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W Vogel

Publications and source records attributed to W Vogel.

At least 127 records · Page 7Linked to original sources
PubMed1999

Lack of evidence for the heterosexual transmission of hepatitis C.

The importance of sexual transmission in the epidemiology of hepatitis C virus (HCV) infection is still controversial. To assess the risk of heterosexual HCV transmission, we examined eighty patients with chronic HCV-associated liver disease and their spouses in a cross-sectional clinical and serological cohort study. Serum samples from index patients and their spouses were assayed for HCV antibodies and HCV RNA. In the couples positive for both, further HCV genotyping was done. A questionnaire addressing points such as additional risk factors for HCV infection, sexual behaviour or duration of partnership was completed by all couples. HCV antibodies were detected in four (5%) spouses, of whom three (4%) were also positive for HCV-RNA. HCV genotyping revealed concordance (genotype 1) in two couples, indicating a risk of interspousal HCV transmission of 2.5%. Spouses of patients with HCV viraemia and chronic liver disease have a low risk for acquiring HCV. Even long-term spouses seem not to be at increased risk. We therefore suggest that the risk of HCV transmission between monogamous sex partners does not depend on the duration of sexual exposure.

Adult↗
PubMed1999

Discoidin domain receptors: structural relations and functional implications.

Multicellular life relies on the presence of extracellular matrix to provide scaffolding for cells and tissue compartments. To provide communication between cells and tissues, a multitude of cell surface receptors are triggered by soluble ligands and components of the extracellular matrix. A large family of these receptors transmit signals through the use of an intrinsic tyrosine kinase function. The subgroup of discoidin domain receptors (DDRs) is distinguished from other members of the receptor tyrosine kinase family by a discoidin homology repeat in their extracellular domains that is also found in a variety of other transmembrane and secreted proteins. Sequence comparisons show that non-mammalian orthologs of DDRs exist: three closely related genes in Caenorhabditis and one in the sponge Geodia cydonium. Recently, various types of collagen have been identified as the ligands for the two mammalian discoidin domain receptor tyrosine kinases, DDR1 and DDR2. The binding of collagen to DDRs results in a delayed but sustained tyrosine kinase activation. Both receptors display several potential tyrosine phosphorylation sites that are able to relay the signal by interacting with cytoplasmic effector proteins. The potential cross-talk to other receptors for collagen and the clinical aspects of DDR function are discussed.

Animals↗
PubMed1999

Stereoselectivity of bupivacaine in local anesthetic-sensitive ion channels of peripheral nerve.

BACKGROUND: The local anesthetic bupivacaine exists in two stereoisomeric forms, R(+)- and S(-)-bupivacaine. Because of its lower cardiac and central nervous system toxicity, attempts were made recently to introduce S(-)-bupivacaine into clinical anesthesia. We investigated stereoselective actions of R(+)-and S(-)-bupivacaine toward two local anesthetic-sensitive ion channels in peripheral nerve, the Na+ and the flicker K+ channel. METHODS: In patch-clamp experiments on enzymatically demyelinated peripheral amphibian nerve fibers, Na+ and flicker K+ channels were investigated in outside-out patches. Half-maximum inhibiting concentrations (IC50) were determined. For the flicker K+ channel, simultaneous block by R(+)-bupivacaine and S(-)-bupivacaine was analyzed for competition and association (k1) and dissociation rate constants (k(-1)) were determined. RESULTS: Both channels were reversibly blocked by R(+)- and S(-)-bupivacaine. The IC50 values (+/- SEM) for tonic Na+ channel block were 29+/-3 microM and 44+/-3 microM, respectively. IC50 values for flicker K+ channel block were 0.15+/-0.02 microM and 11+/-1 microM, respectively, resulting in a high stereopotency ratio (+/-) of 73. Simultaneously applied enantiomers competed for a single binding site. Rate constants k1 and k(-1) were 0.83+/-0.13x10(6) M(-1) x S(-1) and 0.13+/-0.03 s(-1), respectively, for R(+)-bupivacaine and 1.90+/-0.20x10(6) M(-1) x s(-1) and 8.3+/-1.0 s(-1), respectively, for S(-)-bupivacaine. CONCLUSIONS: Bupivacaine block of Na+ channels shows no salient stereoselectivity. Block of flicker K+ channels has the highest stereoselectivity ratio of bupivacaine action known so far. This stereoselectivity derives predominantly from a difference in k(-1), suggesting a tight fit between R(+)-bupivacaine and the binding site. The flicker K+ channel may play an important role in yet unknown toxic mechanisms of R(+)-bupivacaine.

