The role of genetics in the response to tuberculin and to other mycobacterial sensitins.
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Animals↗
Biomedical subjects
M W Bentzon
Publications and source records attributed to M W Bentzon.
Sensitivity to tuberculin and sensitins in Swedish children.
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Antigens↗
Production, assay and partial characterization of guinea pig interleukin 2.
Optimum conditions for the production and assay of guinea pig interleukin-2 (IL-2) have been established. The mitogenic activities of serial dilutions of guinea pig IL-2 preparations were compared in cultures of guinea pig peripheral blood lymphocytes prestimulated for 7 days with phytohemagglutinin (PHA) used at 1 microgram/ml. Parallel log dose-log response curves were used for quantitative comparisons. Optimum IL-2 yields were obtained from cultures of lymph node lymphocytes stimulated for 20 h with Concanavalin A (ConA) at 5 micrograms/ml. Guinea pig T cell lines reactive to mycobacterial antigens were propagated for several months using our IL-2 preparations. The molecular weight of guinea pig IL-2 was estimated to be 30,000 using S-200 gel filtration. The species specificities of guinea pig, human, mouse and rat IL-2s were examined. It was shown that guinea pig T lymphocyte blasts were stimulated only weakly with human IL-2 and not at all with mouse and rat IL-2.
Animals↗
[Immunity to tetanus and diphtheria in children aged 8 to 11].
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Adolescent↗
Acute phase proteins and clinical synovitis activity in patients with rheumatoid arthritis.
A number of laboratory variables, including Hb., ESR and several phase proteins, fluctuated in concord with the clinical signs of synovitis activity in patients with rheumatoid arthritis during a controlled study of 3 disease-modifying anti-rheumatic drugs (DMARD). The correlation between laboratory variables and clinical synovitis was significant in a large patient population but the correlation coefficients were not of such magnitude that any of the laboratory variables reflected clinical synovitis activity in a reliable manner in the individual patients. In patients treated with azathioprine, the response of the Hb, (and consequently of the ESR), was reduced compared to patients given other DMARD. This phenomenon was caused by the bone marrow suppressing effect of azathioprine. However, the effect of azathioprine on the clinical synovitis activity did not differ from that of the 2 other drugs. Similar results were found by reviewing the literature about controlled trials of DMARD. In the present trial the clinical evaluation was performed under optimal conditions. In daily clinical practice the evaluations of the joints may be less than optimal since they may be performed by different rheumatologists with varying experience. Consequently, it may be difficult to do without the unreliable laboratory variables mentioned in the routine assessments of disease activity, unless the quality of routine evaluations of synovitis activity is improved considerably.
Acute-Phase Proteins↗
The quantitative estimation of diphtheria and tetanus toxoids. 1. The flocculation test and the Lf-unit.
Considerable confusion exist in the quantitative estimation of diphtheria and tetanus toxoids. The present paper is the first in a series of papers comparing various quantitative methods. It describes the flocculation test, gives a mathematical model for the three-dimensional reaction surface, and suggests different designs which facilitate the unbiased calculation of the end-point.
Analysis of Variance↗
Evaluation of vaccination requirements to secure continuous antitoxin immunity to tetanus.
To investigate minimal requirements for tetanus revaccination to secure continuous protection, recently recommended by WHO, 637 subjects with documented vaccination history were studied. Antitoxin concentration in serum relative to time corresponded to a steep decline in the first years after vaccination continuing exponentially. By multiple regression analyses duration of immunity after three-dose primary vaccination was calculated to be 5 years (upper 95% confidence limit of estimated risk of serum antitoxin concentration below 0.01 IU ml-1 still less than 0.1%). Serum antitoxin concentration relative to time after revaccination depended upon age at revaccination and interval from primary vaccination. When given in childhood 5 years after primary vaccination revaccination was calculated to offer protection for approximately equal to 21 years, but protection was considerably shorter when given to the elderly. Cross-sectional and longitudinal analyses were compared and statistical approaches were introduced which may be generally applicable for evaluation of vaccination programmes. It was concluded that a vaccination programme consisting of primary vaccination in infancy and one revaccination 5 years later will secure continuous protection to about the age of 25 years. This is considerably simpler than programmes recommended in many countries, in which risk of hyperimmunization is apparent.
Adult↗
Combined imipenem/cilastatin and tobramycin therapy of multiresistant Pseudomonas aeruginosa in cystic fibrosis.
