Biomedical subjects

R Walter

Publications and source records attributed to R Walter.

At least 19 recordsLinked to original sources

PubMed2005

T-kininogen can either induce or inhibit proliferation in Balb/c 3T3 fibroblasts, depending on the route of administration.

T-kininogen (T-KG) is a precursor of T-kinin, the most abundant kinin in rat serum, and also acts as a strong and specific cysteine proteinase inhibitor. Its expression is strongly induced during aging in rats, and expression of T-KG in Balb/c 3T3 fibroblasts results in inhibition of cell proliferation. However, T-KG is a serum protein produced primarily in the liver, and thus, most cells are only exposed to the protein from the outside. To test the effect of T-KG on fibroblasts exposed to exogenous T-KG, we purified the protein from the serum of K-kininogen-deficient Katholiek rats. In contrast to the results obtained by transfection, exposure of Balb/c 3T3 fibroblasts to exogenously added T-KG leads to a dose-dependent increase in [3H]-thymidine incorporation. This response does not require kinin receptors, but it is clearly mediated by activation of the ERK pathway. As a control, we repeated the transfection experiments, using a different promoter. The results are consistent with our published data showing that, under these circumstances, T-KG inhibits cell proliferation. We conclude that T-KG exerts opposite effects on fibroblast proliferation, depending exclusively on the way that it is administered to the cells (transfection versus exogenous addition).

Aging↗

PubMed2005

The anticholinergic drug propiverine inhibits the protein kinase C activity in the rat urinary bladder.

UNLABELLED: There is ample evidence that non-cholinergic protein kinase C (PKC) mediated signal transduction pathways are involved into regulation of bladder smooth muscle contractions. To evaluate whether the anticholinergic and calcium modulating drug propiverine exerts intracellular effects by inhibition of the PKC, male inbred LEW 1A rats were pretreated with 0.6, 2, 6 and 60 mg/kg body weight for 5 days. Furthermore, competition assays with partially purified PKC were performed with propiverine in vitro. The activities of the membrane-bound and soluble PKC were assessed by 32P enrichment of lysine-rich histone. RESULTS: The active, membrane-bound PKC decreased by about 60% accompanied by increase of the soluble form after propiverine in doses above 0.6 mg/kg. 100 nM of the drug inhibited the PKC also in vitro whereas the propiverine metabolites M5 and M6 and atropine were without any effect. CONCLUSIONS: Propiverine was identified to be an inhibitor of the protein kinase C. Its contribution to the noncholinergic control of hyperactive detrusor smooth muscle cells needs further investigation.

Animals↗

PubMed2004

Compact sources as the origin of the soft gamma-ray emission of the Milky Way.

The Milky Way is known to be an abundant source of gamma-ray photons, now determined to be mainly diffuse in nature and resulting from interstellar processes. In the soft gamma-ray domain, point sources are expected to dominate, but the lack of sensitive high-resolution observations did not allow for a clear estimate of the contribution from such sources. Even the best imaging experiment revealed only a few point sources, accounting for about 50% of the total Galactic flux. Theoretical studies were unable to explain the remaining intense diffuse emission. Investigating the origin of the soft gamma-rays is therefore necessary to determine the dominant particle acceleration processes and to gain insights into the physical and chemical equilibrium of the interstellar medium. Here we report observations in the soft gamma-ray domain that reveal numerous compact sources. We show that these sources account for the entirety of the Milky Way's emission in soft gamma-rays, leaving at most a minor role for diffuse processes.

Journal Article↗

PubMed2003

Influence of propiverine on hepatic microsomal cytochrome p450 enzymes in male rats.

The bladder spasmolytics propiverine was shown to induce hepatic cytochrome P450 (P450) and aminopyrine and aniline oxidation in rats. To characterize the type of enzyme induction and its dose dependence, activities of seven hepatic microsomal P450-dependent monooxygenases were measured in 72 male LEW1A albino rats (body weight 236-295 g) after oral treatment with 0.5, 2, 6, and 60 mg/kg of propiverine hydrochloride for 5 days and compared with the effects of 40 mg/kg beta-naphthoflavone, 10 mg/kg phenobarbital, and 20 mg/kg dexamethasone (each group, n = 8). CYP2B expression was measured by Western blotting. Furthermore, the inhibitory potency of propiverine on P450 enzymes was evaluated in competition assays with three most specific monooxygenases. Results show that Propiverine induced several monooxygenases and CYP2B expression dose dependently. The effects were well comparable with a phenobarbital-type inducer with 60 mg/kg being equipotent to 10 mg/kg phenobarbital. Furthermore, propiverine in low concentrations inhibited pentylresorufin O-dealkylase (for CYP2B) in vitro. In conclusion, propiverine is a phenobarbital-type inducer on hepatic P450 enzymes in rats in doses about 100-times above the therapeutic doses in man.

