Biomedical subjects
W Vogel
Publications and source records attributed to W Vogel.
Visualization of the conservation of synteny between humans and pigs by heterologous chromosomal painting.
By comparative gene mapping, extended conservation of synteny between different mammalian species has become apparent. Mapping in these species could be accelerated by exact visualization of the chromosomal segments that exhibit conserved synteny. We have hybridized human chromosome-specific DNA libraries onto porcine metaphase spreads to examine the extent of conservation of synteny between the two species. The hybridization signals on pig chromosomes are of variable quality, but the analysis allowed us to assign for all human autosomes homologous chromosomal segments in the pig karyotype. Extended conservation of synteny was observed, often comprising whole chromosomes. In our analysis 47 segments of conserved synteny common to the human and pig karyotype were identified. Intrachromosomal rearrangements by inversion within and between these segments are described. These rearrangements are common events during evolution. Our analysis shows that conservation of synteny between human and pig is three times more than between humans and mice and, consequently, is characterized by fewer, but larger conserved segments.
Distinct structural characteristics of discoidin I subfamily receptor tyrosine kinases and complementary expression in human cancer.
Mammary carcinoma kinase 10 (MCK-10) and colon carcinoma kinase 2 (CCK-2) constitute a subclass of receptor tyrosine kinases characterized by a discoidin I motif in the extracellular domain and a large cytoplasmic juxtamembrane (JM) region. While the ectodomain structure suggests a common role in cell aggregation, the JM domains of MCK-10 and CCK-2 are structurally most divergent and display features that suggest an involvement in signal generation and definition. MCK-10 occurs in at least three isoforms, which contain alternatively spliced consensus sequences for internalization and SH3 domain interaction. The presence of the 37 amino acid insert affects receptor autophosphorylation and changes ectodomain glycosylation. Proteolytic cleavage within the extracellular domain of MCK-10 generates a membrane-anchored kinase domain and releases a soluble ectodomain fragment including the discoidin I homology domain. CCK-2 and MCK-10 expression was found in connective and epithelial tissues, respectively, which in cancers of epithelial origin results in mutually exclusive expression in stroma and tumor cells, indicating a possible involvement of this class of RTKs in tumor invasion.
Interferon-alpha induces circulating tumor necrosis factor receptor p55 in humans.
In the present studies we investigated the effect of interferon-alpha (IFN alpha) on the release of the soluble (extracellular) form of the tumor necrosis factor p55 receptor (TNFsRp55), because TNFsRp55 is a natural antagonist of tumor necrosis factor (TNF)-induced inflammation and also might be part of the antiinflammatory properties of IFN alpha. Plasma levels of TNFsRp55 were measured by a specific radioimmunoassay in five healthy volunteers and in five patients with chronic hepatitis C treated with IFN alpha. Levels showed a significant increase after a single injection of 5.0 million U IFN alpha in both healthy and hepatitis patient groups. Peak values (3.5 to 4.5 ng/mL) were observed within 12 hours of beginning treatment. Thereafter, levels promptly declined, reaching baseline values within 24 hours. TNF alpha and C-reactive protein (CRP) levels were below the detection limit in the same plasma samples. In addition, IFN alpha suppressed significantly interleukin (IL)-1 alpha-induced TNF alpha protein synthesis by human peripheral blood mononuclear cells. These results suggest that the antiinflammatory properties of IFN alpha may be, in part, also due to the induction and/or release of TNF soluble receptors and the suppression of TNF alpha synthesis.
The X-chromosomal human biglycan gene BGN is subject to X inactivation but is transcribed like an X-Y homologous gene.
