PubMed Health⌕ Search

Biomedical subjects

W König

Publications and source records attributed to W König.

At least 37 records · Page 2Linked to original sources
PubMed1999

[Characteristics of the hepatitis C virus and viral predictors of therapeutic response].

NATURAL HISTORY OF HEPATITIS C-INFECTION AND VIRAL CHARACTERISTICS: Hepatitis C-virus (HCV) infection is a major cause of non-A, non-B-hepatitis and, additionally, is associated with liver cirrhosis and hepato-cellular carcinoma. The high degree of chronificity of HCV-infection is reasonable due to antigenic variability of neutralizing epitopes leading to incomplete immunoresponse with subsequent virus persistence. Besides genetic variants of HCV within a virus population (quasispecies nature of HCV), different genotypes are classified being genetically and phenotypically distinct, and geographically restricted in part. Genotyping of HCV is not only important for phylogenetic and epidemiological studies, but also a predictive marker for pathogenesis and therapy. VIRAL PREDICTORS OF HCV THERAPY: In a meta-analysis of 18 therapeutical studies of chronical HCV infections, genotype 1 and high levels of viremia determined markedly the response to interferon therapy. In this context, clinical trials have proven the effect of a combined therapy with interferon and ribavirin. Especially patients with HCV genotype 1 or high levels of viremia had a real benefit from combined antiviral therapy in comparison to monotherapy with interferon. CONCLUSION AND FUTURE CONCEPTS: Besides recent concepts improving the therapeutical response to HCV infection, further effort is necessary to develop more successful strategies for eradication of hepatitis C virus. In this context, variations of interferon therapy should be evaluated (e.g. higher and daily doses, longer duration of interferon therapy, "retarded" interferon (PEG-IFN). In addition, new therapeutical concepts should be performed including a combination of interferon with other known antiviral agents (amantadine), a combination with immunomodulators (GM-CSF, thymosin alpha 1), the development of new antiviral agents (inhibitors of viral proteases, helicases and polymerases) and the exploration of anti-viral, molecular strategies (specific ribozymes, antisense oligonucleotides and DNA-vaccination). Nevertheless, the development of an effective vaccination should be the most important challenge for the future.

Adjuvants, Immunologic↗
PubMed1999

Cetirizine counter-regulates interleukin-8 release from human epithelial cells (A549)

BACKGROUND: Cetirizine, a H1-receptor antagonist, exerts besides its well-known anti-allergic potential an array of anti-inflammatory activities. In particular epithelial cells activated in the presence of cetirizine showed a reduced ICAM-1 cell surface expression and a diminished release of sICAM-1. OBJECTIVE: We wondered whether cetirizine might influence the release of interleukin-8 (IL-8) from human epithelial cells activated with agonists distinct from histamine. METHODS: We used the human lung epithelial cell line A549 for our in vitro studies. IL-8 release was determined by IL-8 enzyme immunoassay, the intracellular staining for IL-8 and NF-kB was analysed by FACS analysis and IL-8 mRNA steady state level was studied by Northern blot analysis. Confluent epithelial cell monolayer were pre-incubated with cetirizine (0.01 -1.0 micromol/L) for 30 min and afterwards activated with pro-inflammatory cytokines (TNF-alpha IL-1beta, IL-6, IFN-gamma) or different agonists (PMA, NaF, respiratory syncytial virus [RSV]) for 24 h. RESULTS: Epithelial cells stimulated with TNF-alpha IL-1beta, PMA and RSV, respectively, showed a significantly increased release of IL-8. Pre-incubation with cetirizine diminished the IL-8 release from cells activated with TNF-alpha or PMA in a significant manner. The reduced IL-8 release coincided with a diminished percentage of cells expressing IL-8. Northern blot analysis revealed a reduced steady state level of IL-8 mRNA in cells pretreated with cetirizine and stimulated with TNF-alpha. Furthermore, a decreased amount of accessible DNA-binding sites of the nuclear factor kappa B (NF-kB) was determined by FACS analysis. CONCLUSIONS: These results suggest that cetirizine reduced the release of IL-8 from A549 cells stimulated with PMA and TNF-alpha, respectively, by lowering IL-8 gene expression. Therefore, cetirizine might exert anti-inflammatory effects beyond its H1-receptor antagonistic activity in the course of inflammatory respiratory tract disorders such as bronchial asthma and allergic rhinitis.

