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Biomedical subjects

W Jelkmann

Publications and source records attributed to W Jelkmann.

At least 55 records · Page 3Linked to original sources
PubMed1999

Prediction of severe ovarian hyperstimulation syndrome by free serum vascular endothelial growth factor concentration on the day of human chorionic gonadotrophin administration.

In this prospective study the concentration of circulating vascular endothelial growth factor (VEGF) was followed in 10 patients with severe ovarian hyperstimulation syndrome (OHSS) after ovarian stimulation and in 15 patients without OHSS. VEGF was assayed by means of two different commercially available kits as either free or total VEGF in serum. The concentration of free VEGF was significantly higher on the days of human chorionic gonadotrophin (HCG) administration (309.4 +/- 165.0 versus 190.3 +/- 127.8 pg/ml, P < 0.05) and embryo transfer (315.0 +/- 125.2 versus 209.3 +/- 137. 2 pg/ml, P < 0.05) in the OHSS compared to the control group. No such difference existed with respect to total circulating VEGF. In addition, there was no significant rise in the free or in the total serum VEGF concentration in the OHSS patients or the controls from the day of HCG administration up to the days of oocyte retrieval or embryo transfer. A cut-off concentration of 200 pg/ml free serum VEGF concentration on the day of HCG treatment resulted in a sensitivity of 90% and a specificity of 80% for the prediction of OHSS development. This is the first report on the parallel measurement of free and total VEGF in serum following ovarian stimulation. The value of the proposed cut-off concentration should be confirmed in a study of a larger group of women.

Adult↗
PubMed1999

The minor coat protein of beet yellows closterovirus encapsidates the 5' terminus of RNA in virions.

Filamentous particles of beet yellows closterovirus (BYV) are built of two related capsid proteins, of which the minor species, p24, forms a 75 nm tail at one end of the virion. In the present work, we used polyclonal antibodies against p24 for isolating the 'tailed' virion segments from sonicated BYV particle preparations. The [gamma-32P]ATP-labelled RNA obtained from the antibody-selected particle segments consistently showed stronger hybridization with the 5'-terminal BYV cDNA clones than with the 3'-terminal cDNA clones. These data clearly indicate that it is the 5'-terminal portion of the closterovirus RNA genome that is encapsidated by p24.

Capsid↗
PubMed1999

Effects of neopterin and 7,8-dihydroneopterin on hypoxia-induced renal erythropoietin production.

Activation of the human cellular immune system is associated with greatly increased formation of the pteridines neopterin and 7,8-dihydroneopterin. It has been postulated that pteridines play a role in the pathogenesis of the anaemia of inflammation. Herein, we studied effects of pteridines on renal function, primarily on the synthesis of erythropoietin (Epo). The experiments were performed with isolated rat kidneys which were perfused hypoxically (pO2 26 mmHg) at constant pressure (100 mmHg) in a serum-free recirculation system for 3 h. The results show that the rate of the production of Epo was significantly lowered when neopterin or 7,8-dihydroneopterin were added to the perfusate. Neopterin (200 microM) also reduced the renal Epo mRNA level. Both pteridines increased renal vascular resistance. 7,8-Dihydroneopterin lowered urine flow and glomerular filtration rate more potently than neopterin. Renal O2 consumption and parameters of exocrine renal function (fractional reabsorption rates of sodium, glucose and water) were not altered by the pteridines, while the glomerular permeability was greatly increased. These results suggest that activated macrophages may not only inhibit the synthesis of Epo by generating cytokines and reactive O2 species but also by the release of pteridines. In vivo, high concentrations of pteridines in renal tissue may aggravate the anaemia of inflammation.

Animals↗
PubMed1998

Foveavirus, a new plant virus genus.

