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Biomedical subjects

L Stenke

Publications and source records attributed to L Stenke.

At least 37 records · Page 2Linked to original sources
PubMed1991

Deficient lipoxin synthesis: a novel platelet dysfunction in myeloproliferative disorders with special reference to blastic crisis of chronic myelogenous leukemia.

The capacity to convert exogenous leukotriene A4 to lipoxins (LXs) was investigated in platelet suspensions from patients with myeloproliferative disorders (MPD) (n = 22) and healthy control subjects (n = 14). Platelets isolated from the controls produced mainly LXA4, but also 6(S)-LXA4 and the all-trans isomers of lipoxins A4 and B4, as determined by high-performance liquid chromatography and computerized UV spectroscopy. In comparison to control levels, the mean LX synthesis was significantly lower in platelets from the MPD patients (438.7 +/- 62.8 and 157.4 +/- 31.2 pmol LXA4 per 10(9) platelets, respectively; mean +/- SEM; P = .0001). Platelets from six of the patients showed a particularly low capacity to produce LXs, resulting in LX levels below the detection limit or less than 7% of mean control levels. Notably, all these patients were in blastic crisis of chronic myelogenous leukemia (CML). This severely deficient LX production was paralleled by a dramatically attenuated conversion of arachidonic acid to 12-HETE (12-hydroxyheptadecatrienoic acid), a product formed via the prostaglandin endoperoxide synthase pathway, was normal. In addition, longitudinal studies of CML patients showed that blastic metamorphosis was associated with a markedly reduced capability to synthesize LXs, while this capacity improved after retransformation into a second chronic phase. The results reveal deficient LX synthesis as a novel platelet dysfunction in MPD, particularly in blastic crisis of CML in which an essentially abolished 12-lipoxygenase activity may be a general phenomenon.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1991

Formation and proliferative effects of lipoxins in human bone marrow.

Lipoxins A4 and B4 together with the all-trans lipoxin (LX) isomers were produced by normal human bone marrow cell suspensions after incubation with ionophore A23187. Both LXA4 and LXB4 enhanced the growth of myeloid progenitor cells in semisolid agar in the presence of suboptimal concentrations of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). Lipoxin A4 at 10(-10) M stimulated the colony formation in 13 out of 15 tested human bone marrows with a mean (+/- SEM) increase of 47 +/- 11% (p = 0.001). A similar stimulatory effect was observed after addition of LXB4 (10(-10) M). The monohydroxyeicosatetraenoic acids 5-, 12- and 15-HETE did not affect colony growth. In addition, LXA4 (10(-8) M) efficiently counteracted the increased colony formation induced by leukotriene C4 (10(-10) M), suggesting an antagonistic relationship between these lipoxygenase products. The results support a role for lipoxins in the regulation of human myelopoiesis.

Bone Marrow↗
PubMed1991

On the mechanism of transcellular lipoxin formation in human platelets and granulocytes.

Endogenous arachidonic acid was converted to lipoxins A4, B4 and (6S)-lipoxin A4, in ionophore-A23187-stimulated mixtures of human platelets and granulocytes, while no lipoxins were formed when these cells were incubated separately. However, pure platelet suspensions transformed exogenous leukotriene A4 to lipoxins, including lipoxin A4 and (6S)-lipoxin A4, but not lipoxin B4. This compound was produced exclusively in the presence of granulocytes. A common unstable tetraene intermediate in lipoxin formation, 15-hydroxy-leukotriene A4 [5(6)-epoxy-15-hydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid], was indicated by trapping experiments with methanol. Thus, identical profiles of less polar tetraene-containing derivatives were formed from leukotriene A4 in platelet suspensions, from exogenous 15-hydroxyeicosatetraenoic acid in granulocyte suspensions and from endogenous substrate in mixed platelet/granulocyte suspensions. Evidence for the involvement of 12-lipoxygenase in platelet-dependent lipoxin formation was obtained. Thus, lipoxin synthesis from leukotriene A4 and 12-hydroxyeicosatetraenoic acid production from arachidonic acid by human platelets was equally inhibited by 15-hydroxyeicosatetraenoic acid with 50% inhibition obtained at 7.0 microM and 8.2 microM, respectively. In experiments with subcellular preparations from platelets, lipoxin synthesis was observed in both the particulate and soluble fraction and was paralleled by the 12-lipoxygenase activity. Furthermore, lipoxin formation from leukotriene A4 in platelet sonicates was dose-dependently inhibited by exogenous arachidonic acid. Finally, 12-lipoxygenase-deficient platelets from a patient with chronic myelogenous leukemia were totally unable to produce lipoxins from exogenous or granulocyte-derived leukotriene A4. It is concluded that the transcellular lipoxin synthesis is dependent on the platelet 12-lipoxygenase and proceeds via the unstable intermediate, 15-hydroxy-leukotriene A4. This tetraene epoxide is transformed to lipoxin B4 by a granulocyte epoxide hydrolase activity or to lipoxin A4 and lipoxins A4/B4 isomers by enzymatic or nonenzymatic hydrolysis.

