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Biomedical subjects

P O Iversen

Publications and source records attributed to P O Iversen.

At least 19 recordsLinked to original sources
PubMed2006

Fat-soluble vitamins in breast-fed preterm and term infants.

OBJECTIVE: To examine the supply and status of fat-soluble vitamins in very low birth weight (VLBW) infants compared to a reference group of normal birth weight (NBW) infants. DESIGN: A longitudinal study of VLBW infants in the early neonatal period. Blood samples were drawn at 1 week of age and at discharge from hospital. Plasma was analyzed for the fat-soluble vitamins: retinol, 25-OH-vitamin D, alpha-tocopherol and phylloquinone (vitamin K(1)) using high-performance liquid chromatography. SUBJECTS: A total of 40 VLBW infants were included in the study. A reference group of 33 NBW infants was randomly selected from one of our previous studies. RESULTS: The VLBW infants received fortified human milk, and daily oral vitamin supplement (Multibionta). In VLBW infants, plasma retinol concentrations decreased and plasma 25-OH-vitamin D increased during the study period. VLBW infants had significantly lower plasma retinol (0.3 vs 0.7 mu M) and higher plasma 25-OH-vitamin D (166 vs 25 nM) at discharge compared to NBW infants. Plasma phylloquinone concentration in VLBW infants was very high (53 ng/ml) at one week of age, especially in the youngest infants (192 ng/ml), but decreased rapidly during the study period resulting in low/normal plasma concentrations (0.9 ng/ml) at discharge. CONCLUSIONS: We observed alterations in plasma concentration of retinol and 25-OH-vitamin D in VLBW infants in the early neonatal period, resulting in marked differences between VLBW at discharge and NBW. Further trials are needed to evaluate whether changes in vitamin supplementation may improve clinical outcome in VLBW infants.

Antioxidants↗
PubMed2005

Angiogenesis and hemostasis in hematological neoplasias.

Angiogenesis is essential for tumor growth and metastasis. This is firmly established in solid tumors, but accumulating evidence suggests that this is also an important event in hematological neoplasias. Angiogenesis is therefore a putative target for therapy. The potential application of different angiogenesis inhibitors is currently under intense clinical investigation, and we will here review a number of these trials. The association between cancer and thromboembolic disease is even better documented, and again, this is not limited to solid tumors. It appears that many patients with hematological malignancies have a dysfunctional hemostatic system, with increased risk of thromboembolism. Furthermore, effective antithrombotic therapy seems to reduce the risk of cancer progression and even prolongs overall survival. In this review we will thus discuss the mechanisms involved in the regulation of angiogenesis and hemostasis and present evidence for a shared biology. A number of factors regulating the hemostatic system also have pro- or anti-angiogenic properties. Tissue factor (TF) and TF pathway inhibitor (TFPI) seem to play a central role, and there are several lines of evidence suggesting a close cooperation between TF/TFPI and pro-angiogenic factors like members of the vascular endothelial growth factor family. A better understanding of this shared biology may reveal new targets, and will probably increase the safety of targeting the blood supply.

Angiogenesis Inhibitors↗
PubMed2004

Macrophages in spleen and liver direct the migration pattern of rat neutrophils during inflammation.

OBJECTIVE: The exact fate of polymorphonuclear neutrophilic granulocytes (PMN; neutrophils) after their mobilization from the bone marrow is not known. It is believed that they, after a relatively short lifespan (1-3 d), become apoptotic and phagocytosed by macrophages. We have recently shown that transfused neutrophils sequestrate not only in lungs, liver and spleen, but also to a large extent in the bone marrow, possibly because of uptake by macrophages. Hence, we studied if inactivation of macrophages would alter the pattern of neutrophil migration. METHODS: We used transfused congenic or syngeneic neutrophils in rats with or without sterile peritonitis, induced by a casein preparation (Bacto-Tryptone). To perturb macrophage function, we either killed them with liposome-encapsulated clodronate or overloaded them with inert phagocytosable particles. Transfused neutrophils were tracked with flow cytometric or radiometric methods. RESULTS: Not more than a small portion of the neutrophils migrated to the inflamed peritoneal cavity under any circumstance. Their ecotaxis to liver and spleen was reduced in rats with liver and spleen macrophages either congested with polystyrene particles or depleted by clodronate. The bone marrow uptake and blood retention of transfused neutrophils were increased in macrophage-depleted rats 18 h after transfusion. In rats depleted of liver macrophages only, the sequestration in the liver was reduced, without detectably changed uptake in bone marrow and spleen. CONCLUSION: Macrophages are instrumental to the neutrophil migration stream in the organism, and their function in this regard is robust and not easily decreased by inert phagocytosable particles or a killing agent.