Blotting, Northern↗
PubMed1999

Analysis of the Gly40Ser polymorphism in the glucagon receptor gene in a German non-insulin-dependent diabetes mellitus population.

A heterozygous polymorphism changing GGT40 (Gly) to AGT40 (Ser) in the glucagon receptor gene (GCG-R) was reported to be associated with non-insulin-dependent diabetes mellitus (NIDDM). A possible involvement of this polymorphism in impaired glucose tolerance was also suggested in a French population. However, the prevalence of this polymorphism differs markedly among different ethnic groups, whereby the results in German populations were found to be contradictory. We thus investigated the association of this mutation with NIDDM and healthy subjects in 508 German subjects (196 NIDDM, and 312 controls). None of the control subjects, but one of the NIDDM patients demonstrated the Gly40Ser polymorphism. Since no first-degree relative of the index patient had this genetic variance, a de novo mutation is suggested. Although the frequency of the Gly40Ser polymorphism in NIDDM observed in France is not confirmed in our population, this genetic variance is also evident in Germany.

Adult↗
PubMed1998

Prevalence of Helicobacter pylori resistance to several antimicrobial agents in a region of Germany.

To evaluate the prevalence of resistance among Helicobacter pylori in Germany, the minimum inhibitory concentrations of amoxicillin, tetracycline, clarithromycin, and metronidazole were determined by means of the E test, for 271 Helicobacter pylori isolates cultured from biopsies taken during routine endoscopies in 1996 and 1997. The prevalence of metronidazole resistance was 32.1%, with resistance found more frequently in women (38.5%) than in men (24.4%). Clarithromycin resistance was rare (3.3%). Eight of nine strains resistant to clarithromycin were also resistant to metronidazole. Resistance to either metronidazole or clarithromycin was significantly (P=0.022) higher in patients with duodenal ulcer. No strain was found to be resistant to amoxicillin or tetracycline.

Adult↗
PubMed1998

Total parenteral nutrition with glutamine dipeptide after major abdominal surgery: a randomized, double-blind, controlled study.

OBJECTIVE: To assess the efficacy of glutamine (Gln) dipeptide-enriched total parenteral nutrition (TPN) on selected metabolic, immunologic, and clinical variables in surgical patients. SUMMARY BACKGROUND DATA: Depletion of Gln stores might lead to severe clinical complications. Recent studies indicate that the parenteral provision of Gln or Gln-containing dipeptides improves nitrogen balance, maintains the intracellular Gln pool, preserves intestinal permeability and absorption, and shortens hospital stay. METHODS: Twenty-eight patients (age range, 42-86 years, mean 68 years) undergoing elective abdominal surgery were allocated, after randomization, to two groups to receive isonitrogenous (0.24 g nitrogen kg(-1) day(-1)) and isoenergetic (29 kcal/122 kJ kg(-1) day(-1)) TPN over 5 days. Controls received 1.5 g of amino acids kg(-1) day(-1), and the test group received 1.2 g of amino acids and 0.3 g of L-alanyl-L-glutamine (Ala-Gln) kg(-1) day(-1). Venous heparinized blood samples were obtained before surgery and on days 1, 3, and 6 after surgery for routine clinical chemistry and for the measurement of plasma free amino acids. Lymphocytes were counted and the generation of cysteinyl-leukotrienes from polymorphonuclear neutrophil granulocytes was analyzed before surgery and on days 1 and 6 after surgery. Nitrogen balances were calculated postoperatively on days 2, 3, 4, and 5. RESULTS: No side effects or complaints were noted. Patients receiving Gln dipeptide revealed improved nitrogen balances (cumulative balance over 5 days: -7.9 +/- 3.6 vs. -23.0 +/- 2.6 g nitrogen), improved lymphocyte recovery on day 6 (2.41 +/- 0.27 vs. 1.52 +/- 0.17 lymphocytes/nL) and improved generation of cysteinyl-leukotrienes from polymorphonuclear neutrophil granulocytes (25.7 +/- 4.89 vs. 5.03 +/- 3.11 ng/mL). Postoperative hospital stay was 6.2 days shorter in the dipeptide-supplemented group. CONCLUSION: We confirm the beneficial effects of Gln dipeptide-supplemented TPN on nitrogen economy, maintenance of plasma Gln concentration, lymphocyte recovery, cysteinyl-leukotriene generation, and shortened hospital stay in surgical patients.

