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Biomedical subjects

S Werner

Publications and source records attributed to S Werner.

At least 145 records · Page 8Linked to original sources
PubMed1996

In vitro testing of artificial heart valves: comparison between Newtonian and non-Newtonian fluids.

The in vitro testing of artificial heart valves is often performed with simple fluids like glycerol solutions. Blood, however, is a non-Newtonian fluid with a complex viscoelastic behavior, and different flow fields in comparable geometries may result. Therefore, we used different polymer solutions (Polyacrylamid, Xanthan gum) with blood-like rheological properties as well as various Newtonian fluids (water, glycerol solutions) in our heart valve test device. Hydrodynamic parameters of Björk-Shiley heart valves with a tissue annulus diameter (TAD) of 21-29 mm were investigated under aortic flow conditions. Major results can be summarized as follows. The mean systolic pressure differences depend on the model fluids tested. Closing time and closing volume are not influenced by the rheological behavior of fluids. These parameters depend on TAD and the pressure differences across the valve. In contrast, rheological behavior has a pronounced influence upon leakage flow and leakage volume, respectively. Results show furthermore that the apparent viscosity data as a function of shear rate are not sufficient to characterize the rheological fluid behavior relevant to hydrodynamic parameters of the heart valves investigated. Therefore, similarity in the yield curves of non-Newtonian test fluids mimicing blood is only a pre-requisite for a suitable test fluid. More information about the viscous and elastic component of the fluid viscosity is required, especially in geometries where a complex flow field exists as in the case of leakage flow.

Acrylic Resins↗
PubMed1996

Keratinocyte growth factor is highly overexpressed in inflammatory bowel disease.

Recently we demonstrated an important function of keratinocyte growth factor (KGF) in wound re-epithelialization. As KGF is mitogenic for various epithelial cells, we speculated about a role of KGF in epithelial repair processes of other organs as seen in a variety of inflammatory diseases. Here we demonstrate a strikingly increased expression of KGF in surgical specimens from patients suffering from Crohn's disease and ulcerative colitis. The levels of KGF expression strongly correlated with the degree of inflammation as assessed by histological analysis of adjacent tissue and expression analysis of the pro-inflammatory cytokine interleukin-1 beta. The highest levels of KGF mRNA and protein were found in mesenchymal cells of the lamina propria, particularly in highly inflamed areas. As the KGF receptor is expressed in intestinal epithelial cells, KGF seems to act in a paracrine manner to stimulate proliferation of these cells. These data suggest a crucial role of KGF in epithelial repair after injury caused by inflammatory processes.

Blotting, Western↗
PubMed1996

Inhibitory effects of diazepam in rat vas deferens: role of calcium.

Diazepam and Ro5-4864 effects on noradrenaline-induced rat vas deferens contractions were studied. We investigated whether central or peripheral type benzodiazepine receptors were involved, by studying the effects of the selective central or peripheral benzodiazepine receptor antagonists, flumazenil (Ro 151788) or PK 11195 respectively. Diazepam interactions with GABA, adenosine, theophylline, and hypercalcic medium (3.5 mM) were studied. Also, we investigate diazepam effect on KCl depolarized vas deferens. Results showed that diazepam (10(-4) to 1.7 x 10 (-4) M) and Ro 5-4864 (10(-5) to 5.5 x 10(-5) M) inhibited NA-induced vas deferens contractions and that neither flumazenil nor PK 11195 antagonized diazepam or Ro 5-4864 inhibitory effects respectively. GABA, adenosine and theophylline did not modify neither NA vas deferens response nor diazepam inhibitory action. Diazepam effect was significantly reduced in and 3.5 mM calcium medium and KCl vas deferens response was inhibited by diazepam 1.3 x 10(-5) and 1.3 x 10(-4) M. It is concluded that in rat vas deferens diazepam effect seems to be related with calcium mobilization.

Adenosine↗
PubMed1995

Nitric oxide synthase-immunoreactive, adrenergic, cholinergic, and peptidergic nerves of the female rat urinary tract: a comparative study.