Ten patients with cystic fibrosis (CF) and chronic broncho-pulmonary Pseudomonas aeruginosa infection were given imipenem/cilastatin (100 mg/kg/day) in combination with tobramycin (15 mg/kg/day). Forced vital capacity and forced expiratory volume in the first second improved significantly in nine out of ten patients, and most of the patients improved clinically. P. aeruginosa was not eradicated in any patient and resistance against imipenem developed in all patients during treatment. A concomitant increase in MIC of piperacillin and ceftazidime occurred during treatment. In-vitro bactericidal synergy of imipenem and tobramycin was noted in 57% of pretreatment isolates. Seven patients complained of adverse reactions, mainly gastrointestinal, and treatment of three patients was discontinued after 5, 8, and 12 days of therapy, because of rash or nausea and vomiting. The side effects were considered to be due to imipenem/cilastatin. Because of the rapid development of imipenem resistance despite combination therapy, the high proportion of side effects, and the risk of induction of beta-lactam resistance, imipenem/cilastatin cannot be recommended for routine treatment of CF-patients with P. aeruginosa infection.
Adolescent↗
Biological activity in sensitized guinea pigs of MPB 70, a protein specific for some strains of Mycobacterium bovis BCG.
MPB 70 is a protein found in large quantities in the culture filtrate (CF) of the Tokyo and some other strains of Mycobacterium bovis BCG, and it has a remarkable degree of specificity for these strains. We estimated the molecular weight of MPB 70 to 22,000 by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). SDS-PAGE and immunoblotting showed that MPB 70 was present in high quantities in CF from BCG Tokyo, that it could be also demonstrated in BCG Copenhagen, and that it was absent in CF from M. tuberculosis H37Rv. When the purified MPB 70 preparation used in the present study was run in SDS-PAGE, blotted and stained with a polyclonal rabbit or a monoclonal mouse anti-MPB 70 antibody, several bands in addition to the main 22 kDa band were seen, indicating a tendency of the MPB 70 molecules and/or fragments thereof to form very stable aggregates with themselves. The biological activity of MPB 70 was studied in groups of guinea pigs sensitized with live BCG of the Tokyo and Copenhagen strains. Guinea pigs from both groups developed reactivity to tuberculin PPD as assessed by skin tests and lymphocyte stimulation tests with peripheral blood or lymph node lymphocytes. In addition, a strong and persistent reactivity to MPB 70 was demonstrated in the BCG Tokyo group with both methods. Guinea pigs sensitized with the Copenhagen strain were only weakly reactive to MPB 70. Skin reactions in guinea pigs that had been repeatedly tested with MPB 70 and tuberculin were compared with reactions in animals tested only once. Reactions to MPB 70 in BCG Tokyo sensitized guinea pigs were suppressed by repeated tests, whereas tuberculin reactions were boosted by the interim tests. The levels of specific anti-MPB 70 antibodies were higher in BCG Tokyo- than in BCG Copenhagen-sensitized guinea pigs. MPB 70 has a high degree of specificity and is a strongly immunogenic protein, which may prove useful in studies of mycobacterial immunology.
Animals↗
Susceptibility to diphtheria in populations vaccinated before and after elimination of indigenous diphtheria in Denmark. A comparative study of antitoxic immunity.
The need for routine diphtheria revaccination is still controversial. Only single cases of diphtheria have been observed in Denmark since the mass vaccinations in the 1940s and the introduction of routine vaccination of infants in 1950, despite the fact that general revaccination has not been recommended. An investigation of antitoxin immunity in 1.188 probands 2-69 years of age, randomly or cluster selected, indicated that immunity in the Danish population is still above the limit generally believed to guard against diphtheria epidemics (around 70% being immune in a population). The highest frequency of susceptibility (46%) was found among females 30-39 years of age. Serum antitoxin concentrations in 529 subjects with documentation for complete primary vaccination 1-40 years previously corresponded to a continuous fall-off. Relative to time from vaccination, individuals born when diphtheria occurred frequently in Denmark had significantly higher antitoxin levels than those born later, and among children susceptibility had increased considerably as compared to observations in the 1950s. These phenomena were explained by the effect of natural immune stimulation previously. The present concept of relatively high frequencies of immune subjects also in other western countries may not be valid in the future, when the number of subjects born after the elimination of indigenous diphtheria increases. General revaccinations seem required to maintain herd immunity.
Adolescent↗
Comparative in vitro activities of pefloxacin, ofloxacin, enoxacin and ciprofloxacin against 256 clinical isolates.
