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Biomedical subjects

B Pettersson

Publications and source records attributed to B Pettersson.

At least 19 recordsLinked to original sources
PubMed1992

On the biochemical modulation of 6-mercaptopurine by methotrexate in murine WEHI-3b leukemia cells in vitro.

The chemicals 6-mercaptopurine (6-MP) and methotrexate (MTX) are the cornerstones in the maintenance treatment of acute lymphoblastic leukemia. The intracellular metabolism of 6-MP to 6-thioguanosine nucleotides (TGN) via 6-thioinosine 5'-monophosphate (TIMP) is crucial for its cytotoxic effect. MTX inhibits purine de novo synthesis and thereby increases the intracellular PRPP being a substrate for the phosphoribosylation of 6-MP to TIMP. Hypoxanthine has been shown to inhibit the uptake of 6-MP over the cell membrane and the phosphoribosylation of 6-MP to TIMP. We have previously shown that the conversion of TIMP to TGN decreases at 6-MP concentrations above 5 microM in vitro. The aim of the present study was therefore to investigate the effect of MTX increasing the PRPP and TIMP concentrations and of hypoxanthine decreasing the TIMP concentration on the formation of TGN from TIMP. Murine myelomonocytic leukemia cells (WEHI-3b) were treated with 6-MP in vitro. The drug concentration was kept constant by continuous addition of 6-MP during the experiment. With this technique, the concentration of TGN begins to decrease already at 6-MP concentrations above 2 microM. The addition of 0.2 microM MTX 6 h before 6-MP strongly inhibited the purine de novo synthesis, decreased the ATP, and increased the PRPP concentration 4-fold. The intracellular concentrations of TIMP and to a lesser extent TXMP also increased. The concentrations of the TGN were, however, basically unaffected by the preincubation with MTX. Simultaneous addition of 20-50 microM hypoxanthine and 6-MP decreased the accumulation of all cellular 6-MP metabolites. It is concluded that the synergistic cytotoxic effect of the combination of 6-MP and MTX is not based on biochemical modulation of the 6-MP metabolism by MTX.

Animals↗
PubMed1992

Reduced risk of hip fracture in women with endometrial cancer.

The effect of excessive endogenous oestrogens on the risk of hip fracture was investigated in a population-based cohort of 2111 women with endometrial carcinoma who were followed up from age 50 years regarding the occurrence of a first hip fracture. Overall, 77 cases of hip fracture were observed, as against 120.8 expected, which meant a significantly reduced relative risk, standardized incidence ratio (SIR) = 0.6, 95% confidence interval (CI): 0.5-0.8. This possible protective effect was significant for cervical fractures, SIR = 0.6 (95% CI: 0.4-0.8), but not for trochanteric, SIR = 0.8 (95% CI: 0.5-1.1). Age at endometrial cancer diagnosis was not a determinant of the risk of hip fracture. A lowered relative risk was present regardless of age at diagnosis and persisted during the entire follow-up period and into advanced ages. A case-control analysis within the cohort, and based on medical record data, indicated that a higher weight might be associated with a greater protective effect, as compared with a lower weight. Exposure to exogenous oestrogens was infrequent and could not have explained the present results. We conclude that persistent influence of oestrogens, notably of endogenous origin, can reduce the risk of hip fractures, and that this protective effect may be long-lasting and extend to advanced ages.

Adult↗
PubMed1992

The use of a bladder pressure warning device during transurethral prostatic resection decreases absorption of irrigation fluid.

During a period of 4 weeks 102 patients underwent transurethral prostatic resection (TURP). Of these, 50 were randomly allocated to the use of an intravesical pressure device which warned the surgeon at a pressure elevation of 1.5 kPa. Ethanol (1%) was used as a marker in the irrigation fluid (glycine 2.2%), and absorption of ethanol-tagged irrigation fluid was detected by measurements in the expired air. In 28 patients absorption took place (in 8 of the 50 patients equipped with the warning device and in 20 of the 52 without the device). The greatest absorption was seen in the group without the device. No differences were found between the groups with regard to age, resected mass, resection time, resection speed, or haemorrhage. Patients who absorbed irrigation fluid were slightly older and bled more, and the resected mass was larger. The use of a pressure warning device reduces the amount of irrigation fluid absorbed and the number of patients who absorb irrigation fluid, and minimises the risk of the TUR syndrome.

Absorption↗
PubMed1991

Trends in thyroid cancer incidence in Sweden, 1958-1981, by histopathologic type.