Adult↗
PubMed1998

Interleukin-8 release from human neutrophils after phagocytosis of Listeria monocytogenes and Yersinia enterocolitica.

The release of interleukin-8 (IL-8) from human neutrophils was investigated after their internalisation of the invasive bacteria Listeria monocytogenes and Yersinia enterocolitica. Three pairs of bacterial strains were used to study the influence of listeriolysin O, invasiveness and Yersinia virulence plasmid (pYV)-encoded proteins on neutrophil cytokine synthesis. The neutrophils secreted IL-8 into the culture supernate after exposure to all strains tested. With L. monocytogenes, the virulence factor listeriolysin O had no effect on IL-8 secretion, whereas a non-invasive mutant induced greater IL-8 release than the corresponding invasive strain. With Y. enterocolitica, expression of virulence plasmid-encoded proteins appeared to be responsible for diminished IL-8 release. Northern blot analysis showed that the induced IL-8 release was always accompanied by an enhanced level of cytoplasmic IL-8 mRNA. Cytokine priming of neutrophils with granulocyte macrophage colony-stimulating growth factor (GM-CSF), unlike granulocyte colony-stimulating factor (G-CSF), led to further enhancement of IL-8 secretion induced after internalisation of the bacteria. Again, the increased IL-8 release, from GM-CSF primed neutrophils, was accompanied by an increased level of cytoplasmic IL-8 mRNA. The results emphasise the role of IL-8 in neutrophil-mediated host defence mechanisms during the acute phase of L. monocytogenes and Y. enterocolitica infection.

Animals↗
PubMed1998

LDL size distribution in relation to insulin sensitivity and lipoprotein pattern in young and healthy subjects.

OBJECTIVE: Smaller LDL particles are associated with an increased risk for coronary artery disease and have been found predominantly in subjects with the insulin resistance syndrome. Although insulin resistance has been suggested to be a basic defect, little is known about the relation between this predisposing factor (and associated metabolic disturbances) and LDL size distribution in young and metabolically healthy subjects. In the present study, we investigated the relation between insulin sensitivity, lipoprotein distribution, and LDL patterns in young adults to increase the understanding of the development of metabolic risk factors in an early phase of the life span. RESEARCH DESIGN AND METHODS: Young, clinically healthy subjects (n = 50; age 21.1-30.6 years) were enrolled in the study. Glucose metabolism was characterized by peripheral insulin sensitivity assessed by a hyperinsulinemic-euglycemic clamp and by levels of fasting insulin, C-peptide, and glucose. Lipoproteins were measured, and LDL fractions were additionally characterized by the diameter of the major LDL peak, estimated by 2-16% polyacrylamide gradient gel electrophoresis. Cholesterol ester transfer was estimated with a fluorescent spectroscopic method that measures the transfer of fluorescent cholesteryl linoleate between exogenous donor and acceptor particles. In this assay system, cholesterylester transfer protein (CETP) activity was only influenced by the plasma CETP concentration therefore reflecting more likely the CETP mass. RESULTS: In the entire study group, 47 subjects had LDL phenotype A (LDL diameter > 25.75 nm) and 3 subjects had an intermediate phenotype (25.50-25.75 nm). An interrelation between LDL size and LDL triglyceride (LDL-TG) per apolipoprotein (apo) B (Spearman's rank correlation analysis; r = -0.78; P < 0.001) or LDL cholesterol ester (CE) per apoB (r = 0.58, P < 0.001) was found, and 39% of the plasma samples studied were characterized by a monodispersed LDL pattern. Furthermore, LDL diameters correlated negatively with total TGs (men: r = -0.52, P < 0.001; women: r = -0.61, P < 0.001) and positively with insulin sensitivity (total population: r = 0.54, P < 0.001). In addition, LDL size was inversely related to the [VLDL + LDL cholesterol (CH)]/HDL-CH ratio and positively to the HDL-CE/TG ratio, which were both related vice versa to CETP activity levels. A direct relation between CETP activity levels and LDL size or composition was not observed. In a linear regression analysis including parameters of lipoprotein metabolism (TG, HDL cholesterol, CETP activity level), glucose metabolism (insulin sensitivity, fasting insulin), and sex, only TGs predicted significantly for 62% of LDL size variability. If the total study population was evaluated according to quintiles of insulin sensitivity, increasing TGs (analysis of variance, Scheffé test; P < 0.05) and CETP activity levels (P < 0.05) were combined with decreasing LDL particle diameters (P < 0.05) and with a preponderance of a monodispersed LDL pattern (60%) in the most insulin-resistant group. CONCLUSIONS: Among parameters of the lipoprotein and glucose metabolism, total TG is the single most important factor affecting LDL size variability, even in young adults. If the study population is evaluated according to insulin sensitivity, lipoprotein pattern is altered in a more atherogenic manner in the most insulin-resistant subjects. In this group, increasing TG and CETP activity levels are associated with decreasing LDL particle diameters and preponderance of a monodispersed LDL pattern. Although increasing CETP levels are combined with this particular lipoprotein profile, a direct relation to LDL size and composition is not found.

