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Biomedical subjects

T Andersson

Publications and source records attributed to T Andersson.

At least 253 records · Page 14Linked to original sources
PubMed1986

Leukotriene B4 stimulation of phagocytes results in the formation of inositol 1,4,5-trisphosphate. A second messenger for Ca2+ mobilization.

Inositol trisphosphate (InsP3) production and cytosolic free Ca2+ ([Ca2+]i) elevations induced by leukotriene B4 (LTB4)-receptor activation were studied in the human promyelocytic-leukaemia cell line HL60, induced to differentiate by retinoic acid. The myeloid-differentiated HL60 cells respond to LTB4 by raising their [Ca2+]i with a dose-response relationship similar to that shown by normal human neutrophils. The observations of the LTB4 transduction mechanism were compared with those of the transduction mechanism of the chemotactic peptide fMet-Leu-Phe in HL60 cells differentiated with dimethyl sulphoxide. Both LTB4 and fMet-Leu-Phe triggered a rapid (less than 5 s) elevation of [Ca2+]i, which occurred in parallel with the InsP3 production from myo-[3H]inositol-labelled cells. The threshold concentrations of the agonists, for InsP3 production, were found at 10(-9) M, a slightly higher concentration than that required to detect [Ca2+]i elevations. No significant changes were noted in the phosphoinositide levels upon stimulation with LTB4. Exposure to Bordetella pertussis toxin before LTB4 stimulation abolished both the increased formation of InsP3 and the rise of [Ca2+]i. LTB4 and fMet-Leu-Phe elicited elevations of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] with no detectable lag time, followed by slower and more sustained inositol 1,3,4-trisphosphate elevations. Stimulation with various leukotriene analogues revealed a good correlation between both total InsP3 as well as Ins(1,4,5)P3 formation and elevations of [Ca2+]1. Thus LTB4 receptor activation results in an increased production of Ins(1,4,5)P3 via a transduction mechanism also involving a nucleotide regulatory protein, as previously described for the fMet-Leu-Phe transduction mechanism.

Calcium↗
PubMed1986

Calcium binding to bone gamma-carboxyglutamic acid protein from calf studied by 43Ca NMR.

Calcium binding to bone gamma-carboxyglutamic acid protein (BGB) from calf has been studied using 43Ca NMR. The temperature dependence of the 43Ca NMR signal has been used to calculate the calcium ion exchange rate, koff. The dependence of the 43Ca NMR band shape on the [Ca2+]/[BGP] ratio fits well to a chemical equilibrium model having a single Ca2+-binding site with an association constant in the range of 5 X 10(3)-1 X 10(5) M-1. The pH dependence of the 43Ca NMR line-width shows a single apparent pKa value of 5.1.

Amino Acid Sequence↗
PubMed1986

Defective chemiluminescence response in differentiated HL60 cells due to impaired degranulation.

In the presence of dimethyl sulfoxide, the promyelocytic leukemic cell line, HL60, differentiates into apparently mature polymorphonuclear leukocytes. When correlating the superoxide production from HL60 cells with the number of phagocytozing and NBT-positive cells, no difference was observed in comparison with normal peripheral blood leukocytes. In contrast, the luminol-dependent chemiluminescence was greatly impaired in the differentiated HL60 cells. Analysis of degranulation, i.e., release of myeloperoxidase and N-acetyl-beta-glucosaminidase- and myeloperoxidase-mediated iodination by HL60 cells, suggested that the defective chemiluminescence response observed in HL60 cells may be due to impaired release of myeloperoxidase from azurophilic granulae. This may lead to impaired microbicidal activity in these cells.

Cell Differentiation↗
PubMed1986

Superoxide production and chemiluminescence induced in differentiated HL-60 cells by the chemoattractant formyl-methionyl-leucyl-phenylalanine.

