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PubMed1993

Botulinum neurotoxin C1 blocks neurotransmitter release by means of cleaving HPC-1/syntaxin.

The anaerobic bacterium Clostridium botulinum produces several related neurotoxins that block exocytosis of synaptic vesicles in nerve terminals and that are responsible for the clinical manifestations of botulism. Recently, it was reported that botulinum neurotoxin type B as well as tetanus toxin act as zinc-dependent proteases that specifically cleave synaptobrevin, a membrane protein of synaptic vesicles (Link et al., Biochem. Biophys. Res. Commun., 189, 1017-1023; Schiavo et al., Nature, 359, 832-835). Here we report that inhibition of neurotransmitter release by botulinum neurotoxin type C1 was associated with the proteolysis of HPC-1 (= syntaxin), a membrane protein present in axonal and synaptic membranes. Breakdown of HPC-1/syntaxin was selective since no other protein degradation was detectable. In vitro studies showed that the breakdown was due to a direct interaction between HPC-1/syntaxin and the toxin light chain which acts as a metallo-endoprotease. Toxin-induced cleavage resulted in the generation of a soluble fragment of HPC-1/syntaxin that is 2-4 kDa smaller than the native protein. When HPC-1/syntaxin was translated in vitro, cleavage occurred only when translation was performed in the presence of microsomes, although a full-length product was obtained in the absence of membranes. However, susceptibility to toxin cleavage was restored when the product of membrane-free translation was subsequently incorporated into artificial proteoliposomes. In addition, a translated form of HPC-1/syntaxin, which lacked the putative transmembrane domain at the C-terminus, was soluble and resistant to toxin action. We conclude that HPC-1/syntaxin is involved in exocytotic membrane fusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Edrophonium responsiveness not necessarily diagnostic of myasthenia gravis.

Uneqivocally positive edrophonium tests, both clinically and electrophysiologically, were observed in a classic case of the Lambert-Eaton myasthenic syndrome. A review of the literature revealed that a positive edrophonium response has been reported in a majority of cases of myasthenia gravis (MG) and overlap myasthenic syndrome and in some cases of the Lambert-Eaton myasthenic syndrome, botulism, congenital myasthenic syndrome, drug-induced myasthenic syndrome, the Guillain-Barre syndrome, and amyotrophic lateral sclerosis. From this, we conclude that an unequivocally positive edrophonium test alone is not necessarily diagnostic of MG and that the diagnosis of MG should be based on the clinical features together with edrophonium-responsiveness and other laboratory findings.

Edrophonium↗
PubMed1995

Type A and B neurotoxin genes in a Clostridium botulinum type AB strain.

The genetic structure of neurotoxin genes in a Clostridium botulinum strain producing both type A and B neurotoxins (type AB) was investigated. Analyses by polymerase chain reaction (PCR) using type-specific primers corresponding to the coding regions for N-terminals of light-chains and C-terminals of heavy-chains of type A and type B neurotoxins, and Southern hybridization of total DNA showed that the type AB strain I.P.7212 carries at least one copy each of type A and B neurotoxin genes. Partial nucleotide sequences obtained by direct sequencing of the PCR products indicate that the type A and B genes carried by this strain are not classical type A and non-proteolytic type B genes, but are similar to the type A gene present in a strain which had caused infant botulism in Kyoto and the type B gene present in a proteolytic type B strain.

Base Sequence↗
PubMed1994

Clostridial neurotoxins as tools to investigate the molecular events of neurotransmitter release.

The clostridial neurotoxins responsible for tetanus and botulism are eight different proteins, composed of two disulfide-linked polypeptide chains. They bind specifically to the presynaptic membrane via the heavy chain, while the light chain enters the cytosol of the neurons, where it displays a zinc-endopeptidase activity directed to proteins of the neuroexocytosis apparatus. Tetanus neurotoxin and botulinum neurotoxin serotypes B, D, F and G cleave specifically and at single different peptide bonds VAMP/synaptobrevin, a component of small synaptic vesicles. In contrast, the other neurotoxins catalyze the hydrolysis of proteins of the presynaptic membrane. Serotypes A and E of botulinum neurotoxin cleave SNAP-25, at different sites located within the carboxyl-terminus, while the specific target of serotype C is syntaxin.

