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PubMed1987

Management of tetanus.

Two cases of tetanus are presented, and the diagnosis, clinical features, and management of tetanus are reviewed. The first patient, an 86-year-old woman, had marked muscle rigidity but was able to breathe spontaneously. A dark eschar with purulent drainage was noted on her left foot, but Clostridium tetani was not isolated. She was placed in a semidark room and was treated with penicillin G; tetanus immune globulin (TIG) 5000 units i.m.; tetanus toxoid 0.5 mL i.m.; diazepam, chlorpromazine, and morphine for sedation, muscle relaxation, and analgesia; ranitidine for stress ulcer prophylaxis; heparin for prevention of deep-vein thrombosis; and peripheral-vein nutrition. Her condition improved gradually, and she was discharged to a rehabilitation institute after 32 days. The second patient, a 46-year-old woman, experienced progressive descending paralysis and required ventilatory support. She had a periodontal abscess, but cultures of the drainage were negative. She was placed in a semidark room and treated with erythromycin, TIG, tetanus toxoid, diazepam, pancuronium bromide, morphine, ranitidine, and heparin. Autonomic instability occurred during the second and third weeks, but cardiac output was maintained without treatment. The patient was extubated after five weeks, and was transferred out of the intensive-care in the following week. The diagnosis of tetanus is based primarily on characteristic findings of muscle rigidity and reflex spasms; cultures for C. tetani are of limited value. A history of trauma or injury is common. Pulmonary infections and cardiovascular instability are the most common complications. Therapy consists of ventilatory support; control of neuromuscular symptoms with benzodiazepines, narcotics, and neuromuscular blockers; antibiotic therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1977

Structure of tetanus toxin. II. Toxin binding to ganglioside.

The interaction between tetanus toxin and ganglioside containing 2 N-acetylneuraminic acid residues linked in sequence to one another has been investigated using a new method involving radioactively labeled ganglioside and tetanus toxin adsorbed to Sephadex matrix. Binding between the two components was demonstrated, and it was calculated that in the nanomolar concentration range, tetanus toxin becomes half-saturated at about 5 X 10(-8) M concentration of ganglioside. Removal of the ceramide portion from the ganglioside resulted in the complete loss of binding activity, whereas removal of the terminal N-acetylneuraminic acid residue from the intact ganglioside had no effect. Among the fragments derived from tetanus toxin (Helting, T. B., and Zwisler, O. (1977) J. Biol. Chem. 252, 187-193), only the heavy chain polypeptide exhibited a binding activity of the same order of magnitude as that observed for the native toxin. The light chain polypeptide showed no interaction with ganglioside and among the fragments derived from the toxin by digestion with papain, only Fragment C, at a high protein concentration, displayed marginal binding activity. Using monovalent antibodies directed against specific regions of the tetanus toxin molecule, it was demonstrated that antibodies directed against Fragment C uniquely interfere with the binding process. Anti-light chain serum was ineffective, as well as antitetanus toxoid serum previously absorbed with Fragment C. It is concluded that the binding site for ganglioside is located on the heavy chain portion of tetanus toxin, possibly in or near the region comprised by Fragment C.

Binding Sites↗

PubMed1984

Absence of naturally acquired tetanus antitoxin in the free-ranging Cayo Santiago rhesus monkeys (Macaca mulatta).

Tetanus is enzootic in the free-ranging rhesus monkey colony on Cayo Santiago. The disease accounts for 25% of all mortalities in the population. The high prevalence of tetanus provided a unique opportunity to study the potential roles of geophagia, wounding, and clinical tetanus infections on the development of naturally acquired tetanus antitoxin in rhesus macaques. Eighty-six unvaccinated monkeys, including six that recovered from tetanus, were serosurveyed using a mouse toxin neutralization test. None of the animals had detectable antitoxin titers (less than 0.001 AU/ml), suggesting that natural immunity to tetanus is either rare or nonexistent in the Cayo Santiago colony.

Animals↗

PubMed1997

Diphtheria and tetanus immunity among blood donors in Toronto.