We report the mRNA and protein expression levels of human biglycan (BGN) in patients with different numbers of sex chromosomes. BGN maps to the distal long arm of the X chromosome, band Xq28, near the second pseudoautosomal region. BGN expression levels are reduced in 45,X Turner patients and increased in patients with additional sex chromosomes. This is suggestive of a pseudoautosomal gene or a gene that escapes X inactivation and that has an active Y chromosomal copy. However, we also provide evidence from hybrid cell lines that BGN is subject to X inactivation and that there is no homolog on the Y chromosome. This evidence excludes an escape from X inactivation. Moreover, additional Y chromosomes increase BGN expression levels, despite the absence of a Y chromosomal BGN gene. Therefore, another explanation has to be invoked. The "pseudoautosomal expression" of BGN may be attributed to a gene or genes that escape X inactivation and that regulate the transcriptional activity of BGN. This is the first report concerning an X chromosomal gene that does not show the conventional correlation between gene dosage and expression rate known from other X chromosomal genes.
Life-threatening gastrointestinal bleeding after liver transplantation due to hepatic artery pseudoaneurysm perforating into the common bile duct. A case report.
A 54-year-old male presented with acute rejection and life-threatening gastrointestinal bleeding 2 months following orthotopic liver transplantation. Since no bleeding was identified in the entire gastrointestinal (GI) tract, hematobilia was first suspected and an arteriocholedochal fistula angiographically confirmed. Two days after resection of a pseudoaneurysm of the hepatic artery (HA) with primary repair and closure of the bile duct fistula, hepatic artery thrombosis (HAT) occurred. Various attempts to revascularize the HA eventually failed. Two weeks later, a CT scan showed necrotic areas within the two left lateral segments. At relaparotomy, major parts of the bile duct were found to be necrotic, and the biliary anastomosis was therefore abandoned and necrotic tissue removed. HAT was otherwise well tolerated by the graft and, at a further relaparotomy some weeks later, a hepaticojejunostomy was performed. Two years after transplantation the patient is well with a normally functioning graft.
ZOO-FISH analysis: cat and human karyotypes closely resemble the putative ancestral mammalian karyotype.
DNA in situ hybridization with human chromosome specific DNA libraries was applied to compare the karyotypes of humans (Homo sapiens, 2n = 46) and cats (Felis catus, 2n = 38). For the autosomes alone, 30 segments of conserved synteny were revealed. The arrangement of these segments in the feline karyotype differs by only seven single chromosome breaks and one intrachromosomal inversion from their arrangement in humans. Comparison of these data with those recently obtained for pig and those available from conventional gene mapping studies in mice and cattle has allowed us to develop a model of karyotype evolution in mammals. The cat and human karyotypes, with 36 and 44 autosomes respectively, were found to be very similar to a putative ancient mammalian founder karyotype. It would appear that during evolution to the human karyotype the status quo has been conserved for at least some 100-120 million years. There has been no need to alter the well-balanced gene arrangement of the mammalian founder karyotype.
Modulation of delayed rectifier K+ channel activity by external K+ ions in Xenopus axon.
The effect of external K+ ions upon the activation of delayed rectifier K+ channels was studied in demyelinated amphibian nerve fibres by means of the patch-clamp technique. In external 105 mM K+ solution (high-Ko) macroscopic K+ currents activated at more negative potentials (approximately -15 mV) than in external Ringer (2.5 mM K+). Since the rapid substitution of external Ringer with high-Ko solution at holding potentials of -70 mV and -60 mV directly activated K+ concentration from 5 mM to 10,20,50 and 105 mM gradually increased the open probability of the channels. Although Rb+ ions were less permeant through the channels, they were more potent in their interaction with the binding site and shifted K+ channel activation to more negative potentials. In contrast, external Cs+ ions had only a weak effect on the binding site. Thus, external K+ ions at physiological concentrations modulate the activation of delayed rectifier K+ channels at potentials between -90 mV and -60 mV.
Reversible hepatic veno-occlusive disease in an infant after consumption of pyrrolizidine-containing herbal tea.
