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PubMed1999

A chronic focal epilepsy with mossy fiber sprouting follows recurrent seizures induced by intrahippocampal tetanus toxin injection in infant rats.

Studies were conducted to characterize a chronic epileptic condition that follows recurrent seizures induced by intrahippocampal tetanus toxin injection in infancy. Wistar rat pups received a single injection of tetanus toxin in the right CA3 region on postnatal day 10. Animals were monitored for epileptiform activity by video electroencephalographic or visual observation during the following three to five days. Repeat evaluation six months later demonstrated interictal discharges in 79% (11 of 14) and electrographic seizures in 42% (six of 14) of adult rats with tetanus toxin-induced seizures in infancy. Five of the animals had interictal activity which occurred focally in either the left (n = 2) or right (n = 3) hippocampus. One animal had focal interictal activity independently in these regions and in the left and right cortical regions. The remaining five animals had interictal activity in the hippocampus and synchronously in the ipsilateral cortex or the contralateral hippocampus. Electrographic seizures were focal (nine of 14) or bilateral (five of 14) in onset. The behaviors that accompanied these seizures were quite variable. Clonic face and forelimb movements were observed in some animals. However, a significant portion of rats had electrographic seizures with no associated behavioral change. Timm staining was performed on hippocampal sections from experimental and control animals. There was a significantly greater Timm score (aberrant Timm granules) in the inner molecular layer of the dentate gyrus in tetanus toxin-treated rats than in control rats. Our findings suggest that intrahippocampal tetanus toxin injection in infant rats results in a chronic focal epilepsy that persists for at least six months and is associated with aberrant mossy fiber sprouting in the dentate gyrus. The model described here contributes significantly to the evidence for chronic effects of recurrent seizures in early life, and provides a model for investigation of the molecular and cellular events that contribute to the development of chronic epilepsy.

Aging↗
PubMed2002

Tetanus toxoid microspheres consisting of biodegradable poly(lactide-co-glycolide)- and ABA-triblock-copolymers: immune response in mice.

Tetanus toxoid (TT) was microencapsulated using poly(lactide-co-glycolide) (PLGA) with molar compositions of 50:50, 75:25 or an ABA-triblock-copolymer consisting of PLGA A-blocks attached to a central polyoxyethylene-B-block with a W/O/W (water/oil/water) double emulsion technique. The TT microspheres (MS) were evaluated with respect to protein integrity during antigen release in-vitro and compared with aluminum-adsorbed TT in a mouse model for in-vivo induction of tetanus-specific antibodies as well as protection against a subcutaneous tetanus toxin challenge. The more hydrophilic ABA-triblock-copolymer protected the TT against the deleterious microenvironmental conditions in the degrading MS and provided a prolonged antigen release. In spite of the distinct differences in the in-vitro release patterns MS from PLGA and ABA-triblock-copolymer did not show significant differences in the in-vivo induction of tetanus-specific antibodies. Both preparations elicited antibody titers nearly as high as conventional aluminum-adsorbed TT, which lasted for 29 weeks and were protective against a challenge with 100 x LD(50) tetanus toxin. TT-MS boosted mice which were preimmunized with aluminum-adsorbed as well as with microencapsulated TT. TT-MS are suitable candidates for single shot vaccine delivery systems which elicit a long lasting and protecting immune response.

Animals↗
PubMed1997

Increased susceptibility to tetanus toxin-induced seizures in immature rats.

Studies were undertaken to compare tetanus toxin-induced electrographic and behavioral seizure activity in immature and adult rats. Multifocal epileptiform activity was induced by unilateral hippocampal injection of tetanus toxin in 10-day-old immature and in 90-120-day-old adult rats. Bilateral cortical surface electrodes and, in some animals, hippocampal depth electrodes were placed and serial video EEG was recorded for 2 h during the week following tetanus toxin injection. Tetanus toxin-induced interictal spike frequency was significantly higher and seizure duration was significantly longer in immature compared to adult rats. Immature rats tended to have more frequent seizures compared with adults, but the difference was not statistically significant. Ictal behaviors were different for the two groups with immature rats commonly demonstrating wild running seizures which were not seen in adult rats. These findings suggest that there are age-dependent differences in electrographic and behavioral seizure expression in the tetanus toxin seizure model and that the epileptic syndrome in immature rats is more severe.

Aging↗
PubMed1978

Relationship between lymphocyte response to tetanus toxoid and age of lymphocyte donor.