The distribution and frequency of NO synthase (NOS)-immunoreactive (IR) nerves in relation to the general autonomic innervation, adrenergic, cholinergic and some peptidergic nerves, were investigated in the female rat urinary tract. NOS nerves were very frequent in the smooth musculature of the urethra together with cholinergic, adrenergic and neuropeptide Y (NPY)-IR nerves, whereas vasoactive intestinal peptide (VIP)-IR and calcitonin-gene-related peptide (CGRP)-IR nerves were much less abundant. NOS-IR, CGRP-IR and cholinergic nerves were also frequent in the longitudinal smooth musculature of the distal ureters and the ureteral orifices into the bladder, where no adrenergic, NPY-IR and VIP-IR nerves were found. In contrast, in the detrusor NOS-IR nerves were scarce. Bilateral pelvic ganglionectomy very pronouncedly decreased the number of any of the populations of nerves studied, whereas bilateral pelvic decentralization selectively reduced the number of CGRP-IR nerves in all structures and locations. Outflow obstruction very overtly reduced the number of NOS-IR nerves in parallel with the general autonomic innervation. Thus, in the rat female urinary tract, NOS-containing nerves particularly occur in regions with sphincteric functions such as urethra and ureteric orifices. In these regions NO may exert a transmitter role, both directly or by interaction with other transmitters/modulators.

Adrenergic Fibers↗
PubMed1995

Regulation of vascular endothelial growth factor expression in cultured keratinocytes. Implications for normal and impaired wound healing.

Recent in situ hybridization studies had demonstrated a strong increase in vascular endothelial growth factor (VEGF) mRNA expression in the hyperproliferative epithelium during wound healing. To determine potential mediators of VEGF induction during this process, we analyzed the regulation of VEGF expression in cultured human keratinocytes. We found a large induction of VEGF expression upon treatment of quiescent cells with serum, epidermal growth factor, transforming growth factor-beta 1, keratinocyte growth factor, or the proinflammatory cytokine tumor necrosis factor alpha, respectively. Since all these factors are present at the wound site during the early phase of wound healing, they might also be responsible for VEGF induction after cutaneous injury. To determine the importance of increased VEGF production for wound repair, we compared the time course of VEGF mRNA expression during wound healing of healthy control mice with the kinetics of VEGF expression during skin repair of genetically diabetic db/db mice which are characterized by impaired wound healing. In normal mice we found elevated VEGF mRNA levels during the period when granulation tissue formation occurs. In contrast, VEGF mRNA levels even declined during this period in db/db mice, suggesting that a defect in VEGF regulation might be associated with wound healing disorders.

Animals↗
PubMed1995

Disruption of the gene encoding the 78-kilodalton subunit of the peripheral arm of complex I in Neurospora crassa by repeat induced point mutation (RIP).

We have used the procedure of sheltered RIP to generate mutants of the 78-kDa protein of the peripheral arm of Neurospora crassa complex I. The nuclei containing the mutations were initially isolated as one component of a heterokaryon but subsequent analysis showed that nuclei containing null alleles of the gene could be propagated as homokaryons. This demonstrates that the gene does not serve an essential function. Sequence analysis of one allele shows that 61 transition mutations were created resulting in 39 amino-acid changes including the introduction of four stop codons. Mutant strains grow at a slower rate than wild-type and exhibit a decrease in the production of conidia. Electron paramagnetic spectroscopy of mutant mitochondria suggest that they are deficient in Fe-S clusters N-1, N-3, and N-4.

Amino Acid Sequence↗
PubMed1995

An evaluation of knee extensor and knee flexor torques and EMGs in patients with patellofemoral pain syndrome in comparison with matched controls.