Animals↗
PubMed2002

Inhibitors of angiogenesis selectively reduce the malignant cell load in rodent models of human myeloid leukemias.

Angiogenesis is essential for growth and metastasis of solid tumors and probably also for hematological malignancies. Angiogenic inhibitors, like endostatin (ES) and PI-88, retard cancer growth. We tested these in mice with juvenile myelomonocytic leukemia (JMML), and in rats with acute myeloid leukemia (BNML). Eight weeks after transplantation and with a continuous drug treatment for the last 4 weeks, the leukemic cell mass decreased from almost 90% of all bone marrow cells to about 15 and 45% with ES, to about 35 and 55% with PI-88, and to about 10 and 25% with ES + PI-88 in the leukemic mice and rats, respectively. The numbers of normal human bone marrow cells transplanted into mice were unchanged by the treatments. The microvessel density in leukemic animals given ES or PI-88 was 10-50% of that in untreated animals. Notably, simultaneous treatment with ES and PI-88 led to a reduction of about 95% in JMML mice and 85% in BNML rats. In vitro proliferation of either JMML or BNML cells was not significantly altered by either drug, demonstrating the selectivity of ES and PI-88 as angiogenic inhibitors. In conclusion, anti-angiogenic therapy may be a valuable adjunct to conventional treatment of leukemia.

Acute Disease↗
PubMed2001

Regulation of extracellular volume and interstitial fluid pressure in rat bone marrow.

The volume and fluid pressure characteristics of the intact bone marrow is incompletely understood. We used microspheres and lipoproteins for measurements of intravascular volume (IVV) and EDTA for interstitial fluid volume (IFV) within the rat bone marrow. Interstitial fluid pressure (IFP) was determined with micropipettes connected to a servo-controlled counter-pressure system. Both the microspheres and the lipoproteins yielded estimates of IVV of approximately 1 ml/100 g. After a brief reactive hyperemia, IVV increased to 2.5 ml/100 g, whereas IFV decreased with approximately 1.5 ml/100 g, so that total extracellular volume did not change. Baseline bone marrow IFP was 9.7 mmHg. The hyperemia led to a transient twofold increase in IFP, whereas a marked blood loss decreased IFP by almost one-half. These novel data suggest that extracellular volume and IFP within the bone marrow can be measured with tracer methods and the micropuncture technique. The responses of IVV, IFV, and IFP during changes in blood flow to the bone marrow suggest a tight regulation and are thus compatible with those for a low-compliant tissue.

Animals↗
PubMed2001

DNA enzyme targeting TNF-alpha mRNA improves hemodynamic performance in rats with postinfarction heart failure.

Tumor necrosis factor-alpha (TNF-alpha) probably affects the pathogenesis of heart failure. Here we have investigated the therapeutic potential of a nuclease-resistant DNA enzyme that specifically cleaves TNF-alpha mRNA. A phosphorothioate-modified DNA enzyme was designed to retain similar cleavage activity as its unmodified version, and that inhibited the expression of TNF-alpha in vitro. To test its efficacy in vivo, postinfarction congestive heart failure was induced in anesthetized rats by ligation of the left coronary artery. A 4-wk treatment with the DNA enzyme induced a substantial reduction in left ventricular end-diastolic pressure and lung weight concomitant with an increase in arterial blood pressure and myocardial blood flow compared with controls. The concentration of TNF-alpha in coronary sinus blood was markedly lowered on treatment, and myocardial TNF-alpha mRNA was substantially reduced. Recovery studies showed that the DNA enzyme cleavage activity was present within the myocardium throughout the observation period and had no apparent toxic effects. Our findings indicate that DNA enzyme-based therapy may hold promise in the treatment of this debilitating disease.

Animals↗
PubMed2000

Depressed immunity and impaired proliferation of hematopoietic progenitor cells in patients with complete spinal cord injury.

The bone marrow is supplied with both sensory and autonomic neurons, but their roles in regulating hematopoietic and immunocompetent cells are unknown. Leukocyte growth and activity in patients with stable and complete spinal cord injuries were studied. The innervation of the bone marrow below the injury level lacked normal supraspinal activity, that is, a decentralized bone marrow. Lymphocyte functions were markedly decreased in injured patients. Long-term colony formation of all hematopoietic cell lineages, including dendritic cells, by decentralized bone marrow cells was substantially reduced. It was concluded that nonspecific and adaptive lymphocyte-mediated immunity and growth of early hematopoietic progenitor cells are impaired in patients with spinal cord injuries. Possibly, this reflects cellular defects caused by the malfunctioning neuronal regulation of immune and bone marrow function.

