Biomedical subjects
Publications and source records attributed to M Andersson.
We have previously reported that male DBA/1 mice are more susceptible to collagen-induced arthritis than are females. Here we report that oophorectomy makes female mice as susceptible to collagen arthritis as are normal males. Induction of collagen-induced arthritis in mice is a T cell-dependent process. The role of female sex hormones in modulating T cell-dependent autoimmune diseases is discussed.
The incidence of arthritis and the antibody response to mouse and to rat type II collagen after immunization with native rat type II collagen was studied in different mouse strains, including wild mouse-derived strains belonging to the H-2p/H-2q family. High serum levels of antibodies to mouse and rat type II collagen were seen only in H-2q mice, whereas mice belonging to the p, w3, w5, and w17 haplotypes displayed low type II collagen-specific antibody responses. Mice from three different H-2q-carrying strains (DBA/1, NFR/N, and B10.G) with different non-major histocompatibility complex genes were all susceptible to collagen arthritis, but they displayed a varying incidence of arthritis and varying clinical features. No arthritis was seen in non-H-2q mice, except in the B10.CAS2 strain where a few mice developed arthritis despite very low serum levels of type II collagen-specific antibodies. We conclude that small differences in the A beta chain of class II transplantation antigens are of importance for the development of arthritis and for the stimulation of a high response after immunization with type II collagen.
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The plasma pharmacokinetics of adriamycin and 4'epi-adriamycin were studied in patients with malignant tumors of the liver after simultaneous regional administration of equal amounts of the two anthracyclines by the arterial route. The use of a highly selective liquid chromatographic analytical method permitted quantification of plasma concentrations of the two drugs as well as their corresponding 13-hydroxy metabolites. The plasma concentrations of each drug followed a three-compartment open model. On average the area under the plasma concentration time curve (AUC) and the maximum plasma concentration (Cmax) were 2.1 and 1.7 times larger for adriamycin than for 4'epi-adriamycin, respectively. 4'Epi-adriamycin was eliminated faster than adriamycin, the terminal half-life time being on the average 1.5 times higher for adriamycin. These findings are in agreement with what has previously been observed after intravenous administration. The plasma concentrations of the 13-hydroxy metabolites did not exceed 30 ng ml-1. The AUC values of these metabolites were on average 20% of the AUC values of the intact drugs.
Myopotential inhibition during permanent pacing with unipolar leads is a well-recognized clinical problem. A study was undertaken to determine if implantation of the generator in abdominal subcutaneous tissue instead of the conventional pectoral implantation site would reduce the incidence of this inhibition. Forty patients with either an abdominal (group A, n = 20) or a pectoral (group P, n = 20) generator implantation site were subjected to a standardized protocol of muscle provocation and 24-hour ECG. Pulse generators were programmed to the lowest sensitivity level (average, 2.0 mV). Pauses exceeding the stimulation interval were analyzed. During muscle provocation 85% of the patients in group P displayed inhibition, as against 5% in group A (p less than 0.001). During 24-hour ECG, the corresponding values were 95% and 15%, respectively (p less than 0.001). We concluded that abdominal generator implantation significantly reduces the incidence of myopotential inhibition in patients with unipolar pacemaker leads.