Animals↗

PubMed2002

Influence of prestorage leucocyte depletion and storage time on rheologic properties of erythrocyte concentrates.

BACKGROUND AND OBJECTIVES: Rheological blood properties were studied during storage. MATERIALS AND METHODS: Blood viscosity, erythrocyte morphology and ATP levels were determined in filtered samples (Leukotrap WB filter system) and their unfiltered counterparts during storage with saline-adenine-glucose-mannitol (SAG-M) for 42 days. RESULTS: Prestorage leucocyte depletion decreased blood viscosity at a high shear rate and reduced the degree of anisocytosis of erythrocytes. During storage, erythrocytes underwent a time-dependent echinocytic shape transformation, which increased the suspension viscosity at high and low shear rates. On day 42, high shear viscosity in filtered units remained lower than in unfiltered counterparts, the mean cellular volume and red blood cell distribution width (RDW) were lower and erythrocytic ATP levels were higher. CONCLUSIONS: Prestorage leucocyte depletion by Leukotrap WB filters improves biophysical properties of erythrocyte concentrates throughout storage, which is, however, outweighed by a time-dependent echinocytic shape transformation and deterioration of these properties.

Adenosine Triphosphate↗

PubMed2002

Blood viscosity and platelet function in patients with obstructive sleep apnea syndrome treated with nasal continuous positive airway pressure.

Patients with obstructive sleep apnea syndrome (OSA) have a high incidence of cardiovascular events. We measured whole blood viscosity at high (94.5 s(-1)) and low (0.1 s(-1)) shear rate, hematocrit, fibrinogen, and platelet hemostatic function (PTA-100) at 7-8 p.m. and 7-8 a.m. in 8 controls and 13 patients, once with the established nasal continuous positive airway pressure (NCPAP) treatment and once without. OSA patients had a higher plasma viscosity (1.37+/-0.11 vs. 1.19+/-0.11 mPa.s in the evening, p<0.05) and fibrinogen (2.61+/-0.49 vs. 2.11+/-0.29 g/l, p<0.05) than controls, without diurnal difference, and similar values with or without NCPAP. Whole blood viscosity and hematocrit were similar in controls and patients before and after a night with or without NCPAP. Platelet activity was significantly higher in the morning than in the evening in controls and patients with or without NCPAP. We conclude that blood viscosity and platelet activity are similar in controls and patients with OSA on a long-term treatment with NCPAP, which is not worsened by a single night without NCPAP. The increase of plasma viscosity and fibrinogen in OSA patients as well as the general increase of platelet aggregation in the morning may contribute to the increased incidence of cardiovascular events.

Aged↗

PubMed2001

T-kininogen inhibits fibroblast proliferation in the G(1) phase of the cell cycle.

By using synthetic protease inhibitors, several investigators have demonstrated that cysteine proteinases are required for cell proliferation. Kininogens are potent and specific physiological inhibitors of cysteine proteinases. We have used several mouse fibroblast-derived cell lines that express biologically active T-kininogen under the control of the mouse metallothionein promoter to test its effect on cell proliferation. Our results indicate that expression of T-kininogen results in diminished proliferative capacity, as measured by reduced cell numbers, both in logarithmically growing cultures and in G(0) cells induced to proliferate in response to serum. Furthermore, both fluorescence-activated cell sorting (FACS) analysis and incorporation of radioactive precursors into DNA suggest that the cells are unable to progress from G(0) through the S phase of the cell cycle in response to serum stimulation. However, we find that T-kininogen-expressing cell lines are still capable of responding to growth factors present in the serum, both by activating the ERK pathway and by expressing early genes, such as c-Fos and c-Jun. Thus, our results suggest that inhibition of cysteine proteinases by T-kininogen leads to inhibition of cell proliferation between the G(1) and S phases of the cell cycle.

