ROUGH MUTANTS OF SALMONELLA TYPHIMURIUM. I. GENETICS.
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Biomedical subjects
Publications and source records attributed to T V SUBBAIAH.
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A controlled comparison by the Tuberculosis Chemotherapy Centre, Madras, of the merits of home as compared with sanatorium treatment for pulmonary tuberculosis showed that, at the end of a year of chemotherapy with isoniazid plus p-aminosalicylic acid (PAS), the response of the home patients closely approached that of the sanatorium patients. The present report reviews the progress of those patients in the controlled comparison whose disease had attained bacteriological quiescence by the end of the year of combined chemotherapy. During the second year, half of the patients received further chemotherapy, with isoniazid alone, and half received a placebo, calcium gluconate. During the third year, half of those who were treated with isoniazid in the second year and whose disease remained quiescent continued to receive that drug and all the remaining patients with quiescent disease received the placebo. In the second and third years all the patients were treated at home and administered the medicaments to themselves.It has been concluded from this follow-up study that in the second and third years there was relatively little difference between the progress of the patients whose disease attained quiescence following a year of domiciliary treatment with isoniazid plus PAS and that of those whose disease attained quiescence following a year's treatment with the same drugs in sanatorium; that a second or third year of further treatment with isoniazid alone gave no better results than a year of combined chemotherapy, followed by careful observation of the patient and further chemotherapy if relapse occurred; and that the relapse rate among the patients with residual cavitation at the end of the year of combined chemotherapy was slightly higher than that among the patients with no residual cavitation at the end of the first year.
A series of studies has been undertaken by the Tuberculosis Chemotherapy Centre Madras, with the ultimate object of finding out whether differences in the virulence of the tubercle bacilli isolated from Indian tuberculous patients before the start of chemotherapy are related to the severity of the patients' disease and to the subsequent response to treatment. This paper-the second in the series-presents the results of a comparative investigation of the virulence in the guinea-pig of tubercle bacilli obtained from Indian and from British tuberculous patients before treatment. In this investigation, which was carried out at the Centre and at the Microbiological Research Establishment, Porton, England, the virulence of the Indian and the British cultures was assessed by guinea-pig mortality, by the "root-index of virulence" (based on the post-mortem tuberculous disease score and the survival period of the animal), and by the results of spleen culture. The Indian cultures were found, on the average, to be less virulent and to show a w der range of virulence than the British cultures, both in the Porton and in the Madras series of experiments. A further indication of the heterogeneity of the Indian tubercle bacilli was provided by the results of tuberculin tests: whereas the British cultures appeared to be homogeneous in their ability to induce tuberculin allergy in the guinea-pig, the Indian cultures showed considerable variation in this respect.
In order to find out whether chemotherapy with isoniazid affects the virulence in the guinea-pig of tubercle bacilli that do not develop resistance to the drug, virulence tests were carried out on isoniazid-sensitive cultures obtained from 20 South Indian tuberculous patients before treatment and after three months of chemotherapy with isoniazid. No significant difference in virulence was observed between the cultures obtained on admission to treatment and those obtained after three months of chemotherapy. This is a finding with important implications for large-scale surveys of the distribution of attenuated strains of tubercle bacilli from untreated patients in India and other countries. Detailed and repeated inquiries as to previous chemotherapy are not important in such surveys, provided that sensitivity tests are done on all the cultures.
A series of studies on the virulence in the guinea-pig of tubercle bacilli isolated before treatment from Indian tuberculous patients admitted to a controlled comparison of different regimens of domiciliary chemotherapy has recently been undertaken by the Tuberculosis Chemotherapy Centre, Madras. The main object of these studies was to determine whether the differences in virulence of the tubercle bacilli obtained from Indian patients before the start of chemotherapy were related to the severity or type of the patients' disease at that time and to the subsequent response to treatment. Before these relationships could be investigated, however, it was necessary to find out whether the results of the virulence tests, which were carried out over a period of two-and-a-half years at the Centre and at the Microbiological Research Establishment, Porton, England, could be considered as a unified whole-that is, as if they had all been done on the same day in the same laboratory.A proportion of the cultures was stored at - 20 degrees C for 44-78 weeks, but this did not affect their virulence. Inter-experimental variation was found to be small in the Porton series of tests and undetectable in the Madras series, and the results in the latter series could be successfully adjusted to those in the former by allowing for differences in the means and standard deviations of the distributions for the two series. The measure of virulence used was found to be reasonably acceptable for the analysis of variance technique. Suggestions are made as to ways of improving the efficiency of the experimental design in future studies.
