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Biomedical subjects

K Müller

Publications and source records attributed to K Müller.

At least 73 records · Page 4Linked to original sources
PubMed2001

Changes in vimentin in human macrophages during apoptosis induced by oxidised low density lipoprotein.

Macrophage apoptosis contributes to the development of human atherosclerotic lesions. Oxidised LDL may be involved in macrophage death in vivo. We examined morphological and biochemical changes to the vimentin filament network during apoptosis of human macrophages. Only oxidised LDL, but not native or acetylated LDL, induced apoptosis, wherein vimentin was cleaved into fragments of 48-50, 46, 29 and 26 kDa. The use of caspase inhibitors suggested that caspase-6 mediates the formation of the 26 and 46 kDa fragments of vimentin. We were unable to demonstrate any significant involvement of caspase-3 in vimentin cleavage. However, caspase-3 was clearly activated during apoptosis whilst caspase-6 expression in macrophages was minimal. Vimentin filament breakdown occurred early during apoptosis and vimentin immunoreactivity was present in apoptotic bodies. However, the application of caspase inhibitors had no effect on the morphology of the vimentin network in apoptotic cells, suggesting that filament breakdown is not mediated by caspase proteolysis. Similar changes in vimentin were also seen in gliotoxin-induced apoptosis.

Apoptosis↗
PubMed2001

10-Phenylbutyryl-substituted anthracenones as inhibitors of keratinocyte growth and LTB(4) biosynthesis.

A recent observation that phenylbutyryl anthracenone 2, an analogue of the antipsoriatic anthralin, is a potent inhibitor of leukotriene B(4) (LTB(4)) biosynthesis has prompted a search of other anthracenones with improved antiproliferative activity. In that direction, a limited number of analogues related to 2 have been prepared and evaluated in the HaCaT keratinocytes proliferation and in the polymorphonuclear leukocyte LTB(4) assay. The 4-methoxy analogue 2a and the side chain methylated 2l retain the full inhibitory activity of 1 against LTB(4) biosynthesis while their antiproliferative activity is markedly enhanced and comparable to that of the antipsoriatic anthralin. In contrast to anthralin, cytotoxic effects against cell membranes are strongly reduced as documented by the LDH activity released from cytoplasm of keratinocytes.

Administration, Topical↗
PubMed2001

2-arylalkyl-substituted anthracenones as inhibitors of 12-lipoxygenase enzymes. 1. Structure-activity relationships of the terminal aryl ring.

A series of 2-arylmethyl-substituted anthracenones were synthesized and tested as inhibitors of three types of 12-lipoxygenase isoforms in epidermal homogenate of mice, bovine platelets and porcine leucocytes. Their inhibitory activities were compared with those to inhibit the 5-lipoxygenase enzyme in bovine leucocytes. Structure-activity relationships are described with particular emphasis on modifications of the terminal aryl nucleus. The ability of the compounds to selectively inhibit the 12-lipoxygenase enzymes was dependent on a high overall lipophilicity of the inhibitor, whereas compounds with decreased lipophilicity were also inhibitors of the 5-LO enzyme. Among the more lipophilic inhibitors, the unsubstituted 2-phenylmethyl analogue 6a as well as the carboxylic acid ester 6q appeared to be selective inhibitors of platelet-type 12-LO isoform.

Animals↗
PubMed2001

Highly efficient transduction of endothelial cells by targeted artificial virus-like particles.

Targeting the tumor vasculature by gene therapy is a potentially powerful approach, but suitable vectors have not yet been described. We have designed a new type of liposomal vector, based on the composition of anionic retroviral envelopes, that is serum-resistant and nontoxic. These artificial virus-like envelopes (AVEs) were endowed with a cyclic RGD-containing peptide as a targeting device for the a(v)beta3-integrin on tumor endothelial cells (ECs). The packaging of plasmid DNA complexed with low-molecular-weight, nonlinear polyethyleneimine into these AVEs yielded artificial virus-like particles (AVPs) that transduced ECs with efficiencies of up to 99%. In contrast, transduction of a variety of other cell types by these RGD-AVPs was comparably inefficient under the same experimental conditions. This EC selectivity was mediated, in part, but not exclusively, by the RGD ligand, as suggested by the reduced, but still relatively high, transduction efficiency seen with AVPs lacking RGD. The interaction of anionic lipids of the AVPs with ECs may therefore contribute to the observed selective and highly efficient transduction of this cell type. These findings suggest that the targeted AVE technology is a useful approach to create highly efficient nonviral vectors.