3T3 Cells↗

PubMed2001

Tetrahydrobiopterin increases myocardial blood flow in healthy volunteers: a double-blind, placebo-controlled study.

OBJECTIVES: Tetrahydrobiopterin (BH4) is a regulatory cofactor for the activity of nitric oxide synthases. Vasodilating properties of BH4 have been reported in vitro and in vivo. The influence of BH4 on myocardial blood flow (MBF), however, is largely unknown. We therefore performed a double-blind, placebo-controlled study to investigate the effect of intravenous BH4 on MBF in healthy volunteers. METHODS AND RESULTS: Resting MBF was assessed in 15 subjects receiving either intravenous BH4 (10 mg/kg) or placebo using positron emission tomography (PET) and [13N]ammonia. From a mean baseline MBF of 0.91 +/- 0.09 ml/min/g, MBF increased to 1.18 +/- 0.10 ml/min/g after BH4 (n = 10; p = 0.0042). In contrast, in the group receiving placebo mean MBF remained unchanged (non-significant decrease from 0.97 +/- 0.19 to 0.84 +/- 0.11 ml/min/g; n = 5; p = 0.36). Systemic haemodynamics and ECGs remained unaffected in both groups. BH4 was very well tolerated. CONCLUSION: Systemically administered BH4 is safe and effectively increases resting MBF in healthy volunteers.

Adult↗

PubMed2001

Effects of high-altitude exposure on vascular endothelial growth factor levels in man.

Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen and permeability factor that is inducible by hypoxia. Its contribution to high-altitude illness in man is unknown. We measured VEGF levels in 14 mountaineers at low altitude (490 m) and 24 h after their arrival at high altitude (4,559 m). At high altitude, VEGF increased from [mean (SEM)] 32.5 (9.2) to 60.9 (18.5) pg.ml(-1) (P < 0.004) in the arterial blood, and from 15.9 (2.9) to 49.3 (15.9) pg.ml(-1) (P= 0.0001) in the mixed venous blood. Whereas at low altitude venous and arterial VEGF levels were not statistically different from each other (P= 0.065), the VEGF concentration was significantly lower in venous than in arterial blood samples at high altitude (P=0.004). The pulmonary capillary VEGF concentration remained unchanged at high altitude [14.8 (2.5) vs 17.1 (5.4) pg.ml(-1), P=0.85]. VEGF levels in the nine mountaineers who developed symptoms of acute mountain sickness (AMS), and in the six subjects who had radiographic evidence of high-altitude pulmonary edema were similar to those in subjects without symptoms. VEGF was not correlated with either AMS scores, mean pulmonary arterial pressures, arterial partial pressure of O2, or alveolar-arterial O2 gradients. We conclude that VEGF release is stimulated at high altitude, but that VEGF is probably not related to high-altitude illness.

Adult↗

PubMed2001

Commercial taxane formulations induce stomatocytosis and increase blood viscosity.

1. Taxanes are antineoplastic drugs which have cardiovascular side effects of unknown mechanism. We investigated their influence on blood viscosity and erythrocyte morphology. 2. Whole blood was incubated in vitro with increasing concentrations of Taxol, Taxotere, paclitaxel (0-100 microM) and the vehicles Cremophor-EL and Tween 80 (0-5% vol) for 1 h at 37 degrees C. Plasma and whole blood viscosity (Haematocrit 45%) were measured and erythrocyte morphology was assessed on glutaraldehyde-fixed cells. The same investigations were performed in seven patients before and after a Taxol-infusion. 3. Taxol and Taxotere induced a dose- and time-dependent stomatocytic shape transformation of erythrocytes. Paclitaxel alone had no effect, but the vehicles cremophor-EL and Tween 80, used in Taxol and Taxotere, respectively, induced a comparable degree of stomatocytosis. This suggests a preferential intercalation of these substances into the inner hemileaflet of the membrane lipid bilayer. Associated with this shape change a dose-dependent increase in plasma and whole blood viscosity was observed. Neither shape nor viscosity changes were reversible upon removal of the agents. After the infusion of 130-300 mg Taxol in patients a slight shift towards stomatocytosis and an increase in whole blood viscosity at high shear rate from 5.09+/-0.30 to 5.44+/-0.38 mPa.s (P<0.05) were confirmed. 4. Commercial taxane drug formulations induce stomatocytosis and increase blood viscosity, which is due to their formulation vehicles. These findings may contribute to the understanding of the cardiovascular side effects of these drugs.