Time trends in the incidence of malignant neoplasms of the thyroid were examined for Sweden for the period 1958-81, 5,838 cases being studied. Autopsy-diagnosed cases were excluded. Mean annual changes in the age-standardized rates over this period were 1.9% and 1.2% for women and men, respectively, for all thyroid carcinomas combined; 4.9% and 2.1% for papillary carcinoma; 0.9% and 2.1% for follicular carcinoma; and -1.0% and -2.1% for anaplastic carcinoma. Age, period and cohort models were fitted. There was a progressive increase in papillary cancer incidence for cohorts born since 1919. This increase cannot be satisfactorily explained as an artefact of trends in classification, and probably reflects a real increase in incidence. A less marked increase was seen for follicular cancer, and there was a decline for cohorts born since 1939. While the risk of papillary and anaplastic carcinoma was lower in iodine-deficient areas, follicular cancer risk was twice as high in these areas, for men only. There was a steady decline of anaplastic cancer in both sexes after 1965, largely attributable to a decline in cohorts born since 1924.

Age Factors↗
PubMed1991

Determination of 2-chloro-2'-deoxyadenosine in human plasma.

The first high performance liquid chromatographic method for determination of the plasma concentration of 2-chloro-2'-deoxyadenosine (CdA) in patients, which is significantly more sensitive than the previously used RIA method, is presented. CdA is a purine analogue with useful clinical activity against lymphoproliferative disorders and it has recently been found to be the single most active agent in the treatment of hairy cell leukaemia. Guaneran (6-nitroimidazol-6-thioguanine) was added to 1 mL plasma as the internal standard and CdA was extracted using ethyl acetate. A Perkin-Elmer C18, 3 mu, 8 cm column was used for the separation of CdA and the internal standard from endogenous compounds in the sample with a mixture of sodium phosphate buffer 10 mM, methanol and acetonitrile (85:10:5, pH = 3.0) as the mobile phase. The sensitivity of the method (1 nM) allows the determination of CdA in plasma 24 h after the administration of 0.14 mg/kg as a 2 h infusion.

2-Chloroadenosine↗
PubMed1990

On the paradoxically concentration-dependent metabolism of 6-mercaptopurine in WEHI-3b murine leukemia cells.

The intracellular metabolism of 6-mercaptopurine (6-MP) was studied in a murine leukemia cell line, WEHI-3b. Cells were incubated 3 to 24 h with 10 nM to 50 microM 6-MP. Nucleotides were extracted with perchloric acid, and the 6-thiopurine nucleotides were isolated on mercurial cellulose. The endogenous ribonucleotides in the perchloric acid extracts as well as 6-thiopurine nucleotides were separated and quantified with anion exchange high-performance liquid chromatography. The concentration of 6-thioinosinate (6-TIMP) and 6-thioxantinate (6-TXMP) increased with an increasing 6-MP dose. The concentration of the 6-thioguanosine nucleotides (6-TGN) increased with 6-MP concentrations between 10 nM and 1 microM. However, further increase in 6-MP concentration led to a decrease in the formation of 6-TGN. At 50 microM 6-MP, the concentration of 6-thioguanosine 5'-triphosphate was one fifth of that seen at 1 microM. The incorporation of 6-[35S]mercaptopurine into DNA was also slightly higher at 1 microM compared with 50 microM. The cytocidal effect on clonogenic cells was one log greater at 1 microM 6-MP compared with 50 microM 6-MP. The decrease of 6-TGN was accompanied not only by an increased 6-TIMP concentration but also by an inhibition of the purine de novo synthesis and consequently by a decrease of the cellular ATP concentration. The ATP concentration in the cells treated with 1 microM 6-MP could be reduced to the level seen in cells treated with 50 microM 6-MP by simultaneous incubation with 0.3 microM antimycin A. This decrease of ATP concentration was accompanied by a reduction of 6-TGN and to a lesser extent of 6-TXMP. These experiments suggest that the "self-limiting" phenomenon in the metabolism of 6-MP might be caused by a depletion of ATP by inhibition of purine de novo synthesis presumably by 6-TIMP.

Animals↗
PubMed1990

Trends in endometrial cancer incidence and mortality in Sweden, 1960-84.