Animals↗
PubMed1995

Processing of tetanus and botulinum A neurotoxins in isolated chromaffin cells.

Tetanus and botulinum A neurotoxins were introduced into the cytosol of chromaffin cells by means of an electric field in which the plasma membrane is forced to form pores of approximately 1 micron at the sites facing the electrodes. As demonstrated by electron microscopy, both [125I] and gold-labelled tetanus toxin (TeTx) diffuse through these transient openings. Dichain-TeTx, with its light chain linked to the heavy chain by means of a disulfide bond, causes the block of exocytosis to develop more slowly than does the purified light chain. The disulfide bonds, which in both toxins hold the subunits together, were cleaved by the intrinsic thioredoxin-reductase system. Single chain TeTx, in which the heavy and light chains are interconnected by an additional peptide bond, was far less effective than dichain-TeTx at blocking exocytosis, which indicates that proteolysis is the rate-limiting step. The toxins were degraded further to low-molecular weight fragments which, together with intact toxins and subunits, were released by the cells. The intracellular half-life of [125I] dichain-TeTx was approximately three days. The number of light-chain molecules required to maintain exocytosis block in a single cell, as calculated by two different methods, was less than 10. The long duration of tetanus poisoning may result from the persistence of intracellular toxin due to scarcity of free cytosolic proteases. This may also hold for the slow recovery from botulism.

Adrenal Medulla↗
PubMed1984

[Gunshot injuries in peacetime and their therapy].

Between 1976 and 1982 46 patients with gunshot injuries (43 m., 3 f.) were seen at the University of Heidelberg Department of Surgery. Frequent causes of injury in 42 adults (40 m., 2 f.) and 4 children (3 m., 1 f.) were suicide attempts (19) and carelessness in the handling of shotguns (11). Criminal offence was related to nine injuries; no retrospective classification of the event causing the injury was possible in further seven cases. Affected in descending order of frequency were brain and lung (10 each), soft tissue of thigh (9), intraabdominal organs (5), heart (4), liver and bone (3 each), blood vessels (2) and facial skull, penis, buttock, neck and mediastinum (1 each). Six patients suffered from combined injuries, in three cases a combined abdomino-thoracic injury was seen. Whilst suicidal injuries of the skull are related to poor prognosis, other peacetime gunshot wounds are less problematic when compared to military gunshot wounds due to the lower speed of the projectiles. Therapeutic procedures follow the general rules of open treatment of injuries including prophylaxis against tetanus and botulism as well as systemic antibiotic therapy. In general abdominal and abdomino-thoracic gunshot wounds as well as vascular injuries require immediate surgical procedure. In isolated thoracic injuries a conservative approach may be justified depending on the situation. The same rule applies to fractures caused by gunshots.

Abdominal Injuries↗
PubMedDate not supplied

DNA vaccination using the fragment C of botulinum neurotoxin type A provided protective immunity in mice.

Botulinum neurotoxin (BoNT) is one of the most toxic substances known to produce severe neuromuscular paralysis. The currently used vaccine is prepared mainly from biohazardous toxins. Thus, we studied an alternative method and demonstrated that DNA immunization provided sufficient protection against botulism in a murine model. A plasmid of pBoNT/A-Hc, which encodes the fragment C gene of type A botulinum neurotoxin, was constructed and fused with an Igkappa leader sequence under the control of a human cytomegalovirus promoter. After 10 cycles of DNA inoculation with this plasmid, mice survived lethal doses of type A botulinum neurotoxin challenges. Immunized mice also elicited cross-protection to the challenges of type E botulinum neurotoxin. This is the first study demonstrating the potential use of DNA vaccination for botulinum neurotoxins.

Animals↗
PubMed1998

[Autonomic disorders in polyneuropathies].