Adult↗
PubMed2000

Increased cellular hypoxia and reduced proliferation of both normal and leukaemic cells during progression of acute myeloid leukaemia in rats.

The microenvironmental changes in the bone marrow, spleen and liver during progression of the transplantable promyelocytic leukaemia in the Brown Norwegian rat (BNML) have been studied. We used flow cytometry to estimate cellular hypoxia and proliferation based on in vivo pulse-labelling with a mixture of 2-nitroimidazole linked to theophylline (NITP) and bromodeoxyuridine (BrdUrd). The leukaemic cells were identified with the RM124 antibody. In rats inoculated with leukaemic cells the fraction of RM124+ cells was significantly increased from day 20 onwards in the spleen and from day 27 in the bone marrow and liver, reaching a level of 65-87% in these organs at day 32. At day 32, the NITP+ fraction of RM124+ cells had increased significantly in the bone marrow and spleen to 88% and 90%, respectively. The corresponding fractions of NITP+ normal cells reached 63% and 65%, respectively. From day 13 to day 32, the DNA-synthesizing (BrdUrd+) fraction of RM124+ cells in the bone marrow decreased significantly from 52% to 25%, and of normal cells from about 20% to 6%. In the bone marrow and spleen at day 27 and 32, the S-phase and G2/M-phase fractions according to DNA content were higher for the NITP+ than for the NITP- cells. This could partly be explained by an impaired cell cycle progression due to hypoxia. Nevertheless, we found indications of leukaemic cells that were simultaneously labelled with NITP and BrdUrd, in the bone marrow and spleen. These latter findings suggest that in contrast to normal cells some of the leukaemic cells can proliferate even during hypoxia, and this subpopulation may consequently renew and expand the leukaemic cell load.

Acute Disease↗
PubMed1999

Simultaneous antagonism of interleukin-5, granulocyte-macrophage colony-stimulating factor, and interleukin-3 stimulation of human eosinophils by targetting the common cytokine binding site of their receptors.

Human interleukin-5 (IL-5), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-3 are eosinophilopoietic cytokines implicated in allergy in general and in the inflammation of the airways specifically as seen in asthma. All 3 cytokines function through cell surface receptors that comprise a ligand-specific alpha chain and a shared subunit (beta(c)). Although binding of IL-5, GM-CSF, and IL-3 to their respective receptor alpha chains is the first step in receptor activation, it is the recruitment of beta(c) that allows high-affinity binding and signal transduction to proceed. Thus, beta(c) is a valid yet untested target for antiasthma drugs with the added advantage of potentially allowing antagonism of all 3 eosinophil-acting cytokines with a single compound. We show here the first development of such an agent in the form of a monoclonal antibody (MoAb), BION-1, raised against the isolated membrane proximal domain of beta(c). BION-1 blocked eosinophil production, survival, and activation stimulated by IL-5 as well as by GM-CSF and IL-3. Studies of the mechanism of this antagonism showed that BION-1 prevented the high-affinity binding of (125)I-IL-5, (125)I-GM-CSF, and (125)I-IL-3 to purified human eosinophils and that it bound to the major cytokine binding site of beta(c). Interestingly, epitope analysis using several beta(c) mutants showed that BION-1 interacted with residues different from those used by IL-5, GM-CSF, and IL-3. Furthermore, coimmunoprecipitation experiments showed that BION-1 prevented ligand-induced receptor dimerization and phosphorylation of beta(c), suggesting that ligand contact with beta(c) is a prerequisite for recruitment of beta(c), receptor dimerization, and consequent activation. These results demonstrate the feasibility of simultaneously inhibiting IL-5, GM-CSF, and IL-3 function with a single agent and that BION-1 represents a new tool and lead compound with which to identify and generate further agents for the treatment of eosinophil-dependent diseases such as asthma.

Animals↗
PubMed1999

Human cytokines modulate arterial vascular tone via endothelial receptors.

