Positron emission tomography applied in the study of pituitary adenomas.
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Adenoma↗
Biomedical subjects
M Bergström
Publications and source records attributed to M Bergström.
Genetic variation in Con A-induced production of interleukin 2 by porcine peripheral blood mononuclear cells.
Genetic variation in concanavalin A (Con A)-induced proliferation and interleukin 2 (IL-2) production by peripheral blood mononuclear cells (PBMC) was studied in blood collected from 96 piglets, aged 7 weeks. The piglets were the offspring of seven sires and 24 dams. Pronounced differences between litters from various dams were observed in the immune parameters measured. Also, large individual differences in the magnitudes of Con A-induced proliferation and IL-2 production were seen for PBMC collected from individual pigs within each litter. Both the time course and magnitude of IL-2 activity showed genetic variation, as results from the offspring of the seven sires differed significantly. However, only the time course, not the magnitude, of proliferation differed among the offspring groups. It was possible to establish a rank order for the sires based on the IL-2 production of PBMC by their offspring. As IL-2 has a key role in regulating the immune response, mitogen-induced IL-2 activity seems to be a good candidate as a general marker for cell-mediated immunity in pigs.
Animals↗
Inhibition of the growth of cultured human meningioma cells by recombinant interferon-alpha.
In this paper the results of investigations on the effect of interferon-alpha (IFN-alpha) on the growth of meningioma cells in culture is reported. A consecutive series of six meningiomas and one meningioma/neurofibroma derived from a patient with neurofibromatosis type 2 was investigated and it was found that the growth of all seven tumours in response to mitotic stimuli (fetal bovine serum or epidermal growth factor) is strongly inhibited by IFN-alpha. Maximal response varied between 100% and 70% inhibition of the incorporation of tritiated thymidine. In some cases an inhibitory response was obtained already at very low doses (less than or equal to 10 U of IFN-alpha per ml). These results indicate that further clinical investigation of the application of IFN-alpha to the treatment of meningioma is warranted.
Adult↗
Effects of the PAF-analog and -antagonist CV-6209 on cultured human glioma cell lines.
Cell lines of human glioma (U-343 MGa and U-251 MG) and human glia (U-533 CG) origin were cultured as monolayers and exposed to CV-6209, an alkyl-phospholipid analog and antagonist of platelet activating factor. This drug had very potent antiproliferative effects on the studied human glioma cell lines; IC50 was 0.9 microM after 48 h treatment and 0.2 microM after 2 weeks treatment. At these doses no growth inhibitory effect was noted on the normal glia cells. The effects on the glioma cells were reversible in the dose intervals, where cell proliferation, 3H-thymidine and 14C-methionine uptakes were greatly inhibited. The simultaneous administration of platelet activating factor [(R)PAF] did not influence the antiproliferative effects of CV-6209 on the cells cultured as monolayers. The structurally similar analog CV-3988 also had antiproliferative effects, although at 10 times higher concentration than CV-6209. Two other, structurally unrelated, PAF-antagonists (WEB-2086 and TCV-309) gave effects only at very high concentrations. The U-343 MGa cell line was also exposed to CV-6209 when growing as multicellular spheroids. The studies on the spheroid cultures also demonstrated good antitumoral effects with decreases of both the volume growth and the thymidine uptake. The simultaneous administration of (R)PAF reversed the inhibitory effect of CV-6209 on thymidine incorporation. This study demonstrates a strong antitumoral effect at low concentrations of CV-6209. The antiproliferative effects were probably primarily related to the ether-lipid structure and not to the PAF-antagonistic properties. The good antitumoral effect of CV-6209 on both monolayer and spheroid cultures and the possible PAF-antagonistic properties are discussed.
Cell Division↗
Application of (methyl-11C)-methionine in the multicellular spheroid system.