OBJECTIVE: To determine the diphtheria and tetanus antitoxin levels among blood donors in Toronto. DESIGN: Cross-sectional seroprevalence study. SETTING: Two fixed-site blood-donation clinics in Toronto from September to November 1994. PARTICIPANTS: Blood donors 20 years of age or older were eligible to participate; of the 781 eligible donors, 710 (90.9%) participated in the study. MAIN OUTCOME MEASURES: Diphtheria and tetanus antitoxin levels and factors associated with disease susceptibility, such as vaccination history, country of birth, age and sex. A diphtheria antitoxin level lower than 0.01 lU/mL and a tetanus antitoxin level lower than 0.15 lU/mL were considered nonprotective. RESULTS: Among the participants, 147 (20.7%) had a diphtheria antitoxin level in the nonprotective range, and 124 (17.5%) had a tetanus antitoxin level that was nonprotective. Increasing age and lack of written vaccination records were associated with susceptibility to the 2 diseases. Birth outside Canada was significantly related to tetanus susceptibility. CONCLUSION: Adults over 50 years of age who did not know their vaccination history were the least likely to be protected against diphtheria and tetanus. The greatest benefit of any immunization strategy would be gained by targeting this group.

Adult↗

PubMed1997

[Treatment with human tetanus immunoglobulins in the Emergency Department. Effects of informed consent].

BACKGROUND: The impact of informed consent to tetanus prophylaxis with human immunoglobulins on patients treated in the Emergency Department has been evaluated. METHODS: Tetanus vaccination history was investigated in 1435 patients in 1995 and in 1300 patients in 1996 with post-traumatic skin lesions. RESULTS: The study has shown that in 1995, 55% and in 1996 49.5% of the total patients studied had not received vaccine for tetanus or boosters for over 10 years. These patients had been proposed the treatment with human tetanus immunoglobulins (TIG). The research was performed comparing the consent obtained before (from 17/5 to 15/7/1995) and after (from 17/5 to 15/7/1996) the introduction of the informed consent. The survey was divided into 15-day periods. In 1995 prophylaxis with human immunoglobulins was refused by 42 patients out of 831 (5%) while, in the following year, by 284 out of 641 (44.3%). Every period examined has shown highly significant differences (p < 0.000). CONCLUSIONS: Informing the patients that tetanus prophylaxis with human immunoglobulins can expose them to the risk, at present remote, of transmission of viral infections, has caused a heavy rise of denials to the suggestion of treatment with human immunoglobulins. The amount of the treated patients and the time that was devoted to informed consent would make Emergency Department one of the main places for effective and widespread tetanus prophylaxis. However a greater activity of outer structures would also be hoped for.

Adolescent↗

PubMed1989

Tetanus toxin as a marker for small-cell lung cancer cell lines.

Tetanus toxin labeling of human lung cancer cell lines was investigated using direct and indirect immunofluorescence and immunohistochemical staining. Cells of characterized permanent cell lines, eight small-cell lung cancer (SCLC) cell lines of classic subtype, six SCLC cell lines of variant subtype and seven non-small-cell lung cancer (NSCLC) cell lines, were incubated with a saturating concentration of tetanus toxin. For staining, fluorescein-isothiocyanate-(FITC)-conjugated anti-(tetanus toxin) antibodies were used or a mouse monoclonal anti-(fragment C) antibody with subsequent binding of FITC-conjugated anti-(mouse Ig) antibody or peroxidase-anti-peroxidase complex. Only SCLC showed an intense fluorescence/immunoreactivity restricted to the cell membrane. Quantitative analysis of tetanus toxin labeling by flow cytometry revealed the percentage of positive cells to be between 35% and 95% in SCLC without obvious differences between the classic and variant subtypes of SCLC. In NSCLC the percentage of positive cells was lower than 10%. These results demonstrate that SCLC in contrast to NSCLC can be labeled with tetanus toxin, emphasizing the neuroendocrine properties of this tumor, and that tetanus toxin labeling may become a useful diagnostic marker for SCLC cells in cytology.