Arachidonic Acids↗
PubMed1990

The effect of different agitation modes on platelet metabolism, thromboxane formation, and alpha-granular release during platelet storage.

Platelet concentrates (PCs), prepared by plateletpheresis, were stored in aliquots in polyvinylchloride blood bags for 5 days at 22 degrees C under rapid, slow, or no agitation. Nonagitated PCs were also stored in a 98-percent oxygen atmosphere. In nonagitated PCs, pO2, lactate production, and platelet factor 4 (PF 4) concentration increased, whereas the ATP level and pH dropped rapidly. These changes were somewhat minimized in nonagitated PCs stored in oxygen. There was no significant difference between the two agitated groups. The increase in PF 4 correlated inversely to the decrease in ATP: r = -0.91, p less than 0.001, n = 24. The formation of thromboxane B2 (TxB2) after stimulation with arachidonic acid or collagen was significantly higher in slowly agitated PCs on Day 5 than on Day 0 (p less than 0.01). Nonagitated PCs produced lower levels of TxB2 (collagen stimulation) on Day 5 (p less than 0.05). In unstimulated PCs, the levels of TxB2 and ATP were inversely correlated on Day 5 (r = -0.70, p less than 0.001, n = 20). In vivo survival was performed after 72 hours of storage; mean survival (+/- SD) was 6.5 (+/- 0.3) days for nonagitated oxygenated PCs and 6.8 (+/- 0.7) days for agitated PCs. In nonagitated PCs, anaerobic metabolism increased, although oxygen diffusion through the container wall was sufficient. Agitation seems to facilitate the diffusion of oxygen through the storage medium. Nonagitated PCs were stored safely for 24 hours; this period can be extended to at least 72 hours when aerobic metabolism is maintained.

Blood Cells↗
PubMed1990

Elevated white blood cell synthesis of leukotriene C4 in chronic myelogenous leukaemia but not in polycythaemia vera.

Leukotriene (LT) formation was studied in ionophore A23187-stimulated white blood cell (WBC) preparations from patients with chronic myelogenous leukaemia (CML; n = 14), polycythaemia vera (PV; n = 10) and two control groups consisting of patients with non-malignant inflammatory disease (n = 4) and normal healthy donors (n = 25). The synthesized products were identified and quantitated using high-performance liquid chromatography combined with computerized UV-spectroscopy. White blood cell preparations from the CML patients produced more LTC4 (40.2 +/- 7.9 pmol/10(6) WBC, mean +/- SEM) than WBC from the healthy donors (9.0 +/- 1.8), P less than 0.0005. In contrast, the formation of LTB4 was normal and there was no increase in the total leukotriene synthesis (the sum of LTC4, LTB4, 20-OH-LTB4 and the delta 6-trans-isomers of LTB4). The ratio between leukotrienes C4 and B4 was strongly elevated in the CML group; 1.67 +/- 0.25 v. 0.37 +/- 0.07 in the controls, P less than 0.0005. No significant correlation was observed between the levels of LTC4 and the number of known LTC4 producing cells (such as monocytes, eosinophils and basophils) in the CML WBC preparations. In contrast, a correlation was found between the sum of neutrophilic granulocytes and metamyelocytes in these suspensions and the amount of LTB4 formed; r = 0.600, P less than 0.05. A number of other laboratory or clinical variables of the CML patients (including total white blood cell and platelet counts, differential counts, previous cytotoxic treatment, time from diagnosis, time from last treatment, post study survival and age) did not significantly correlate with the formation of leukotrienes. No abnormality in the production of LTB4 or LTC4 was observed in granulocyte and WBC preparations from the patients with polycythaemia vera and non-malignant inflammatory disease, respectively. The results indicate a selectively increased LTC4 producing capacity in CML.

Adult↗
PubMed1990

Mitoxantrone, etoposide and cytarabine in the treatment of acute nonlymphocytic leukemia.

In a phase I/II study mitoxantrone and etoposide, in combination with cytarabine, were given to 26 patients with refractory, relapsed, and previously untreated acute nonlymphocytic leukemia. Therapy consisted of mitoxantrone 12 mg/m2/day for 3 days, etoposide 100 mg/m2/day and cytarabine 1 g/m2 twice a day for 5 days. A total of 14 complete remissions (CR, 54%) were noted. Among refractory patients 5 of 10 achieved a CR as compared to 5 of 6 in the previously untreated group. A favorable response was also seen in patients with late relapse off treatment (3/4 CR) while patients relapsing on therapy did worse (1/6 CR). The results suggest a high antileukemic activity and a moderate toxicity for this drug combination.

Adolescent↗
PubMed1988

Decreased blood natural killer cell activity and immunoglobulin synthesis in vitro in aplastic anemia.