The relationship between concentric and eccentric isokinetic torques and EMGs of quadriceps and hamstring muscles in patients with unilateral patellofemoral pain was studied in 27 patients (13 males, 14 females). The patients and a group of controls matched for age, gender, and physical activity were tested on a Kin-Com dynamometer at 60 degrees/s and 180 degrees/s angular velocity. EMGs were recorded for eight of the patients and their matched controls. In addition, the reproducibility of isokinetic measurements made under the same conditions but on different occasions in patients with patellofemoral pain was evaluated. Twenty-one patients (11 males, 10 females) underwent testing of their quadriceps and hamstring muscles two or three times on a Kin-Com dynamometer. This was performed both concentrically and eccentrically in their painful leg while the patients evaluated their knee pain using Borg's pain scale. The data show that the patients had a significantly lower agonist as well as antagonist EMG activity during knee extension measurements in their painful leg compared with the controls. However, there were no differences in either agonist or antagonist EMG activities during knee flexion measurements between the patients and the controls. The quadriceps muscle torque was considerably weaker in the patients' painful leg compared with both their asymptomatic leg and with the controls. Peak torque for knee extension was reached at a mean of 66 degrees of knee flexion for both patients and controls. However, the patients showed a considerably wider range within which they produced their peak torque in their painful leg than in their asymptomatic and also in comparison with the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Expression of hsp90 beta messenger ribonucleic acid in patients with familial glucocorticoid resistance--correlation to receptor status.

We have previously shown an increased specific DNA-binding of liganded unactivated glucocorticoid receptor (GR) to the LTR-region of MMTV DNA in a patient with primary cortisol resistance and receptor thermolability indicating a defective interaction of GR with hsp90. In some patients, however, no apparent receptor abnormality was found in spite of a characteristic phenotype. mRNA expression levels of hsp90 beta were analysed in cultured fibroblasts from patients with known receptor defects, such as thermolability, decreased ligand binding affinity and low receptor expression levels, and from patients with a cortisol resistant phenotype but no detected receptor alteration. Fibroblasts from patients with GR defects expressed higher hsp90 beta mRNA levels as compared to patients with no receptor defects or to healthy controls. These data indicate that GR defects are associated with increased hsp90 beta mRNA levels.

Adrenocortical Hyperfunction↗
PubMed1995

Accumulation and persistence of DNA adducts of the synthetic steroid cyproterone acetate in rat liver.

Cyproterone acetate (CPA) is a synthetic steroid which is widely used in antiandrogenic and gestagenic drugs. We have recently shown that CPA induces DNA adducts in cultured rat hepatocytes and in rat liver (1). In the present investigation, we studied the persistence and accumulation of CPA-derived DNA adducts in the liver of rats using the 32P-postlabeling technique. To study the persistence of CPA-DNA adducts, rats were treated with a single oral dose of 10 (female rats) or 100 mg CPA/kg body wt (male rats). Four DNA adducts were detected in the liver of both gender. In female rats, maximal total DNA adduct levels of 3.40 +/- 0.04 adducts/10(6) nucleotides were observed after 1 week. Eleven weeks later, 40% of the adducts determined after 1 week were still detectable. In male rats, maximal hepatic DNA adduct levels of approximately 98 +/- 3/10(9) nucleotides were attained after 2 weeks. The adduct level decreased during the following 4 weeks to approximately 40% of the earlier observed maximal level. To study the accumulation of the CPA-DNA adducts, rats were treated daily with a low oral dose of 50 micrograms CPA/kg body wt for 42 days. During this treatment period, the level of the four adducts increased continuously from approximately 10 to approximately 380 adducts/10(9) nucleotides in the liver of female rats. DNA adducts were formed at much lower levels in male rats; only one type of DNA adduct was detectable, the level of which increased to approximately 6 adducts/10(9) nucleotides after 42 days. In conclusion, CPA induces DNA adducts in rat liver; binding of the steroid is much higher in female compared to male rats. The CPA-DNA adducts show a high persistence and as a consequence of their long half life, CPA-DNA adducts accumulate significantly in the liver of rats.

Androgen Antagonists↗
PubMed1995

DNA-damaging activity of the cyproterone acetate analogues chlormadinone acetate and megestrol acetate in rat liver.