Trends in incidence of and mortality from invasive endometrial cancer in Sweden in 1960-84 were analyzed. The study was based on virtually all 20,371 patients given this diagnosis and 4,887 patients who died of the disease in that period. Only minor changes occurred in age-standardized incidence in pre-menopausal women, in whom the rates declined consistently during the last 15 years, especially in the youngest age groups. Among post-menopausal women, an early increase was followed by stable rates in women over 60 and decreasing rates at ages 50-59 years. In contrast, mortality rates decreased consistently over the study period. Multivariate regression analyses indicated that birth cohort was a more important determinant of incidence and mortality than was time period. The relative risk of developing endometrial cancer increased by about 20 percent in women born around 1900 as compared with 1880, and by an additional 40 percent from the 1910 cohort to the maximum risk attained in those born around 1930. In successively younger birth cohorts, the risk markedly and continuously declined. These strong birth-cohort effects after 1910 may be reasonably explained by the change from the risk-increasing estrogen-only replacement therapy introduced in the 1960s to the less harmful use, starting about 10 years later, of combined estrogen-progestogen regimens; and further, by the protective exposure of a large proportion of pre-menopausal women to oral contraceptives. Mortality, however, decreased steadily in successive cohorts from those born in 1890, indicating that the increase in incidence was referable mainly to non-lethal cancers.

Aged↗
PubMed1990

Determination of plasma azathioprine and 6-mercaptopurine in patients with rheumatoid arthritis treated with oral azathioprine.

Two specific high-performance liquid chromatography methods for determining plasma concentrations of azathioprine and 6-mercaptopurine after oral administration of azathioprine are presented. It was shown that azathioprine is unstable in the blood samples unless immediately cooled in ice water. The 2-amino analog, guaneran, was used as internal standard for azathioprine, which was extracted from plasma with ethylacetate. A Nucleosil C18 column was used for the separation. The detection limit was 6 nM. For quantification of 6-mercaptopurine, 6-thioguanine was used as internal standard. Plasma was deproteinized with HClO4 and the sample was purified on mercurial cellulose. A Beckman ODS column was used and the detection limit was 5 nM. Pharmacokinetic data from two patients are presented. Unchanged azathioprine was seen until 6 h after an oral dose of 32 mg/m2.

Administration, Oral↗
PubMed1990

Evaluation of a system for classification of stones and their sites in kidneys treated with extracorporeal shock wave lithotripsy.

The results of treatment with extracorporeal shock wave lithotripsy (ESWL) were recorded in 1067 patients with renal calculi during their first admission to hospital. All treatments were performed in an unmodified Dornier HM3 lithotripter according to the original recommendations whereby the generator voltage was usually set between 18 and 23 kV. The stones in kidneys treated with ESWL alone were first classified into four different types (A. B. C. D) and after which a further subgrouping was carried out according to the number and sites of stones in the renal pelvis or calyces. The number of shock-waves. the energy index. the duration of treatment, and length of hospital stay as well as the therapeutic results after four weeks and six months were recorded for the different subgroups. An approximate estimate of the stone volume was calculated from measurements on a plain abdominal radiograph. The mean stone volume, number of shock waves, energy index, duration of treatment, and length of hospital stay increased progressively and significantly from group A to group D. The stone volumes and the energy indexes in the different subgroups within each type were distributed around levels that clearly differed between the types. Although minor variations were observed similar patterns also were recorded for the retreatment rate, the total duration of treatment, and the length of hospital stay. The therapeutic result, expressed as satisfactory disintegration, showed roughly similar results within each group but, as expected, the success rate decreased when more complicated stones were treated. Although stones located in the renal pelvis were often bigger than calyceal stones, the former seemed to disintegrate more easily.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation Studies as Topic↗
PubMed1989

Risk of endometrial cancer after treatment with oestrogens alone or in conjunction with progestogens: results of a prospective study.