Adult↗
PubMed1998

[Molecular effects of a microbicidal substance on relevant microorganisms: electron microscopic and biochemical studies on povidone-iodine].

The microbicidal activity of the broad spectrum antimicrobial agent povidone-iodine is due to the strong oxidizing effects of free iodine on functional groups of amino acids, nucleotides and double bonds of unsaturated fatty acids. While the chemical mechanism of action of PVP-iodine is well understood, the actual sequence of events on the cellular and molecular level that causes rapid cell death has not been fully understood. The aim of this study was to elucidate effects of povidone-iodine on cell ultrastructure by electron microscopy and to monitor changes in enzyme activity and nucleotide efflux. Staphylococcus aureus, E. coli and C. albicans, medically relevant gram-positive, gram-negative and yeast micro-organisms, served as models. In the presence of povidone-iodine, rapid partitioning of the cytoplasm and pronounced coagulation of nuclear material was noted. Especially C. albicans exhibited a rapid, dose-dependent "loosening" of the cell wall; cells remained intact without lysis, rupture or wall breakage. Changes in beta-galactosidase and nucleotide concentrations were measured in E. coli. A rapid and dose-dependent loss of cellular beta-galactosidase activity was found, with no increase in the supernatant; loss of cellular nucleotides corresponded with an increase in the supernatant. Electron microscopy and biochemical observations support the conclusion that povidone-iodine interacts with cell walls of micro-organisms causing pore formation or generating solid-liquid interfaces at the lipid membrane level which lead to loss of cytosol material, in addition to enzyme denaturation. The chemical mechanism of action explains the fact that povidone-iodine does never generate resistance in micro-organisms.

Anti-Infective Agents, Local↗
PubMed1997

Arachidonic acid induces DNA-fragmentation in human polymorphonuclear neutrophil granulocytes.

We analyzed DNA-fragmentation in human polymorphonuclear neutrophil granulocytes (PMNs) from healthy donors after addition of exogenous arachidonic acid (AA) and eicosapentaenoic acid (EPA) by flow cytometry (propidium iodide staining of DNA and DNA strand break detection). The PMNs were incubated from 30 min up to 48 hours in RPMI 1640 which was supplemented with different concentrations of AA or EPA (5-40 microM). In contrast to EPA the addition of AA led to a significant increase in apoptosis up to 67.8% compared to the RPMI-control whereas the addition of EPA led to an inhibition of DNA-fragmentation. When the cells were incubated with MK 886 (1 microM, inhibitor of leukotriene biosynthesis) an increase in DNA-fragmentation (up to 63.3%) was observed. Conversely, in the presence of indomethacin (1 microM, inhibitor of prostanoid synthesis) an inhibition in DNA-fragmentation (up to 60.9%) occurred. Furthermore, preincubation of PMNs with pentoxifylline (1mM, phosphodiesterase inhibitor) reduced AA-stimulated DNA-fragmentation up to 43.4%. These data provide evidence for the involvement of AA and distinct AA metabolites in the regulation of apoptosis in human PMNs.

Apoptosis↗
PubMed1997

Influence of a total parenteral nutrition enriched with omega-3 fatty acids on leukotriene synthesis of peripheral leukocytes and systemic cytokine levels in patients with major surgery.