In a randomized trial the antineoplastic and toxic effects of doxorubicin (ADR), mitomycin (MMC), and the combination of the two were evaluated in postmenopausal patients with advanced breast cancer using the following treatment regimens: ADR (75 mg/m2 by iv bolus every 3 weeks); MMC (20 mg/m2 by iv bolus every 6 weeks); and ADR (45 mg/m2 by iv bolus every 3 weeks) and MMC (10 mg/m2 by iv bolus every 6 weeks). One hundred one patients were entered in the study. Entrance to single-agent MMC therapy was stopped after allocation of 12 patients because of unacceptable side effects, especially nausea and vomiting, and the suggestion of minor efficacy. One of these patients had partial response, eight had no change, and three had progressive disease. The patients in the ADR and ADR plus MMC group were similar as to the following: age (median, 60 years); menopausal age; disease-free interval; performance status, extent of previous cytotoxic therapy (approximately 90% were pretreated) and radiation therapy; and dominant site of disease but with significantly more involved organ sites in the ADR plus MMC group. Among evaluable patients (42 in the ADR group and 39 in the ADR plus MMC group), response rates were as follows: complete response--21 versus five; partial response--26 versus 44; no change--40 versus 38; and progressive disease--12 versus 13 (P greater than 0.10). Median times to disease progression were 5.2 and 7.8 months, respectively (log-rank test, P = 0.03), but survival times were similar, 9.3 and 10.2 months, respectively (log-rank test, P greater than 0.40). For the two treatment groups suppression of wbc count was similar, while anemia, thrombopenia, and nausea and vomiting were significantly more common among the ADR plus MMC-treated group. Five treatment-induced deaths were observed in the ADR plus MMC group (one from sepsis; two from diffuse hemorrhage; and two from cardiomyopathy), compared to none in the ADR group. In conclusion, this study disclosed no major advantage of the combination of ADR plus MMC compared to ADR alone as second-line treatment of advanced breast cancer, but results from other studies may imply a possible role of MMC as part of second-line combination chemotherapy regimens.
Postmenopausal patients with advanced measurable and/or evaluable breast cancer entered a phase II trial of multiple agent cytotoxic therapy combined with endocrine therapy. Cycles of PNMF (prednimustine, novantrone, methotrexate, and 5-fluorouracil) were repeated every 4 weeks as follows: P, 100 mg/m2 PO on days 1 to 5; M, 40 mg/m2 IV on day 1; F, 600 mg/m2 IV on day 1, and N, 14 mg/m2 IV on day 8. The endocrine therapy was tamoxifen given continuously, 10 mg three times daily. As of May 1985, 32 eligible patients had entered the study, 20 of whom had been treated for a sufficient time to enable evaluation of response. Ten patients responded (one complete, nine partial), five experienced no change, and five patients experienced progressive disease. The treatment regimen was fairly well tolerated, the dose-limiting factor being the hematologic toxicity. Conclusions from the trial must await the inclusion of more patients and longer time of follow-up.
A chromogenic substrate kit for the determination of factor VIII activity (COATEST Factor VIII) has been evaluated in five different laboratories, one of them using a semi-automated procedure. This chromogenic method was compared to one-stage clotting assays for factor VIII determination in plasmas from healthy subjects, carriers of hemophilia A, severe, mild and moderate hemophilia A as well as von Willebrand's patients. In all these cases, a high correlation between these two methods was obtained (r = 0.96-0.99, n = 385) with a good agreement of the assigned potencies at all levels of factor VIII. A good correlation (r = 0.94) was also obtained for the levels of factor VIII after infusion of concentrates in six severe hemophiliacs or after administration of DDAVP to von Willebrand's patients. The chromogenic method is insensitive to preactivation of factor VIII by thrombin, thus yielding valid potency assignments also in these situations. The precision was higher with the chromogenic method than with the one-stage clotting assays (C.V. = 2-5% vs 4-15%). Altogether, the new chromogenic substrate method has proven itself suitable for determination of factor VIII in plasma and concentrates.
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A simple, time-saving and efficient immunization method suitable for the production of mouse monoclonal antibody secreting hybridomas is described. Draining lymph nodes isolated 9 days after a primary immunization were used as the source of antibody producing cells. No systemic spread of antibody producing cells or specific antibodies could be detected. The present protocol was employed to generate a panel of collagen type II reactive monoclonal antibodies. Most of the monoclonals so generated were found to be of the IgG class.