Animals↗

PubMed1976

Haemodynamic changes during experimental tetanus toxicity in dogs.

Haemodynamic variables were compared in control dogs, dogs with local tetanus toxicity and dogs with generalised tetanus toxicity. The results showed an increase in the inotropic and chronotropic activation of the heart in both groups of tetanus dogs, but there was no significant change in the mean systemic blood pressure and the common carotid occlusion reflex was unchanged. Spontaneous fluctuations in the systemic blood pressure were observed in some dogs with tetanus, and occurred more often in those with generalised tetanus. The modification of these fluctuations by beta-adrenergic blockade and diazepam, suggest that they are of autonomic neural origin. It is suggested that these changes in the cardiovascular system are the results of neurophysiological and biochemical changes in the sympathetic nervous system, which have been reported to occur in tetanus.

Animals↗

PubMed1981

Expression of surface membrane IgG on pokeweed mitogen-reactive anti-tetanus toxoid antibody-producing cells.

Anti-tetanus toxoid antibody-producing cells, differentially expressing surface membrane IgM, were analyzed for the additional expression of surface membrane IgG. micron+ and micron- cells were rosetted with anti-gamma-ox red blood cells and separated by density centrifugation into fractions enriched or depleted of gamma + cells. These B-cell subsets were assayed for the production of IgM and IgG anti-tetanus toxoid antibody and total IgM and IgG. The results indicated that the majority of anti-tetanus toxoid antibody synthesis in the micron- fraction was by gamma + cells. In the microm+ fraction, however, both IgM and IgG anti-tetanus toxoid antibody production was detected in the micron+ gamma- and micron+ gamma+ fraction. The inclusion of isotype-specific antisera during the first 2 days of culture further established that gamma was expressed on the surface of the majority of the precursors for IgG anti-tetanus antibody production in vitro. Studies performed to determine the culture requirements of micron- and micron+ cells revealed that production of IgG anti-tetanus toxoid antibody by both cell subsets was dependent on T cells and pokeweed mitogen. However, some micron- cells could produce IgG in the presence of T cells alone.

Animals↗

PubMed2006

Cellular and humoral immune responses to a tetanus toxoid booster in perinatally HIV-1-infected children and adolescents receiving highly active antiretroviral therapy (HAART).

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) infected children treated with highly active antiretroviral therapy (HAART) may develop a significant reduction of plasma viremia associated with an increase in CD4+ T-cell counts. Functional capacity of this reconstituted immune system in response to recall antigens is important to maintain protective immunity to vaccine-preventable diseases. We therefore determined cellular and humoral immune responses to tetanus toxoid (TT) booster in perinatally HIV-1-infected children and adolescents receiving HAART. METHODS: Immune responses were prospectively evaluated pre- and post-tetanus booster using lymphocyte proliferation assay (LPA) stimulation index (SI > or = 3.0) and tetanus antibody (TAb > or = 0.15) in 15 patients. The median interval from primary tetanus immunization series was 6 years (range 2-12 years). We compared patients by their virological response to HAART (complete responders, CR, n=7; incomplete responders, ICR, n=8). RESULTS: There were no significant differences in median age 12.6 years (CR: 12.9; ICR: 10.6) or median CD4 T-cell pre-booster (CR: 35%/819; ICR: 26%/429) between groups. Tetanus LPA responses were observed in one patient prior to booster and in seven patients post-booster. In contrast, 38% of patients had protective TAb pre-booster, but 92% developed protective TAb post-booster. All of the CR and 5/6 ICR patients developed protective TAb. CONCLUSIONS: HIV-1-infected children and adolescents had modest LPA responses to tetanus following booster, similar to HIV-1-infected adults. However, the majority of patients developed protective TAb levels after booster and maintained the response. Shorter intervals may need to be considered for TT immunization boosters in HIV-1-infected pediatric patients, as only 38% had protective TAb at baseline.

Antibody Formation↗

PubMed1977

Role of gangliosides in the uptake and retrograde axonal transport of cholera and tetanus toxin as compared to nerve growth factor and wheat germ agglutinin.