OBJECTIVE: To determine the relative risk of developing endometrial neoplasia after treatment with oestrogens alone or in conjunction with progestogens. DESIGN: Prospective cohort follow up study, average observation period 5.7 years for each patient. To have a 90% chance of detecting a relative risk of 2.0 with 95% significance the study required 78,000 person years of observation. SETTING: Community based cohort. PATIENTS: Women aged over 35 who were prescribed non-contraceptive oestrogens in the Uppsala health care region during April 1977 to March 1980 were identified from pharmacy records. Of all prescriptions issued, 95% were identified. Patients from the cohort who developed endometrial neoplasia were identified from the cancer registry of the Uppsala health care region. Compliance, sociodemographic data, and lifetime exposures to oestrogen and cyclically added progestogen were assessed by questionnaire in a sample of the cohort. The final cohort consisted of 23,244 patients (133,373 person years). The prevalence of university education, oophorectomy, and hysterectomy was higher in the cohort than the general population; no other confounding factors were identified. MEASUREMENTS: The total number of person years was divided into exposure groups by inference from the data from the questionnaire. Compensation was made for the excess of hysterectomies. Specimens from all cases of endometrial neoplasia in the cohort and 90% of cases in the general population were studied blind histopathologically. Characteristics of treatment of all women who had endometrial neoplasia were assessed by questionnaire. Relative risks and 95% confidence intervals were calculated. RESULTS: Seventy four cases of carcinoma and 33 cases of premalignant lesions occurred in the cohort. The relative risk of endometrial carcinoma was 1.8 (95% confidence interval 1.1 to 3.2) after exposure to any oestrogen compound without progestogen for more than six years; 2.2 (1.2 to 4.4) after more than three years' exposure to conjugated oestrogens without progestogen; and 2.7 (1.4 to 5.1) after more than three years' exposure to oestradiol compounds without progestogen. When carcinoma and premalignant lesions were considered together the results were similar but the relative risk was higher. Risk of carcinoma did not increase when progestogens were cyclically added to oestrogens for the entire treatment period (relative risk 0.9 (0.4 to 2.0]. CONCLUSIONS: Use of oestrogens without progestogens is associated with a twofold to threefold increase in risk of endometrial neoplasia. Use of progestogens either removes this increased risk or delays its onset. A further follow up of the cohort is essential to analyse the risks with greater statistical power.

Adult↗
PubMed1989

Are prophylactic antibiotics necessary during extracorporeal shockwave lithotripsy?

A randomised clinical study was carried out on patients admitted for ESWL treatment in order to establish the requirement for prophylactic treatment with antibiotics during this procedure. Patients with clinical signs of urinary tract infection, evidence of infectious stones or a positive urine culture were excluded. All other patients were consecutively randomised into 3 groups which were given either trimethoprim + sulphamethoxazole or mecillinam (Group A), methenamine hippurate (Group B), or no treatment at all (Group C). Evaluation with respect to clinical signs of infection was done immediately after the treatment and 4 weeks later. In addition, a urine culture was performed 2 weeks after ESWL, i.e. 1 week after completing treatment with antibiotics and methenamine hippurate. With respect to infectious complications there were no differences between Groups A and C, between Groups B and C or between Group A and B+C, whereas an unexplained slightly higher infectious rate was recorded for Group B compared with Group A. In all patients the occurrence of bacteriuria was low (6.7%) despite the fact that almost 30% of patients had a ureteric catheter during the ESWL procedure. Patients with ureteric catheters did not present with more infectious complications than those without. All patients had a bladder catheter during ESWL. It was concluded that prophylactic treatment with antibiotics during ESWL treatment is unnecessary in all situations where an infectious aetiology is unlikely.

Adult↗
PubMed1979

Flavoprotein-linked substrate oxidation in preparations of hamster brown adipocytes. A discrimination between internally and externally oxidized substrates.

Noradrenaline-stimulated oxidative metabolism in isolated hamster brown fat cells is very reproducible between different cell preparations, 565 +/- 81 (S.D.) nmol O/min per 10(6) cells (n = 25). In contrast, the oxygen consumption rate induced by the addition of succinate or sn-glycerol 3-phosphate strongly varies between different cell preparation, although these substances have been reported to be potent substrates for isolated hamster brown fat cells. By filtration and by successive washings we demonstrate that the flavoprotein-linked substrate oxidation is mainly dependent on extracellular succinate and sn-glycerol 3-phosphate-oxidizing enzymes. These enzymes originate from damaged and broken cells and are present in different amounts in different cell preparations. In discriminating between intra- and extracellular succinate oxidation 5,5'- dithiobis(2-nitrobenzoate) is used as an inhibitor of the extracellular portion. This application of 5,5'-dithiobis(2-nitrobenzoate) ought to be useful also in other cell or tissue preparations. Added succinate can, however, be oxidized by the intact brown adipocyte but at very low rate, probably as a result of a limited transport rate over the membrane(s). In the presence of noradrenaline, added succinate can potentiate the noradrenaline-inducible oxygen consumption by catalytically increasing the oxidative capacity of the citric acid cycle. Our conclusions is that the only effectors which significantly increase oxidative metabolism in intact isolated hamster brown fat cells are catecholamines and free fatty acids. Provided the cells are uncoupled, also pyruvate can function as substrate for these cells.

Adipose Tissue, Brown↗