Foveavirus is a novel genus of plant viruses with helically constructed filamentous particles ca. 800 nm long, typified by apple stem pitting virus (ASPV). Virions do not contain lipids or carbohydrates, have a positive sense, single-stranded, polyadenylated RNA genome 8.4 to 9.3 kb in size, and a single type of coat protein with a size of 28 to 44 kDa. The genome of definitive viral species is made up of five ORFs encoding respectively, the replication-related proteins (ORF 1), the putative movement proteins (ORF 2 to 4, constituting the triple block gene), and the coat protein (ORF 5). Virions accumulate in the cytoplasm, where replication is likely to occur with a strategy comparable to that of potexviruses, based on direct expression of the 5'-proximal ORF, and expression of downstream ORFs through subgenomic RNAs. No vector is known. Virus transmission is by grafting, and dispersal is through infected propagating material. The genome structure and organization (i.e., number and order of genes) closely resembles that of the genera Potexvirus, Carlavirus and Allexvirus, but ORF 1 and the coat protein cistron (ASPV only) are significantly larger.

Open Reading Frames↗
PubMed1998

Effects of modulators of the production and degradation of hydrogen peroxide on erythropoietin synthesis.

Erythropoietin (Epo) synthesis is suppressed in normoxia and stimulated in hypoxia. To test the hypothesis that the cellular H2O2 level is important in the control of Epo synthesis, we have studied effects of modulators of H2O2 generation and degradation on Epo production in human hepatic cell cultures (hepatoma lines HepG2 and Hep3B). In addition, we measured the activities of antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase) in cultures following hypoxia exposure or H2O2 treatment. The results show that the formation of immunoreactive Epo was stimulated in normoxic cultures by treatment with exogenous catalase thus mimicking the effect of hypoxia (24 h incubation periods). Epo production was also stimulated when scavengers of reactive O2 species (tetramethylthiourea, dihydrorhodamine) were added to the cells. On the other hand, stimulators of H2O2 generation (xanthine oxidase, glucose oxidase, NADH, NADPH) lowered Epo production in hypoxic cultures. Hypoxia exposure decreased superoxide dismutase activity and H2O2 treatment reduced catalase activity thus influencing the endogenous antioxidant defense system. These findings support the concept that reactive O2 species, primarily H2O2, act as messengers in the O2-dependent control of the hepatic production of Epo. Changes in the cellular activities of antioxidant enzymes appear to play only a minor role in this process.

Carcinoma, Hepatocellular↗
PubMed1998

Serum erythropoietin concentration in anaemia of visceral leishmaniasis (kala-azar) before and during antimonial therapy.

Serum erythropoietin (Epo) concentrations and variables of red cell and iron status were studied in 27 Sudanese patients who were treated with sodium stibogluconate for visceral leishmaniasis (kala-azar). Blood haemoglobin increased from 6.4 (+/- 1.7 SD) to 9.5 (+/- 1.4) g/dl during treatment. Serum ferritin decreased concomitantly. Serum iron levels were unchanged whereas the total iron binding capacity increased slightly. The pre-treatment serum Epo concentration in relation to the blood haemoglobin concentration was not as high as expected from the one in primary haematological diseases, indicating that there is a relative lack of Epo in anaemic kala-azar patients. Serum Epo further decreased during stibogluconate therapy. The normal dependence of the serum Epo level on the blood haemoglobin concentration was lost during mid-term antimonial treatment, but it recovered thereafter. Cell culture studies with the human hepatoma cells HepG2 showed that stibogluconate (> or = 30 microg/ml) inhibited Epo gene expression. Thus, effective treatment of kala-azar with stibogluconate results in improvement of anaemia, although the drug itself may impair Epo production.

Adult↗
PubMed1998

Tumor necrosis factor-alpha production by human hepatoma cell lines is resistant to drugs that are inhibitory to macrophages.

Little is known about the potential of immunomodulatory agents to lower tumor necrosis factor-alpha (TNF-alpha) synthesis in tissues of nonmonocytic origin. We studied effects of diverse drugs on the formation of immunoreactive TNF-alpha in the human hepatoma cell lines HepG2 and Hep3B, in which TNF-alpha production was induced by treatment (3 h incubation periods) with interleukin-1beta (IL-1beta, 300 pg/ml) or phorbol myristate acetate (PMA, 100 nmol/l). TNF-alpha production in IL-1beta-stimulated or PMA-stimulated hepatocyte cultures was not altered following the addition of dihydrocortisone (< or = 1 microg/ml), dibutyryl-cAMP (db-cAMP, < or = 100 micromol/l), adenosine (< or = 1 mmol/l), thalidomide (< or = 25 microg/ml), or cyclosporine (< or = 300 ng/ml). TNF-alpha production was inhibited by taurolidine (> or = 300 microg/ml), but this inhibition was associated with reduced cell viability. Pentoxifylline (1 mg/ml) did not influence PMA-induced TNF-alpha production, but it augmented IL-1beta-induced TNF-alpha production. Measurements of TNF-alpha mRNA by RT-PCR indicated that pentoxifylline exerted its effect posttranscriptionally. Additional studies with PMA-treated human whole blood cultures confirmed that pentoxifylline, db-cAMP, and adenosine reduced TNF-alpha production by leukocytes. These results provide first evidence to assume cell type-specific effects of immunomodulatory drugs on TFN-alpha synthesis, which may be relevant with respect to their clinical application.