Previous investigations have shown that tetanus toxin is transported retrogradely in all peripheral neurons whereas the transport of NGF is confined to adrenergic and sensory neurons. Other macromolecules with molecular weights and general physiochemical properties similar to NGF and tetanus toxin (e.g., cytochrome C, insulin, horseradish peroxidase and bovine serum albumin) are not transported to a detectable extent if injected in comparable molar concentrations. For tetanus toxin, which is transported in all peripheral neurons, it has be assumed that it's retrograde transport depends on properties common to all neurons. In view of the relatively high ganglioside content of the neurons and the high affinity of tetanus toxin for the trisialoganglioside GT1, we studied the influence of gangliosides on the retrograde transport of tetanus toxin as compared to NGF. We included into the study cholera toxin which is known to have a high affinity for the monosialoganglioside GM1 and wheat germ agglutinatinin, a lectin with specific affinity for glycoproteins with N-acetyl-glucosamine residues. Both cholera toxin and wheat germ agglutinin were transported efficiently in all peripheral neurons. Preincubation of 125I-cholera toxin with monosialoganglioside GM1 completely blocked its retrograde axonal transport. The transport of NGF and wheat germ agglutinin was affected neither by various purified gangliosides nor by a mixture of bovine brain gangliosides. The transport of tetanus toxin was only reduced by 50% both by the trisialoganglioside GT1 and the bovine ganglioside mixture.

Adrenergic Fibers↗

PubMed1982

The binding of tetanus toxin to retinal cells.

An indirect immunofluorescence assay demonstrated intense binding of tetanus toxin to a minority of cells cultured from neonatal rat retina. These labelled cells were typically spheroid cells bearing long processes. Flat cells and smaller spheroid cells without long processes were essentially unlabelled. A similar assay performed on frozen sections of rat retina showed that tetanus toxin bound intensely to the inner plexiform layer, moderately to the outer plexiform and inner nuclear layers, and only very slightly to the outer nuclear layer. The localization of tetanus toxin bound to frozen sections was confirmed by autoradiography of [125I]tetanus toxin binding. In contrast, the monoclonal antibody A4 bound to all layers of the retina (except that of the outer segments). In cell cultures the monoclonal antibody Ran-2 bound to the flat cells but to neither class of spheroid cells. These data imply that tetanus toxin binds more intensely to retinal neurones than to photoreceptors and other retinal cell types. By assisting identification of cells dissociated from retina, assays of tetanus toxin binding should prove useful in the isolation of specific retinal cell-types.

Animals↗

PubMed1983

The regulatory roles of T4 and T8 subsets in tetanus toxoid-induced in vitro immunoglobulin production.

A new mitogenic system for in vitro immunoglobulin production induced by tetanus toxoid is presented and the role of T4 and T8 subsets in tetanus toxoid-induced in vitro immunoglobulin production is investigated. Purified T, T4, T8, and B cells from normal individuals previously immunized but not boosted with tetanus toxoid were cultured in helper and suppressor assays and the number of immunoglobulin-secreting cells were enumerated after culture using a hemolytic plaque assay. The regulatory roles of T4 and T8 cells in this tetanus toxoid system were compared with the role of these subsets after pokeweed mitogen stimulation. Although most of the immunoglobulin produced in the tetanus toxoid system was polyclonal, there were differences in the time course, the magnitude of the responses, the radiosensitivity of the subsets, and optimal T- to B-cell ratios for immunoglobulin production which distinguish the tetanus toxoid and pokeweed mitogen systems.

Antibodies, Bacterial↗

PubMed1996

Gangliosides in phospholipid bilayer membranes: interaction with tetanus toxin.