Anesthetics, Local↗
PubMed1999

The natural course of hepatitis C virus infection 18 years after an epidemic outbreak of non-A, non-B hepatitis in a plasmapheresis centre.

BACKGROUND: The natural history of hepatitis C virus (HCV) infection is variable and factors determining the course of the illness are unclear. AIMS: To determine the natural course of HCV infection in a well characterised group of patients 18 years after an epidemic outbreak of non-A, non-B hepatitis at a plasmapheresis centre. METHODS: Between 1994 and 1996, 20 of 30 affected individuals were studied. HCV infection was confirmed using second and third generation ELISA test kits. HCV RNA was detected by a polymerase chain reaction (PCR) method and HCV genotyping was performed by analysing amplicons from the conserved 5'-non-translated region generated by nested PCR. Thirty two liver biopsies were carried out in 14 patients. RESULTS: HCV antibodies were detected in all subjects. Eighteen patients had abnormal liver enzymes and 17 were HCV RNA positive, all of whom were infected with genotype 1a. Ninety per cent of this cohort showed evidence of chronic HCV infection with 50% having progressive liver disease and 20% cirrhosis 18 years after acute onset of non-A, non-B hepatitis. Considerable variation in disease outcome occurred between individuals and no correlation with clinical features of the acute illness was found. CONCLUSIONS: Variability in the consequences of HCV infection in cases infected with the same virus suggests that host factors are important in determining disease outcome. The factors which determine differences in the natural history of the disease still remain to be elucidated.

Acute Disease↗
PubMed1999

Expression of MUC-1 epitopes on normal bone marrow: implications for the detection of micrometastatic tumor cells.

PURPOSE: The expression of the carcinoma-associated mucin MUC-1 is thought to be restricted to epithelial cells and is used for micrometastatic tumor cell detection in patients with solid tumors, including those with breast cancer. Little is known, however, about the expression of MUC-1 epitopes in normal hematopoietic cells. MATERIALS AND METHODS: MUC-1 expression was analyzed by flow cytometry and immunocytology on bone marrow (BM) mononuclear cells and purified CD34+ cells from healthy volunteers, using different anti-MUC-1-specific monoclonal antibodies. In addition, Western blotting of MUC-1 proteins was performed. RESULTS: Surprisingly, 2% to 10% of normal human BM mononuclear cells expressed MUC-1, as defined by the anti-MUC-1 antibodies BM-2 (2E11), BM-7, 12H12, MAM-6, and HMFG-1. In contrast, two antibodies recognizing the BM-8 and the HMFG-2 epitopes of MUC-1 were not detected. MUC-1+ cells from normal BM consisted primarily of erythroblasts and normoblasts. In agreement with this, normal CD34+ cells cultured in vitro to differentiate into the erythroid lineage showed a strong MUC-1 expression on day 7 proerythroblasts. Western blotting of these cells confirmed that the reactive species is the known high molecular weight MUC-1 protein. CONCLUSION: Our data demonstrate that some MUC-1 epitopes are expressed on normal BM cells and particularly on cells of the erythroid lineage. Hence the application of anti-MUC-1 antibodies for disseminated tumor cell detection in BM or peripheral blood progenitor cells may provide false-positive results, and only carefully evaluated anti-MUC-1 antibodies (eg, HMFG-2) might be selected. Furthermore, MUC-1-targeted immunotherapy in cancer patients might be hampered by the suppression of erythropoiesis.

Antibodies, Monoclonal↗
PubMed1999

[Genetic analysis of familial prostatic cancer: localization of a gene predisposing to prostatic cancer (PCaP) on chromosome 1q 42.2-43].