UNLABELLED: Veno-occlusive disease was diagnosed in an 18-month-old boy who had regularly consumed a herbal tea mixture since the 3rd month of life. The boy developed portal hypertension with severe ascites. Histology of the liver showed centrilobular sinusoidal congestion with perivenular bleeding and parenchymal necrosis without cirrhosis. The tea contained peppermint and what the mother thought was coltsfoot (Tussilago farfara). The parents believed the tea aided the healthy development of their child. Pharmacological analysis of the tea compounds revealed high amounts of pyrrolizidine alkaloids. Seneciphylline and the corresponding N-oxide were identified as the major components by thin-layer chromatography, mass spectrometry and NMR spectroscopy. We calculated that the child had consumed at least 60 micrograms/kg body weight per day of the toxic pyrrolizidine alkaloid mixture over 15 months. Macroscopic and microscopic analysis of the leaf material indicated that Adenostyles alliariae (Alpendost) had been erroneously gathered by the parents in place of coltsfoot. The two plants can easily be confused especially after the flowering period. The child was given conservative treatment only and recovered completely within 2 months. CONCLUSION: In all cases of veno-occlusive disease pyrrolizidine alkaloids ingestion should be excluded. The identity of collected plant material should be verified by pharmaceutically trained experts and information of composition, dosage and mode of administration should be included in guidelines for herbal preparations.
Fulminant hepatic failure in a child as a potential adverse effect of trimethoprim-sulphamethoxazole.
UNLABELLED: Trimethoprim-sulphamethoxazole (TMP-SMZ) is considered a safe drug for treatment of infectious bacterial diseases in children. Side-effects are rare and generally take the form of a hypersensitivity reaction to the sulphamethoxazole component of the drug. Hepatic injury usually presents as a transient elevation of liver enzymes, which is of little clinical relevance. Fulminant liver failure due to TMP-SMZ has been reported in only six adults and never in children. We here report a 5-year-old girl who developed fulminant liver failure 3 weeks after her third exposure to TMP-SMZ. After a biphasic clinical course she underwent successful liver transplantation. CONCLUSION: Trimethoprim-Sulphamethoxazole may cause fulminant liver failure in children. The disease can run a biphasic clinical course and liver transplantation must be considered as the therapeutic option for these patients.
Development of granulomatous hepatitis during treatment with interferon-alpha 2b.
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Prognosis and life expectancy in chronic liver disease.
The aim of the present was to define prognosis and life expectancy in patients with chronic liver disease of different etiologies and to relate them to an age- and sex-matched normal population. After a follow-up of 15 years, life expectancy of 620 patients with chronic liver disease was retrospectively calculated and compared with an age- and sex-matched normal population. Among patients with cirrhosis, prognosis was dependent upon Child classification (P = 0.001). Patients with alcoholic cirrhosis and fatty liver disease were younger (P = 0.01) and had a lower life expectancy than patients with other causes of chronic liver disease (P = 0.004). Patients with hepatitis B and hepatitis C cirrhosis showed a comparable prognosis and a significantly lower life expectancy than the age- and sex-matched population. Cryptogenic and autoimmune liver diseases showed a comparable life expectancy but a significantly shorter life expectancy than the normal population. In patients with alpha 1-antitrypsin deficiency-associated cirrhosis, a high viral coinfection rate was found (P = 0.01). For patients with noncirrhotic hemochromatosis, prognosis was poorer than that for the age- and sex-matched population. In patients with asymptomatic primary biliary cirrhosis, chronic persistent hepatitis B, and alpha 1-antitrypsin deficiency without cirrhosis, life expectancy was equal to that of the normal population. Prognosis and life expectancy in chronic liver disease depend on stage, cause, and symptoms of chronic liver disease; age; and possibilities of treatment. In patients with hereditary liver disease, additional viral infection of alcohol abuse lead to a significant deterioration of life expectancy. Patients with alcoholic chronic liver disease have the poorest prognosis.
Copper-induced acute rhabdomyolysis in Wilson's disease.
Wilson's disease is a lethal defect in copper metabolism causing a continual increase in tissue copper concentrations that become toxic to the liver, brain, kidney, eye, skeletal system, and several other tissues and organs. The liver is unique among these in being both the site of the etiologic biochemical abnormality and the organ that is always affected by copper toxicosis. Although myocardial muscle involvement has been reported in association with Wilson's disease, copper deposits in peripheral muscle tissue have not yet been described. A case of a young patient with Wilson's disease who developed recurrent episodes of acute rhabdomyolysis is presented, and the accumulation of copper in muscle tissue as a possible complication is discussed.