Only a few cytokines have been tested for their possible role in modulating vascular function. Moreover, no direct effect of cytokines on vascular tone has yet been thoroughly studied. We therefore examined whether a wide range of well-defined cytokines could directly affect vascular tone in isolated human arterial and venous segments from various organs. We found that the cytokines stem cell factor (maximal response with 1 mM), granulocyte colony-stimulating factor (0, 1 mM) and erythropoietin (1 mM) relaxed, while tumor necrosis factor alpha (0.1 mM), interleukin (IL) 6 (10 mM) and IL-10 (0.1 mM) induced contraction of arterial but not of venous segments. The cytokines (maximal concentration tested was 1 mM) IL-3, IL-5, IL-13, macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor had no apparent effects on either arterial or venous tone. These vascular effects were endothelium-dependent as denuded arteries did not respond to any cytokine, and inhibition of nitric oxide synthase or endothelin receptor A abrogated the cytokine-induced changes in vascular tone. With immunohistochemistry we found receptors for the active cytokines on the arterial endothelium. In conclusion, several cytokines may modulate arterial vascular tone via endothelium-dependent mechanisms. Therefore cytokines might significantly modify blood supply to inflamed or ischemic tissues with elevated local concentrations of cytokines.

Adult↗
PubMed1998

Modulation of granulocyte-macrophage colony-stimulating factor gene expression by a tumor necrosis factor specific ribozyme in juvenile myelomonocytic leukemic cells.

The human cytokines tumor necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) both promote growth and survival of malignant cells from children with juvenile myelomonocytic leukemia (JMML). It has been postulated that TNF stimulates GM-CSF gene expression in an autocrine manner. We found here that the specific inhibition of TNF gene expression by a catalytic RNA molecule (ribozyme) also downregulated the expression of GM-CSF in JMML cells. GM-CSF protein, GM-CSF-dependent colony formation, and viability of JMML cells were reduced. The observed effect was specific, because synthesis of interleukin-1beta, another cytokine produced by JMML cells, was not affected by the ribozyme treatment. The stimulatory effect of TNF on GM-CSF gene expression in JMML cells probably takes place at the transcription level, because the ribozyme treatment decreased GM-CSF mRNA. No apparent toxicity of the ribozyme was detected in normal bone marrow progenitor cells. Thus, the inhibition of TNF gene expression in JMML cells by ribozymes may be a novel therapeutic approach for this disorder.

Base Sequence↗
PubMed1998

[Substance abuse among patients in a department of general medicine].

We conducted a survey of alcohol and drug habits among patients hospitalized in our department during a six month period. Alcohol and drug abuse was found among 185 (11%) of the patients, with a male-to-female ratio of 2.3. The median age was 52 years for women and 53 for men. Generally, the levels of education and employment were low among the alcohol and drug abusing patients. In contrast to our experience, most general practitioners in our catchment area considered alcohol and drug abuse as a minor problem in their patients. During the last 25 years only seven of 54 medical clinics in Norway have performed a systematic registration of alcohol and drug habits among their patients. Patients with alcohol and drug abuse constituted a marked proportion of hospitalized patients in our clinic, and they consumed a substantial portion of our resources.

Adult↗
PubMed1998

[Tropical pyomyositis].

Tropical pyomyositis is rarely observed among permanent residents of temperate or cold climates and is, to our knowledge, not described among Norwegians. It is a clinical entity comprising general symptoms of infection and abscesses in skeletal muscles. We present one case of tropical pyomyositis acquired in the Dominican Republic. The patient, a female, had an insidious progression of the disease with fever, chills, and general malaise. On admission she had also developed multiple abscesses affecting muscles of the extremities. She required surgical drainage in addition to antibiotics. Cultures from purulent material revealed Staphylococcus aureus.

Adult↗
PubMed1998

No neuronal regulation of murine bone marrow function.

Bone marrow is innervated by efferent (sympathetic) and afferent nerves, but it is not clear whether these nerves affect cell formation or release in any significant way. To elucidate this problem, we studied mice neonatally sympathectomized with 6-hydroxydopamine and adult mice in which one hind limb was surgically denervated. Progenitor and transit cell numbers and proliferative activity were estimated in bone marrow, blood, and spleen. In addition, we performed unilateral electrical stimulation of nerve fibers to tibial marrow and applied a cell mobilizing stimulus (bleeding, granulocyte colony-stimulating factor injection, or intraperitoneal injection of a chemotactic substance) to investigate cell egress from the marrow. Blood flow to hindleg bone marrow was assessed with the radioactive microsphere technique. Except for a smaller bone marrow cell population and lower body weight in neonatally sympathectomized mice, we found no clear indications that bone marrow innervation influenced cell production. Also, the innervation did not detectably affect cell release from the marrow. Electrical stimulation of hind limb nerves did not change the blood flow to the marrow, whereas it markedly decreased blood flow to the overlying muscle. We therefore conclude that no obvious function can be ascribed to tibial marrow innervation in the mouse.

Animals↗
PubMed1998

Changing bone marrow micro-environment during development of acute myeloid leukaemia in rats.