OBJECTIVES: To conduct genetic linkage analysis in order to localize predisposition genes for hereditary prostate cancer (CaP), as various epidemiological studies have demonstrated a family aggregation in 15 to 25% of cases, and the development of hereditary forms in 5 to 10% of cases of CaP. MATERIAL AND METHODS: A genetic study on 47 French and German families included 122 patients and 72 subjects considered to be healthy after PSA assay. This study was conducted by linkage analysis of 364 microsatellite markers distributed throughout the genome (on average every 10 cM). RESULTS: Parametric and nonparametric linkage analysis identified a locus on chromosome 1q 42.2-43, which could be with a gene predisposing to CaP (called PCaP). The primary site was confirmed by several markers, using 3 different genetic models. The maximum LOD score (probability of linkage between the locus and the disease) on two-point analysis was 2.7 for the D1S2785 marker. Parametric and nonparametric multipoint analysis provided an HLOD score and an NPL score of 2.2 and 3.1, respectively (with P = 0.001). Heterogeneity analysis with calculations of LOD scores by multipoint analysis estimated that up to 50% of hereditary CaPs were related to this locus, with a heterogeneity probability of 157/1. Analysis of a subgroup of 9/47 families characterized by early onset CaP (before the age of 60 years) confirmed the very high probability of localization of a predisposition gene at locus 1q42.2-43 for these families (multipoint LOD score and NPL score of 3.31 and 3.32, respectively; with P = 0.001). CONCLUSION: The identification of predisposition genes will eventually allow identification within certain families of those subjects who have inherited the genetic abnormality and who therefore present a high risk of CaP. It will then be possible to perform targeted screening of CaP in order to diagnose CaP as early as possible.

Adult↗
PubMed1998

Mammalian Grb2 regulates multiple steps in embryonic development and malignant transformation.

Proteins with SH2 and SH3 domains link tyrosine kinases to intracellular pathways. To investigate the biological functions of a mammalian SH2/SH3 adaptor, we have introduced a null mutation into the mouse gene for Grb2. Analysis of mutant embryonic stem cells, embryos, and chimeras reveals that Grb2 is required during embyrogenesis for the differentiation of endodermal cells and formation of the epiblast. Grb2 acts physiologically as an adaptor, since replacing the C terminus of the Ras activator Sos1 with the Grb2 SH2 domain yields a fusion protein that largely rescues the defects caused by the Grb2 mutation. Furthermore, Grb2 is rate limiting for mammary carcinomas induced by polyomavirus middle T antigen. These data provide genetic evidence for a mammalian Grb2-Ras signaling pathway, mediated by SH2/SH3 domain interactions, that has multiple functions in embryogenesis and cancer.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Properties and functions of calcium-activated K+ channels in small neurones of rat dorsal root ganglion studied in a thin slice preparation.

1. Properties, kinetics and functions of large conductance calcium-activated K+ channels (BKCa) were investigated by the patch-clamp technique in small neurones (Adelta- and C-type) of a dorsal root ganglion (DRG) thin slice preparation without enzymatic treatment. 2. Unitary conductance of BKCa channels measured in symmetrical high K+ solutions (155 mM) was 200 pS for inward currents, and chord conductance in control solution was 72 pS. Potentials of half-maximum activation (V ) of the channels were linearly shifted by 43 mV per log10 [Ca2+]i unit (pCa) in the range of -28 mV (pCa 4) to +100 mV (pCa 7). Open probabilities increased e-times per 15-32 mV depolarization of potential. 3. In mean open probability, fast changes with time were mainly observed at pCa > 6 and at potentials > +20 mV, without obvious changes in the experimental conditions. 4. BKCa channels were half-maximally blocked by 0.4 mM TEA, measured by apparent amplitude reductions. They were completely blocked by 100 nM charybdotoxin and 50 nM iberiotoxin by reduction of open probability. 5. Two subtypes of small DRG neurones could be distinguished by the presence (type I) or absence (type II) of BKCa channels. In addition, less than 10 % of small neurones showed fast (approximately 135 V s-1) and short ( approximately 0.8 ms) action potentials (AP). 6. The main functions of BKCa channels were found to be shortening of AP duration, increasing of the speed of repolarization and contribution to the fast after-hyperpolarization. As a consequence, BKCa channels may reduce the amount of calcium entering a neurone during an AP. 7. BKCa channel currents suppressed a subsequent AP and prolonged the refractory period, which might lead to a reduced repetitive activity. We suggest that the BKCa current is a possible mechanism of the reported conduction failure during repetitive stimulation in DRG neurones.

Algorithms↗
PubMed1998

Na+-activated K+ channels in small dorsal root ganglion neurones of rat.