Rat striatal synaptosomal tyrosine hydroxylation was inhibited dose- and pH dependently by a number of dopamine agonists. The catecholic agonists apomorphine and (-)N-n-propylnorapomorphine inhibited synaptosomal tyrosine hydroxylase completely, with IC50 values of around 0.3 mumol/l at pH 6.6. The noncatechol agonists pergolide and bromocriptine and the putative dopamine autoreceptor agonists 3-PPP(-), 3-PPP(+), HW-165 and B-HT 920 produced only partial inhibition of synaptosomal tyrosine hydroxylation at high concentrations. Comparison of the inhibition of synaptosomal and soluble tyrosine hydroxylase indicated that the inhibition produced by apomorphine could be ascribed to a direct effect on the enzyme, whereas this was not the case for the noncatechol agonists. The inhibition produced by pergolide and 3-PPP(-) was not antagonised by either dopamine receptor or alpha-adrenoceptor antagonists. The present results have been compared with results reported in the literature for inhibition of synaptosomal tyrosine hydroxylation and for two other tests of dopamine autoreceptor agonist activity (inhibition of dopamine release from striatal slices in vitro, and inhibition of the gamma-butyrolactone induced increase in dopamine synthesis in vivo). It is concluded that inhibition of striatal synaptosomal tyrosine hydroxylation by dopamine agonists does not fulfil the criteria required for it to be considered as a useful measure of dopamine autoreceptor function.
Early region E3 of adenovirus-2 encodes a glycoprotein, E19, that associates with class I MHC antigens. The interaction occurs concomitantly with abrogated terminal glycosylation of class I antigen heavy chains, as shown by pulse-chase and Endo H digestion experiments. Also the viral protein remains in the high mannose form throughout the chase period. These results do not reflect a general impairment of terminal glycosylation of membrane proteins. Immunofluorescence analyses demonstrated that in virally infected cells E19 and class I antigens accumulate in the perinuclear region. Class I antigens gradually disappear from the cell surface. A diminished cell surface expression of class I antigens may be a means by which adenoviruses evade immune surveillance.
The time trend and the distribution of malignant mesothelioma in Denmark are described on the basis of all notifications of cancer cases to the Danish Cancer Registry during the period 1943-1980. The age and sex adjusted incidence rates of pleural as well as peritoneal mesothelioma are increasing with time and reached in the latest 3-year registration period 1978-1980 a remarkably high total incidence of 14.7 cases per million men and 7.0 cases per million women. Towards the end of the observation period, however, the rate of increase was stagnating and for the younger age-groups even a fall in incidence of this malignancy was noted, perhaps reflecting the introduction of compulsory hygienic precautions in the handling of asbestos in Denmark. The incidence and time trend of peritoneal mesothelioma was similar among males and females while pleural mesothelioma was three times more common among males compared with females and showed an increase in incidence 15 years previous to females. For pleural mesothelioma in men notified through the 10-year period 1968, 1977, a significant excess was associated with residence in areas with high degrees of urbanization and in ship building towns.
Probes isolated from DR and DQ beta cDNA and genomic clones were used in hybridizations to restriction enzyme-digested DNA from human homozygous typing cells (HTC) as well as other DR homozygous cells in order to estimate the number of beta genes in the DR/DQ class II region. Varying numbers of DR beta genes were found in HTC of different DR specificities, from possibly one in DR 8 cells to three in cells of DR 2 to 7. The DR beta genes of different specificities seem to be related to one another in a distinct fashion. In contrast, all HTC contain two DQ beta genes per chromosome. The restriction site polymorphism of DQ beta genes is considerably more extensive than that of DQ serology, although one of the genes seems to be nonpolymorphic. In addition to the two DP beta genes identified previously, a minimum of three to five DQ and DR beta genes exist in the human haploid genome.
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Triazine dyes, bound to polyethylene glycol, have been used to influence the partition of some enzymes within a dextran-polyethylene glycol-water two-phase system. The enzymes, present in a protein extract from baker's yeast, included glucose 6-phosphate dehydrogenase, glyceraldehyde phosphate dehydrogenase, 3-phospho-glycerate kinase and alcohol dehydrogenase. The partition coefficients of the enzymes could be changed by a factor of 10-500 in favour of the polyethylene glycol-rich phase, while the partition of bulk protein was much less affected. The influence of the concentration of polymer-bound dye and phase-forming polymers, temperature, pH, kind and concentration of salt and the presence of nucleotides on this affinity partitioning effect was studied. The extraction was effective even at high concentrations of dye and protein (40 g/l). A partial purification (32-fold) of glucose 6-phosphate dehydrogenase was carried out by an extraction in five steps.
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