Prognosis in nonalcoholic steatohepatitis.
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Absence of Sry in species of the vole Ellobius.
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Local anesthetics potently block a potential insensitive potassium channel in myelinated nerve.
Effects of some local anesthetics were studied in patch clamp experiments on enzymatically demyelinated peripheral amphibian nerve fibers. Micromolar concentrations of external bupivacaine depolarized the excised membrane considerably. The flicker K+ channel was found to be the most sensitive ion channel to local anesthetics in this preparation. Half-maximum inhibiting concentrations (IC50) for extracellular application of bupivacaine, ropivacaine, etidocaine, mepivacaine, lidocaine, and QX-314 were 0.21, 4.2, 8.6, 56, 220, and > 10,000 microM, respectively. The corresponding concentration-effect curves could be fitted under the assumption of a 1:1 reaction. Application from the axoplasmic side resulted in clearly lower potencies with IC50 values of 2.1, 6.6, 16, 300, 1,200, and 1,250 microM, respectively. The log(IC50)-values of the local anesthetics linearly depended on the logarithm of their octanol:buffer distribution coefficients with two regression lines for the piperidine derivatives and the standard amino-amides indicating an inherently higher potency of the cyclic piperidine series. Amide-linked local anesthetics did not impair the amplitude of the single-channel current but prolonged the time of the channel to be in the closed state derived as time constants tau c from closed-time histograms. With etidocaine and lidocaine tau c was 133 and 7.2 ms, and proved to be independent of concentration. With the most potent bupivacaine time constants of wash in and wash out were 1.8 and 5.2 s for 600 nM bupivacaine. After lowering the extracellular pH from 7.4 to 6.6, externally applied bupivacaine showed a reduced potency, whereas at higher pH of 8.2 the block was slightly enhanced. Intracellular pH of 6.4, 7.2, 8.0 had almost no effect on internal bupivacaine block. It is concluded that local anesthetics block the flicker K+ channel by impeding its gating but not its conductance. The slow blocker bupivacaine and the fast blocker lidocaine compete for the same receptor. Lipophilic interactions are of importance for blockade but besides a hydrophobic pathway, there exists also a hydrophilic pathway to the binding site which could only be reached from the cytoplasmic side of the membrane. Under physiological conditions, blockade of the flicker K+ channel which is more sensitive to bupivacaine than the Na+ channel might lead via membrane depolarization and the resulting sodium channel inactivation to a pronounced block of conduction in thin fibers.
Interleukin-1 receptor antagonist in differential diagnosis of inflammatory bowel diseases.
BACKGROUND: Immunoregulatory properties of cytokines may mediate disordered inflammatory events in inflammatory bowel diseases (IBDs). On the basis of data obtained in experimental colitis, the hypothesis has been advanced that in IBD the balance between interleukin-1 (IL-1) and the naturally occurring IL-1 receptor antagonist (IL-1ra) might influence disease expression. OBJECTIVE: We studied the profiles of IL-1ra and acute phase proteins produced by activated macrophages to determine whether the level of IL-1ra in peripheral blood is a marker of disease activity in IBD and a possible differential diagnostic marker. PATIENTS AND METHODS: Levels of IL-1ra, serum neopterin, urinary neopterin, alpha 1-glycoprotein and C-reactive protein (CRP) were measured in 80 patients with ulcerative colitis, Crohn's disease or infectious colitis. RESULTS: Levels of IL-1ra were markedly increased in patients with active ulcerative colitis or active Crohn's disease compared with those in patients with infectious colitis. Patients with active Crohn's disease had significantly higher serum IL-1ra levels than patients with active ulcerative colitis. Moreover, a positive correlation was found between levels of C-reactive protein, alpha 1-glycoprotein, and serum neopterin and the level of IL-1ra in active Crohn's disease but not in active ulcerative colitis, strongly suggesting that the pathogenesis of the two conditions differs. CONCLUSION: Levels of IL-1ra in the peripheral blood of patients with IBD are of clinical relevance, representing a potent marker of disease activity and a possible differential diagnostic marker.
Homodyne correlation measurements with weak local oscillators.
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