RP1, a group of genes specifying resistance to carbenicillin, neomycin, kanamycin, and tetracycline and originating in a strain of
Pseudomonas aeruginosa
, was freely transmissible between strains of
P. aeruginosa, Escherichia coli
, and
Proteus mirabilis
. Acquisition of the multiple drug resistance specified by RP1 by these strains was accompanied by acquisition of an extrachromosomal satellite of covalently closed circular deoxyribonucleic acid of molecular weight about 40 million daltons and of buoyant density 1.719 g/cm
3
(60% guanine plus cytosine).
A mutant of the repressed R factor Rla and two mutants of the derepressed R factor Rldrd-19 showing a twoto fourfold increase in resistance to all of the antibiotics to which the wild-type R factors mediate resistance were studied. The increased resistance was due to a two-to fourfold increase in the number of R-factor copies per chromosome. The production of drug-metabolizing enzymes was linearly correlated to the gene dosage. There was also a linear correlation between resistance to the drugs and the production of the corresponding enzymes. The mutations were also expressed in Proteus mirabilis PM1. In Proteus, R factors are split into two plasmids, resistance transfer factor and the resistance part. The mutation in one of the mutant R factors seems to be located in the resistance part. A second fi+ R factor (R100) was introduced into strains already carrying Rldrd-19 or the mutant R factor Rldrd-19B2. In the first case, R100 and Rldrd-19 segregated with equal probability when the bacteria were grown on antibiotic-free medium, whereas, in the second case, R100 was rapidly and preferentially excluded. The R factor Rla mediates resistance to ampicillin, chloramphenicol, streptomycin, and sulfonamide. In a previous communication (21) a mutant of Rla was described (RlBl) that caused a two-to threefold increase in the resistance to all four of these antibiotics and also a two-to threefold increase in pair formation in conjugation experiments. In this paper, RlBl and two similar mutants of the derepressed Rl mutant Rldrd-19 (18) are studied further. The increased resistance is shown to be due to an increased number of Rl copies per chromosome. This permitted a study of the gene dosage effect, showing that there is a linear correlation between enzyme synthesis and number of gene copies. There is also a linear correlation between resistance and enzyme production. MATERIALS AND METHODS Bacterial strains and R factors. Escherichia coli K-12 strains EC1002 (leu, nalr, strr; it is a derivative of C600) and EC1005 (met, nalr; a derivative of
An outbreak of R-factor-mediated carbenicillin resistance in
Pseudomonas aeruginosa
in burned patients in March 1969 was followed by a second outbreak 6 months later. No R-factor-carrying
P. aeruginosa
strains were detected in the intervening period but R-factor-determined lactamase was commonly encountered, particularly in
Klebsiella aerogenes
strains. A comparison of the molecular properties of the R factors in pseudomonads from the first and second phases with those in the
Klebsiella
strains from the intervening period showed them to be very closely related. A single R-factor type therefore may have been maintained in the Burns Unit between the two
Pseudomonas
outbreaks as a plasmid conferring resistance to ampicillin in
K. aerogenes
.
Congenital defects and other disorders have been reported in association with malignant liver tumours. In order to assess their significance, a population-based survey was undertaken on children aged less than 15 years diagnosed with malignant liver tumours during the 30 years 1957-1986. The cases were identified from information collected by the West Midlands Regional Children's Tumour Registry. Pertinent data were extracted from their clinical records, and the original biopsy and any necropsy material were reviewed by a panel of three paediatric pathologists. Of the 50 eligible cases registered, eight were excluded because histology review showed that they had non-malignant conditions (3) or malignancies of extrahepatic origin (4) or because no pathological material was available (1). The diagnoses in the remaining 42 cases were hepatoblastoma (27), hepatocellular carcinoma (3), rhabdomyosarcoma (6), rhabdoid tumour (3) and yolk sac tumour (3). The incidence of primary malignant liver tumours was 1.20 per 10(6) person years and that of the hepatoblastoma sub-group was 0.77 (average childhood population of the West Midlands for the time period being 1,166,500). The presenting clinical, radiological and biochemical features were similar to those reported in other series and the ethnic and social class distributions were unremarkable compared with the local population. Congenital defects or other possibly related features were present in nine (21%) patients. Our results, taken with other reports, suggest that hepatoblastoma is a malignant tumour related to maldevelopment, possibly associated with 11p or 5q mutations, whereas hepatocellular carcinoma is more usually a complication of metabolic and other disorders which lead to cirrhosis.
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