprise a light chain disulfide linked a heavy chain, are the most lethal biotoxins known to mankind. By inhibiting neurotransmitter release, BoNTs cause severe neuroparalytic disease, botulism. A series of important findings in the past 10 years which displayed the molecular targets of BoNTs and hence proposed a four-step action mechanism to explain BoNT intoxication greatly advanced the study of antibotulismic drug. In this article, we reviewed these progresses and anti-botulismic compounds found in recent years. These compounds function due to their facilitation on neurotransmitter release or to their interference on the binding, internalization, translocation, and endopeptidase activity of the toxins. Toosendanin is a triterpenoid derivative extracted from a digestive tract-parasiticide in Chinese traditional medicine. Chinese scientists have found that the compound is a selective prejunctional blocker. In spite of sharing some similar action with BoNT, toosendanin can protect botulism animals that have been administrated with lethal doses of BoNT/A or BoNT/B for several hours from death and make them restore normal activity. The neuromuscular junction preparations isolated from the rats that have been injected with toosendanin tolerate BoNT/A challenge. Toosendanin seems to have no effect on endopeptidase activity of BoNT, but blocks the toxin approach to its enzymatic substrate.

Botulismo y toxina botulínica / Botulism and botulinum toxin

El botulismo es una toxi-infección producida por la bacteria anaerobia Clostridium botulinum por medio de una potentísima toxina, la toxina botulínica, de la cual existen ocho serotipos diferentes. Ésta es capaz de provocar en humanos al menos cuatro cuadros clínicos diferentes por bloqueo de la transmisión neuromuscular, y que pueden variar en gravedad desde la casi ausencia de síntomas hasta la muerte por parálisis respiratoria. Paradójicamente, la toxina botulínica se presenta también como un arma terapéutica eficaz y segura en decenas de enfermedades, si bien gran parte de estas potenciales aplicaciones está aún en fase de investigación. (AU)

Preparing for bioterrorism: category A agents.

September 11, 2001, brought the possibility of biologic acts of terrorism against the United States into the national consciousness. As the American people brace themselves for this new threat to the national well-being, clinicians must understand how to prevent, recognize, and treat the biologic agents that could be used in terrorist attacks. This article discusses the most likely biologic agents, including diagnostic laboratory procedures, treatment options, psychological effects, special populations, and reporting requirements.

[A new approach to the prevention and treatment of lesions caused by bacterial toxins: prospects for using inhibitors of ADP ribosylation]. / Novyi podkhod k profilaktike i lecheniiu porazhenii bakterial 'nymi toksinami: perspektivy primeneniia ingibitorov ADF-ribozilirovaniia.

The damaging action of a number of bacterial toxins is determined by their capacity for blocking the specific functions of regulatory proteins of eukaryotic cells by ADP-ribosylation. Experiments, made with the use of type B botulinic toxin and 3,N-butyrylaminobenzamide as an example, have demonstrated that specific ADP-ribosylation inhibitors are capable of making up a new group of highly active antagonists of microbial toxins.