Aged↗

PubMed2001

Bone marrow involvement in Whipple's disease: rarely reported, but really rare?

Infection with Tropheryma whippelii, the causative agent of Whipple's disease, involves nearly every organ. Involvement of bone marrow may be an overlooked area of Whipple's disease. We report a case of lymphoma-like Whipple's disease with bone marrow involvement together with a brief review of the literature on this topic. Despite minimal documentation, bone marrow may be commonly involved in Whipple's disease and, although not specific, diastase-resistant periodic acid-Schiff (PAS)-positive macrophages in bone marrow may offer an important clue to diagnosis using PAS histology of upper endoscopic biopsies, polymerase chain reaction or electron microscopy.

Adult↗

PubMed2001

Influence of D- and L-glucose on erythrocytes and blood viscosity.

BACKGROUND: Elevated blood glucose levels are associated with substantial morbidity and mortality. The pathomechanism behind it is not well understood. The aim of the present study was to investigate the effect of glucose on blood rheology. MATERIALS AND METHODS: Blood from healthy volunteers was incubated with various concentrations of D- and L-glucose for 1 h at 37 degrees C. Whole blood viscosity at haematocrit 45% was measured at high and low shear rate (94.5 and 0.1 s(-1)). Erythrocyte shape and volume were assessed. Haemoglobin solutions were incubated with D-glucose for up to 96 h and the viscosity was measured. RESULTS: D-glucose dissolved in H2O and diluted with isotonic NaCl, added to whole blood (additional D-glucose concentrations 0-80 mM), led to a red cell swelling and an increase in blood viscosity at low shear rate (0.1 s(-1)). This process was reversible upon removal of D-glucose. L-glucose, which is not transported into the red cell by the D-glucose-specific transport protein GLUT-1, had no effect. When D-glucose was dissolved and diluted in autologous plasma, haematocrit and viscosity remained unaffected, but L-glucose decreased both values. Incubation of a haemoglobin solution with D-glucose at 37 degrees C led to a time-dependent increase in glycosylated haemoglobin (HbA1C) up to 8%, but left the viscosity unchanged. CONCLUSION: Blood glucose tested in a wide range of concentrations did not affect blood viscosity and morphological or biophysical properties of erythrocytes.

Blood Viscosity↗

PubMed2001

Geographic pattern of genetic variation in Pinus resinosa: area of greatest diversity is not the origin of postglacial populations.

Genetic diversity is low in natural populations of red pine, Pinus resinosa, a species that has a vast range across north-eastern North America. In this study, we examined 10 chloroplast microsatellite or simple sequence repeats (cpSSR) loci in 136 individuals from 10 widespread populations. Substantial variation for the cpSSR loci was observed in the study populations. The contrast with red pine's lack of variation for other types of loci is likely to be due to the higher mutation rates typical of SSR loci. The amount of variation is lower than that generally found for cpSSR loci in other pine species. In addition, the variation exhibits a striking geographical pattern. Most of the genetic diversity is among populations, with little within populations, indicating substantial isolation of and genetic drift within many populations in the southern half of the species distribution. The greatest diversity now occurs in the north-eastern part of New England, which is especially intriguing because this entire area was glaciated. Thus the centre of diversity cannot be the origin of postglacial populations, rather it is likely caused by admixture, most probably because of influences from two separate refugia. Furthermore, the pattern indicates that the spread of red pine since the last glaciation is rather more complex than usually described, and it likely includes more than one refugia, complex migration routes, and postglacial-retreat isolation and genetic drift among shrinking populations in regions of the present southern range.

Chloroplasts↗

PubMed2001

Epistemology at work: the ontological relationship between feminist methods, intersubjectivity and nursing research--a research exemplar.

This article explores the importance of strong epistemological and ontological links in nursing research by examining the design and process of a recent research project. The research topic concerns the relationship between self-concept and nursing practice. In this article, the authors demonstrate that commitment to a methodologically consistent process and the necessary associated epistemological and ontological positions provides a depth and structure to nursing research. It is the authors' belief that such consistency within research acts to strengthen the research process, and consequently strengthens nursing's research base and knowledge.

Feminism↗

PubMed2001

No influence of C-peptide, insulin, and glucagon on blood viscosity in vitro in healthy humans and patients with diabetes mellitus.