Human glioma (U-343 MGa) and human colon carcinoma (HT-29) cell lines were cultured as multicellular spheroids, and the accumulations of the L- and D-enantiomers of 11C-methionine were investigated. The accumulation of radioactivity in the spheroids was expressed as relative counts, by dividing the radioactivity measured in the spheroid with the radioactivity of the same volume of the incubation medium. The experiments were verified using 14C-labeled L- and D-methionine. The influence of spheroid volume, specific activity, incubation time, washing time, and the environmental temperatures were investigated. The spheroid model was used to determine the effect of the lipoxygenase inhibitors BW A4C and AA-861, the ether-phospholipid type PAF-antagonist CV-6209 and the protein synthesis inhibitor cycloheximide on methionine uptake. The results showed that 11C-L-methionine can be applied in the study of drug effects on multicellular tumor cell aggregates.
Benzeneacetamides↗
PET as a tool in the clinical evaluation of pituitary adenomas.
Positron emission tomography (PET) was used in over 400 examinations in patients with pituitary adenoma. It was demonstrated that PET with carbon-11-methionine can give valuable complementary information in the diagnosis of this tumor due to PET's ability to adequately depict viable tumor tissue in contrast to fibrosis, cysts and necrosis. Furthermore, PET with dopamine D2 receptor ligands can characterize the degree of receptor binding and thus give information as to the prerequisites for dopamine agonist treatment. Most important is the very high sensitivity given by PET with carbon-11-methionine in the evaluation of treatment effects. It is concluded that when properly used PET can be fully justified in the clinical handling of patients with pituitary adenomas and other intracranial tumors.
Adenoma↗
Contraction characteristics of the human quadriceps muscle during percutaneous electrical stimulation.
Percutaneous electrical stimulation was used to study the force response of the quadriceps muscle. The normal frequency dependence of force was investigated in muscles at rest and after fatiguing contractions. A comparison between force response during fatigue induced by electrical stimulation at different frequencies and by voluntary work suggested equal changes in contractility, irrespective of the fatigue-inducing procedure. In fresh muscle we found a linear relation between stimulation period (10-100 ms) and force. At fatigue the relation changes with maximal deviation from linearity at a 50-ms period (20 Hz). There is a rapid recovery of high frequency force whereas the low frequency response remains low even after 30 min rest. At very low frequencies there is initially unexpectedly high force in fatigued muscle. This could be a result of increased fusion of twitches with initially prolonged relaxation time. To study the twitch summation we compared experimental results in a wide frequency range with computer-simulated twitch summations and present the frequency dependence of summation processes in human quadriceps muscle.
Adult↗
Effect of iscoms and their adjuvant moiety (matrix) on the initial proliferation and IL-2 responses: comparison of spleen cells from mice inoculated with iscoms and/or matrix.
In the iscom, antigen is attached by hydrophobic interactions to a matrix which is built up by the adjuvant Quil A and lipids. Thus, the iscom presents antigen in multiple copies on a small particle with a built-in adjuvant. By studying the specific antibody response, in vitro proliferation and IL-2 secretion by splenocytes from mice following different in vivo treatments with iscoms and/or matrix, we attempted to distinguish between nonspecific stimulatory effects, caused by the matrix or iscoms, and specific responses to the antigens incorporated into iscoms. The results strongly suggest that matrix and also iscoms exert a nonspecific adjuvant activity by a transient high spontaneous proliferation of cells collected within 2 weeks after administration of iscoms or matrix. This high rate of proliferation was preceded by suppressed proliferation, 3 days after injection with matrix or iscom. The adjuvant component included in iscoms, i.e., the matrix, does not excert a mitogenic stimulation in vitro or influence the levels of specific antibodies in serum. Specific responses to the antigens included in iscoms were recorded both as increasing levels of serum antibodies and as iscom-induced proliferation of immune spleen cells in vitro. The recruitment of IL-2 was only related to the specific stimulation induced by the antigens in iscom.