1. Whole-cell Na+-activated K+ (KNa) channel currents and single KNa channels were studied with the patch-clamp method in small (20-25 micrometer) dorsal root ganglion (DRG) neurones in slices of rat dorsal root ganglia. 2. The whole-cell KNa channel current was identified as an additional K+-selective leakage current which appeared after cell perfusion with internal solutions containing different [Na+]. The concentration for half-maximal activation of KNa channel current was 39 mM and the Hill coefficient was 3.5. At [Na+]i above 12 mM, KNa channel current dominated the unspecific leakage current. The ratio of maximum KNa channel current to unspecific leakage current was 45. 3. KNa channel current was not activated by internal Li+. It was suppressed by external 20 mM Cs+ but not by 10 mM tetraethylammonium. 4. Single KNa channels with a conductance of 142 pS in 155 mM external K+ (K+o)-85 mM internal K+ (K+i) solutions were observed at a high density of about 2 channels micrometer-2. 5. In two-electrode experiments, a direct correlation was seen between development of whole- cell KNa channel current and activation of single KNa channels during perfusion of the neurone with Na+-containing internal solution. 6. Under current-clamp conditions, KNa channels did not contribute to the action potential. However, internal perfusion of the neurone with Na+ shifted the resting potential towards the equilibrium potential for K+ (EK). Varying external [K+] indicated that in neurones perfused with Na+-containing internal solution the resting potential followed the EK values predicted by the Nernst equation over a broader voltage range than in neurones perfused with Na+-free solution. 7. It is concluded that the function of KNa channels has no links to firing behaviour but that the channels could be involved in setting or stabilizing the resting potential in small DRG neurones.

Action Potentials↗
PubMed1998

Uneven distribution of K+ channels in soma, axon and dendrites of rat spinal neurones: functional role of the soma in generation of action potentials.

1. A novel method of 'entire soma isolation' was used to describe the distribution of voltage-gated K+ channels between soma, axon and dendrites of dorsal horn neurones identified in spinal cord slices of newborn rat. 2. The soma contained 36 % of total inactivating (KA) current but only 15 % of delayed rectifier (KDR) current. The axon initial segment possessed almost half (47 %) of the total KA current and 38 % of KDR current. In contrast, dendrites contained a small portion (17 %) of KA but 47 % of KDR current. 3. Under current-clamp conditions, the soma isolated from axon and dendrites was not able to generate action potentials. It passively conducted weak (</= -50 mV) and amplified pronounced (-50 to 0 mV) depolarizations but inhibited strong (>/= 0 mV) depolarizations. 4. It is concluded that the soma plays a complex role in the excitability of spinal dorsal horn neurones. It conducts passively or amplifies excitatory postsynaptic potentials on their way from dendrites and soma to the axon initial segment but it inhibits back-propagation of the action potential from the axon to the dendrites.

4-Aminopyridine↗
PubMed1998

Large conductance Ca(2+)-activated K+ channels in the soma of rat motoneurones.

Properties of large conductance Ca(2+)-activated K+ channels were studied in the soma of motoneurones visually identified in thin slices of neonatal rat spinal cord. The channels had a conductance of 82 +/- 5 pS in external Ringer solution (5.6 mM Ko+/(/)155 mM Ki+) and 231 +/- 4 pS in external high-Ko solution (155 mM Ko+/(/)155 mM Ki+). The channels were activated by depolarization and by an increase in internal Ca2+ concentration. Potentials of half-maximum channel activation (E50) were -13, -34, -64 and -85 mV in the presence of 10(-6), 10(-5), 10(-4) and 10(-3) M internal Ca2+, respectively. Using an internal solution containing 10(-4) M Ca2+, averaged KCa currents showed fast activation within 2-3 msec after a voltage step to +50 mV. Averaged KCa currents did not inactivate during 400 msec voltage pulses. External TEA reduced the apparent single-channel amplitude with a 50% blocking concentration (IC50) of 0.17 +/- 0.02 mM. KCa channels were completely suppressed by externally applied 100 mM charybdotoxin. It is concluded that KCa channels activated by Ca2+ entry during the action potential play an important role in the excitability of motoneurones.

Animals↗
PubMed1998

The acute-phase protein alpha 1-antitrypsin inhibits transferrin-receptor binding and proliferation of human skin fibroblasts.

Transferrin (Tf) is required for proliferation of most cells, because cellular iron uptake is mainly mediated by binding of Tf to its specific cell surface receptors (TfR). The acute-phase protein alpha 1-antitrypsin (alpha 1-AT) completely inhibits binding of diferric Tf to TfRs on human skin fibroblasts in a dose-dependent fashion. The inhibition is competitive as proved in equilibrium saturation binding and kinetic studies. In saturation binding experiments alpha 1-AT apparently increased the dissociation constant (KD), but did not change the maximal density of binding sites (Bmax). As shown in kinetic studies, this reduction of the affinity of Tf to its receptor caused by alpha 1-AT was due to a decrease of the association rate constant (k + 1), whereas the dissociation rate constant (k - 1) remained unchanged. Furthermore, alpha 1-AT almost completely prevented internalization of the Tf-TfR complex. These interactions demonstrated biological implication, as alpha 1-AT reduced the proliferation of human fibroblasts up to maximal 30% of control. The inhibitory potency of alpha 1-AT was already seen in physiologic concentrations; the maximal effect, however, was achieved at concentrations above the normal range, which are attained in the course of inflammation and infection. Therefore, we suppose that alpha 1-AT as an endogenous factor modulates the complex mechanism of fibrogenesis not only by its known antiproteolytic function but also by inhibiting the proliferation of fibroblasts.