BACKGROUND: Many polyneuropathies manifest autonomic disturbances. Diabetic neuropathy, the most frequent neuropathy in the western world, serves as model of the symptomatology of autonomic disturbances. DIABETIC NEUROPATHY: Clinical symptoms comprise pupillary and cardiovascular dysfunction such as orthostatic hypotonia and syncopes, thermoregulatory, gastrointestinal symptoms, disturbances in urogenital and respiratory function and unawareness of hypoglycemia. OTHER NEUROPATHIES: This article also describes autonomic symptoms in alcoholic neuropathy, in Guillain-Barré syndrome, in paraneoplastic polyneuropathies, in toxic neuropathies, in acute and subacute autonomic neuropathy, in amyloidosis, in porphyria, in familiar dysautonomia, in HIV infection and in botulism.

Autonomic Nervous System Diseases↗
PubMed2003

Syndromic surveillance using automated collection of computerized discharge diagnoses.

The Syndromic Surveillance Information Collection (SSIC) system aims to facilitate early detection of bioterrorism attacks (with such agents as anthrax, brucellosis, plague, Q fever, tularemia, smallpox, viral encephalitides, hemorrhagic fever, botulism toxins, staphylococcal enterotoxin B, etc.) and early detection of naturally occurring disease outbreaks, including large foodborne disease outbreaks, emerging infections, and pandemic influenza. This is accomplished using automated data collection of visit-level discharge diagnoses from heterogeneous clinical information systems, integrating those data into a common XML (Extensible Markup Language) form, and monitoring the results to detect unusual patterns of illness in the population. The system, operational since January 2001, collects, integrates, and displays data from three emergency department and urgent care (ED/UC) departments and nine primary care clinics by automatically mining data from the information systems of those facilities. With continued development, this system will constitute the foundation of a population-based surveillance system that will facilitate targeted investigation of clinical syndromes under surveillance and allow early detection of unusual clusters of illness compatible with bioterrorism or disease outbreaks.

Bioterrorism↗
PubMed2006

Clostridial neurotoxins: structure-function led design of new therapeutics.

The neurotoxins produced by various species of Clostridia are the causative agents of botulism and tetanus. The ability of the toxins, specifically those of the botulinum neurotoxin family, to disrupt neurotransmission has been exploited for use in several medical indications and now represents the therapeutic option of choice in a number of cases. Clostridial neurotoxins have been discovered to have a multi-domain structure that is shared between the various proteins of the family, and it has also been determined that each domain contributes a specific role to the holotoxin. The extensive use of recombinant expression approaches, along with solution of multiple crystallographic structures of individual domains, has enabled researchers to explore structurefunction relationships of the toxin domains more closely. These advances have facilitated a greater understanding of the potential use of individual domains for a wide variety of purposes, including the development of new therapeutics.

Anti-Dyskinesia Agents↗
PubMed2003

Ganglioside-liposome immunoassay for the detection of botulinum toxin.

A rapid and highly sensitive receptor immunoassay for botulinum toxin (BT) has been developed using ganglioside-incorporated liposomes. Botulism outbreaks are relatively rare, but their results can be very severe, usually leading to death from respiratory failure. To exert their toxicity, the biological toxins must first bind to receptors on the cell surface, and the trisialoganglioside GT1b has been identified as the cell receptor for BT. Therefore, in this study, GT1b was used to prepare the ganglioside-liposomes by spontaneous insertion into the phospholipid bilayer. In a sandwich-based, hybrid receptor immunoassay, BT is detected as a colored band on a nitrocellulose membrane strip, where BT bound to the GT1b-liposomes are captured by anti-BT antibodies immobilized in a band across the strip. The intensity of the colored band can be visually estimated, or measured by densitometry using computer software. The limit of detection (LOD) for BT in the lateral-flow assay system was 15 pg mL(-1), which is comparable to the limits of detection achieved with the most sensitive assays previously reported. However, this rapid assay can be completed in less than 20 min. These results demonstrate that the sandwich assay using GT1b-liposomes for detection of BT is rapid and very sensitive, suggesting the possibility for detecting BT in field screening, simply and reliably, without the need for complex instrumentation.