An investigation of the in vitro responsiveness of peripheral blood lymphocytes to tetanus toxoid was undertaken to determine the extent to which such reactivity might reflect in vivo reactions to tetanus toxoid immunization. It was found that lymphocyte transformation in the presence of tetanus toxoid, as measured by the uptake of tritiated thymidine, did not differ significantly for the group giving local or systemic reactions to tetanus toxoid and an immune control group. However, a striking inverse relation between lymphocyte reactivity to tetanus toxoid and age of the cell donors of both groups became clear. Such an age-related decline in the in vitro responsiveness of peripheral blood lymphocytes to a specific antigen has apparently had not been reported previously in man.

Adult↗
PubMed1998

Beta-amino-thiols inhibit the zinc metallopeptidase activity of tetanus toxin light chain.

Tetanus neurotoxin is a 150-kDa protein produced by Clostridium tetani, which causes the lethal spastic paralytic syndromes of tetanus by blocking inhibitory neurotransmitter release at central synapses. The toxin light chain (50 kDa) has a zinc endopeptidase activity specific for synaptobrevin, an essential component of the neuroexocytosis apparatus. Previous unsuccessful attempts to block the proteolytic activity of this neurotoxin with well-known inhibitors of other zinc proteases led us to study the design of specific inhibitors as a possible drug therapy to prevent the progressive evolution of tetanus following infection. Starting from the synaptobrevin sequence at the level of the cleavage site by tetanus neurotoxin (Gln76-Phe77), a thiol analogue of glutamine demonstrated inhibitory activities in the millimolar range. A structure-activity relationship performed with this compound led us to determine the requirement for the correct positioning of the thiol group, the primary amino group, and a carboxamide or sulfonamide group on the side chain. This resulted in the design of a beta-amino-(4-sulfamoylphenyl)glycine-thiol, the first significantly efficient inhibitor of tetanus neurotoxin with a Ki value of 35 +/- 5 microM.

Enzyme Inhibitors↗
PubMed2000

Identification of novel small molecule ligands that bind to tetanus toxin.

Tetanus toxin belongs to a family of clostridial protein neurotoxins for which there are no known antidotes. Another closely related member of this family, botulinum toxin, is being used with increasing frequency by physicians to treat severe muscle disorders. Botulinum toxin has also been produced in large quantities by terrorists for use as a biological weapon. To identify small molecule ligands that might bind to the targeting domain of tetanus and botulinum toxins and to facilitate the design of inhibitors and new reagents for their detection, molecular docking calculations were used to screen a large database of compounds for their potential to bind to the C fragment of tetanus toxin. Eleven of the predicted ligands were assayed by electrospray ionization mass spectrometry (ESI-MS) for binding to the tetanus toxin C fragment, and five ligands (45%) were found to bind to the protein. One of these compounds, doxorubicin, was observed to have strong hydrophobic interactions with the C fragment. To check the ligands for their ability to compete with ganglioside binding, each was also tested using a GT1b liposome assay. Doxorubicin was the only ligand found to competitively bind the tetanus toxin C fragment with an appreciable binding constant (9.4 microM).

Binding Sites↗
PubMed2001

Tetanus immunization in pregnant women. Serum levels of antitetanus antibodies at time of delivery.

The objective of this study was to determine the tetanus immunity status of pregnant women at the time of delivery according to tetanus toxoid (TT) vaccination coverage during their most pregnancy. The serum anti-tetanus antibody levels of 493 mothers who had live births at a hospital in Ankara were determined by enzyme-linked immunosorbent assay (ELISA). Protected women were defined as those with serum antibody levels > or = 0.6 IU/ml. Overall, 69.0% of mothers had protective tetanus antibody titers at the time of delivery. The rates of protection for mothers who had received no vaccination, one TT dose, or two TT doses during pregnancy were 46.4, 93.5, and 95.6%, respectively. Vaccinating every pregnant woman with at least one dose of TT would be an affordable and effective way to protect against neonatal tetanus, and would be a step toward eliminating the deaths that continue to occur due to this preventable disease in Turkey.

Adolescent↗
PubMed1997

Metal substitution of tetanus neurotoxin.

Tetanus neurotoxin was depleted of its catalytic Zn2+ ion, and the apotoxin was reconstituted with different transition metal ions. The Mn2+- and Co2+-tetanus neurotoxins are highly active in the proteolysis of vesicle-associated membrane protein/synaptobrevin, the natural substrate of this toxin, whereas Cu2+ and Fe2+ minimally supported proteolytic activity. The visible absorbance spectrum of Co2+-tetanus neurotoxin shows a maximum at 538 nm with a molar absorption coefficient of 82 M(-1) x cm(-1). These results indicate that the Zn2+ environment at the active site of tetanus neurotoxin is different from those of known Zn2+-endopeptidases and provide a structural basis for the definition of tetanus neurotoxin, and the related clostridial neurotoxins, as an independent family of metalloproteases.

