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Biomedical subjects

G Mellgren

Publications and source records attributed to G Mellgren.

At least 19 recordsLinked to original sources
PubMed2005

Identification and quantification of tamoxifen and four metabolites in serum by liquid chromatography-tandem mass spectrometry.

We have developed a method for the determination of tamoxifen (tam) and its metabolites 4-hydroxytamoxifen (4OHtam), N-demethyltamoxifen (NDtam), N-dedimethyltamoxifen (NDDtam), tamoxifen-N-oxide (tamNox), and 4-hydroxy-N-demethyltamoxifen (4OHNDtam) in 50 microl human serum. Serum proteins were precipitated with acetonitrile. Deuterated-tamoxifen (D5 tam) was added as internal standard. Sample supernatant was injected into an on-line reversed-phase extraction column coupled with a C18 analytical column and analytes were detected by tandem mass spectrometry. The lower limits of quantification were 0.25 ng/mL for 4OHtam, NDtam and tam, 1.0 ng/mL for NDDtam and tamNox. Ranges of within- and between-day variation were 2.9-15.4% and 4.4-12.9%, respectively.

Breast Neoplasms↗
PubMed2003

Tamoxifen administration and metabolism in nude mice and nude rats.

We investigated the kinetics of tamoxifen (tam) in immunodeficient mice and rats after oral treatment and compared drug and metabolite profile in nude rat serum and tissues after oral and subcutaneous (s.c.) routes of administration. The serum levels were compared to those observed in man. After oral dosing in mice, tam and the potent metabolite 4-hydroxytamoxifen (4-hydroxytam), were detectable in liver and lung tissue, but not in serum. The levels of 4-hydroxytam in these tissues were significantly higher than those of tam, a profile opposite to that observed in rat and man. In rats and man, the 4-hydroxytam/tam serum concentration ratios were 0.16 and 0.02, respectively. Compared to oral route, the s.c. pellets yielded only trace amounts of the demethylated derivatives of tam in rats. Thus, the kinetics of tam observed in the present study suggest that the nude rat may represent a preferable animal model in studying the pharmacokinetics of tam and that, the oral route yielded higher serum and tissue levels of tam and metabolites than equivalent s.c. pellet implants.

Administration, Oral↗
PubMed2000

Influence of hemofiltration on plasma cytokine levels and platelet activation during extra corporeal membrane oxygenation.

OBJECTIVE: Extra corporeal circulation of human blood is used daily in lifesaving procedures such as open-heart surgery and extracorporeal membrane oxygenation (ECMO). But extracorporeal circulation also induces activation of various cascade reactions in the blood. The objective of this study was to evaluate the effects of hemofiltration on cytokine release and removal as well as on platelet activation and consumption. MATERIAL AND METHODS: Two complete ECMO systems, each of them holding a hollow fiber oxygenator, a bladder box, PVC tubing and a roller pump were perfused for 24 h with fresh, heparinized human blood. A hemofilter was added to one of the paired systems. Blood samples were collected from both circuits before start, and at 0.5, 1, 3, 12 and 24 h of perfusion. A total of 8 paired experiments was performed. RESULTS: The plasma concentration of interleukin (IL)1beta, IL-6 and IL-8, as well as of IL-1 receptor antagonist (IL-1ra) increased over time in both systems, but consistently lower levels were observed in the filter circuits compared to the controls. Only minor parts of these cytokines could be assayed in the ultrafiltrate. No significant difference in platelet count and platelet membrane expression of glycoprotein Ib was observed between the circuits. CONCLUSIONS: By adding a hemofilter to the ECMO circuit, it is possible to reduce the plasma concentration of interleukins without significantly affecting platelet activation and consumption.

Cytokines↗
PubMed1998

A child with a t(11;19)(q14-21;p12) in a pulmonary mucoepidermoid carcinoma.

We report on a mucoepidermoid carcinoma (MEC) of the lung in a 6-year-old girl with a t(11;19)(q14-21;p12) as the sole karyotypic abnormality. An apparently identical t(11;19) has been reported previously in a MEC originating from the major and minor salivary glands. Our findings indicate that the t(11;19) is intimately associated with the mucoepidermoid phenotype and may be used as a diagnostic marker for this tumour type.

Biomarkers, Tumor↗
PubMed1998

Effect of nitric oxide gas on platelets during open heart operations.