Adjuvants, Immunologic↗
PubMed1998

Proinflammatory cytokines lowering erythropoietin production.

The plasma level of erythropoietin (Epo) in anemic patients suffering from inflammation is often low in relation to the blood hemoglobin concentration. Various proinflammatory cytokines have been tested for their action on the synthesis of Epo. Interleukin 1 (IL-1) and tumor necrosis factor-alpha(TNF-alpha) suppress Epo gene expression in isolated perfused rat kidneys and in human hepatoma cell cultures. IL-6 inhibits in the kidney, and conflicting results have been reported for its effect on Epo synthesis in hepatic cells. Several other cytokines tested were without effect. Thus, mainly IL-1 and TNF-alpha seem to be responsible for the defect in Epo production in severe systemic and renal inflammatory diseases.

Animals↗
PubMed1998

Serum concentration of vascular endothelial growth factor cannot predict the course of severe ovarian hyperstimulation syndrome.

Vascular endothelial growth factor (VEGF) is stated to be a possible promoter of the development and the severity of ovarian hyperstimulation syndrome (OHSS). The secretion of VEGF in granulosa cells seems to be human chorionic gonadotrophin (HCG) dependent. In this prospective study, the data of 10 patients suffering from severe OHSS with ascites and pleural effusions (haematocrit, fluid balance, serum HCG, serum oestradiol) were analysed. The serum VEGF concentration declined during the period of clinical improvement but provided no additional diagnostic information for the further course of OHSS. VEGF was neither an early marker of improvement, nor of worsening of the clinical picture of the OHSS. Serum oestradiol concentrations and serum VEGF concentrations showed a statistical correlation (r = 0.33, P < 0.001). There was no correlation between haematocrit and VEGF, nor between serum HCG and VEGF. To conclude, although VEGF may be involved in the pathogenesis of OHSS, it is not an important clinical marker for the course of an OHSS.

Ascites↗
PubMed1998

The influence of acute sterile inflammation on erythropoiesis in rats.

Many different cell types, coordinated by proinflammatory mediators, take part in the acute inflammatory reaction, but there is a lack of evidence regarding the role of erythroid cells in such conditions. In this study, changes in bone marrow, splenic, and peripheral blood erythroid cells and in erythropoietin (Epo) blood levels were investigated up to 72 hours after polyvinylpyrrolidone (PVP)-induced sterile inflammation in male Wistar rats (two intraperitoneal injections of 15 mL 3.5% PVP at 18-hour intervals). Transient changes within progenitor erythroid cells were observed in the bone marrow. Significant increases in the number of splenic immature erythroid progenitors (BFU-E) 6 hours and mature erythroid progenitors (CFU-E), erythroblasts, and orthochromatic erythroblasts 48 and 72 hours after the induction of inflammation pointed to stimulated splenic erythropoiesis. This was confirmed by semiquantitative assessment of splenic smears, which demonstrated expansion of erythroid cells at hours 48 and 72. The changes observed in the bone marrow and spleen indicated that during acute inflammation erythropoiesis was stimulated and that the spleens of PVP-treated rats were favorable to erythroid development. The significant increase in the percentage of peripheral blood reticulocytes 48 and 72 hours after PVP-induced inflammation provided evidence that effective erythropoiesis occurred. In spite of the stimulated erythropoiesis, serum levels of Epo remained unchanged, implying that other non-Epo regulatory molecules may be responsible for erythroid cellular changes.