The interaction between tetanus toxin and its fragments with gangliosides and negatively charged phosphatidylglycerols has been studied in phosphatidylcholine host membranes by protein circular dichroism measurement, calorimetry to determine lipid phase transitions, and by fluorescence spectroscopy to follow the toxin-induced pore formation by measuring the release of intravesicular entrapped dye. CD-spectroscopic secondary structure analysis showed conformational change of the toxin only in the presence of GT1b clearly demonstrating the involvement of the ganglioside headgroups for this lipid-protein-interaction. In a dot-blot analysis we showed that fragment C binds to GT1b in reconstituted vesicles and that this fragment is then accessible to a fragment C specific antibody which is only possible if fragment C is exposed at least partially on the surface of the vesicle. Our calorimetric study demonstrates the preferential binding of tetanus toxin to ganglioside GT1b. However, this protein is also able to bind to other gangliosides and also to negatively charged phospholipids causing phase separation due to electrostatic interaction. Since tetanus toxin preferentially binds short chain phosphatidylglycerol, we conclude that the protein adopts lipids with respect to charge, head group structure and chain length from the bulk phase. One consequence of this lipid-protein interaction is the ability of tetanus toxin to permeabilize lipid vesicles. Pore formation is favoured in the presence of GT1b in phosphatidylcholine membranes but only at a sufficiently high enough ganglioside content. Gangliosides others than GT1b are less effective in pore formation. In the presence of negatively charged phosphatidylglycerol tetanus toxin causes a dye release which in contrast to GT1b-containing vesicles is not saturable. We conclude that tetanus toxin acts in combination with a given number of GT1b molecules. Twenty ganglioside molecules are found to be necessary to form the stable pore. Other negatively charged lipids also cause the toxin to intercalate into the membrane but in this case the release velocity is determined by the formation of membrane defects.

Circular Dichroism↗

PubMed1991

Tetanus toxin inhibits neurotensin-induced mobilization of cytosolic protein kinase C activity in NG-108 cells.

There is considerable literature on the pathogenesis of tetanus toxin poisoning; however, the mechanism of action and intracellular substrate of this toxin have not been defined. It was demonstrated that the NG-108 neuroblastoma x glioma cell line is a suitable model in which to study the mechanism of tetanus toxin action, from binding of the toxin to inhibition of transmitter release. Further, it has been shown that tetanus toxin pretreatment attenuates the ability of phorbol myristate acetate to mobilize cytosolic protein kinase C (PKC) in this cell line. In the present study a 4-hr tetanus toxin pretreatment (10(-10)-10(-13) M) completely inhibited the mobilization of cytosolic PKC induced by a 30-min exposure to 10 microM neurotensin. Pretreatment with 10(-10) M tetanus toxin for periods as short as 1 hr was sufficient to attenuate the ability of neurotensin to mobilize cytosolic PKC; however, a 30-min pretreatment had no significant effect. At a concentration of 10(-11) M, it was necessary to pretreat the cells for greater than 1 hr to significantly attenuate neurotensin-mobilized PKC activity. The exact role that PKC plays in the secretory process is not yet known; however, these findings suggest that the effect of tetanus toxin on neurotransmitter release is accompanied by an alteration in PKC metabolism in differentiated NG-108 cells.

Animals↗

PubMed1992

Immunogenicity of combined diphtheria, tetanus, and pertussis vaccine given at 2, 3, and 4 months versus 3, 5, and 9 months of age.

In the UK an accelerated schedule for immunisation against diphtheria, tetanus, and pertussis (injections at 2, 3, and 4 months of age) was introduced in 1990 to replace the more widely spaced schedule of 3, 5, and 9 months. There is concern, however, that the new schedule may be less immunogenic and therefore less protective than the old schedule. We have measured serum concentrations of antibodies against diphtheria, pertussis, and tetanus in infants immunised according to the two regimens. Both schedules resulted in protective concentrations of antibody against tetanus and diphtheria and in satisfactory antibody responses to three pertussis antigens (filamentous haemagglutinin, pertussis toxin, fimbriae). However, immunisation by the old schedule led to significantly higher antibody concentrations against both diphtheria and tetanus than did immunisation by the new schedule (p less than 0.01). In infants immunised with the new schedule, postimmunisation antibody concentrations against tetanus toxoid and against two pertussis antigens (pertussis toxin and fimbriae) were significantly lower in infants in whom preimmunisation (maternally derived) antibody concentrations were high (p less than 0.02). The findings suggest that with an accelerated immunisation schedule maternal antibodies can have an inhibitory effect on the responses to immunisation against tetanus and pertussis.

