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C Weber

Publications and source records attributed to C Weber.

At least 181 records · Page 10Linked to original sources
PubMed1997

Gastric ulcer healing in the rat: kinetics and localisation of de novo procollagen synthesis.

BACKGROUND AND AIMS: To gain further insight into the role of the extracellular matrix during healing of peptic ulcers, sequential changes of procollagen expression were studied over 30 days of ulcer healing. MATERIALS AND METHODS: Procollagens alpha 1 (I), alpha 1 (III), and alpha 1 (IV) RNA and their polypeptides were assessed in acetic acid induced rat gastric ulcers by in situ hybridisation and immunohistochemistry. RESULTS: Three days after ulcer induction, intense hybridisation signals were obtained with all probes, with procollagen alpha 1 (I) showing the highest transcript levels. Procollagen gene expression remained elevated up to day 15, but was reduced to initial low levels on day 30. Immunohistochemical staining documented increased deposition of the three procollagen types parallel to their respective transcript levels, again with type I showing the earliest and the most prominent deposits. The highest procollagen transcript levels were found in the intact submucosa surrounding the ulcer margins, followed by the muscularis propria and the serosa, with the lamina propria exhibiting the lowest transcript levels. CONCLUSION: The procollagens studied are regulated differentially at the transcriptional and post-transcriptional levels. The early onset and long duration of procollagen expression as well as the involvement of all layers of the gastric wall points to their central structural and functional role in gastric ulcer healing.

Acetic Acid↗
PubMed1997

alpha-Tocopheryl succinate inhibits monocytic cell adhesion to endothelial cells by suppressing NF-kappa B mobilization.

The adherence of monocytes to activated endothelium is an early event in atherogenesis. Because antioxidants have been considered to be of antiatherosclerotic potential, we investigated the effects of alpha-tocopherol (TCP) and its acetate and succinate esters on monocyte adhesion to cytokine-stimulated human umbilical vein endothelial cells (HUVEC). Endothelial cells were treated with TCP, alpha-tocopherol acetate (TCP acetate), or alpha-tocopheryl succinate (TCP succinate) before stimulation with tumor necrosis factor-alpha (TNF-alpha; 10 U/ml, 6 h) or interleukin-1 beta (IL-1 beta; 10 U/ml, 6 h). Cytokine-stimulated cell surface expression of vascular cell adhesion molecule-1 (VCAM-1, CD106) and E-selectin (ELAM-1, CD62E), but not of intercellular adhesion molecule-1 (ICAM-1, CD54), was time- and dose-dependently inhibited by TCP succinate but not by TCP or TCP acetate. TCP succinate (200 microM, 24 h) reduced TNF-induced VCAM-1 and E-selectin expression from a specific mean fluorescence intensity of 151 +/- 28 to 12 +/- 4 channels and from 225 +/- 38 to 79 +/- 21 channels, respectively. Succinate alone had no effect. Decreased adhesion molecule expression was associated with a reduction of monocytic cell adhesion. TCP succinate (20 microM, 72 h), but not TCP (200 microM, 72 h), reduced U-937 cell adhesion to TNF-alpha-stimulated (10 U/ml, 6 h) HUVEC by 30% (P < 0.025) and to IL-1 beta-stimulated HUVEC by 56% (P < 0.010). Electrophoretic mobility-shift assays of HUVEC nuclear proteins revealed a decrease in TNF-alpha-stimulated nuclear factor-kappa B (NF-kappa B) activation after pretreatment of HUVEC with TCP succinate but not with TCP, TCP acetate, or succinate alone. In conclusion, we demonstrate that the vitamin E derivative TCP succinate prevents monocytic cell adhesion to cytokine-stimulated endothelial cells by inhibiting the activation of NF-kappa B, further emphasizing the antiatherosclerotic potential of lipid soluble antioxidants.

Biological Transport↗
PubMed1997

Sleep apnea in patients receiving growth hormone.