BACKGROUND: The increased bleeding tendency observed after cardiopulmonary bypass is caused in part by thrombocytopenia and impaired platelet function induced by the procedure. Previous in vitro studies have shown that nitric oxide (NO) added to the oxygenator sweep gas reduces platelet activation during experimental perfusion. We evaluated the effect of 40 ppm of NO, added to the oxygenator sweep gas, on platelet consumption and activation in patients undergoing cardiopulmonary bypass. METHODS: Twenty patients scheduled to undergo cardiopulmonary bypass were randomized to either the control or the NO arm of the study. Their platelet count, plasma beta-thromboglobulin level, platelet membrane glycoprotein Ib and IIb/IIIa levels, adenosine diphosphate-induced platelet aggregation, plasma nitrate level, and plasma hemoglobin were assayed before, during, and after cardiopulmonary bypass. RESULTS: After operation, slightly higher platelet counts were observed in the NO-treated patients than in the control patients, which might indicate a lower degree of platelet adhesion to the artificial surfaces of the extracorporeal circuit. However, this difference did not reach statistical significance. In addition, a difference in platelet membrane expression of glycoprotein Ib was seen between the NO and control groups after operation; the platelets of the control patients had significantly higher glycoprotein Ib expression than those of the NO-treated patients. The results of platelet aggregometry indicated preserved platelet function in both the NO-treated and control patients. The blood methemoglobin levels also were low in both groups. CONCLUSIONS: Nitric oxide might reduce the platelet consumption encountered during cardiopulmonary bypass without having any adverse effect on platelet function, as reflected by the preserved aggregation response seen in our patients. However, the best route of NO administration and the optimum dose remain to be established.

Adenosine Diphosphate↗
PubMed1998

Induced cell trauma during in vitro perfusion: a comparison between two different perfusion systems.

The purpose of this study was to compare blood cell activation during in vitro long-term perfusion using 2 parallel in vitro extracorporeal membrane oxygenation (ECMO) systems. We compared two substantially different perfusion systems, an assistance respiratoire extra corporelle (AREC) system on one hand, containing an AREC pump, silicon tubing, and a hollow-fiber oxygenator, and a centrifugal pump system, on the other hand, containing a Biomedicus centrifugal pump, PVC tubing, and a membrane oxygenator. We measured the platelet count using an automated blood cell counter. Platelet activation was evaluated using a flow cytometric technique for the platelet membrane expression of glycoproteins and ELISA for the plasma concentration of beta-thromboglobulin (beta-TG), a platelet specific protein released into the blood upon platelet activation. The neutrophil count was assayed using an automated blood cell counter and the plasma concentration of cytokines using an ELISA kit. A significant difference between the two systems was observed in terms of the platelet membrane expression of glycoprotein (GP)Ib (p=0.0001) and GPIIb/IIIa (p=0.0037), indicating a lower degree of platelet activation in the AREC system. The concentration of neutrophils was significantly lower in the centrifugal system (p=0.002) compared to the AREC system. The neutrophil membrane expression of CD11b was significantly lower (p=0.0067) in the AREC system, indicating a lower degree of neutrophil activation compared to the centrifugal pump system. A significantly lower degree of hemolysis, as expressed by plasma hemoglobin, was observed in the AREC pump system (p=0.0491). In conclusion, lower degrees of the platelet membrane expression of GPIb and GPIIb/IIIa and of the neutrophil membrane expression of CD11b were observed in the AREC system, indicating a lower degree of platelet and neutrophil activation in this system. No significant difference between the two systems as to the plasma concentration of interleukin (IL)-1beta, IL-6, or IL-8 could be recorded. Further studies are warranted to specify the role of each individual component of the two systems.

Blood Platelets↗
PubMed1998

Cytokine release during long-term extracorporeal circulation in an experimental model.

The objective of this study was to determine the degree of leukocyte activation, as measured by cytokine release, in circulating blood during experimental extracorporeal circulation. Complete in vitro extracorporeal membrane oxygenation (ECMO) circuits were used, and 9 experiments were performed. Whole blood stored at 37 degrees C was used as the control. Blood samples were withdrawn before the start of perfusion and at 24 h of perfusion. Statistically significant releases of interleukin (IL)-1beta, IL-8, and IL-1 receptor antagonist were observed in the perfusion circuits compared to both the control blood and baseline values. Also, increases in plasma tumor necrosis factor (TNF)alpha and IL-6 were seen after 24 h of perfusion although these changes did not reach statistical significance. These results indicate that extracorporeal circulation induced leukocyte activation and cytokine release. These reactions might, as an additional trauma, deteriorate the situation in an already severely ill patient. A search for methods to counteract this untoward activation seems warranted.