Animals↗
PubMed2002

Skin and Soft Tissue Infections in Injection Drug Users.

Skin and soft tissue infections (SSTIs) are common among injection drug users (IDUs). Subcutaneous and intramuscular injection ("skin-popping") and the injection of "speedballs" (a mixture of heroin and cocaine) are important risk factors for SSTIs in this patient population. Female IDUs appear to be at greater risk of SSTIs than male IDUs, probably because of more difficult venous access. There are conflicting data regarding the impact of HIV and human T-cell lymphotrophic virus II infection on the risk of SSTIs in IDUs; however, an expanding body of evidence suggests that immunosuppressive effects of the drugs themselves may play a role. Most information regarding the microbiology of SSTIs in IDUs comes from data on skin and subcutaneous abscesses, where Staphylococcus aureus and organisms that originate from the oral flora predominate. Clonal outbreaks and uncommon infections including tetanus, wound botulism, and a sepsis/myonecrosis syndrome due to Clostridium species have been recently reported in IDUs.

Journal Article↗
PubMed2001

Foodborne Illnesses.

Foodborne illnesses cause a substantial human and financial burden. Despite sanitary infrastructure improvements, the incidence of foodborne bacterial infections due to non-typhoidal salmonellae (NTS), Campylobacter jejuni, and enterohemorrhagic Escherichia coli (EHEC) has risen over the last two decades. Overall, viruses account for two thirds of all foodborne illness. Most foodborne illnesses are self-limited. Supportive therapy with rehydration and the correction of electrolyte abnormalities is usually sufficient. Antibiotics play a beneficial role in the treatment of patients with certain foodborne diseases, such as listeriosis and typhoid fever, and all patients with tissue invasive or bloodstream infections. Immunocompromised patients should be treated presumptively. Antibiotics are of variable efficacy for the treatment of many infections limited to the gastrointestinal tract, and recommendations differ between pathogens. Antibiotics are generally helpful for shigellosis and cholera, and possibly beneficial for campylobacteriosis. However, antibiotics are potentially harmful in uncomplicated NTS and EHEC gastroenteritis and generally should not be used. Toxin-mediated food poisoning usually does not require specific therapy. The exception is botulism, for which botulinum antitoxin is highly efficacious if used early in the course of illness. Empiric therapy for gastroenteritis is possibly beneficial, though the magnitude of benefit is modest and incurs the risk of inadvertently treating NTS or EHEC. The choice of antibiotic should be based on local resistance patterns and the results of susceptibility testing.

Journal Article↗
PubMed1992

Sequences of the botulinal neurotoxin E derived from Clostridium botulinum type E (strain Beluga) and Clostridium butyricum (strains ATCC 43181 and ATCC 43755).

Recently, it has been shown that two Clostridium butyricum strains (ATCC 43181 and ATCC 43755), isolated from cases of infant botulism, produce a botulinal neurotoxin type E (BoNT/E). Here we have determined the nucleotide sequences of the BoNT/E genes of these two C. butyricum strains and from C. botulinum E strain Beluga. We show that the sequences of the BoNT/E genes from the two C. butyricum strains are identical and differ in only 64 positions resulting in 39 amino acid changes (97% identity at the amino acid level) from that derived from C. botulinum. Our data suggest a transfer of the BoNT/E gene from C. botulinum to the originally nontoxigenic C. butyricum strains.

Amino Acid Sequence↗
PubMed1985

Synergistic interaction of 4-aminopyridine with neostigmine at the neuromuscular junction.