Among 145 patients treated with recombinant human growth hormone (GH), four developed sleep apnea (two obstructive, two mixed) associated with tonsillar and adenoidal hypertrophy in three. These four patients had no local risk factors predisposing to upper airway obstruction (i.e., frequent pharyngitis or sinusitis). Clinical and/or polysomnographic features of sleep apnea improved following cessation of GH therapy in one patient, and following tonsillectomy and adenoidectomy in all patients. The present observations indicate that, albeit rarely, obstructive and/or central sleep apnea may occur in children treated with GH. Polysomnography should be considered if symptoms of snoring, interrupted sleep, daytime somnolence-particularly if associated with tonsillar hypertrophy-appear in children during GH therapy.

Adenoidectomy↗
PubMed1997

The coenzyme Q10 content of the average Danish diet.

The average dietary intake of coenzyme Q10 and coenzyme Q9 of the Danish population was determined, based on food consumption data from a national dietary survey. Selected food items in edible form were analyzed for the coenzyme Q content by HPCL with UV-detection, and their contribution to the total intake calculated. The effect of cooking was a 14-32% destruction of coenzyme Q10 by frying, and no detectable destruction by boiling. The average coenzyme Q10 intake of the Danish population was estimated to 3-5 mg/day, primarily derived from meat and poultry (64% of the daily intake), while cereals, fruit, edible fats, and vegetables only make minor contributions. The intake of coenzyme Q10 is approximately 1 mg/day, primarily derived from vegetable fats and cereals. The alpha-tocopherol content of the selected food samples was analyzed by HPLC with fluorescence detection, and the calculated average intake of alpha-tocopherol was comparable to the estimate from the dietary survey (7-8 vs. 7.4 mg alpha-tocopherol/day, respectively). The commercially available dietary supplements (capsules) provide 10-30 mg CoQ10/day, thus the average diet. The optimal dietary intake of coenzyme Q10 is unknown.

Animals↗
PubMed1997

Permeability and adsorption capacity of dialysis membranes to lipid A.

Hemodialysis membranes were tested in vitro for possible penetration by low molecular weight endotoxins containing lipid A. Using lipid A from Escherichia coli as a model substance for this kind of pyrogen, different dialyzers (F4, E3. Acepal 1300, Altraflux, F 40, Polyflux 110, Filtral 12, F 60) were challenged by tangential filtration in aqueous medium. All membranes exhibited impermability to lipid A (as well as to LPS from Pseudomonas aeruginosa), which was proved by additional experiments using culture filtrates of Pseudomonas aeruginosa in bicarbonate dialysis fluid, as well as by employing miniaturized dialyzers with synthetic lipid A as a contaminant. Furthermore, the highest adsorption capacities were found for polysulfone and polyamide membranes.

Adsorption↗
PubMed1997

Stress experienced by parents of children with cochlear implants compared with parents of deaf children and hearing children.

OBJECTIVE: To compare the stress experienced by parents of children with cochlear implants with that experienced by parents of deaf children and hearing children. STUDY DESIGN: The Parenting Stress Index and problem-oriented interviews were used with the parents of these three groups of children. RESULTS: Parents of deaf children were found to experience greater levels of stress than parents in the other two groups. CONCLUSION: Parents of children with cochlear implants experience about the same level of stress as parents of hearing children.

Child↗
PubMed1996

Differential regulation of beta 1 and beta 2 integrin avidity by chemoattractants in eosinophils.