Adult↗
PubMed1998

The effect of albumin priming solution on platelet activation during experimental long-term perfusion.

The objective of this study was to evaluate the effect of albumin priming on platelet consumption and activation during long-term perfusion. Two identical in vitro extracorporeal membrane oxygenation circuits were used; one was primed with Ringer's solution containing human serum albumin, the other with Ringer's solution only. Fresh heparinized human blood was pooled, divided between the two systems and circulated for 24 h at 37 degrees C. Platelet count, plasma concentration of betathromboglobulin (BTG), platelet membrane density of glycoprotein (GP) Ib and of GPIIb/IIIa were assayed before the start and at 0.5, 1, 3, 12 and 24 h of perfusion. In total, seven experiments were performed. We found that during the first hour of perfusion, slightly higher platelet counts (p = 0.058) and lower BTG values (p = 0.0005) were observed in the circuits primed with albumin, compared to the control circuits. No statistically significant differences were observed for the platelet membrane expression of GPIb and GPIIb/IIIa. We conclude that albumin priming appears to transiently prevent platelet consumption and activation during long-term perfusion.

Extracorporeal Membrane Oxygenation↗
PubMed1998

The effect of cardiopulmonary bypass on blood cell filterability in children undergoing cardiac surgery.

BACKGROUND: The extended use of cardiopulmonary bypass (CPB) in cardiac surgery is limited because of damage to blood which in adults has been assessed by alterations in blood cell rheology. Blood trauma assessment in children is difficult because of the restrictions in sample volume and frequency but needs to be established from time to time in order to study the tolerance to new surgical and extracorporeal techniques. MATERIALS AND METHODS: Fourteen pediatric patients undergoing cardiac surgery with CPB for congenital heart disease corrections were studied. Whole blood, red blood cell and white blood cell rheology (filterability) were monitored before, during and after CPB using the St. George filtrometer that used small amounts of blood. RESULTS: The results showed that all the rheologic parameters were altered during the blood trauma of CPB and were outside the reference values before, during and after CPB. CONCLUSIONS: This suggested that blood cell rheologic disturbances did not recover soon after CPB and this may be of interest in long term follow-up to understand responses and recovery patterns to disease and interventions associated with pediatric heart surgery using CPB.

Blood Cell Count↗
PubMed1997

Gap junctions and growth control in liver regeneration and in isolated rat hepatocytes.

The hepatocytes in the mature normal liver are tightly coupled through gap junctions, except during compensatory hyperplasia (regeneration) after partial hepatectomy when the gap junctions become down-regulated. The significance of this down-regulation has been a long-standing enigma. The present study of hepatocytes in primary culture and in the regenerating liver aimed at defining the relationship, if any, between hepatocyte gap junctional communication and proliferation. Gap junctional down-regulation in the regenerating liver appeared to be a specific phenomenon because desmosomes and the surface contact area between neighboring hepatocytes remained constant. All agents and conditions (dexamethasone in vivo; dexamethasone, cyclic adenosine monophosphate, serum, and high cell density in vitro) delaying gap junctional down-regulation also increased the lag before the cells reached competence to enter S phase. This raised the possibility that hepatocyte DNA replication was inhibited through preservation of gap junctions. However, we disproved this assumption by showing that the DNA replication (more specifically the G1/S transition rate constant) was inhibited even in hepatocytes completely devoid of gap junctional communication. The teleological advantage of linking gap junctional down-regulation to hepatocyte G1 progression therefore may not be to trigger DNA replication but to ensure that proliferating hepatocytes and hepatocytes responsible for liver-specific metabolic functions maintain separate pools of metabolites and signaling molecules.

Animals↗
PubMed1997

Transcriptional regulation of the bovine CYP17 gene by cAMP.