The antibacterial activity of four new fluoroquinolone carboxylic acids, pefloxacin, ofloxacin, enoxacin and ciprofloxacin, against 256 clinical isolates was investigated by means of an agar dilution method. Generally, all quinolones tested had a high activity against Gram-negative bacteria. More than 90% of Enterobacteriaceae strains were inhibited by a quinolone concentration of 0.4 microgram/ml. Also strains usually resistant to conventional beta-lactam antibiotics, and sometimes to third-generation cephalosporins, like Enterobacter spp., Serratia spp, and Yersinia spp. were susceptible to the tested quinolones. Ciprofloxacin was 5 to 25-fold more potent on a weight basis against Enterobacteriaceae than the other quinolones. Neisseria meningitidis, Neisseria gonorrhoeae, and Haemophilus influenzae were extremely susceptible to the new quinolones. Ciprofloxacin was about 10 times more potent against Pseudomonas aeruginosa than the other quinolones, and was the only quinolone that was sufficiently active against all tested P. aeruginosa strains (MIC less than or equal to 0.4 microgram/ml). The activity against Gram-positive bacteria was considerably lower. All the quinolones investigated had an acceptable activity against many of the methicillin-sensitive and methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci. The majority of the Streptococcus spp. tested was quinolone-resistant, and was Listeria monocytogenes. Generally, it was evident that ciprofloxacin was more potent on a weight basis than the other quinolones, but this difference was counterbalanced by a higher achievable serum concentration for ofloxacin. Some of the investigated fluoroquinolones might constitute valid therapeutical alternatives to beta-lactam antibodies and aminoglycosides in the treatment of serious bacterial infections.
Anti-Bacterial Agents↗
Experimental pneumococcus infection in mice: comparative in vitro and in vivo effect of cefuroxime, cefotaxime and ceftriaxone.
In a mouse model using intraperitoneal inoculation of Streptococcus pneumoniae type 3, the 50% effective dose, ED50, after single doses one hour post-inoculation was considerably lower for ceftriaxone (CRO) than for cefuroxime (CXM) and cefotaxime (CTX), in spite of the same minimal inhibitory concentration, MIC, of 0.02 mcg/ml against the pneumococcus for all 3 drugs. The bactericidal activity as measured by time-kill curves was similar for the 3 drugs, as was the post-antibiotic effect in vitro. Protein binding in mouse serum was considerably higher for CRO (87%) than for both CTX (35%) and CXM (15%), respectively. Of pharmacokinetic parameters investigated on doses equal to the ED50s, the time the serum antibiotic concentration remained above the MIC (delta T(MIC)) was the factor that varied the least among 3 drugs. Therefore, the superior in vivo effect for CRO is not due to higher intrinsic activity against the pathogen but to the long serum-elimination half-life resulting in an extended delta T(MIC), probably related to the high serum protein binding.
Animals↗
Influence of previous gold treatment and other patient variables on outcome of treatment with disease modifying anti-rheumatic drugs (DMARD) in patients with rheumatoid arthritis.
Based on a 2-year controlled double-blind trial of levamisole, penicillamine, and azathioprine (L, P, and A), a computer aided search for predictive factors of outcome was instituted. Already at month 4 several indicators of synovitis activity were able to discriminate between patients staying in the trial for 24 months and patients whose treatment was discontinued before that time. Patients who had previously received gold therapy responded less favourably to L, P, and A than those who had not received gold. This reduction of response was more pronounced in gold resistant patients than in patients whose gold treatment had been discontinued for other reasons. The only phase protein (of several) with a predictive value was haptoglobin. If, after 4 months of treatment, haptoglobin did not normalize, this finding indicated a lack of response to treatment or a deterioration of synovitis activity during the following 4 months. The response to treatment was not influenced by HLA-types, sex, age, or clinical synovitis, disease duration, functional or anatomical aberrations at the start of treatment. The shape of the response curve as reflected by means of monthly measurements of serum-albumin and ESR was not related to disease duration, HLA-types, or previous gold treatment.
Arthritis, Rheumatoid↗
An evaluation of the polyacrylamide gel electrophoresis fractionation method for the production of Mycobacterium tuberculosis skin test preparations. II. Comparative skin testing on guinea-pigs.
As part of a cooperative inter-laboratory WHO supported project for the fractionation of Mycobacterium tuberculosis skin test preparations, four fractions (designated 15, 7, 4.75 and 3.5%) were evaluated by comparative skin tests on sensitized guinea-pigs. The 7% fraction was the most potent in both homologously and heterologously sensitized animals, and the 4.75% and 3.5% gel fractions showed the lowest activity. Significant levels of cross-reactivity in guinea-pigs immunized with M. bovis BCG, M. kansasii, M. avium and M. intracellulare were demonstrated for all fractions examined, thus reflecting the antigenic relationships among these mycobacteria. These four fractions may qualify as starting material for further studies aiming at a reduction of skin test cross-reactivity.
Animals↗
ELISA for the routine determination of antitoxic immunity to tetanus.