The CC chemokines regulated on activation normal T expressed and secreted (RANTES) and monocyte chemotactic protein 3 (MCP-3), and the anaphylatoxin C5a, induce activation, degranulation, chemotaxis, and transendothelial migration of eosinophils. Adhesion assays on purified ligands showed differential regulation of beta 1 and beta 2 integrin avidity in eosinophils. Adhesiveness of VLA-4 (alpha 4 beta 1, CD29/CD49d) for vascular cell adhesion molecule 1 or fibronectin was rapidly increased but subsequently reduced by RANTES, MCP-3, or C5a. The deactivation of VLA-4 lead to cell detachment, whereas phorbol 12-myristate 13-acetate induced sustained activation of VLA-4. In contrast, chemoattractants stimulated a prolonged increase in the adhesiveness of Mac-1 (alpha M beta 2, CD11b/CD18) for intercellular adhesion molecule 1. Inhibition by pertussis toxin confirmed signaling via G protein-coupled receptors. Chemoattractants induced transient, while phorbol 12-myristate 13-acetate induced sustained actin polymerization. Disruption of actin filaments by cytochalasins inhibited increases in avidity of VLA-4 but not of Mac-1. Chemoattractants did not upregulate a Mn2+-inducible beta 1 neoepitope defined by the mAb 9EG7, but induced prolonged expression of a Mac-1 activation epitope recognized by the mAb CBRM1/5. This mAb inhibited chemoattractant-stimulated adhesion of eosinophils to intercellular adhesion molecule 1. Thus, regulation of VLA-4 was dependent on the actin cytoskeleton, whereas conformational changes appeared to be crucial for activation of Mac-1. To our knowledge, this is the first demonstration that physiological agonists, such as chemoattractants, can differentially regulate the avidity of a beta 1 and a beta 2 integrin expressed on the same leukocyte.

CD18 Antigens↗
PubMed1996

Increased adhesiveness of isolated monocytes to endothelium is prevented by vitamin C intake in smokers.

BACKGROUND: To explore pathophysiological mechanisms of cigarette smoking involved in atherogenesis, we compared adhesiveness of isolated blood monocytes with endothelium and plasma levels of the aqueous phase antioxidant vitamin C in nonsmokers and smokers before and after supplementation, using a novel monocyte adhesion assay with fixed human endothelial cells. METHODS AND RESULTS: Monocyte adhesion to unstimulated human umbilical vein endothelial cells ranged from 0.17% to 0.51% in the nonsmoker group (0.37+/-0.09%, mean +/-SD, n=13). In smokers with a 1 to 2 packs per day consumption, monocyte adhesion was increased to 0.71+/-0.17% (mean +/-SD, n=10, P<.001), ranging from 0.46% to 0.99%. Increased adhesiveness was mediated by the integrin CD11b/CD18, as shown by inhibition with a monoclonal antibody to CD11b but not associated with altered CD11b surface expression. Plasma vitamin C levels were reduced in smokers (48.2+/-14.1 micromol/L) versus nonsmokers (67.7+/-17.6 micromol/L; P<.025), while no significant differences were found in retinol, vitamin E, or beta-carotene levels. This confirms that the radical scavenger vitamin C reacts sensitively to oxidative stress induced by cigarette smoke in human plasma. Consistently, dietary supplementation with vitamin C (2 g per day) for 10 days raised plasma levels to 82.6+/-11.0 micromol/L (n=10, P<.001) in smokers and decreased monocyte adhesion to values found in nonsmokers (0.38+/-0.18%, P<.001). In contrast, vitamin C intake did not affect monocyte adhesiveness in nonsmokers (0.37+/-0.14%, n=6) despite increasing plasma levels to 82.9+/-11.8 micromol/L. CONCLUSIONS: Our data show that cigarette smoking increases CD11b-dependent monocyte adhesiveness in humans. Restoring reduced plasma vitamin C concentrations in smokers by oral supplementation decreased monocyte adhesion to values found in nonsmokers.

Adult↗
PubMed1996

Involvement of tyrosine phosphorylation in endothelial adhesion molecule induction.

Induction of endothelial adhesion molecules by the cytokine tumor necrosis factor-alpha (TNF) can occur independently of protein kinase C and activation of a protein tyrosine kinase (PTK) has recently been implicated in the upregulation of vascular cell adhesion molecule 1 (VCAM-1) by interleukin-4 (IL-4) on endothelial cells. We demonstrate that the PTK inhibitors herbimycin A or genistein suppress induction of endothelial VCAM-1 and E-selectin, as well as subsequent monocytic cell adhesion to endothelial cells stimulated by TNF. Inhibition studies indicate that specific tyrosine phosphorylation following PTK activation is involved in the mobilization of the transcription factor, nuclear factor kappa B, and VCAM-1 mRNA expression. This may have implications for pathophysiological conditions that involve the upregulation of these molecules (e.g. inflammation and atherosclerosis).