Antibodies, Bacterial↗

PubMed1994

Comparative study of Lederle/Takeda acellular and Lederle whole-cell pertussis-component diphtheria-tetanus-pertussis vaccines in infants in Germany.

In preparation for a large efficacy trial in Germany, a pilot study was initiated in December 1990. In this study 149 infants were enrolled; with double-blind randomization 75 received Lederle/Takeda acellular pertussis component diphtheria-tetanus-pertussis vaccine (APDT) and 74 received Lederle whole-cell pertussis component diphtheria-tetanus-pertussis vaccine (DTP). The mean age at first dose was 3.5 months, and the second and third doses followed at 6-week intervals. Reactions were relatively mild with both vaccines; in general they were less frequent following APDT. The IgG antibody responses to lymphocytosis promoting factor (LPF) and fimbriae-2 were similar in both groups whereas the responses to pertactin and filamentous haemagglutinin (FHA) were greater in APDT recipients. DTP recipients had greater responses to tetanus and diphtheria toxoids. When age of first dose was examined (8-12 weeks versus 16-20 weeks), it was found that young age had a suppressive effect on antibody responses in DTP but not APDT recipients to LPF toxoid, pertactin, fimbriae-2, and tetanus and diphtheria toxoids. High values of transplacentally acquired antibody lessened the response to LPF toxoid and tetanus toxoid in DTP recipients and to tetanus toxoid in APDT vaccinees. The IgG immune response to LPF toxoid, FHA and fimbriae-2 was found to be more uniform in APDT recipients than in DTP vaccinees. An IgA antibody response to fimbriae-2 was noted in 13% of DTP recipients but in no APDT vaccinees. The broad immunogenicity and mild reactogenicity of this APDT vaccine justifies its use in the German efficacy trial.

Antibodies, Bacterial↗

PubMed1986

Carotid chemoreceptor reflex in rats during experimental tetanus toxicity.

The effects of stimulation of carotid body chemoreceptors on blood pressure, heart rate and ventilation were compared in normal rats and rats with local or generalised tetanus toxicity induced by injection of the toxin. Carotid chemoreceptor stimulation in an increase in blood pressure and a decrease in heart rate in both control and tetanus rats. However, while chemoreceptor stimulation resulted in increases in ventilation of 115% and 123% in normal rats and rats with local tetanus respectively, the increase in rats with generalised tetanus was only 29%. The experiments indicate that normal rats and rats with tetanus toxicity exhibit identical pressor and heart rate responses to stimulation of carotid chemoreceptors whereas the ventilatory response is attenuated in the tetanus rats.

Animals↗

PubMed1992

The light chain of tetanus toxin inhibits calcium-dependent vasopressin release from permeabilized nerve endings.

The effects of tetanus toxin and its light and heavy chain subunits on vasopressin release were investigated in digitonin-permeabilized neurosecretory nerve terminals isolated from the neural lobe of the rat pituitary gland. Exocytosis was induced by challenging the permeabilized nerve endings with micromolar calcium concentrations. Tetanus toxin inhibited vasopressin release only in the presence of the reducing agent dithiothreitol. This effect was irreversible. The purified light chain of tetanus toxin strongly inhibited exocytosis in a dose-dependent manner with half-maximal effect at c. 10 nM. The action of the light chain was observed after only 2.5 min of preincubation. Separated heavy chain subunit had no effect on hormone secretion. Inhibition of vasopressin release could be prevented by preincubating the light chain of tetanus toxin with an immune serum against tetanus toxin. The data clearly demonstrate that in mammalian neurosecretory nerve endings tetanus toxin acts at a step downstream from the activation by Ca2+ of the exocytotic machinery and that the functional domain of this toxin is confined to its light chain.

Animals↗