Acute-Phase Proteins↗
PubMed1998

Further observations of true mosaic trisomy 17 ascertained in amniotic fluid cell cultures.

Three new cases of true mosaic trisomy 17 (MT17) were diagnosed in amniotic fluid cells. Postnatal chromosome analysis from lymphocytes did not confirm the trisomic cell line, and follow-up studies showed normal psycho-motor development of the children, in one case up to the age of 4 1/2 years. We suggest that there are similarities between MT17 and MT20, in which the majority of pregnancies result in deliveries of healthy babies.

Adult↗
PubMed1998

Chromosomal changes during progression of transitional cell carcinoma of the bladder and delineation of the amplified interval on chromosome arm 8q.

The cascade of genetic alterations leading to malignant transformation has been described for adenocarcinoma of the colon but is not established for other common tumor entities. In the present study, different stages of transitional cell carcinoma (TCC) of the bladder are analyzed by comparative genomic hybridization. A dynamic pattern of the chromosomal changes during tumor progression is described. Deletion of chromosome arm 9q is the earliest genetic alteration in pTa tumors. In stage pT1 carcinomas, losses of 9q, 9p, and 11p and gain of 1q and 8q are the most common. In addition to the changes specific for earlier stages, gain of 5p and 20q becomes prominent in carcinomas stage > or =pT2. Association analysis reveals a remarkable cooccurrence of 9p deletion with gain of 5p and 20q in > or =pT2 tumors. In order to determine more precisely the size of the amplified segment and the degree of amplification on chromosome arm 8q in stage pT1 tumors, this region was analyzed by semiquantitative PCR using polymorphic microsatellite markers. These studies revealed an up to 13-fold amplification. The common region of amplification could be narrowed down to 8q22.3 and between GAAT1A4 and D8S1834 (about 7 cM).

Carcinoma, Transitional Cell↗
PubMed1998

Correlation between granulocyte/macrophage-colony-forming units and CD34+ cells in apheresis products from patients treated with different chemotherapy regimens and granulocyte-colony-stimulating factor to mobilize peripheral blood progenitor cells.

We examined the efficiency of disease-specific "standard" chemotherapies epirubicin, cyclophosphamide (EC); cyclophosphamide, vincristine, doxorubicin, etoposide, prednisolone (CHOEP); epirubicin, ifosfamide (EPI/IFOS) for peripheral blood progenitor cell (PBPC) mobilization in comparison to well-characterized mobilization protocols, i.e. etoposide, ifosfamide, cisplatin, epirubicin (VIPE) and dexamethasone, carmustine, etoposide, cytarabine, melphalan (DexaBEAM). Twenty-seven patients with various malignancies underwent 75 apheresis procedures for PBPC collection. Median cell yields from all 75 aphereses were 1.18 x 10(5) mononuclear cells/kg [range (0.28-3.7) x 10)8)], 1.4 x 10(5) granulocyte/macrophage-colony-forming units (CFU-GM)/kg [range (0.2-11) x 10(5)] and 3.3 x 10(6) CD34+cells/kg [range (0.35-17.7) x 10(6). CD34+/ CD90+ cells could be mobilized by all mobilization regimens used. The difference observed in the mobilization of CD34+ cells was only of low significance when the mobilization regimens were compared, whereas the mobilizations of MNC and CFU-GM were significantly different between the groups. Breast cancer patients treated with the VIPE regimen (including pretreated women) had a significantly higher CFU-GM rate than patients treated with EC (P=0.0005). Mobilized CD34+ PBPC were correlated with CFU-GM in all apheresis products. The linear correlation coefficients differed for the various mobilization groups: DexaBEAM (r=0.9, P < 0.0001), VIPE (r=0.68, P=0.0024), CHOEP (r=0.52, P=0.022), EPI/ IFOS (r=0.34, P=0.11) and EC (r=0.23, P=0.2). We conclude that clonogenic assays can provide additional information about the autotransplant quality, particularly when alternative or new mobilization regimens are being investigated.

Antigens, CD34↗