Cell Adhesion↗
PubMed1996

Effect of the lipase inhibitor orlistat on the pharmacokinetics of four different antihypertensive drugs in healthy volunteers.

OBJECTIVE: To study the influence of the lipase inhibitor orlistat on the pharmacokinetics of the antihypertensive drugs atenolol, furosemide, captopril and nifedipine. METHODS: Four open-label, crossover studies were performed on six to eight healthy male volunteers. Orlistat was given in doses of 50 mg 3 times daily mid-meal for 7 (nifedipine and captopril) or 8 days (atenolol and furosemide). The four antihypertensive drugs (atenolol 100-mg tablet, furosemide 40-mg tablet, captopril 50-mg tablet and nifedipine 20-mg slow-release tablet) were administered in single doses twice, once before and once together, with orlistat at the end of the orlistat treatment period. RESULTS: The plasma concentration time profiles and the pharmacokinetic parameters estimated for these drugs were in the expected range, except for furosemide, whose bioavailability was lower than reported in the literature. This was probably due to the fact that furosemide was given during a meal. There were minor, but statistically significant, differences in one of the pharmacokinetic parameters of furosemide and nifedipine (no difference for captopril and atenolol) when these drugs were given alone and in combination with orlistat: the half-life of furosemide was slightly longer, the time to peak plasma concentrations of nifedipine was slightly longer. None of these are considered to be clinically significant changes. CONCLUSIONS: The lipase inhibitor orlistat given 50 mg 3 times daily does not alter the pharmacokinetics of atenolol, furosemide, nifedipine and captopril to a clinically significant extent.

Adrenergic beta-Antagonists↗
PubMed1996

Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects.

INTRODUCTION: Bosentan (Ro 47-0203) is a potent and mixed ETA-and ETB-receptor antagonist. Its activity has been studied in a variety of preclinical disease models. METHODS: Two double-blind placebo-controlled studies were performed to investigate the pharmacokinetics and pharmacodynamics of bosentan after single oral and intravenous doses in healthy volunteers; doses of 3, 10, 30, 100, 300, 600, 1200, and 2400 mg were given in a single ascending oral dose study, and doses of 10, 50, 250, 500, and 750 mg were given in a single ascending intravenous dose study (six subjects received active drug and two received placebo at each dose level). In an open-label crossover added to the second study, six subjects received a single oral dose of 600 mg and a single intravenous dose of 250 mg in randomized order. At regular intervals, blood pressure, pulse rate, and skin responses to intradermally injected endothelin-1 (ET-1) were recorded, and plasma levels of ET-1, proendothelin-1 (big ET-1), and ET-3, and drug and urinary levels of ET-1 and drug were determined. RESULTS: Systemic plasma clearance and volume of distribution decreased with increasing dose to limiting values of around 6 L/hr and 0.2 L/kg, respectively. The absolute bioavailability was 50% and appeared to decrease with doses above 600 mg. Plasma ET-1 increased maximally twofold (oral) and threefold (intravenous), and this increase was directly related to bosentan plasma concentrations according to an Emax model. Bosentan reversed the vasoconstrictor effect of ET-1 measured in the skin microcirculation. There was a tendency toward decreased blood pressure (approximately 5 mm Hg) and increased pulse rate (approximately 5 beats/min), neither was clearly dose dependent. Oral bosentan was well tolerated. Vomiting and local intolerability was observed at the higher intravenous doses. CONCLUSION: Bosentan is an orally bioavailable, well-tolerated, and active ET-1 antagonist with a low clearance and a moderate volume of distribution. Its intravenous use is limited because of local intolerability.

Administration, Oral↗
PubMed1996

Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats.