Binding Sites↗
PubMed2003

Tetanus immunity in long-term care facilities.

OBJECTIVES: To investigate the correlates of tetanus immunity in the elderly residing in a long-term care facility in Hawaii. DESIGN: Cross-sectional. SETTING: A nursing home in Honolulu, Hawaii. PARTICIPANTS: Sixty subjects aged 65 and older: 30 men and 30 women. MEASUREMENTS: The interview included demographic information, immunization history, military service information, and other potential risk factors for tetanus. Serum tetanus antibody titers were measured. RESULTS: The data showed that 76.7% (46/60) had adequate tetanus titers. This is in stark contrast to previous studies, which have reported immunity rates of 27% to 46% in similar populations. There were significant associations between immunity and prior history of military service. There were no significant associations between immunity and past history of immunization, education, socioeconomic status, or sex. CONCLUSION: History of immunization from patients, families, or medical charts may be unreliable indicators of tetanus immunity. Recognizing patterns of and barriers to immunization could have important consequences for public health policy in long-term care institutions.

Aged↗
PubMed1982

Tetanus toxin fragment forms channels in lipid vesicles at low pH.

Single-walled asolectin vesicles loaded with K+ at pH 7.00 released their K+ content upon incubation with tetanus toxin fragment B but only when the incubation was at pH below 5.00. Whole tetanus toxin exhibited only a weak releasing activity. Toxin light alpha chain and the carboxyl-terminal 48,000-dalton moiety of the heavy chain (fragment IIC) were unable to provoke K+ release from vesicles at any pH. K+ release from lipid vesicles could also be detected with tetanus toxin heavy beta chain at low pH. Furthermore, using a detergent binding assay ([3H]Triton X-100), we have also shown that an hydrophobic domain, localized in the 50,000-dalton terminal polypeptide of tetanus toxin heavy chain, is detectable at pH 3.60 but not at pH 5.00. These results lead us to conclude that the ability of tetanus toxin fragment B to release K+ from asolectin vesicles at low pH is due to the 50,000-dalton amino-terminal polypeptide of the heavy chain present in toxin fragment B. We propose that this phenomenon is caused by channel formation across the vesicle membrane as has been observed for the 23,000-dalton amino-terminal moiety of diphtheria toxin fragment B.

Amino Acid Sequence↗
PubMed2005

Decreased in vitro cellular response to tetanus toxoid and tuberculin in patients using topical corticosteroids.

Topical corticosteroids are the mainstay of treatment in inflammatory skin diseases. Corticosteroids penetrate human skin, especially when the penetration barrier is damaged. Whether long-term application of topical corticosteroids can lead to alteration of immune responses is not clear. We sought to examine the impact of topical corticosteroids on immune responses in patients using long-term topical corticosteroids. Peripheral blood mononuclear cell proliferation in response to tetanus toxoid and tuberculin stimulation was studied, and tetanus toxoid-specific antibodies were examined with ELISA. The results showed that, compared with the control group, the stimulation indices of patients' peripheral blood mononuclear cell to tetanus toxoid and tuberculin stimulations were lowered, which was especially significant in the tetanus toxoid group. No significant decrease was found in serum levels of tetanus toxoid-specific antibody. The results suggest that topical corticosteroids can suppress cell-mediated immune response in patients using long-term topical corticosteroids.

Administration, Cutaneous↗
PubMed1978

Selective binding, uptake, and retrograde transport of tetanus toxin by nerve terminals in the rat iris. An electron microscope study using colloidal gold as a tracer.