The transcription of steroid hydroxylase genes is controlled by ACTH and cAMP in the adrenal cortex. In most instances the regulation appears to rely on transcription factors traditionally not associated with cAMP-dependent gene expression. For the non-traditional factors it remains necessary to elucidate the coupling of increases in intracellular cAMP and cAMP-dependent protein kinase (PKA) activity to the function of these proteins. The bovine CYP17 gene, which encodes the steroid 17 alpha-hydroxylase, contains two discrete DNA elements within its promoter and upstream region (CRS1 and CRS2) that individually can confer cAMP responsiveness. The CRS1 element is a target for PKA signalling and for negative regulation via the protein kinase C signal transduction pathway. The homeodomain protein Pbx1 enhances CRS1-dependent transcription, but additional CRS1-binding proteins remain to be identified. Furthermore it is not known how PKA regulates the activity of Pbx1 or its possible binding partners. Closer to the promoter, the nuclear orphan receptors SF-1 and COUP-TF have overlapping binding sites in CRS2 and they bind in a mutually exclusive manner with very similar affinities; 8 and 10 nM, respectively. SF-1 stimulates whereas COUP-TF inhibits transcription from the bovine CYP17 promoter. Together, the data suggest that cAMP-dependent control of the amounts of the activator SF-1 vs. the repressor COUP-TF could influence CRS2-dependent transcription. In addition, PKA may influence the phosphorylation of SF-1, thus increasing its activity. In vitro, PKA will elicit phosphorylation of SF-1. However, although SF-1 can be immunoprecipitated from adrenocortical cells as a phosphroprotein, we have not been able to show cAMP-dependent increase in net phosphorylation in intact cells. More careful examination of individual phosphorylation sites in SF-1 may still reveal hormone- and cAMP-induced phosphorylation of SF-1.

Animals↗
PubMed1997

Glucose metabolism and insulin secretion in children with cyanotic congenital heart disease.

The aim of the study was to reveal differences in carbohydrate metabolism in children with cyanotic congenital heart diseases (CHD). Thirteen children with diseases of these kinds were investigated with regard to glucose tolerance and insulin secretion and comparisons were made with healthy controls of the same age. Investigations included an intravenous glucose tolerance test, insulin response to the glucose load in plasma and insulin secretion rate. The results reveal lower fasting glucose levels and signs of a higher insulin secretion rate in the relatively few patients in the CHD group where C-peptide measurements were performed, but no differences in glucose tolerance. The reasons for the differences are unclear, but the chronic increases in circulating catecholamines in combination with the impaired nutritional status of these children with CHD are probably the most important factors. We conclude that these divergences in carbohydrate metabolism should be emphasized in the care of children with CHD.

C-Peptide↗
PubMed1997

Synergistic antiproliferative actions of cyclic adenosine 3',5'-monophosphate, interleukin-1beta, and activators of Ca2+/calmodulin-dependent protein kinase in primary hepatocytes.

cAMP and Ca2+ acted together with the acute phase cytokine interleukin-1beta (IL-1beta) to inhibit hepatocyte DNA replication. At sub-basal activity of cAMP-dependent protein kinase (PKA), neither IL-1beta nor the Ca2+-elevating hormone vasopressin affected hepatocyte proliferation. Basal level of PKA activity permitted IL-1beta action. Increased PKA activity also permitted vasopressin action and sensitized further towards IL-1beta, which acted at 10-50 pM concentrations. Vasopressin acted via Ca2+/calmodulin-dependent protein kinase II (CaMKII), and its action was mimicked by the serine/threonine phosphatase inhibitor microcystin, which activates CaMKII. Inhibitors (KN93 and KT5926) of CaMKII selectively counteracted the effects of vasopressin and microcystin on hepatocyte proliferation at concentrations similar to those required to inhibit CaMKII in vitro. Two-dimensional gel electrophoresis of 32P-prelabeled hepatocytes revealed a common set of proteins phosphorylated in response to vasopressin and microcystin. Their phosphorylation was counteracted by CaMKII inhibitor (KT5926). Phosphorylation of the CaMKII substrate phenylalanine hydroxylase (PAH; EC 1.14.16.1) was used as an endogenous marker of CaMKII activation. It was found that treatment of the cells with vasopressin or microcystin increased the phosphorylation of PAH, and that the vasopressin-induced PAH phosphorylation was inhibited by KT5926. In conclusion, the Ca2+-elevating hormone vasopressin potentiated the antiproliferative effects of cAMP and IL-1beta through CaMKII activation.