OBJECTIVE: Nutritive immunomodulation of patients after major surgery. DESIGN: Prospective, randomized controlled double-blind study. PATIENTS: Forty patients undergoing major intestinal surgery. Patients were divided into two groups: one received a total parenteral nutrition enriched with omega-3 fatty acids for 5 days postoperatively, the other an isocaloric, control nutrition. MATERIALS AND METHODS: We analyzed the leukocyte ability to release leukotrienes from whole blood leukocytes stimulated with the calcium ionophore A23187 (5 micromol/L) by reverse phase high-performance liquid chromatography and circulating cytokines by enzyme-linked immunosorbent assay. RESULTS: Leukocytes from patients of the omega-3 fatty acids group generated significantly higher amounts of less biologically active leukotriene B5 as compared to the control group (p < or = 0.001). This was accompanied by a significant decrease in the generation of proinflammatory leukotriene B4 (p < or = 0.006) in the study group. In contrast to interleukin-1beta, interleukin-6, and interleukin-10 systemic levels of tumor necrosis factor-alpha (p < or = 0.05) were postoperatively decreased in the study group. CONCLUSION: Our data provide evidence that a total parenteral nutrition enriched with omega-3 fatty acids modulates the lipid mediator pattern and systemic tumor necrosis factor-alpha levels.

Adult↗
PubMed1997

Role of haemolytic and non-haemolytic phospholipase C from Pseudomonas aeruginosa in interleukin-8 release from human monocytes.

A massive accumulation of neutrophils, mainly due to enhanced interleukin-8 (IL-8) levels, is believed to contribute to the deleterious effects of Pseudomonas aeruginosa lung infection, e.g., in cystic fibrosis (CF). Antibodies to phospholipase C, an exoenzyme of P. aeruginosa, are detected early and at high levels in CF patients. However, P. aeruginosa produces at least two types of phospholipase C (PLC), one haemolytic (PLC-H) and the other non-haemolytic (PLC-N), both with mol.wts of c. 77 kDa. Experiments were performed to evaluate the potential contribution of P. aeruginosa PLC to neutrophil accumulation during infection. Therefore, P. aeruginosa PLC-H and PLC-N were compared with regard to IL-8 generation from human monocytes. Purified PLC-H as well as culture supernates (mol.wt > 50 kDa) of a P. aeruginosa strain capable of producing both PLC-H and PLC-N, and mutant strains deficient in the production of one or other phospholipase, or both, were examined. Purified PLC-H (only at low concentrations up to 1 unit/4 x 10(5) monocytes), induced a dose-dependent increase in IL-8 release and IL-8-specific mRNA expression over that of unstimulated cells (at 4-, 12- and 24-h incubation times). Higher concentrations of PLC-H led to a decrease in IL-8 release and IL-8-specific mRNA expression. These findings were confirmed by the results obtained with the supernates of cultures of mutant strains of P. aeruginosa PAO1 that produced either a PLC-H or PLC-N or neither. Stimulation and inhibition of IL-8 release and mRNA expression were associated with a culture supernate fraction of mol. wt > 50 kDa and containing PLC-H. These results contribute to the understanding of the role of both P. aeruginosa PLC in IL-8 generation during their interaction with human monocytes.

Cells, Cultured↗
PubMed1997

Composition of staphylococcal bi-component toxins determines pathophysiological reactions.

Staphylococcus aureus produces numerous bi-component toxins, e.g., Panton-Valentine leukocidin (Luk-PVL) and gamma-haemolysin, which consist of type S and F proteins. Previous studies showed that Luk-PVL induces inflammatory mediator release from human granulocytes that might reflect the in-vivo effects, e.g., dermonecrosis by Luk-PVL. Clinical isolates not only harbour the two genes coding for Luk-PVL (S-protein: LukS-PVL, F-protein: LukF-PVL) but also the three genes encoding gamma-haemolysin (S-protein: HlgA, HlgB; F-protein: HlgC). The interaction of all the possible potential toxins with human granulocytes was studied with regard to the generation of oxygen metabolites (chemiluminescence response), enzyme activity (beta-glucuronidase) and histamine release as well as interleukin (IL)-8 generation. The data clearly show that the individual subunits (S, F) differ in their activities. The following activities were obtained for the S components: LukS-PVL > HlgC > HlgA; the F components LukF-PVL and HlgB were similarly active. Thus, the toxins LukS-PVL/LukF-PVL and LukS-PVL/HlgB were the most potent inducers of inflammatory mediator release from human granulocytes, followed by HlgC/LukF-PVL and HlgC/HlgB and to a lesser degree by the toxins HlgA/LukF-PVL and HlgA/HlgB. The data indicate that class S components and class F components are interchangeable and give toxins with genuine biological activities.