Acute Disease↗
PubMed1997

Effects of erythropoietin on endothelin-1 synthesis and the cellular calcium messenger system in vascular endothelial cells.

A rise in blood pressure is the main side effect of erythropoietin (EPO) treatment in patients with renal anemia. The mechanisms, however, by which EPO may cause hypertension are still unclear. We therefore investigated the effects of EPO on endothelin (ET) synthesis and cytosolic free calcium concentration ([Ca2+]i) in vascular endothelial cells. Porcine endothelial cells were isolated from thoracic aorta, pulmonary artery, and vena cava. Studies were performed with cells of the first subculture. ET concentrations were measured radioimmunologically. Changes in [Ca2+]i were determined with the fluorescent probe fura-2. Cytotoxicity was assessed by sodium 3'-[1-(phenyl-amino-carbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)ben zene sulfonic acid hydrate (XTT) assay. ET synthesis was similar in cells of different vascular origins and was time-dependent, reaching approximately 2 pmol ET/mg protein within 12 h of incubation. EPO (12 to 200 U/mL) stimulated ET release time- and dose-dependently by up to 83.2% (P < .01) within 12 h in the absence of fetal calf serum and heparin. EPO induced an immediate significant rise in [Ca2+]i from 58 +/- 12 nmol/L to 495 +/- 85 nmol/L (P < .01) with a subsequent slow return to 257 +/- 3 nmol/L. During 2 h of incubation, the Ca-ionophore A 23187 (10(-8) mol/L) moderately but significantly stimulated endothelial ET synthesis. However, the Ca-channel blocker verapamil, the intracellular Ca-release blocker TMB-8, and nickel, an unspecific calcium channel blocker, had no consistent effects on [Ca2+]i or ET synthesis. The protein kinase C inhibitor H-7 stimulated basal [Ca2+]i and cellular ET synthesis. The tyrosine kinase inhibitor genistein suppressed the EPO-induced rise in [Ca2+]i and cellular ET synthesis. From these data we conclude that EPO may stimulate ET synthesis in vascular endothelial cells by activation of an EPO-receptor and via intracellular signalling mechanisms that comprise tyrosine kinase activation and a rise in [Ca2+]i. Therefore, the systemic hypertensive effects of EPO may be due at least in part to local stimulation of vascular endothelial ET synthesis via calcium mobilization.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1997

Cobalt chloride and desferrioxamine antagonize the inhibition of erythropoietin production by reactive oxygen species.

We have recently proposed a H2O2-generating b-type cytochrome as part of the cellular oxygen sensor that controls O2-dependent erythropoietin (Epo) production in the human hepatocellular carcinoma cell line HepG2. H2O2 could act as an intracellular signaling molecule because its production in HepG2 cells is strictly dependent on the pericellular PO2. High cellular levels of H2O2 inhibit hypoxia-induced Epo production while low levels-as under hypoxic conditions-allow full expression of the Epo gene. Since cobalt chloride (CoCl2) and the iron chelator desferrioxamine (DSF) both mimic the hypoxic induction of Epo production we studied the influence of CoCl2 and DSF on the formation and on the action of reactive O2-species with respect to Epo production. Both chemicals reduced the H2O2-dependent 123-dihydrorhodamine fluorescence in HepG2 cells. The inhibition of Epo production by exogenous H2O2 was completely antagonized by DSF. This might indicate that H2O2 exerts its inhibition through a Fenton type reaction. On the other hand, NADPH and pyrogallol which stimulate the production of O2- inhibited Epo production. CoCl2 antagonized their effects. From our results we propose different sites of interaction with the putative signaling chain for DSF and CoCl2. While DSF appears to reduce the action of the H2O2 molecule, CoCl2 might act further upstream through the induction of H2O2-scavenger systems or by interfering with its production.

Cell Line↗
PubMed1997

Effects of antioxidant vitamins on renal and hepatic erythropoietin production.