Antineoplastic Agents↗
PubMed2001

[Coordinative treatment and quality of life - a randomised trial of nurses with back pain].

BACKGROUND DATA: The influence of strength training on back conditions has been demonstrated quite well, whereas coordinative training being a major component of physical therapy regarding preventive and rehabilitative treatment of back pain is used only occasionally and has been evaluated even more rarely. One has to consider this fact regarding the still growing number of musculo-skeletal diseases. AIM OF STUDY: The influence of several preventive therapies (coordination training in spacecurl, kinaesthetics/back protective patient transfer) has been investigated with regard to coordination, back pain and quality of life in a randomised controlled study. METHODS: We used an assessment-set consisting of a specially devised questionnaire regarding job demands, sports activity and back pain and the WHOQOL-BREF for control of quality of life. These methods were combined with body surface electromyography and posturography. Those methods enabled us to determine parameters such as coordination, back pain and quality of life at 3 different stages (untrained individuals) and 4 points (trained individuals) respectively. RESULTS: Trained individuals showed a significant reduction of back pain frequency (p = 0.016) before and after training. In comparison there was no difference in untrained individuals. Furthermore trained individuals showed an increase in quality of life of 5.4 % (p = 0.028), whereas again there was no difference in untrained individuals. Somatic diagnostics (body surface electromyography, posturography) showed significant changes only in the trained group. CONCLUSION: The used coordination training program is enhancing coordination and reducing back pain whilst having a positive effect upon the quality of life of an individual.

Adult↗
PubMed2001

Estrogen sulfamates: a new approach to oral estrogen therapy.

Sulfamate substitution (-O-SO2-NH2) at carbon atom 3 of the steroid skeleton leads to orally active prodrugs of estrogens with much higher systemic, but lower hepatic, estrogenic activity than their parent steroids. This dissociation is achieved by first passage through the liver in erythrocytes, followed by systemic hydrolysis which releases the 'parent' estrogen. In the rat, orally administered tritiated estradiol sulfamate, unlike estradiol, appears in the circulation at high concentrations. At Cmax, approximately one third of the administered dose forms a depot in the circulation (98% in erythrocytes, 2% in plasma). Significant estradiol, estrone and estrone sulfate concentrations were recorded in plasma during depletion of the red blood cell pool. Estradiol sulfamate (J995) has no estrogen receptor affinity per se or estrogenic activity in vitro ( i.e. without hydrolysis). Its oral uterotropic activity in rats is approximately 100 times greater than that of estradiol, however, its hepatotropic activity is only marginally elevated. These functions include bile secretion, the secretion of angiotensinogen, lipoproteins (total and high-density lipoprotein cholesterol) and insulin-like growth factor I (IGF-I). Orally administred estradiol sulfamate led to systemic estrogenic effects without significant hepatic responses, whereas estradiol and other 'conventional' estrogens exerted parallel systemic and hepatic estrogenic effects. Sulfamate technology represents an approach to the use of natural estrogens for fertility control and hormone replacement therapy in both genders. In this context, reduced effects on hemostatic factors, angiotensinogen, bile and IGF-I secretion seem the most important aspects. In addition, blood concentrations of estrogens are less variable than with conventional estrogens.

Administration, Oral↗
PubMed2001

Powder-free, non-sterile gloves assessed in a wound healing centre.

OBJECTIVE: To investigate the relative importance of features of gloves for medical staff working with problem wounds. DESIGN: Prospective, consecutive, crossover, open questionnaire investigation. SETTING: University hospital, Copenhagen, Denmark. SUBJECTS: 38 doctors, nurses, and podiatrists. INTERVENTIONS: Two types of powder-free, non-sterile gloves (No powder Ansell Medical and Skinsense Biogel coated examination glove) were evaluated in the outpatient clinic and the ward of the Copenhagen Wound Healing Center. MAIN OUTCOME MEASURES: Features of gloves regarded as important in the treatment of wounds and a comparison of the features based on the following criteria: much better = 2, better = 1, no difference = 0, worse = -1, much worse = -2. RESULTS: The first questionnaire showed that 84% of the respondents needed a new type of non-sterile glove, and for 66% the price of the glove was a main feature. The study of individual features of gloves showed that "protection" was ranked highest followed by "durability" and "sensitivity". Least important was the "length of the gloves" (p <0.01). The gloves were tested in two different time periods. The Skinsense Biogel glove was evaluated better or much better for "durability" (82%-92% (period 1, 2), p <0.001), "protection" (76%-80%, p <0.001) and "ease of donning" (68%-71%, p <0.001). The Ansell Medical glove was evaluated as better or much better for "tactile sensitivity" (77%-79%, p <0.001). The Skinsense Biogel glove showed more positive changes in skin condition than the Ansell Medical glove. The quality of packing of the Ansell Medical glove in the containers also resulted in more gloves being unusable when unpacked. CONCLUSION: The powder-free, non-sterile gloves were useful in a wound healing department. The Skinsense Biogel glove showed more advantageous features, less changes for the worse in the skin condition, and was better packed in the containers.