1-Methyl-3-isobutylxanthine↗
PubMed1996

Nitric oxide in the oxygenator sweep gas reduces platelet activation during experimental perfusion.

BACKGROUND: Hemorrhage is a major complication experienced in 10% to 35% of neonates treated with extracorporeal life support (ECLS). The increased bleeding tendency is partly due to an ECLS-induced thrombocytopenia and impaired platelet function. In the present study, we evaluated the effect of nitric oxide on the ECLS-induced platelet consumption and activation. METHODS: Two identical in vitro ECLS circuits were primed with fresh, heparin-treated human blood and circulated for 24 hours. Nitric oxide (15, 40, or 77 ppm) was added to one of the oxygenators in each pair. Eight paired experiments were performed. Platelet count, plasma beta-thromboglobulin, platelet serotonin content, plasma nitrate, plasma cyclic guanosine monophosphate, and platelet membrane glycoprotein Ib were assayed before the start and at 0.5, 1, 3, 12, and 24 hours of perfusion. RESULTS: Plasma nitrate and plasma cyclic guanosine monophosphate levels were significantly higher in the nitric oxide circuits than in the control circuits (p < 0.01). Higher platelet counts (p < 0.01) and lower beta-thromboglobulin levels (p < 0.01) were observed in the nitric oxide circuits compared with the control circuits. However, no significant differences in platelet serotonin content or platelet membrane glycoprotein Ib density were noted between the circuits. CONCLUSIONS: Nitric oxide probably reduces platelet consumption and platelet activation during ECLS.

Analysis of Variance↗
PubMed1996

Extracorporeal membrane oxygenation as a bridge to definitive tracheal surgery in children.

Extracorporeal membrane oxygenation was used as a bridge for three infants with complicated long segment congenital tracheal stenosis to tracheal homograft transplantation with cadaveric tracheal homograft and for one child, with an extensive traumatic tracheal laceration caused by aspiration of a sharp foreign body, to definitive tracheal repair. In all four cases mechanical ventilation was impossible and death almost certain without extracorporeal membrane oxygenation.

Cadaver↗
PubMed1996

Skeletal muscle energy substrates, metabolic products and enzyme activity in infants with symptomatic ventricular septal defect.

Muscle biopsy studies were performed on 26 infants with symptomatic ventricular septal defect (VSD) (mean age 4.7 months) and 10 healthy infants (mean age 7.8 months). Analyses were made of muscle energy substrates, metabolic products, muscle enzyme activity, fibre types and fibre sizes. Relatively few differences were noted between the groups. The most important difference was a reduced ATP level in the VSD group. Glucose 6-phosphate concentrations were also lower in the VSD group. These differences could indicate a low metabolic activity in skeletal muscle in infants with heart failure. Most muscle enzyme activity was comparable with the exception of lactate dehydrogenase (LD), which was lower in the VSD group. Within the VSD group, no differences were revealed in muscle substrate concentrations for muscle enzyme activity in terms of the degree of heart failure. We conclude that low energy levels are probably explained by undernourishment and/or reduced blood flow to skeletal muscle and that the lack of other discrepancies in muscle metabolism indicates a desirable relatively normal motor activity in these infants with symptomatic VSD.

Adenosine Triphosphate↗
PubMed1996

Platelet activation and degradation in an experimental extracorporeal system. A comparison between a silicone membrane and a hollow-fibre oxygenator.

Blood platelets are rapidly activated in contact with biomaterials and, therefore, can be used as markers of the biocompatibility of various components in an extracorporeal system. In the present work two different oxygenators, one membrane oxygenator (Avecor) and one hollow-fibre oxygenator ("Lilliput', Dideco) were compared. Complete in vitro extracorporeal membrane oxygenation circuits were perfused with fresh, heparinized human blood for 24 h. Eight experiments were performed with the hollow-fibre oxygenator and five experiments with the membrane oxygenator. Blood gases, electrolytes, glucose and haematocrit were kept within physiological limits. Platelet count, plasma concentration of beta-thromboglobulin, platelet serotonin content, platelet membrane glycoprotein lb and its degradation product glycocalicin, as well as plasma haemoglobin concentration were assayed. As regards most of these variables, significant differences in favour of the hollow-fibre oxygenator were observed.

Extracorporeal Membrane Oxygenation↗