Two forms of the neurodegenerative disorder spinocerebellar ataxia are known to be caused by the expansion of a CAG (polyglutamine) trinucleotide repeat. By screening cDNA expression libraries, using an antibody specific for polyglutamine repeats, we identified six novel genes containing CAG stretches. One of them is mutated in patients with spinocerebellar ataxia linked to chromosome 12q (SCA2). This gene shows ubiquitous expression and encodes a protein of unknown function. Normal SCA2 alleles (17 to 29 CAG repeats) contain one to three CAAs in the repeat. Mutated alleles (37 to 50 repeats) appear particularly unstable, upon both paternal and maternal transmissions. The sequence of three of them revealed pure CAG stretches. The steep inverse correlation between age of onset and CAG number suggests a higher sensitivity to polyglutamine length than in the other polyglutamine expansion diseases.

Adolescent↗
PubMed1996

Sequential regulation of alpha 4 beta 1 and alpha 5 beta 1 integrin avidity by CC chemokines in monocytes: implications for transendothelial chemotaxis.

Leukocyte emigration possibly requires dynamic regulation of integrin adhesiveness for endothelial and extracellular matrix ligands. Adhesion assays on purified vascular cell adhension molecule (VCAM)-1, fibronectin, and fibronectin fragments revealed distinct kinetic patterns for the regulation of very late antigen (VLA)-4 (alpha 4 beta 1) and VLA-5 (alpha 5 beta 1) avidity by the CC chemokines monocyte inflammatory protein (MIP)-1 alpha, RANTES (regulated on activation, normal T expressed and secreted), or monocyte chemoattractant protein (MCP)-1 in monocytes. CC chemokines induced early activation and subsequent deactivation of VLA-4, whereas upregulation of VLA-5 avidity occurred later and persisted. Controlled detachment assays in shear flow suggested that adhesive strength of VLA-4 for VCAM-1 or the 40-kD fragment of fibronectin (FN40) is more rapidly increased and subsequently reduced by MCP-1 than by MIP-1 alpha, and confirmed late and sustained activation of the adhesive strength of VLA-5 for the 120-kD fragment of fibronectin (FN120). Mn2+ or the stimulating beta 1 mAb TS2/16 strongly and stably enhanced monocyte binding to VCAM-1 or fibronectin, and locked beta 1 integrins in a high avidity state, which was not further modulated by CC chemokines. Mn2+ and mAb TS2/16 inhibited CC chemokine-induced transendothelial migration, particularly chemotaxis across stimulated endothelium that involved VLA-4 and VCAM-1. VLA-4 on Jurkat cells is of constitutively high avidity and interfered with migration across barriers expressing VCAM-1. Low but not high site densities of VCAM-1 or FN40 promoted, while FN120 impaired, beta 1 integrin-dependent monocyte chemotaxis to MCP-1 across filters coated with these substrates. Thus, we show that CC chemokines can differentially and selectively regulate avidity of integrins sharing common beta subunits. Transient activation and deactivation of VLA-4 may serve to facilitate transendothelial diapedesis, whereas late and prolonged activation of VLA-5 may mediate subsequent interactions with the basement membrane and extracellular matrix.

Antibodies, Monoclonal↗
PubMed1996

Alternative splicing of exon 14 determines nuclear or cytoplasmic localisation of fmr1 protein isoforms.

Impaired expression of the FMR1 gene is responsible for the fragile X mental retardation syndrome. The FMR1 gene encodes a cytoplasmic protein with RNA-binding properties. Its complex alternative splicing leads to several isoforms, whose abundance and specific functions in the cell are not known. We have cloned in expression vectors, cDNAs corresponding to several isoforms. Western blot comparison of the pattern of endogenous FMR1 proteins with these transfected isoforms allowed the tentative identification of the major endogenous isoform as ISO 7 and of a minor band as an isoform lacking exon 14 sequences (ISO 6 or ISO 12), while some other isoforms (ISO 4, ISO 5) were not expressed at detectable levels. Surprisingly, in immunofluorescence studies, the transfected splice variants that exclude exon 14 sequences (and have alternate C-terminal regions) were shown to be nuclear. Such differential localisation was however not seen in subcellular fractionation studies. Analysis of various deletion mutants suggests the presence of a cytoplasmic retention domain encoded in exon 14 and of a nuclear association domain encoded within the first eight exons that appear however to lack a typical nuclear localisation signal.