The influence of the hormones most involved in glucose homeostasis, C-peptide, insulin and glucagon on blood viscosity was tested in vitro. Whole blood (adjusted to haematocrit 45%) from healthy volunteers (n=24) and patients with diabetes mellitus (n=17) was incubated with 10(-7)-10(-10) M C-peptide, insulin or glucagon. None of these peptide hormones, neither at physiological nor at supraphysiological levels, had an influence on high (94.5 s(-1)) or low (0.1 s(-1)) shear rate viscosity. The small group of diabetic patients had a higher plasma viscosity and increased blood viscosity at 94.5 s(-1), which is in agreement with earlier studies, but decreased viscosity at low shear rate. We conclude that C-peptide, insulin and glucagon have no direct effect on blood viscosity in vitro. It is, therefore, unlikely that microvascular disturbances seen with either deficiency or excess of these hormones is due to haemorheological factors.

Adult↗

PubMed2000

[Reactivation of herpes virus infections by vaccination: evidence or coincidence?].

Varicella zoster and herpes simplex viruses cause latent infections by persisting in human cells. Reactivation has been associated with increasing age, immunosuppression, cancer, stress, fever, exposure to ultraviolet light, and tissue damage. Based on three cases reported to the Swiss Drug Monitoring Centre SANZ, we postulated previously that vaccinations may trigger reactivation of herpes virus infections due to vaccine-induced immunomodulation. In the meantime, 10 new cases of reactivated herpes virus infections soon after vaccinations have been reported. They involved 5 women and 5 men with an age range between 16 and 60. In only one case had a trauma preceded, otherwise healthy subjects with no known relevant comorbidity were vaccinated. The clustering of reports after publication points to a previous underreporting of similar cases. This may be explained by the fact that both vaccinations and reactivations of herpes virus infections are frequent, and a causal link is not suspected. However, these new cases do not prove causality, and extensive epidemiological or experimental studies are needed to elucidate the possible link between vaccination and reactivation of herpes virus infections.

Adult↗

PubMed2000

Modulation of the ERK pathway of signal transduction by cysteine proteinase inhibitors.

Cell proliferation requires the coordinate synthesis and degradation of many proteins. In addition to the well-characterized involvement of the proteasome in the degradation of several cell cycle-regulated proteins, it has been established that cysteine proteinases are also involved in the control of cell proliferation, but their role is currently not understood. By using both synthetic cysteine proteinase inhibitors and overexpression of T-kininogen (T-KG), a physiologically relevant cysteine proteinase inhibitor, we show that inhibition of cysteine proteinases results in a severe inhibition of the ERK pathway of signal transduction. Mechanistically, this effect appears to be the result of stabilization of the ERK phosphatase MKP-1, which leads to an enhanced dephosphorylation (and hence inactivation) of ERK molecules. These results are specific to cysteine proteinase inhibitors and are not observed when either serine proteinases or the proteasome are inhibited. We hypothesize that inhibition of cysteine proteinases in vivo leads to a dysregulation of the ERK pathway, which results in an inability of the cell to transmit to the nucleus the signals generated by the presence of growth factors, thus resulting in loss of cell proliferation.

Amino Acid Sequence↗

PubMed2000

Pharmacological concentrations of arginine influence human whole blood viscosity independent of nitric oxide synthase activity in vitro.

l-Arginine, the natural precursor of NO, is infused in patients to restore endothelial function. Concentrations up to 7.5 mM l-arginine have been measured after parenteral administration. We investigated whether such high concentrations of amino acids influence blood viscosity in vitro. Incubation of whole blood from healthy volunteers with l-arginine, d-arginine, which has no effect on stereospecific NO synthases (NOS), the NOS substrate L-AME, the NOS inhibitor L-NNA, the amino acids l-lysine and l-glutamic acid, and finally NaCl dose-dependently decreased (up to 30% at 10(-2) M) low shear viscosity, which is primarily determined by erythrocyte aggregation. In contrast, the lipophilic NOS inhibitor L-NAME had no effect on low shear viscosity. All molecules failed to influence high shear viscosity, which is primarily determined by red cell deformability, and the erythrocyte shape remained unaltered. We conclude that high concentrations amino acids may decrease blood viscosity at low shear rate independent of NOS activity. This effect may contribute to the improved blood flow after intravascular administration of l-arginine.

Adult↗