Superoxide production and chemiluminescence induced in differentiated HL-60 cells by the chemoattractant formylmethionyl-leucyl-phenylalanine: In order to study the generation of oxidative metabolites in relation to cell differentiation, dimethyl sulfoxide (DMSO) and retinoic acid (RA) differentiated HL-60 cells were stimulated with the chemotactic peptide formylmethionyl-leucyl-phenylalanine (FMLP). The oxidative response was measured as luminol-dependent chemiluminescence, lucigenin-dependent chemiluminescence, and cytochrome c reduction. Cells grown in the presence of DMSO or RA progressively expressed morphological changes, and when the mature cells were exposed to FMLP the cells produced oxidative metabolites. Quantitatively the HL-60 cells grown in the presence of DMSO gave rise to the most pronounced response. No correlation was obtained between superoxide production, luminol-chemiluminescence and lucigenin-dependent chemiluminescence, indicating that different aspects of the oxidative response are elucidated by the three different methods. Furthermore, the experiments show that DMSO and RA-induced differentiation of HL-60 cells leads to granulocyte-like cells with different abilities to produce oxidative metabolites, possibly due to differences in receptor function.

Cell Differentiation↗
PubMed1986

Weekly-dose doxorubicin (WDA) in advanced breast cancer.

Doxorubicin in a weekly fixed dose of 20 mg as i.v. bolus (WDA) was given to 48 patients with mostly pretreated progressing breast cancer. The response rate (CR + PR) was 9/48 (19%), and a further 16 (33%) of the patients achieved stable disease. Myelosuppression was mild and without clinical significance. Other side effects, particularly nausea, vomiting and hair loss were also relatively mild. Cardiac toxicity, however, was seen in six patients. Five of these six patients were previously treated with mitoxantrone or combination chemotherapy containing doxorubicin. Median response duration was 10+ months for responders and 11+ months in patients who had stable disease. It is concluded that weekly-dose doxorubicin has a favourable profile with a low frequency of side effects and that this treatment is an alternative to other cancer chemotherapy in breast cancer, especially when not only CR and PR but even stabilization of disease is considered of benefit to the patient.

Adult↗
PubMed1986

Intra-arterial mitomycin C and intravenous bleomycin as induction chemotherapy in advanced head and neck cancer--a phase II study.

Fifty-six patients with previously untreated, unresectable squamous cell carcinomas of the head and neck region were treated with repeated intra-arterial chemotherapy with mitomycin C using a selective or super-selective angiographic technique, and bleomycin given i.v., followed by radical radiotherapy. In addition, restricted tumour-reductive surgery was done in 18 of these patients. The response rate (CR + PR) after completion of the integrated treatment was 89%, with 63% of the patients showing CR. The toxicity of this regimen was, however, far from negligible. The median survival for this series of patients with advanced head and neck cancers is 19 months, and 17 are still alive after 16 + -66 + months.

Aged↗
PubMed1986

Pharmacokinetics of [14C]omeprazole in patients with impaired renal function.

Pharmacokinetics of [14C]omeprazole and its metabolites were studied after single intravenous and oral doses of 20 and 40 mg, respectively, to 12 patients with chronic renal insufficiency. Blood samples for determination of total radioactivity, omeprazole, OH-omeprazole, sulfone, and sulfide were taken for 24 hours. Urine was collected over 96 hours for determination of total radioactivity and during the first 24 hours for additional assay of omeprazole and metabolites. The mean systemic availability was 70%. The mean plasma t1/2 of omeprazole was 0.6 hours. Unchanged omeprazole was not measurable in urine. Derived pharmacokinetic constants of intact omeprazole were within the range of those reported in healthy individuals. The accumulated 24-hour excretion of radioactive metabolites was related significantly to creatinine clearance. The cumulative excretion of total radioactivity in urine over 96 hours in percent of given dose varied between 25% and 83%.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1986

Endoscopic manometry of the sphincter of Oddi and pancreatic duct in chronic pancreatitis.

Pancreatic duct pressure was studied by endoscopic manometry in 12 patients with chronic pancreatitis and in 9 patients with a normal pancreas (suspected biliary dyskinesia). To study the effect of increased intraduodenal concentration of pancreatic enzymes, the duct pressure was measured before and after intraduodenal enzyme infusion. The mean pancreatic duct pressure was 12 (range, 6-25) mm Hg and 18 (range, 6-38) mm Hg in the pancreatitis and 'control' groups, respectively. The occasional patient in each group who had a high duct pressure also had an elevated sphincter of Oddi pressure. A significant correlation between the two pressures was found in both groups of patients. During intraduodenal infusion of pancreatic enzymes a decrease of the pancreatic duct pressure occurred in only two patients. We conclude that an increased pancreatic duct pressure is not a frequent finding in chronic pancreatitis. An elevation of the duct pressure can also be found in patients without pancreatitis. The sphincter of Oddi pressure appears to be more important for the pancreatic duct pressure than the severity of the pancreatitis. Intraduodenal infusion of enzymes, as done in our study, had an inconsistent effect on the pancreatic duct pressure.