Ambulatory Care Facilities↗
PubMed2001

Effect of feeding regime on the metabolism of ochratoxin A during the in vitro incubation in buffered rumen fluid from cows.

Pure ochratoxin A (OA) was added to buffered rumen fluid collected from two fistulated cows and incubated under anaerobic conditions. Both animals were fed six diets containing grass, grass silage or hay, and two different amounts of concentrate consisting of barley and soybean meal. Four incubations per animal and diet were carried out at consecutive days. The concentration of OA declined exponentially to a very low or non-detectable level under all conditions examined, with half-lives at 0.51 to 2.76 h. The disappearance of OA was accompanied by the appearance of ochratoxin alpha (O alpha) with an average amount of O alpha formed relative to the disappearance of OA near 100%, independent of diet and animal. Based on four incubations per animal and diet the rate of OA disappearance was affected (P < 0.1) by the origin of rumen fluid from two animals, as well as by the type of basic component and amount of concentrate in the diet, with interactions between these factors. The disappearance of OA mostly was accelerated (P < 0.1) by replacing grass silage or hay by fresh grass and by increasing the content of concentrate from 10 to 50% of dry matter. It is concluded that the capacity of the rumen to detoxify OA is not limited by the yield of Oa from OA but is strongly dependent on animal and diet.

Animal Feed↗
PubMed2001

Lipid composition of virosomes modulates their fusion efficiency with cryopreserved bull sperm cells.

Virosomes derived from different fusogenic enveloped viruses have been generated for potential application in gene targeting to sperm cells. Comparative characterization of reconstitution products revealed that virosomes derived from influenza viruses are superior to those generated from Sendai viruses, with respect to the fusion rates with cryopreserved bull sperm cells and to sperm cell vitality after fusion. Modulation of the lipid composition during virosome reconstitution affects fusion sites on target sperms and allows optimization of the fusion rate and sperm cell vitality. A fluorescence-based microscopic fusion assay combined with a vital cell stain revealed that about 90% of sperm cells fused with influenza virosomes containing exogenous cholesterol, sphingomyelin, phosphatidylcholine, and phosphatidylethanolamine. About 85% of the fused sperm cells remained vital. Such optimized influenza-derived virosomes provide the basis for ongoing experiments, which aim at eventually generating biologically active transgenic sperms.

Animals↗
PubMed2001

An activation-independent role of transcription factors in insulator function.

Chromatin insulators are defined as transcriptionally neutral elements that prevent negative or positive influence from extending across chromatin to a promoter. Here we show that yeast subtelomeric anti-silencing regions behave as boundaries to telomere-driven silencing and also allow discontinuous propagation of silent chromatin. These two facets of insulator activity, boundary and silencing discontinuity, can be recapitulated by tethering various transcription activation domains to tandem sites on DNA. Importantly, we show that these insulator activities do not involve direct transcriptional activation of the reporter promoter. These findings predict that certain promoters behave as insulators and partition genomes in functionally independent domains.

Animals↗
PubMed2001

Foreign DNA integration--perturbations of the genome--oncogenesis.

We have been interested in the consequences of foreign DNA insertion into established mammalian genomes and have initially studied this problem in adenovirus type 12 (Ad12)-transformed cells or in Ad12-induced hamster tumors. Since integrates are frequently methylated de novo, it appears that they might be modified by an ancient defense mechanism against foreign DNA. In cells transgenic for the DNA of Ad12 or for the DNA of bacteriophage lambda, changes in cellular methylation and transcription patterns have been observed. Thus, the insertion of foreign DNA can have important functional consequences that are not limited to the site of foreign DNA insertion. These findings appear to be relevant also for tumor biology and for the interpretation of data derived from experiments with transgenic organisms. For most animals, the main portal of entry for foreign DNA is the gastrointestinal tract. Large amounts of foreign DNA are regularly ingested with the supply of nutrients. Starting in 1987/1988, we have been investigating the fate of orally administered foreign DNA in mice. Naked DNA of bacteriophage M13 and the cloned gene for the green fluorescent protein (GFP) of Aequorea victoria have been used as test molecules. Moreover, the plant-specific gene for the ribulose-1,5-bisphosphate carboxylase (rubisco) has been followed in mice after feeding soybean leaves. At least transiently, food-ingested DNA can be traced to different organs and, after transplacental transfer, to fetuses and newborns. There is no evidence for germ line transmission or for the expression of orally administered GFP DNA.