The Brown Norwegian rat transplanted with promyelocytic leukaemic cells (BNML) has been used as a model for human acute myeloid leukaemia. We have previously shown that both the blood supply to the bone marrow and the metabolic rate decrease in relation to the leukaemic development in these rats. Here we have investigated how the development and progression of this leukaemia affect oxygenation, pH and proliferation of normal and leukaemic cells in vivo. Bone marrow pH was measured by a needle electrode. Nitroimidazol-theophylline (NITP) was used to identify hypoxic cells, and we applied bromodeoxyuridine (BrdUrd) to identify DNA replicating cells. The leukaemia progressed slowly until day 27 after which a rapid deterioration could be observed leading to severe changes over the following 5 d. In whole blood there was evidence of progressing metabolic acidosis. In bone marrow the fraction of leukaemic cells increased to > 90% and the pH dropped to about 6.5. The fraction of NITP+ cells increased to > 80% in bone marrow and to about 40% in blood. The fraction of BrdUrd+ cells was unchanged in blood, but decreased in bone marrow both for normal cells (from about 20% to 5%), and for leukaemic cells (from about 45% to 25%), evidently as a result of the severely changed microenvironment. In this study we have demonstrated in vivo the development of an acidic and hypoxic bone marrow hampering normal haemopoiesis during leukaemic growth. Our data support the notion of BNML as a valuable tool for studying leukaemogenesis.

Acute Disease↗
PubMed1997

Inhibition of granulocyte-macrophage colony-stimulating factor prevents dissemination and induces remission of juvenile myelomonocytic leukemia in engrafted immunodeficient mice.

Granulocyte-macrophage colony-stimulating factor (GM-CSF ) and tumor necrosis factor alpha (TNFalpha) have been implicated in the pathogenesis of the fatal childhood disease termed juvenile myelomonocytic leukemia (JMML). We used a severe combined immunodeficient/nonobese diabetic (SCID/NOD) mouse model of JMML and examined the effect of inhibiting these cytokines in vivo with the human GM-CSF antagonist and apoptotic agent E21R and the anti-TNFalpha monoclonal antibody (MoAb) cA2 on JMML cell growth and dissemination in vivo. We show here that JMML cells repopulated to high levels in the absence of exogeneous growth factors. Administration of E21R at the time of transplantation or 4 weeks after profoundly reduced JMML cell load in the mouse bone marrow. In contrast, MoAb cA2 had no effect on its own, but synergized with E21R in virtually eliminating JMML cells from the mouse bone marrow. In the spleen and peripheral blood, E21R eliminated JMML cells, while MoAb cA2 had no effect. Importantly, studies of mice engrafted simultaneously with cells from both normal donors and from JMML patients showed that E21R preferentially eliminated leukemic cells. This is the first time a specific GM-CSF inhibitor has been used in vivo, and the results suggest that GM-CSF plays a major role in the pathogenesis of JMML. E21R might offer a novel and specific approach for the treatment of this aggressive leukemia in man.

Adolescent↗
PubMed1997

Deoxyribonucleic acid triplex formation inhibits granulocyte macrophage colony-stimulating factor gene expression and suppresses growth in juvenile myelomonocytic leukemic cells.

Juvenile myelomonocytic leukemia (JMML) is a severe childhood malignancy. The autocrine production of GMCSF is believed to be responsible for the spontaneous proliferation of JMML cells. A nuclear factor-kappaB (NF-kappaB)/Rel binding site within the GM-CSF gene promoter, termed the kappaB element, plays an important role in controlling transcription from the GM-CSF gene. We investigated the effect of an oligonucleotide GM3, directed to form a DNA triple helix across this kappaB element, on growth and GM-CSF production by JMML cells. Treatment of these cells, either unstimulated or induced by TNFalpha, with GM3 led to a significant and specific inhibition of both GM-CSF production and spontaneous colony formation. This constitutes the first report linking specific triplex-mediated inhibition of gene transcription with a functional outcome; i.e., cell growth. We observed the constitutive presence of NF-kappaB/Rel proteins in the nucleus of JMML cells. The constitutive and TNFalpha-induced NF-kappaB/Rel complexes were identical and were composed mainly of p50 and c-Rel proteins. Treatment of the cells with a neutralizing anti-TNFalpha monoclonal antibody completely abrogated constitutive nuclear expression of NF-kappaB/Rel proteins. These results indicate that the aberrant, constitutive GM-CSF gene activation in JMML is maintained by TNFalpha-mediated activation of NF-kappaB/Rel proteins. Our findings identify the molecular basis for the autocrine TNFalpha activation of the GM-CSF gene in JMML and suggest potential novel and specific approaches for the treatment of this aggressive childhood leukemia.

Binding Sites↗