Adult↗
PubMed1986

Characterization of fMet-Leu-Phe receptor-mediated Ca2+ influx across the plasma membrane of human neutrophils.

N-Formyl-L-methionyl-L-leucyl-L-phenylalanine (fMet-Leu-Phe) stimulation of human neutrophils leads to a rapid increase of the cytosolic free Ca2+ concentration, [Ca2+]i, which is significantly reduced by removal of extracellular calcium. In the present study we show that fMet-Leu-Phe-induced [Ca2+]i increases are, in part, mediated by an increase of the plasma membrane permeability to Ca2+. This conclusion is based on the following evidence. In the presence of extracellular calcium, addition of La3+ reduced the fMet-Leu-Phe-induced [Ca2+]i increase to approximately the same level as that observed in the absence of extracellular calcium. A net increase of the plasma membrane permeability for Mn2+ could be observed after fMet-Leu-Phe stimulation, as revealed by intracellular quenching of the quin2 signal. The influx of Mn2+, like that of Ca2+, was inhibited by La3+ and was more pronounced in the absence of extracellular Ca2+, suggesting competition for the same pathway. Temporal dissociation of intracellular Ca2+ release from stores and Ca2+ influx from the medium could be demonstrated by readdition of calcium to cells stimulated in the absence of this cation. This second [Ca2+]i increase could be abolished either by giving the specific chemotactic peptide receptor antagonist, BOC-Met-Leu-Phe, or Co2+. We could also show that the fMet-Leu-Phe-dependent Ca2+ influx was not due to the activation of voltage-dependent calcium channels since depolarization either by K+ or gramicidin D did not affect the resting [Ca2+]i, nor did it affect a subsequent [Ca2+]i increase induced by fMet-Leu-Phe. Furthermore, nifedipine and verapamil, at concentrations known to block classical voltage-dependent calcium channels, had no significant effects on the Ca2+ influx induced by fMet-Leu-Phe. We suggest that fMet-Leu-Phe promotes influx of Ca2+ ions across the plasma membrane of human neutrophils by opening of receptor-dependent calcium channels.

Adult↗
PubMed1986

The role of the cytosolic free Ca2+ transient for fMet-Leu-Phe induced actin polymerization in human neutrophils.

We have addressed the important question as to if and how the cytosolic free Ca2+ concentration, [Ca2+]i, is involved in fMet-Leu-Phe induced actin polymerization in human neutrophils. Stimulation of human neutrophils with the chemotactic peptide (10(-7) M), known to result in a prompt rise of the [Ca2+]i to above 500 nM, also induced a rapid decrease of monomeric actin, G-actin, content (to 35% of basal) and increase of filamentous actin, F-actin, content (to 320% of basal). A reduction of the fMet-Leu-Phe induced [Ca2+]i transient to about 250 nM, resulted in a less pronounced decrease of G-actin content (to 80% of basal) and increase of F-actin content (to 235% of basal). A total abolishment of the chemotactic peptide induced [Ca2+]i rise, still led to a decrease of the G-actin content (to 85% of basal) and increase of F-actin (to 200% of basal). These results indicate that the [Ca2+]i rise is not an absolute requirement, but has a modulating role for the fMet-Leu-Phe induced actin polymerization. Another possible intracellular candidate for fMet-Leu-Phe induced actin polymerization is protein kinase C. However, direct activation of protein kinase C by phorbol 12-myristate 13-acetate (PMA) only resulted in a minor increase of F-actin content. The recent hypothesis that a metabolite of the polyphosphoinositide cycle, independently of [Ca2+]i and protein kinase C, is responsible for actin polymerization agrees well with these results and by the fact that preexposure to pertussis toxin totally abolished a subsequent increase of F-actin content induced by fMet-Leu-Phe.

Actin Cytoskeleton↗
PubMed1985

Differential induction of cytochrome P-450-dependent monooxygenase, epoxide hydrolase, glutathione transferase and UDP glucuronosyl transferase activities in the liver of the rainbow trout by beta-naphthoflavone or Clophen A50.