Adenoviridae↗
PubMed2001

Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase.

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may exert pleiotropic effects on vascular cells independent of lowering plasma cholesterol. To elucidate the molecular mechanisms involved in these effects, we investigated the impact of statins on production of reactive oxygen species (ROS) in rat aortic vascular smooth muscle cells (VSMC). Exposure of VSMC to angiotensin II caused production of ROS via angiotensin AT1 receptor activation. Pretreatment with atorvastatin inhibited angiotensin II-induced ROS production. Atorvastatin decreased AT1 receptor mRNA levels in a time- and concentration-dependent manner and consistently reduced AT1 receptor density. L-Mevalonate but not hydroxy-cholesterol reversed the inhibitory effect of atorvastatin on AT1 receptor transcript levels. Inhibition of geranylgeranyl-transferase but not of farnesyl-transferase mimicked the effect of atorvastatin on AT1 receptor gene expression. Atorvastatin did not decrease AT1 receptor gene transcription but did reduce the half-life of the AT1 receptor mRNA. AT1 receptor activation by angiotensin II increased the expression of the GTPase rac1, enhanced rac1 GTP-binding activity, and increased the geranylgeranyl-dependent translocation of rac1 to the cell membrane. In contrast, statins inhibited rac1 activity and membrane translocation. Consequently, specific inhibition of rac1 with Clostridium sordellii lethal toxin blocked angiotensin II-induced production of free radicals. Finally, treatment of rats with atorvastatin caused down-regulation of aortic AT1 receptor mRNA expression and reduced aortic superoxide production in vivo. Cholesterol-independent down-regulation of AT1 receptor gene expression and inhibition of rac1, leading to decreased ROS production, demonstrates a novel regulatory mechanism of statins that may contribute to the beneficial effects of these drugs beyond lowering of plasma cholesterol.

Angiotensin II↗
PubMed2001

HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) significantly reduce cardiovascular mortality associated with hypercholesterolemia. There is evidence that statins exert beneficial effects in part through direct effects on vascular cells independent of lowering plasma cholesterol. We characterized the effect of a 30-day treatment with atorvastatin in normocholesterolemic, spontaneously hypertensive rats (SHR). Systolic blood pressure was significantly decreased in atorvastatin-treated rats (184+/-5 versus 204+/-6 mm Hg for control). Statin therapy improved endothelial dysfunction, as assessed by carbachol-induced vasorelaxation in aortic segments, and profoundly reduced angiotensin II-induced vasoconstriction. Angiotensin type 1 (AT(1)) receptor, endothelial cell NO synthase (ecNOS), and p22phox mRNA expression were determined with quantitative reverse transcription-polymerase chain reaction. Atorvastatin treatment downregulated aortic AT(1) receptor mRNA expression to 44+/-12% of control and reduced mRNA expression of the essential NAD(P)H oxidase subunit p22phox to 63+/-7% of control. Aortic AT(1) receptor protein expression was consistently decreased. Vascular production of reactive oxygen species was reduced to 62+/-12% of control in statin-treated SHR, as measured with lucigenin chemiluminescence assays. Accordingly, treatment of SHR with the AT(1) receptor antagonist fonsartan improved endothelial dysfunction and reduced vascular free-radical release. Moreover, atorvastatin caused an upregulation of ecNOS mRNA expression (138+/-7% of control) and an enhanced ecNOS activity in the vessel wall (209+/-46% of control). Treatment of SHR with atorvastatin causes a significant reduction of systolic blood pressure and a profound improvement of endothelial dysfunction mediated by a reduction of free radical release in the vasculature. The underlying mechanism could in part be based on the statin-induced downregulation of AT(1) receptor expression and decreased expression of the NAD(P)H oxidase subunit p22phox, because AT(1) receptor activation plays a pivotal role for the induction of this redox system in the vessel wall.