3T3 Cells↗
PubMed1996

Microspheres based detoxification system: a new method in convective blood purification.

A variety of protein-bound or hydrophobic substances, accumulating as a result of pathologic conditions such as exogenous or endogenous intoxications, are removed poorly by conventional detoxification methods because of low accessibility (hemodialysis), insufficient adsorption capabilities (hemosorption), low efficiency (peritoneal dialysis), or economic limitations (high-volume plasmapheresis). Combining advantages of existing methods with microspheric technology, a module-based system was designed. Major operating parameters of the latter can be modified to allow for adjustment to individual clinical situations. An extracorporeal blood circuit including a plasmafilter is combined with a secondary high-velocity plasma circuit driven by a centrifugal pump. Different microspheric adsorbers can be combined in one circuit or applied in sequence. Thus, a prolonged treatment can be tailored using specially designed selective adsorber materials. Comparing this system with existing methods (high-flux hemodialysis, molecular adsorbent recycling system), results from our in vitro studies and animal experiments demonstrate the superior efficiency of substance removal.

Adsorption↗
PubMed1996

Simultaneous determination of tissue tocopherols, tocotrienols, ubiquinols, and ubiquinones.

A tissue-specific distribution of the various vitamin E forms, tocotrienols and tocopherols, has been found, suggesting that these forms have unique roles in cellular functions. A sensitive procedure is described for the simultaneous determination of individual tocopherols, tocotrienols, ubiquinols, and ubiquinones using gradient high pressure liquid chromatography (HPLC) and electrochemical detection for vitamin E homologues and ubiquinols, and in-line UV detection for ubiquinones. Using this method, the lipophilic antioxidant complement of a variety of hairless mouse tissues was analyzed. Of the vitamin E forms, brain contained virtually only alpha-tocopherol (5.4 +/- 0.1 nmol/g; 99.8%) and no detectable tocotrienols were found. By contrast, skin contained nearly 15% tocotrienols and 1% gamma-tocopherol. In other tissues, the alpha-tocopherol content was higher (20 nmol/g), while each of the other forms represented about 1% of the total (gamma-tocopherol 0.2 to 0.4 nmol/g, alpha-tocotrienol 0.1, gamma-tocotrienol 0.2). Ubiquinol-9 concentrations were highest in kidney (81 nmol/g) and in liver (42 nmol/g), while the highest ubiquinone-9 concentrations were found in kidney (301 +/- 123 nmol/g) and heart (244 +/- 22 nmol/g). Liver contained nearly identical concentrations of each of the redox couple (ubiquinol-9 (41 +/- 16 nmol/g) and ubiquinone-9 (46 +/- 18 nmol/g). The unique distribution of these various antioxidants in the tissues measured suggests their distribution may be dependent upon selective mechanisms for maintaining antioxidant defenses in each tissue.

Animals↗
PubMed1996

Protein A carrying monosize PMMA microbeads for the removal of HIgG from human plasma.

Protein A-incorporated polymethylmethacrylate (PMMA) microbeads were investigated for specific removal of HIgG from human plasma. The microbeads were prepared by a phase inversion polymerization, and activated by periodate oxidation. Protein A was then incorporated by covalent binding onto these microbeads through hydroxyl groups coming from the stabilizer. The amount of incorporated protein A was controlled by the initial concentrations of protein A in the immobilization medium and pH. The maximum protein A immobilization of 0.615 mg protein A/g PMMA, was observed at a pH of 9.5 corresponding to an initial protein A concentration of 0.1 mg/ml. There was no HIgG adsorption onto the plain PMMA microbeads, while high HIgG adsorptions of up to 32 mg HIgG/g PMMA were achieved with human plasma.

Adsorption↗