After administration of beta-naphthoflavone and Clophen A50 to juvenile rainbow trout, activities of hepatic cytochrome P-450-dependent deethylation of 7-ethoxyresorufin was increased 172- and 49-fold, respectively. Glutathione transferase activity towards 1-chloro 2,4 dinitrobenzene and UDP glucuronosyltransferase activities towards p-nitrophenol, 1-naphthol and testosterone were increased 1.4 to 3.0-fold by beta-naphthoflavone or Clophen A50. However, significant increases of the rate of glucuronidation of 1-naphthol by Clophen A50 and of testosterone by both Clophen A50 and beta-naphthoflavone were only determined when the activities were measured in digitonin activated microsomes. Epoxide hydrolase activity was not affected by beta-naphthoflavone or Clophen A50. The time course of induction of the various xenobiotic metabolizing enzymes exhibited different patterns. 7-Ethoxyresorufin-O-deethylase activity reached peak values 3 and 7 days after the administration of beta-naphthoflavone and Clophen A50, respectively. The rate of induction of glutathione transferase activity and UDP glucuronosyltransferase activities towards p-nitrophenol and 1-naphthol were relatively slow and did not reach distinct peak levels. These activities were still on maximum levels 4-6 weeks after the treatment. Glucuronidation of testosterone reached peak values 1 week after treatment with both beta-naphthoflavone and Clophen A50. The dissimilar patterns of induction of the cytochrome P-450-dependent activities and the various conjugation activities may indicate that these xenobiotic metabolizing enzymes are differently regulated in the rainbow trout liver.

Animals↗
PubMed1985

Spectral properties of substrate-cytochrome P-450 interaction and catalytic activity of xenobiotic metabolizing enzymes in isolated rainbow trout liver cells.

A method for the isolation of intact viable rainbow trout liver cells in high numbers is described. The technique involves perfusion of collagenase through the liver. A major part of the cytochrome P-450 in isolated liver cells was present in the oxidized non-substrate bound form. It was observed that 7-ethoxycoumarin was rapidly taken up by the liver cells and bound to cellular cytochrome P-450. The substrate binding spectrum for isolated trout liver cells was slightly modified compared with that obtained with trout liver microsomes. The microsomal affinity of 7-ethoxycoumarin, calculated as the apparent spectral dissociation constant (ks), was elevated 11-fold after fish were treated with beta-naphthoflavone, indicating a qualitative alteration in the nature of the constitutive cytochrome P-450. The metabolism of 7-ethoxycoumarin in isolated liver cells was found to be of a comparable rate to that obtained in liver microsomes. Pretreatment of fish with Clophen A50 or beta-naphthoflavone significantly increased the content of cytochrome P-450 and elevated the rate of 7-ethoxycoumarin deethylation in isolated liver cells. Furthermore, the rate of conjugation of 7-hydroxycoumarin was significantly elevated in liver cells isolated from beta-naphthoflavone treated fish when compared with the control rate. In isolated liver cells, 90% of the 7-hydroxycoumarin formed from deethylation of 7-ethoxycoumarin was further metabolized to conjugated products. However, in beta-naphthoflavone of Clophen A50 treated fish the fraction of conjugated metabolites was markedly decreased, indicating a changed balance between cytochrome P-450 dependent reactions and conjugation reactions in the cell.

Animals↗
PubMed1985

Mitoxantrone as a first-line treatment of advanced breast cancer.

Forty-two women with measurable or evaluable advanced breast cancer who had received neither prior chemotherapy for advanced disease nor any anthracycline-containing regimen as adjuvant were entered in a phase II study of mitoxantrone (Novantrone; dihydroxyanthracenedione). Patients were aged from 36 to 80 years, performance status was from 0 to 2. All patients had normal hematological status and normal renal and liver function tests. Cardiac scintigraphy and sonography techniques were used to monitor cardiac function. Mitoxantrone was administered at a dose of 14 mg/m2 in 100 ml 5% dextrose solution over 30 minutes, repeated every three weeks. The number of courses per patient ranged from 2 to 12. Of 42 eligible patients 39 were fully evaluable for response and all for drug toxicity. Responses to treatment were: complete response four patients, partial response 10 patients, stable disease 18 patients and progressive disease seven patients. The overall response rate was 36% (95% confidence limits 20-52%). Three patients showed decreased left ventricular ejection fraction but no patient developed signs of overt left ventricular failure during the treatment period. Hematological and gastrointestinal toxicities were mild. Hair loss was minimal. The data indicate that mitoxantrone is an effective agent for the treatment of advanced breast cancer with mild side-effects, especially with respect to nausea/vomiting, hair loss and cardiotoxicity.