Adjuvants, Immunologic↗
Effects of prostaglandin and leukotriene inhibitors on the growth of human glioma spheroids.
Established cell-lines of human glioma origin were cultured as multicellular spheroids or as monolayers. Volume growth and 3H-thymidine labelling were analysed for the spheroids after continuous exposure to drugs interfering with the release of arachidonic acid and the production of prostaglandins and leukotrienes. Comparative measurements were made on monolayer cultures. The cyclo-oxygenase inhibitor indomethacin enhanced growth at intermediate concentrations (0.5-5.0 micrograms/ml) but reduced growth at 50 micrograms/ml. The dual cyclo-oxygenase and lipoxygenase inhibitor ketoprofen had a significant inhibitory effect on growth and cell proliferation of spheroids at high concentration (50 micrograms/ml). The weak lipoxygenase inhibitor NDGA (quinone-form) decreased growth whereas the strong lipoxygenase inhibitor NDGA (hydroquinone-form) did not reduce growth rate but significantly decreased cell proliferation. Quinacrine reduced the spheroid growth rate although dexamethasone had no effects. Thus, inhibitors of the arachidonic acid cascade had growth inhibitory effects in the spheroid tumour model as well as in cells cultured as monolayers.
Arachidonic Acids↗
Effects of the 5-lipoxygenase inhibitors AA-863 and U-60,257 on human glioma cell lines.
The effects of two specific 5-lipoxygenase inhibitors AA-863 and U-60,257 (piriprost) on the growth of two human glioma cell lines, U-343 MGa and U-251 MG were investigated. Both monolayer cultured cells and spheroids were studied. The results of the monolayer studies showed potent and dose dependent inhibitory effects on the proliferation of glioma cells (IC50/one week treatment/of AA-863: 9.0 microM, IC50 of U-60,257: 40.0 microM). The experiments made on the tumor spheroids suggested an inhibitory effect on proliferation and volume growth already at lower doses (AA-863: 0.4-2.0 microM, U-60,257: 1.0-5.0 microM), a dose range where effects were not found in monolayers. At higher doses (AA-863: 10.0-30.0 microM, U-60,257: 30.0-90.0 microM) the experiments with spheroids failed to demonstrate a further inhibitory effect on spheroid volume, probably attributed to phenomena such as swelling of cells, dissociation of spheroid structure and development of necrosis. The clearly dose dependent inhibitory effect on the proliferation of human glioma cells in monolayer culture and the inhibitory effects on spheroid growth with these specific inhibitors indicate a role for lipoxygenase products in the growth of gliomas.
Arachidonate Lipoxygenases↗
Delineation of gliomas with magnetic resonance imaging using Gd-DTPA in comparison with computed tomography and positron emission tomography.
Fourteen patients with cerebral gliomas were investigated by MR imaging using Gd-DTPA (Magnevist), CT with the contrast agent iohexol (Omnipaque) and, as a reference, positron emission tomography (PET) using 11C-L-methionine. Tumour areas with disruption of the blood-brain-barrier (BBB) as seen on MR and CT were compared with areas increased accumulation of methionine in PET. There were 6 patients with high-grade astrocytoma (grade III-IV), 5 with low-grade astrocytoma (grade I-II) and 3 with oligodendroglioma. In 4 high-grade tumours, PET showed a larger tumour or tumour tissue in additional areas, compared with enhancement on MR and CT, while in 2 cases the tumour extension was similar in the three modalities. In the low grade tumour group, the findings on PET differed from those on post-contrast MR or CT in 7 cases. In 3 of these cases, no disruption of the BBB was seen either on MR or on CT. In 2 of our 14 patients CT showed larger enhancement extension than MR and in 2 cases MR was superior to CT in this respect. The enhancement intensity was higher on MR in 4 patients and on CT in 2 patients. No definite difference in the delineation of tumour tissue between the T1 weighted SE sequences was found. The gradient echo sequences FLASH and FISP gave limited information that was less than that provided by the T1 weighted SE sequences. A greater increase in signal intensity in T1 weighted images was usually seen 5 min post-contrast in the high-grade tumours than in the low-grade ones.