Bacterial Proteins↗
PubMed1997

Role of hemolytic and nonhemolytic phospholipase C from Pseudomonas aeruginosa for inflammatory mediator release from human granulocytes.

BACKGROUND: Pseudomonas aeruginosa phospholipase C (PLC) is a critical component in the pathogenesis of severe P. aeruginosa infections. However, P. aeruginosa can produce a hemolytic (PLC-H) as well as a nonhemolytic (PLC-N) variant, both having a MW of about 77 kD. In the past, studies did not distinguish between both types of PLC with regard to the induction of inflammatory mediators from human cells. METHODS: We compared the ability of P. aeruginosa PLC-H and PLC-N to generate leukotriene B4 (by HPLC) and oxygen (O2-) metabolites (luminol-enhanced chemiluminescence), and to release beta-glucuronidase and histamine (fluorophotometry from human granulocytes. Therefore, human neutrophilic granulocytes (PMN; 1 x 10(7)) or human peripheral blood mononuclear cells (5 x 10(6)) were treated with purified P. aeruginosa PLC-H (up to 10 units) as well as culture supernatants (cutoff: MW > 50,000) of P. aeruginosa PAOl capable of producing both PLC-H and PLC-N, and PAOl mutant strains deficient in the production of either or both phospholipases. Controls were PLC-H from Clostridium perfringens and PLC-N from Bacillus cereus. RESULTS: PLC-H-containing P. aeruginosa culture supernatant, purified P. aeruginosa PLC-H as well as PLC-H from P. perfringens activated human leukocytes for a significant (p < 0.05) increase in inflammatory mediator release. In this regard, purified PLC-H (10 units) from P. aeruginosa activated human PMN for a significant increase in the generation of oxygen metabolites (30 +/- 5.4 x 10(3) cpm) and in leukotriene B4 (6.1 +/- 2.0 ng), in the release of beta-glucuronidase (15.8 +/- 1.1%) and of histamine (25.8 +/- 6.2%) as compared to the corresponding control values (3 +/- 1 x 10(3) cpm; 0.2 +/- 0.1 ng; 5.1 +/- 1.0%, 5.1 +/- 1.5%). Culture supernatants containing no PLC or only PLC-N, as well as PLC-N from B. cereus, failed to activate or only slightly stimulated human granulocytes for inflammatory mediator release. CONCLUSION: The data thus provide evidence that P. aeruginosa PLC-H can be a potent inducer of inflammatory mediator release, at least in vitro. Our results therefore contribute to the understanding of the pathophysiological role of P. aeruginosa PLCs.

Bacillus cereus↗
PubMed1997

Effects of Betaisodona on parameters of host defense.

The numbers of patients in intensive care units, with immunosuppression, and of elderly people increase in parallel with antibiotic-resistant microorganisms. Therefore the demand for an effective antisepsis increases. Moreover, it became evident that the pathophysiology and the outcome of infection are dependent on the properties of the microorganisms, e.g. synthesis of endo- and exotoxins, and on the host defense, the immune system. In addition to the microbicidal action, we studied the effects of povidone-iodine (PVP-I, Betaisodona) on the generation, release and activity of exotoxins (alpha-hemolysin, phospholipase C, lipase), as well as on granulocyte-derived tissue-destructive enzymes (elastase, beta-glucuronidase) and microbial-induced cytokine generation from human neutrophils. Our results clearly show that PVP-I does not only kill a wide range of bacteria but also inhibits the generation and release of bacterial exotoxins; furthermore, it also inactivates bacterial exotoxins as well as granulocyte-derived tissue-destructive enzymes and cytokines. These data support the usefulness and efficacy of PVP-I as an effective therapeutic agent to combat infection.

Aged↗