Adult↗
PubMed1985

Influence of environmental temperature on the induction of xenobiotic metabolism by beta-naphthoflavone in rainbow trout, Salmo gairdneri.

The response of hepatic microsomal cytochrome P-450 monooxygenase and UDPglucuronosyltransferase to a common inducer, beta-naphthoflavone, was investigated in rainbow trout acclimated to 5 or 17 degrees C. The hepatic microsomal 7-ethoxycoumarin-O-deethylase, 7-ethoxyresorufin-O-deethylase, and benzo[a]pyrene hydroxylase activities, measured at 5 or 17 degrees C, were induced at both acclimation temperatures. Maximum response of 7-ethoxyresorufin-O-deethylase and 7-ethoxycoumarin-O-deethylase activities to beta-naphthoflavone was obtained with doses of 5 mg/kg and above, both in warm- and cold-acclimated trout. In warm-acclimated trout the maximum degree of induction of cytochrome P-450-dependent activities was already evident on the day following treatment with beta-naphthoflavone (100 mg/kg), whereas these activities reached maximum values after 3 days in cold-acclimated fish. Furthermore, the maximum induced values of 7-ethoxyresorufin-O-deethylase and benzo[a]pyrene hydroxylase activities were higher in cold-acclimated than in warm-acclimated fish. beta-Naphthoflavone treatment caused a slight but significant increase (1.6-fold) in UDPglucuronosyltransferase activity in warm-acclimated fish when measured at 5 or 17 degrees C, whereas in cold-acclimated fish a significant elevation was seen only when the activity was determined at environmental temperature (5 degrees C).

Animals↗
PubMed1985

Xenobiotic biotransformation in the rainbow trout liver and kidney during starvation.

Microsomal cytochrome P-450-dependent activities in the kidney of fish starved for 6 weeks were significantly lower than in fed fish whereas these activities in the liver were only depressed after 12 weeks of starvation. Hepatic cytochrome P-450-dependent activities were depressed to varying extents after 12 weeks of starvation when different substrates were used. The content of hepatic cytochrome P-450 was not affected by starvation. Hepatic UDP-glucuronosyl transferase activities were not affected by starvation. Induction of several hepatic cytochrome P-450-dependent activities by treatment of fish with beta-naphthoflavone was not influenced by starvation. In the kidneys of fish starved for 12 weeks induced levels of cytochrome P-450-dependent benzo(a)pyrene hydroxylase activities were significantly lower than in the kidneys of fed induced fish.

Animals↗
PubMed1985

Mumps virus-induced enhancement of the in vitro cytotoxicity of cord blood lymphocytes.

Purified lymphocytes from the umbilical cord of healthy donors (CBL) displayed lower natural cytotoxicity (NK) and antibody-dependent cellular cytotoxicity (ADCC) than peripheral blood (PBL) from adult donors. In contrast, CBL treated with small amounts of UV-inactivated or live mumps virions expressed the same level of enhanced cytotoxicity (virus-dependent cytotoxicity (VDCC)) against non-infected target cells as PBL. For individual CBL donors there was no correlation between the level of NK and VDCC, indicating involvement of partly distinct effector cell populations. The heterogeneity of the effector cells active in VDCC was confirmed by cell fractionation experiments. The major CBL effector cells in NK and ADCC were found in 'non-T' lymphocyte fractions and/or in fractions containing cells with high-avidity receptors for IgG. In contrast, CBL fractions consisting of about 100% lymphocytes bearing T-cell markers and depleted of Fc gamma R+ cells were strongly cytotoxic in VDCC when T24 cells (human bladder carcinoma) were the targets. With two other target cell types of similar susceptibility to VDCC, the cytotoxic activity of T-cell-containing fractions was less pronounced, indicating that the target cells play an active role in effector cell selection. The surface marker profiles of the VDCC effector cells were the same for CBL and adult PBL. Incubation of CBL with UV-inactivated virions usually gave no significant stimulation of DNA synthesis above that seen in virus-free controls. Taken together, our results suggest that neither specific recognition of viral antigen by T cells nor mitogenic effects of viral material are involved in VDCC generation.

Adult↗