The synthetic progestin cyproterone acetate (CPA) has been recently shown to elicit DNA repair synthesis in cultured rat hepatocytes and to form adducts with rat hepatocyte DNA in vitro and in vivo. In the present study we have examined the genotoxic potential of the structural analogues of CPA, chlormadinone acetate (CMA) and megestrol acetate (MGA) in rat liver cells. CPA strongly induced DNA repair synthesis in hepatocyte cultures from females but not from males. In contrast, CMA and MGA (2-50 microM) did not detectably increase repair synthesis in cultured hepatocytes from either gender. CMA and MGA, however, caused the formation of DNA adducts detectable by the 32P-postlabelling technique. At a concentration of 30 microM, between 30 and 50 adducts/10(9) nucleotides were found with MGA and CMA in cultured hepatocytes of female rats, and between 5 and 20 adducts/10(9) nucleotides were found in hepatocytes of males. By comparison, 30 microM CPA has been found to produce 1670 adducts/10(9) nucleotides in hepatocytes from female rats. CMA and MGA also induced low levels of DNA adducts in vivo. When female rats were treated with 100 mg/kg of CMA or MGA per os, the adduct levels were 2 and 19 adducts/10(9) nucleotides respectively. The results indicate that both CMA and MGA show some genotoxicity in rat liver cells, which is, however, much lower than that for CPA. Our findings further suggest that the high genotoxicity of CPA is associated with the presence of the 1,2 alpha-methylene group, which is absent in CMA and MGA.

Animals↗
PubMed1995

Suppression of keratinocyte growth factor expression by glucocorticoids in vitro and during wound healing.

We have recently demonstrated an important function of keratinocyte growth factor (KGF) in morphogenesis of epithelium and wound re-epithelialization. Furthermore, abnormalities in KGF expression or responsiveness are associated with wound-healing defects. In this study we have analyzed the regulation of KGF expression during wound repair in glucocorticoid-treated mice that are characterized by severe wound healing abnormalities. Induction of KGF mRNA expression after skin injury was significantly reduced in these mice, whereas KGF receptor mRNA levels were only affected to a minor extent by glucocorticoid treatment. The reduced KGF expression during wound healing in steroid-treated animals is at least partially due to a direct effect of glucocorticoids on the KGF expressing mesenchymal cells, because treatment of cultured fibroblasts with dexamethasone reduced KGF mRNA levels in a time- and concentration-dependent manner. The inhibitory effect of glucocorticoids on KGF expression was compensated for by high levels of serum growth factors or pro-inflammatory cytokines, demonstrating that KGF expression is subject to positive and negative regulation. Thus it seems likely that a fine balance of various KGF-regulating factors is important for normal wound healing.

Administration, Topical↗
PubMed1995

Basic fibroblast growth factor is a neurotropic factor in GT1 gonadotropin-releasing hormone neuronal cell lines.

Basic fibroblast growth factor (bFGF) plays an important role in development of the central nervous system and is neurotropic for a variety of neurons. In this study, we investigated whether bFGF is neurotropic for GT1 GnRH neuronal cell lines and if these cells express functional FGF receptors (FGFRs). The GT1 cell lines generated by genetically targeted tumorigenesis display highly differentiated properties of GnRH neurons. Addition of 2 and 10 ng/ml bFGF increased neurite outgrowth of GT1-7 cells and resulted in a significant increase of GT1 cell survival in serum-free medium. However, bFGF had no effect on [3H]thymidine incorporation at 24 or 48 h. RNase protection assays using riboprobes specific for murine FGFRs 1-3 showed that GT1 cells express FGFRs 1 and 3 but not 2. Occupancy of FGFRs with 10 ng/ml bFGF stimulated the sustained tyrosine phosphorylation of both the 42- and 44-kilodalton mitogen-activated protein kinases (MAPKs) for up to 6 h as shown by Western blot analysis. In addition, phosphorylation of the MAPKs was associated with enzyme activation as shown by an in-gel MAPK assay. GT1-1 and GT1-7 cells also express messenger RNA for bFGF, although the level of bioactive bFGF synthesized by GT1 cells appears suboptimal because GT1 cells can further respond to exogenously added bFGF. Thus, we have demonstrated that bFGF is a neurotropic factor in GT1 GnRh neuronal cell lines, raising the possibility that bFGF may play a role in the neurobiology of GnRH neurons.