A series of specific macromolecules (tetanus toxin, cholera toxin, nerve growth factor [NGF], and several lectins) have been shown to be transported retrogradely with high selectivity from terminals to cell bodies in various types of neurons. Under identical experimental conditions (low protein concentrations injected), most other macromolecules, e.g. horseradish peroxidase (HRP), albumin, ferritin, are not transported in detectable amounts. In the present EM study, we demonstrate selective binding of tetanus toxin to the surface membrane of nerve terminals, followed by uptake and subsequent retorgrade axonal transport. Tetanus toxin or albumin was adsorbed to colloidal gold particles (diam 200 A). The complex was shown to be stable and well suited as an EM tracer. 1-4 h after injection into the anterior eye chamber of adult rats, tetanus toxin-gold particles were found to be selectively associated with membranes of nerve terminals and preterminal axons. Inside terminals and axons, the tracer was localized mainly in smooth endoplasmic reticulum (SER)-like membrane compartments. In contrast, association of albumin-gold complexes with nervous structures was never observed, in spite of extensive uptake into fibroblasts. Electron microscope and biochemical experiments showed selective retrograde transport of tetanus toxin-gold complexes to the superior cervical ganglion. Specific binding to membrane components at nerve terminals and subsequent internalization and retrograde transport may represent an important pathway for macromolecules carrying information from target organs to the perikarya of their innervating neurons.

Animals↗
PubMed1979

Selective retrograde transsynaptic transfer of a protein, tetanus toxin, subsequent to its retrograde axonal transport.

The fate of tetanus toxin (mol wt 150,000) subsequent to its retrograde axonal transport in peripheral sympathetic neurons of the rat was studied by both electron microscope autoradiography and cytochemistry using toxin-horseradish peroxidase (HRP) coupling products, and compared to that of nerve growth factor (NGF), cholera toxin, and the lectins wheat germ agglutinin (WGA), phytohaemagglutinin (PHA), and ricin. All these macromolecules are taken up by adrenergic nerve terminals and transported retrogradely in a selective, highly efficient manner. This selective uptake and transport is a consequence of the binding of these macromolecules to specific receptive sites on the nerve terminal membrane. All these ligands are transported in the axons within smooth vesicles, cisternae, and tubules. In the cell bodies these membrane compartments fuse and most of the transported macromolecules are finally incorporated into lysosomes. The cell nuclei, the parallel golgi cisternae, and the extracellular space always remain unlabeled. In case the tetanus toxin, however, a substantial fraction of the labeled material appears in presynaptic cholinergic nerve terminals which innervate the labeled ganglion cells. In these terminals tetanus toxin-HRP is localized in 500-1,000 A diam vesicles. In contrast, such a retrograde transsynaptic transfer is not at all or only very rarely detectable after retrograde transport of cholera toxin, NGF, WGA, PHA, or ricin. An atoxic fragment of the tetanus toxin, which contains the ganglioside-binding site, behaves like intact toxin. With all these macromolecules, the extracellular space and the glial cells in the ganglion remain unlabeled. We conclude that the selectivity of this transsynaptic transfer of tetanus toxin is due to a selective release of the toxin from the postsynaptic dendrites. This release is immediately followed by an uptake into the presynaptic terminals.

Adrenergic Fibers↗
PubMed2001

Incidence of and risk factors for nosocomial pneumonia in patients with tetanus.

From June 1998 through July 2000, 28 patients with tetanus admitted to the Intensive Care Unit for Tetanus and Infectious Diseases at the Hospital das Clínicas of University of Medicine at São Paulo, Brazil, were evaluated to establish what the incidence of nosocomial pneumonia was and what their risk factors were. The degree of severity of tetanus was assessed in all patients by means of APACHE II scores. The mortality rate was 3.6%. There were 63 hospital infections in 20 patients; among these, there were 10 cases of nosocomial pneumonia in 8 patients. Nosocomial pneumonia was associated in univariate analysis with the degree of severity of tetanus, dysautonomy, use of neuromuscular blockers, use of higher doses of diazepam, and lower arterial oxygen and oxygen fractions. In the multiple logistical regression, significance was found for dysautonomy (relative risk, 31.67; 95% confidence interval, 2.68-373.74; P=.006). Dysautonomy was an independent risk factor for pneumonia in patients with tetanus.

Adult↗
PubMed1992

Depressed immune response to tetanus in children with vitamin A deficiency.

A randomized, double-masked, placebo-controlled clinical trial was conducted with 236 preschool children, age 3-6 y, in Indonesia to assess immune status in mild vitamin A deficiency. The immune response to tetanus immunization was used as a measure of immune competence. Clinically normal children (n = 118) and children with mild xerophthalmia (n = 118) were randomly assigned to receive oral vitamin A (60,000 micrograms retinol equivalent) or placebo treatment for a total of four study groups. Two weeks after treatment, children were immunized with diphtheria-pertussis-tetanus vaccine. The immunoglobulin G (IgG) responses to tetanus at baseline and 3 wk following immunization were measured by ELISA. After adjusting for previous tetanus immunization, clinically normal and xerophthalmic children receiving vitamin A had a significantly greater IgG response to tetanus than clinically normal and xerophthalmic children receiving placebo (P less than 0.05). These results suggest that children with mild vitamin A deficiency have a relative immune depression compared with children who have been supplemented to normal vitamin A levels.