Angiotensin Receptor Antagonists↗
PubMed2001

The fate of foreign DNA in mammalian cells and organisms.

We have investigated the consequences of foreign DNA insertions into the genomes of mammalian cells in transgenic cell lines, in adenovirus type 12 (Ad12)-transformed cells, in Ad12-induced tumor cells or in transgenic mice. We have reported previously on the de novo methylation of integrated foreign genomes and on extensive changes in cellular patterns of DNA methylation upon foreign DNA insertion. These studies have been extended and several independent methods have been applied to document these alterations in cellular DNA methylation and gene expression patterns in transgenic cell lines and in transgenic mice. These data are relevant for the mechanism of (viral) oncogenesis and for the interpretation of data gathered in experiments with transgenic animals.

Animals↗
PubMed2000

Primary lumbosacral stability after open posterior and endoscopic anterior fusion with interbody implants: a roentgen stereophotogrammetric analysis.

STUDY DESIGN: After posterior stabilization of the spondylolytic lumbosacral level, mobility of the fused vertebrae could be studied before and after an additional anterior endoscopic interbody fusion using roentgen stereophotogrammetric analysis. OBJECTIVE: To determine the in vivo primary lumbosacral stability of additional anterior interbody fusion after transpedicular screw fixation. SUMMARY OF BACKGROUND DATA: In vitro studies indicate a significant decrease in segmental motion after pedicle screw fixation and additional anterior fusion. Roentgen stereophotogrammetric studies demonstrate the adequacy of transpedicular lumbar instrumentation in posterolateral fusions. There are no studies examining the effect of additional anterior interbody fusion after posterior instrumentation in vivo. METHODS: In this study, 15 patients with low-grade spondylolisthesis at L5-S1 underwent a two-stage open posterior and endoscopic anterior lumbar fusion using carbon fiber (Brantigan I/F) cages. At surgery, tantalum markers were implanted into the fifth lumbar (L5) and the first sacral (S1) vertebra. All the patients were examined by roentgen stereophotogrammetric analysis after the first and second surgical procedures. RESULTS: After implantation of the posterior pedicle system only, the mean intervertebral mobility determined by roentgen stereophotogrammetric analysis was 0.23 mm in the transverse (x), 0.54 mm in the vertical (y), and 1.2 mm in the sagittal (z) axes. After additional anterior endoscopic fusion with carbon cages, the remaining translation between the fused segment L5/S1 decreased to 0.17 mm in the x, 0.16 mm in the y, and 0.44 mm in the z axes. CONCLUSION: Anterior endoscopic lumbosacral fusion significantly increases the primary stability of the posterior fusion with a pedicle system in two axes of motion.

Biocompatible Materials↗
PubMed2000

[Intoxication with propylene glycol in two horses].

Two horses were accidentally administered propylene glycol instead of mineral oil. After discovery of the mistake intensive medical therapy with intravenous fluids, etc. was started, and both animals recovered fully from their clinical symptoms. Veterinarians use propylene glycol as well as paraffin routinely for the treatment of their patients. Mistakes are likely to be made because both medicines and sometimes their packing have a similar appearance. Several incidents have been reported in other countries. A large amount of propylene glycol given to a horse, but also to other animals, can be dangerous and immediate adequate intervention is necessary. The major cause of the problems in case of a propylene glycol intoxication is the high concentration of D-lactate that arises. Clinically, this primarily results in a depression of the central nervous system and in metabolic acidosis. Furthermore colic, diarrhoea and respiratory problems may occur.

Animals↗
PubMed2000

The histone-interacting domain of nuclear factor I activates simian virus 40 DNA replication in vivo.

Efficient initiation of SV40 DNA replication requires transcription factors that bind auxiliary sequences flanking the minimally required origin. To evaluate the possibility that transcription factors may activate SV40 replication by acting on the chromatin structure of the origin, we used an in vivo replication system in which we targeted GAL4 fusion proteins to the minimally required origin. We found that the proline-rich transcriptional activation domain of nuclear factor I (NF-I), which has been previously shown to interact with histone H3, specifically activates replication. Evaluation of a series of deletion and point mutants of NF-I indicates that the H3-binding domain and the replication activity coincide perfectly. Assays with other transcription factors, such as Sp1, confirmed the correlation between the interaction with H3 and the activation of replication. These findings imply that transcription factors such as NF-I can activate SV40 replication via direct interaction with chromatin components, thereby contributing to the relief of nucleosomal repression at the SV40 origin.

Animals↗