Adult↗
[Oncologic consultations in the Stockholm-Gotland region are a well-functioning model].
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Humans↗
[PET--new ways inside the body].
Using positron-emitting short-lived radionuclide tracers, a wide range of substances can now be labelled without their biological properties being affected. Positron emission tomography (PET) enables the distribution and metabolism of the labelled substance to be studied in different organs. By providing quantitative, locational, functional and biochemical information difficult to obtain by other means, PET opens up new possibilities, both diagnostic, pathophysiological and therapeutic, in a broad spectrum of medical practice. The development of the technique is described, with particular reference to its use at Uppsala.
Abdominal Neoplasms↗
High affinity [3H]paroxetine binding to serotonin uptake sites in human brain tissue.
[3H]Paroxetine binding to human brain tissue was characterized. Competition studies in the putamen and frontal cortex revealed single-site binding models for binding sensitive to 5-hydroxytryptamine (5-HT) (Ki 1-3 microM) and citalopram (Ki 0.6 nM), which displaced the same amount of binding. However, desipramine, norzimeldine and fluoxetine displaced additional binding (10-20%) and these competitors fitted two-site binding models with high affinity components in the nanomolar range and low affinity components in the micromolar range. The high affinity components approximated the 5-HT- and citalopram-sensitive binding fraction. Most of the [3H]paroxetine binding sites were protease-sensitive, but the low-affinity (microM) sites appeared to be protease-resistant. Based on these findings, only the [3H]paroxetine binding representing the fraction sensitive to 30 microM 5-HT (or e.g. 0.3 microM norzimeldine), was regarded as specific binding. This binding fraction was saturable with an apparent binding affinity (Kd) of 0.03-0.05 nM throughout the brain. The highest binding densities were obtained in the hypothalamus and substantia nigra (Bmax 500 fmol/mg protein). The basal ganglia reached intermediate densities (Bmax 200 fmol/mg protein), whereas cortical areas had low Bmax values (less than 100 fmol/mg protein). The lowest B max value was noted in cerebellar cortex (30 fmol/mg protein). The [3H]paroxetine binding was competitively inhibited by low concentrations of 5-HT, imipramine and norzimeldine, suggesting that the substrate recognition site for 5-HT uptake was labeled. Compounds active at dopaminergic, noradrenergic, histaminergic, 5-HT1, 5-HT2 and cholinergic muscarinic sites did not affect the binding at 100 microM concentrations. It is concluded that [3H]paroxetine is a marker for the 5-HT uptake site in the human brain, provided that an adequate pharmacological definition of specific binding is performed.
Aged↗
A comparative evaluation of the 75 G OGTT and the 50 G OGTT during pregnancy.
The aim of the present study was to establish reference values for the diagnosis gestational diabetes (GD) by the 75 g OGTT using the 3 hr 50 g OGTT as a reference. Women with an area of greater than or equal to 42 AU in the 50 g OGTT were regarded as gestational diabetics. Sixty-one women with a 3 hr area of greater than or equal to 39 AU in the 50 g OGTT were subject also to a 3 hr 75 g OGTT within one week. 25/61 had GD according to the result of the 50 g OGTT. The 2 hr concentration in the 75 g OGTT had the highest correlation (r = 0.62, p less than 0.001) to the 3 hr-area in the 50 g OGTT. A 2 hr B-glucose concentration of greater than or equal to 8.0 mmol/l in the 75 g OGTT will give about the same number of GD patients (25/61) as a 3 hr-area of greater than or equal to 42 in the 50 g OGTT and have an acceptable sensitivity without too low specificity.
Adult↗
In vivo and in vitro receptor autoradiography of the human brain using an 11C-labelled benzodiazepine analogue.