Animals↗
PubMed1995

Biomarkers as tools in human health risk assessment.

Evaluation of occupational or environmental risk due to exposure to chemicals requires sufficient information on the toxic profiles, mechanisms of action, toxicokinetics, dose-response relation, exposure, and the target dose. Usually exposure is estimated by measuring concentrations of the agent in air, food, water, soil, dust, or other media with which a population or an individual is in contact. However, this external exposure is only a rough estimate for the internal exposure (agent dose or its metabolite at the critical target in the organism). Factors of influence are bioavailability of the chemicals, variations in concentrations and routes of exposure, physical activity, and individual variation in rates of metabolism, distribution, and excretion. All these affect the concentration of the toxic agent at the critical target, which is the most precise information for risk assessment. Thus, internal exposure is best measured by determining the concentration of the toxicant or its ultimate metabolite at the critical site in the target organ or by determining adducts with cellular macromolecules such as proteins, amino acids, DNA, or its bases. The latter are easily available in experimental toxicology from animal experiments but only occasionally from humans. For health surveillance such data usually are not available, because they require invasive procedures such as biopsies. Therefore, more accessible body fluids or tissue are used, such as blood, urine, or adipose tissue, or adducts with macromolecules such as albumin or hemoglobin in the blood, DNA adducts in peripheral lymphocytes, or altered DNA bases in urine such as 8-hydroxyguanine. All of these are indicators for exposure, whereas risk can only be estimated if the correlation between their deviations from normal and the dose-response at the critical target is known.

Animals↗
PubMed1995

[Differentiated evaluation of heart valve stenosis by expanded Bernoulli equation--in vitro studies of model stenoses].

A suitable measure for the hydrodynamic assessment of heart valve stenoses must be independent of flow and should correspond to the morphology of the stenoses. The "effective orifice area" according to Gorlin does not fulfil this requirement, generally, because it is constant only under special conditions. This suggests the development of a multidimensional stenosis model. The idea for doing so is based on hydrodynamic evaluation of different elementary stenosis types in comparison with a valve that behaves like Gorlin's theory. The Bernoulli equation can than be expanded definitely and one gets a set of unknown stenosis parameters corresponding to the elementary stenoses. The clinical relevance of these must be evaluated by morphological evidence and by similarity of the flow-pressure drop characteristics as compared to real heart valve stenoses. A suitable reference valve is the Björk-Shiley valve. This valve was combined with evident elastic and stiff obstacles to opening with the result of flow-pressure drop characteristics similar to biological valves written in terms of flow q: [formula: see text] where q and q2 are mean flow and mean square flow through the valve, respectively. Empirical results reported in the literature can be explained as special cases of the stenosis model as demonstrated by examples. The proposed equation can be interpreted in physically founded terms in contrast with an empirical one. It gives rise to a differentiated evaluation of heart valve stenosis by orifice area (c2), elastic properties of shape and material (c1) and pre-stress (c0) independent on flow. The model can be extended step by step as required.

Aortic Valve↗
PubMed1994

The function of KGF in morphogenesis of epithelium and reepithelialization of wounds.

The function of keratinocyte growth factor (KGF) in normal and wounded skin was assessed by expression of a dominant-negative KGF receptor transgene in basal keratinocytes. The skin of transgenic mice was characterized by epidermal atrophy, abnormalities in the hair follicles, and dermal hyperthickening. Upon skin injury, inhibition of KGF receptor signaling reduced the proliferation rate of epidermal keratinocytes at the wound edge, resulting in substantially delayed reepithelialization of the wound.

Aging↗