Serum samples from 727 persons with different vaccination histories were assessed for tetanus antitoxin content in an enzyme linked immunosorbent assay (ELISA) and tested for tetanus toxin neutralization activity in mice in order to compare the results obtained by the two methods. Neutralizing antibody activities in sera from individuals previously completely vaccinated correlated well with results obtained by ELISA and the accuracy increased with increasing antitoxin concentration in serum. This correlation was observed in sera from persons vaccinated recently as well as in sera from persons vaccinated many years ago. In sera from persons with an incomplete vaccination history ELISA was found to be an unreliable tool for the prediction of in vivo results. Many of these sera had antitoxin levels by ELISA far above the in vivo values, probably due to the presence of non specific or low avidity antitoxin which is detected in ELISA. The lowest ELISA value reliably predictive of protective antibody activity in serum irrespective of vaccination history was found to be 0.16 IU/ml. It was concluded that ELISA is useful for larger population studies as an initial test, but sera with an antitoxin content below 0.16 IU/ml should also be assessed in a neutralization system.
Adult↗
Comparison in sensitized and unsensitized guinea-pigs of tuberculin PPDs RT 23 and PPD-M by skin tests and lymphocyte stimulation tests. Effect of immunization time.
The biological activities of tuberculin PPD RT 23 and the International Standard for Purified Protein Derivative of Mammalian Tuberculin (PPD-M) were compared in sensitized and unsensitized guinea-pigs by skin tests and lymphocyte stimulation (LS) tests. Estimates of relative potency (RP) from skin test results were dependent on the dose level, on the immunogen used, and, in guinea-pigs immunized with killed tubercle bacilli in oil, also on the immunization time. Relative potency estimates from LS results were dependent on the source of the lymphocytes and were different from estimates obtained from skin tests. Lymphocyte stimulation dose-response curves for the tuberculins were qualitatively different. In contrast to RT 23, PPD-M gave rise to non-specific skin reaction in unsensitized guinea-pigs. Both tuberculins were mitogenic to lymph node lymphocytes isolated from unsensitized guinea-pigs, PPD-M being the more mitogenic of the two tuberculins. The present results confirm that qualitatively different tuberculins cannot be unambiguously calibrated in identical terms and thus emphasize that the uncritical use of (international) standards should be avoided in tuberculin calibration.
Animals↗
Experimental infection with Streptococcus pneumoniae in mice: correlation of in vitro activity and pharmacokinetic parameters with in vivo effect for 14 cephalosporins.
A mouse model using intraperitoneal inoculation of Streptococcus pneumoniae type 3 was used to compare in vitro and in vivo effects of 14 cephalosporins, selected to encompass a wide range of minimal inhibitory concentrations (MICs) against the organism. Antibiotics were subcutaneously administered as single doses 1 hr after inoculation of pneumococci, and the effect was measured as the 50% effective dose (ED50). The correlation between log ED50 and log MIC was highly significant (r = .87, P less than .001). Pharmacokinetic properties of the cephalosporins were estimated after a fixed dose of 5 mg per mouse (167 mg/kg) for all drugs. The only correlation that was significant was between log ED50 and the time the serum concentration remained above the MIC for each drug (r = -.90, P less than .001). Ceftriaxone was the most-effective cephalosporin in vivo because of a combination of high in vitro activity and prolonged serum elimination half-life.
Animals↗
Relationship between penicillinase production and the in-vitro activity of methicillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, and cephalothin against strains of Staphylococcus aureus of different phage patterns and penicillinase activity.
A total of 157 strains of Staphylococcus aureus of different phage patterns and penicillinase production were investigated for their susceptibility to methicillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin and cephalothin by an agar dilution method. Only strains of the 52, 52A, 80, 81 complex had significantly higher IC-50 values than the rest of the strains. No correlation was found between penicillinase production and the IC-50 values. Penicillinase susceptibility divided the antibiotics into two groups: one including methicillin, oxacillin and cephalothin, and the other included dicloxacillin, cloxacillin and flucloxacillin. Nineteen strains of S. aureus which existed in both a penicillinase producing and a penicillinase non-producing form were examined for susceptibility to the six antibiotics. The difference between penicillinase positive and penicillinase negative variants was especially marked for flucloxacillin and cephalothin. Methicillin induction prior to susceptibility testing had only a minor influence on the results. Investigation of the stability of methicillin and the four isoxazolyl penicillins against penicillinase production by 37 strains of S. aureus showed methicillin to be the most stable antibiotic. This was followed by dicloxacillin, cloxacillin, flucloxacillin, and oxacillin in that order. The order of stability was identical and independent of phage pattern and quantitative penicillinase production.
Bacteriophage Typing↗