In vitro autoradiography of an 11C-labelled ligand, Ro 15-1788, has been used to visualize benzodiazepine binding sites in large human brain cryo-sections. In parallel, using the same radioligand, an in vivo study of a human healthy volunteer was performed, by means of positron emission tomography (PET). The in vitro and in vivo mapping of the ligand demonstrated a very similar binding pattern, although the poor resolution of PET precluded a full discrimination of fine details. The 11C-autoradiograms showed good spatial resolution, even with distinction of different layers in the cerebral and cerebellar cortex. In a separate experiment, the spatial resolution of 11C-autoradiography was found to be 180 microns, using 80-microns-thick cryo-sections. It is emphasized that in vitro and in vivo studies of the same radioligand give complementary information, which is valuable in the assessment of PET images.
Aged↗
Characterization of [3H]paroxetine binding in rat brain.
The binding of the 5-hydroxytryptamine (5-HT, serotonin) uptake inhibitor [3H]paroxetine to rat cortical homogenates has been characterized. The effect of tissue concentration was examined and, with 0.75 mg wet weight tissue/ml in a total volume of 1,600 microliter, the binding was optimized with an apparent dissociation constant (KD) of 0.03-0.05 nM. Competition experiments with 5-HT, citalopram, norzimeldine, and desipramine revealed a high (90%) proportion of displaceable binding that fitted a single-site binding model. Fluoxetine and imipramine revealed, in addition to a high-affinity (nanomolar) site, also a low-affinity (micromolar) site representing approximately 10% of the displaceable binding. The specificity of the [3H]paroxetine binding was emphasized by the fact that 5-HT was the only active neurotransmitter bound and that the serotonin S1 and S2 antagonist methysergide was without effect on the binding. Both 5-HT- and fluoxetine-sensitive [3H]paroxetine binding was completely abolished after protease treatment, suggesting that the binding site is of protein nature. Saturation studies with 5-HT (100 microM) sensitive [3H]paroxetine binding were also consistent with a single-site binding model, and the binding was competitively inhibited by 5-HT and imipramine. The number of binding sites (Bmax) for 5-HT-sensitive [3H]paroxetine and [3H]imipramine binding was the same, indicating that the radioligands bind to the same sites. Lesion experiments with p-chloroamphetamine resulted in a binding in frontal and parietal cortices becoming undetectable and a greater than 60% reduction in the striatum and hypothalamus, indicating a selective localization on 5-HT terminals. Together these findings suggest that [3H]paroxetine specifically and selectively labels the substrate recognition site for 5-HT uptake in rat brain.
Animals↗
Skeletal muscle glucolysis, glycogenolysis and glycogen phosphorylase during electrical stimulation in man.
Phosphorylase activity, glycogenolytic and glucolytic rates were estimated in human quadriceps muscle during electrical stimulation at 20 Hz. Two stimulation periods of 10 s duration were separated by a pause of 60 s. The blood circulation to the leg was intact or occluded during the experiment. ATP turnover rates and force production were of the same order during the two contraction periods both with and without intact blood flow. Also the increase in phosphorylase a activity (from approximately 30% to approximately 65%) was the same during the contraction periods. Glycogenolytic and glucolytic rates were however about 30% higher (P less than 0.05) during the second contraction compared with the first when circulation was occluded, but similar when the circulation was intact. During the 60 s rest period, the phosphocreatine (PCr) was maintained at a low level and inorganic phosphate (Pi) remained increased under occluded circulation while PCr was resynthesized in the rest period with intact circulation. We conclude that the increased glycogenolytic rate observed during the second contraction with occluded blood circulation was due to the high [Pi] in the muscle and that the increased glucolytic rate was caused by high [Pi] and low [PCr]. In the rest period with anoxia the glycogenolysis was completely inhibited and glucolysis was inhibited by 95% in spite of the changes in [PCr] and [Pi].
Adult↗