The pre- and postsynaptic events at the neuromuscular junction were studied in vitro in rat skeletal muscle exposed to clinically significant concentrations of 4-aminopyridine (4-AP), neostigmine or combinations of the two drugs. Simultaneous application of 4-AP and neostigmine produced increases in the amplitudes of nerve-evoked end-plate potentials which were significantly greater than the summed effects of the drugs applied individually. Such synergism was present at the junctions where transmission was blocked either postsynaptically by d-tubocurarine or presynaptically by low [Ca2+]0 and high [Mg2+]0. Quantal content analysis in the latter preparation indicated that the evoked release of acetylcholine was potentiated significantly more than the amplitude of spontaneous miniature end-plate potentials, suggesting that the site of synergism is predominantly presynaptic. For symptomatic relief and long-term management of the neuromuscular junction disorders, we propose a combined medication of aminopyridine and anticholinesterase at reduced dosages. Such therapy would minimize adverse effects and be particularly effective in the treatment of such presynaptic disorders as the Lambert-Eaton myasthenic syndrome and botulism.

4-Aminopyridine↗
PubMed1990

Ca2(+)-dependent noradrenaline release from permeabilised PC12 cells is blocked by botulinum neurotoxin A or its light chain.

Permeabilisation of PC12 cells with digitonin allowed a direct study of the intracellular action of botulinum neurotoxin A, one of a group of dichain proteins produced by Clostridium botulinum that causes the fatal neuroparalytic condition, botulism. Release of [3H]noradrenaline from these permeabilised cells could be evoked by Ca2+ and this was inhibited specifically by the neurotoxin in a dose-dependent manner (half-maximal dose approximately 2 nM under the conditions used). Inclusion of the reducing agent dithiothreitol (up to 10 mM) had no effect on the level of inhibition. Moreover, electrophoretic analysis showed that this treatment of the toxin in the native state caused negligible reduction of inter-chain disulphide bonds. Toxin-induced blockade of neurotransmitter release was incomplete and could not be overcome by increased Ca2+ concentration (100 microM). The observed toxin-insensitivity of the release from intact PC12 cells must result from inefficient toxin uptake, relative to that in peripheral cholinergic neurones. Refolded light chain alone inhibited exocytosis to the same degree and with similar potency to that of the intact neurotoxin, an effect not altered by the heavy chain. This inhibitory activity of the light chain in PC12 cells accords with observations made in permeabilised chromaffin cells [(1989) J. Biol. Chem. 264, 10354-10360; (1989) FEBS Lett. 255, 391-394] but contrasts with invertebrate neurones, where intracellular injection of the same preparations of both chains were necessary for inhibition of quantal release of acetylcholine [(1988) Proc. Natl. Acad. Sci. USA 85, 4090-4094]. These collective findings may signify an interesting difference in the release process in such diverse systems or denote a dissimilarity in the transport or processing of the toxin when applied into intact neurones or cells permeabilised by detergent or streptolysin.

Animals↗
PubMed1993

Botulinum neurotoxins serotypes A and E cleave SNAP-25 at distinct COOH-terminal peptide bonds.

SNAP-25, a membrane-associated protein of the nerve terminal, is specifically cleaved by botulinum neurotoxins serotypes A and E, which cause human and animal botulism by blocking neurotransmitter release at the neuromuscular junction. Here we show that these two metallo-endopeptidase toxins cleave SNAP-25 at two distinct carboxyl-terminal sites. Serotype A catalyses the hydrolysis of the Gln197-Arg198 peptide bond, while serotype E cleaves the Arg180-Ile181 peptide lineage. These results indicate that the carboxyl-terminal region of SNAP-25 plays a crucial role in the multi-protein complex that mediates vesicle docking and fusion at the nerve terminal.

Amino Acid Sequence↗
PubMed1978

Porphyric polyneuropathy and its pathogenesis in the light of electrophysiological investigations.

Twenty-four patients with acute intermittent porphyria were examined by means of routine electromyographic (EMG) tests, measurements of motor and sensory conduction in peripheral nerves and stimulation fatigue tests. The EMG results gave evidence of an initial, reversible disorder of function of the peripheral neuron, only sometimes followed by evidence of axonal degeneration of the "dying back" type. In stimulation fatigue tests there was some evidence of potentiation but none of fatigue. Attention is drawn to some analogies between the electrophysiological changes in porphyric polyneuropathy and in botulism. It seems that the pathogenesis of porphyric polyneuropathy may be dependent upon a block of cholinergic endings.

Acute Disease↗