An important role in O2 sensing has been assigned to microsomal and membrane-bound b-type cytochromes which generate regulatory reactive O2 species (ROS). Recently, ROS have been shown to suppress the in vitro synthesis of erythropoietin (Epo). We investigated the potential of the antioxidant vitamins A, E and C to enhance renal and hepatic Epo production. Renal effects were studied in isolated serum-free perfused rat kidneys. In control experiments without antioxidant vitamins, Epo secretion amounted to 441 +/- 23 mU/g kidney (mean +/- SEM, N = 5) during the three hour period of hypoxic perfusion (arterial pO2 35 mm Hg). Epo secretion significantly increased to 674 +/- 92 mU/g kidney (N = 7) when vitamins A (0.5 microgram/ml), E (0.5 microgram/ml) and C (10 micrograms/ml) in combination were added to the perfusion medium. The effects of the single vitamins were studied in Epo-producing hepatoma cell cultures (lines HepG2 and Hep3B). Vitamin A induced a dose-dependent increase (half-maximal stimulation at 0.2 microgram/ml) in the production of immunoreactive Epo during 24 hours of incubation (such as 680 +/- 51 U Epo/g cell protein in HepG2 cultures with 3 micrograms/ml retinol acetate compared to 261 +/- 15 U/g in untreated controls; N = 4). In contrast, vitamin E (tested from 0.05 to 500 micrograms/ml) and vitamin C (tested from 2 to 200 micrograms/ml) did not increase Epo production in hepatoma cell cultures. Thus, while vitamins E and C may have the potential to protect cells from oxidative damage, vitamin A exerts a specific stimulation of Epo production. Preliminary evidence suggests that this effect of vitamin A involves increased mRNA levels of hypoxia-inducible factor 1 alpha (HIF-1 alpha).

Animals↗
PubMed1997

Inadequate erythropoietin response to anaemia in HIV patients: relationship to serum levels of tumour necrosis factor-alpha, interleukin-6 and their soluble receptors.

Severe anaemia is a frequent complication in advanced HIV infection. In our study we investigated the interaction between cytokine network, HIV infection and erythropoietin (Epo) response with increasing anaemia levels. No correlations could be established between circulating tumour necrosis factor (TNF)-alpha and any of the examined parameters. However, a negative correlation was found between haemoglobin values and soluble TNF receptor levels (sTNF-R-I: r = -0.54; P < 0.001; sTNF-R II: r = -0.47; P < 0.001) as well as interleukin-6 levels (r = -0.29; P < 0.01). In contrast, no significant increase in log[Epo], counterbalancing haemoglobin decline and paralleling the rise in sTNF receptors, was found. In patients classified as stage III, according to the Centers for Disease Control (CDC) classification, the erythropoietin response was significantly more impaired than in patients from CDC groups I and II (P < 0.01). The results of this study suggest that similar to its action in vitro, activation of the TNF/TNF-R system may impair erythropoietin production in HIV-associated anaemia. Due to the brief half-life of TNF-alpha, this activation is particularly reflected by elevations of soluble TNF receptor levels.

Adult↗
PubMed1997

Complete genome structure and phylogenetic analysis of little cherry virus, a mealybug-transmissible closterovirus.

The 5'-terminal genomic region (8597 nt) of little cherry virus (LChV), a mealybug-borne closterovirus, was cloned from double-stranded RNA, and its sequence determined to complete the 16934 nt sequence of the monopartite LChV RNA genome. In the 5' to 3' direction, the sequence encompasses ORF 1a, encoding the conserved replicative domains of methyltransferase and helicase, and ORF 1b, encoding RNA polymerase. ORFs 1a and 1b partially overlap (in O/+1 configuration), and the LChV replicase is probably expressed by ribosomal frameshifting as a fusion product with a molecular mass of 318 kDa. The N-terminal part of the ORF 1a product contains a papain-like cysteine proteinase (PCP) domain with a predicted cleavage site between Gly-619 and Ser-620. The PCP and the upstream protein domains can be aligned with the equivalent parts of the leader proteins encoded by the whitefly-transmitted lettuce infectious yellows and sweet potato sunken vein closteroviruses. Phylogenetic reconstruction based on the aligned RNA polymerase sequences clearly suggests that the aphid-transmissible and whitefly-transmissible closteroviruses represent two distinct evolutionary lineages, with the mealybug-transmissible LChV being the most remote member of the 'whitefly' lineage.

Amino Acid Sequence↗