This is the last of a series of three reports from the Tuberculosis Chemotherapy Centre Madras, on a study undertaken with the object of finding out whether differences in the virulence in the guinea-pig of tubercle bacilli isolated from South Indian tuberculous patients before the start of chemotherapy are related to the severity of the patients' disease on admission to treatment and to the subsequent response to chemotherapy. The 281 patients in this study were drawn from the patients admitted to a 1-year comparison of four domiciliary chemotherapeutic regimens: (a) 3.9-5.5 mg/kg isoniazid plus 0.2-0.3 g/kg sodium PAS daily, divided into two doses (PH series); (b) 7.8-9.6 mg/kg isoniazid alone daily in one dose (HI-1 series); (c) 7.8-9.6 mg/kg isoniazid alone daily, divided into two doses (HI-2 series); (d) 3.9-5.5 mg/kg isoniazid alone daily, divided into two doses (H series).No evidence was found of an association between the virulence of the organisms and any pretreatment condition of known prognostic importance. There was no association between pretreatment virulence and progress during treatment in the PH series (the most effective regimen). In the other series, however, the progress was more satisfactory in patients infected with organisms of low virulence than in those infected with organisms of high virulence, the association between virulence and progress attaining statistical significance in the combined HI-2 and H series (the least effective regimens) and only just failing to do so in the smaller HI-1 series.Possible explanations are put forward both for the absence of an association between virulence and severity of disease on admission and for the presence of an association between virulence and response in the patients treated with isoniazid alone.
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In a comparison of home and sanatorium treatment for tuberculous patients in India, pretreatment cultures of tubercle bacilli showed a higher average level of resistance to p-aminosalicyclic acid (PAS) than pretreatment cultures from a representative sample of patients in Great Britain. The investigation described in the present paper was therefore undertaken to find out the nature of the difference in the PAS sensitivity of cultures from Indian and British patients. In this investigation, carried out jointly at the Tuberculosis Chemotherapy Centre, Madras, and the Postgraduate Medical School of London, sputum specimens from 147 Indian and 93 British patients were cultured and subjected to sensitivity tests. The tests were set up on slopes containing various concentrations of PAS and inoculated with 10(5) viable units of the cultures, and the minimal concentrations of PAS inhibiting the growth of 20, 50 and 100 colonies were determined. According to the 20-colony end-point-the one commonly used in routine sensitivity tests-the Indian strains were significantly more resistant than the British strains. This difference in sensitivity was not apparent, however, in either the 50-colony or the 100-colony results. The presence of a small proportion of resistant organisms was found to be a general characteristic of the Indian strains, but did not appear to be related to any special tendency for the patient to fail to respond to treatment with PAS. Since a chance increase in the inoculum size might well affect the 20-colony results, the authors recommend a tenfold decrease in the size of the inoculum used in routine PAS-sensitivity tests on Indian patients.
A recent report by the Tuberculosis Chemotherapy Centre, Madras, showed that the response of patients to a year's domiciliary treatment for pulmonary tuberculosis with isoniazid plus p-aminosalicylic acid closely approached that of patients to a year's sanatorium treatment with the same combination of drugs. The present report summarizes the findings of a second year's study, carried out on those patients in the first-year study whose disease had attained bacteriological quiescence by the end of the year of combined chemotherapy. The main objects of this follow-up study were to determine (a) whether relapse in the second year was more frequent among the patients originally treated at home than among those originally treated in sanatorium, (b) whether a second year of antituberculosis chemotherapy, with isoniazid alone, would reduce the relapse rate and (c) the influence of residual cavitation at one year, the so-called "open negative" syndrome, on the results in the second year. During the second year all the patients were treated at home, either with isoniazid or with a placebo, calcium gluconate; in each case the medicine was administered by the patients themselves. It was found that there was very little difference in the relapse rates of the "home" and "sanatorium" groups, that a second year of treatment with isoniazid alone did not influence the likelihood of relapse, and that patients with the open negative syndrome fared slightly less well in the second year than patients without residual cavitation.