Antibody Formation↗
PubMed2002

Antibody response to an eleven valent diphtheria- and tetanus-conjugated pneumococcal conjugate vaccine in Filipino infants.

BACKGROUND: Pneumococcal conjugate vaccines are intended to provide effective protection against pneumococcal infections, but very little information on antibody responses in infants living in countries with high pneumococcal disease burden exists. METHODS: In this study 50 healthy Filipino infants were enrolled at a village health center in Cabuyao to receive 11-valent diphtheria- and tetanus-conjugated pneumococcal vaccine at 6, 10 and 14 weeks of age (primary series) simultaneously with diphtheria-tetanus-whole cell pertussis/polyribosylribitol phosphate conjugated to tetanus toxoid, hepatitis B virus and oral poliovirus vaccines and at 9 months of age (booster dose) simultaneously with measles vaccine. The alum-adjuvanted study vaccine contained pneumococcal polysaccharide of serotypes 1, 4, 5, 7F, 9V, 19F and 23F conjugated to tetanus protein and pneumococcal polysaccharide of serotypes 3, 6B, 14 and 18C conjugated to diphtheria toxoid. Serum samples for enzyme immunoassay analyses were collected at 6, 10 and 14 weeks and 9 and 10 months of age. RESULTS: Very high geometric mean antibody concentrations (GMCs) against most pneumococcal serotypes were observed after the first three doses of vaccine (range, serotype 23F, 3.89 microg/ml to serotype 4, 23.41 microg/ml) with the exception of serotype 6B and 14, with GMCs of 1.12 and 2.18 microg/ml, respectively. The fourth dose increased the GMCs against most serotypes (range, serotype 14, 1.65 to serotype 19F, 33.43 microg/ml). The maternally derived antibodies did not decrease the response to the vaccine. CONCLUSIONS: This first pneumococcal conjugate vaccine study in Asia confirms that the 11-valent diphtheria- and tetanus-conjugated pneumococcal vaccine is highly immunogenic in Filipino infants. The GMCs against most pneumococcal serotypes were substantially higher than described with the same or other pneumococcal conjugate vaccines in other populations.

Antibody Formation↗
PubMed1997

Response to diphtheria and tetanus booster vaccination in pediatric renal transplant recipients.

BACKGROUND: Although inactivated vaccines are recommended for immunocompromized patients, efficacy and safety of diphtheria and tetanus immunization in renal transplant recipients have received little attention so far. The aim of the study was to investigate the response to a standard diphtheria and tetanus booster vaccination in pediatric renal transplant recipients. METHODS: Forty-two children, median age 13.2 years (range, 7.8-18.9 years) with complete primary immunization 9.2 years (0.9-15.4 years) before transplantation were enrolled. Immunosuppression consisted of cyclosporine plus prednisolone in 15 (36%), cyclosporine, azathioprine, and prednisolone in 24 (57%), and tacrolimus plus prednisolone in 3 (7%). Antibodies were measured by enzyme-linked immunosorbent assay before and 1, 6, and 12 months after vaccination. RESULTS: Before vaccination, protective antibody concentrations exceeding 0.1 IU/ml against diphtheria were found in 16 children (38%). Thirty-eight (90%) had protective antibody concentrations against tetanus. After booster immunization, the protection rate against diphtheria rose to 95% at 1 month with a decline to 93% at 6 and 76% at 12 months. Protection against tetanus was complete after vaccination and persisted over the observation. Antibody concentrations were comparable to those reported for healthy children. Statistical analysis showed no influence of allograft function, immunosuppressive regimen, previous cytotoxic therapy, or time between primary immunization and end-stage renal failure on antibody response. Immunization was well tolerated and kidney function remained unaffected in patients with stable allograft function. CONCLUSIONS: Diphtheria and tetanus vaccination can be performed effectively and safely in renal transplant recipients as generally recommended.

Adolescent↗
PubMed1979

The immunology of tetanus.

The results of measurements made in two cases of tetanus suggest that the level of tetanus antibody in the blood cannot be used as a diagnostic test for the disease. The investigation also indicated that an attack of tetanus does not result in a rise in tetanus antitoxin antibody levels. This confirms the opinion that tetanus is not an immunising disease. In the cases described, the pseudocholinesterase level was not of diagnostic value.

Antibodies↗