Natural killer (NK) cell numbers and T lymphocyte subpopulations in peripheral blood were evaluated in six patients with aplastic anemia (AA). The immunophenotyping results were correlated to in vitro tests of NK cell cytotoxicity against K562 cells and of immunoglobulin (Ig) production after pokeweed mitogen (PWM) stimulation. A significant decrease was found both in the percentage of Leu 11 positive cells and in NK cell activity as compared to age- and sex-matched healthy controls. The decrease in NK cell activity could not be entirely compensated by an increase in effector/target cell ratios, thus suggesting not only a quantitative but also a functional defect in NK cells of the AA patients. Three of four AA patients tested showed no major increase of Ig production after PWM stimulation. All these three patients also had fewer "functional T helper" cells (Leu3+/Leu8-) and increased numbers of T suppressor/cytotoxic cells (Leu2+) when compared to controls. No significant differences in numbers of B lymphocytes (B1+) could be found. Our findings suggest a possible linkage between quantitative and qualitative abnormalities in lymphocyte subsets in aplastic anemia. However, no evidence was found to support the hypothesis of increased NK cell activation behind the hemopoietic depression in this disease.

Adolescent↗
PubMed1988

Increased leukotriene C4 production in chronic myelogenous leukemia.

The production of leukotrienes (LT) in peripheral blood leukocyte preparations from 9 patients with chronic myelogenous leukemia (CML) and 9 healthy controls was studied. Leukotriene generation was stimulated by the calcium ionophore A 23187 (1 mumol). Lipoxygenase products were separated and identified using a high performance liquid chromatography (HPLC) technique and computerized spectrophotometry. Leukotriene C4 (LTC4) was formed in significantly larger amounts by cells from the CML patients than cells from the controls; 14.4 +/- 4.3 pmol per 10(6) nucleated cells (mean +/- SE) and 4.0 +/- 1.2 pmol respectively (p less than 0.05). Seven of the 9 patients but none of the controls synthesized equal or higher amounts of LTC4 than LTB4. A highly significant difference in mean values of LTC4/(LTB4 + 20-OH-LTB4) ratios was observed; CML 0.69 +/- 0.08 versus controls 0.12 +/- 0.02, p less than 0.001. These findings suggest an increased LTC4 synthase activity in CML cells. In earlier studies we have found a decreased 12-lipoxygenase activity in CML bone marrow cells.

Calcimycin↗
PubMed1987

Radioactive iodine and cesium in travellers to different parts of Europe after the Chernobyl accident.

Thyroid uptake of 131I was measured in 130 volunteers following the nuclear power plant accident at Chernobyl in April 1986. Ninety of these volunteers had been travelling in different parts of eastern Europe at the time of or immediately after the accident while 40 persons were permanently in Sweden. Also, 28 additional healthy volunteers, living in Sweden, were chosen for a long-term follow-up of the time-course of 134Cs and 137Cs whole body uptake. The highest levels of 131I were found in persons having visited Poland (mean value 3.27 kBq +/- 3.68 SD, extrapolated to April 27) while persons that had stayed in other parts of eastern or northern Europe showed significantly lower levels (p less than 0.01). The whole body burdens of cesium radionuclides were barely detectable immediately after the accident but increased gradually throughout the observed period. After five months nine farmers from a high fallout area in central Sweden had reached mean values of 4.20 kBq (+/- 3.34 SD) of 134Cs and 137Cs while six nonfarmers from the Stockholm area showed significantly lower levels, 0.64 kBq (+/- 0.24 SD, p less than 0.05). The radiation doses from the observed amounts of iodine and cesium isotopes reported in this study reflect only a marginal addition to the already existing dose from the natural environmental background radiation.

Accidents↗
PubMed1987

Leukotriene production by fresh human bone marrow cells: evidence of altered lipoxygenase activity in chronic myelocytic leukemia.

The metabolism of arachidonic acid through the lipoxygenase pathway was studied in suspensions of fresh human bone marrow cells from eight patients with chronic myelocytic leukemia (CML) and 10 normal controls. After the cells were incubated with the calcium ionophore A23187 and arachidonic acid, a technique including reverse- and straight-phase high-pressure liquid chromatography (HPLC) was employed to isolate and detect different lipoxygenase-mediated compounds. The detected compounds included leukotriene B4 (LTB4), with its two major nonenzymatic isomers 6-trans-LTB4 and 12-epi-6-trans-LTB4 5S,12S-DHETE, and the monohydroxy eicosatetraenoic acids 5-HETE, 12-HETE, and 15-HETE. The pattern of lipoxygenase-mediated products from the bone marrows was similar to that previously described from human peripheral blood. Of eight bone marrow samples from CML patients, five expressed values above 600 ng LTB4/10(8) nucleated cells, as compared to only one out of 10 controls. In contrast, the CML patients produced significantly lower amounts of both the double-dioxygenation product 5S,12S-DHETE (56.8 +/- 16.0 ng [mean +/- SE] versus 146.1 +/- 31.3 ng; p less than 0.05) and the monohydroxy acid 12-HETE (965 +/- 351 ng versus 4390 +/- 1801 ng; p less than 0.05), indicating a 12-lipoxygenase deficiency. The present results show that leukotrienes are formed by human bone marrow cells and further suggest the existence of altered lipoxygenase activity in CML.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