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Biomedical subjects

M Müller

Publications and source records attributed to M Müller.

At least 163 records · Page 9Linked to original sources
PubMed2003

Potential benefits of Anaesthesia Information Management Systems for multicentre data evaluation: risk calculation of inotropic support in patients undergoing cardiac surgery.

OBJECTIVE: The aim of this study was to test the hypothesis whether it is easily possible to transfer and apply the methods of data extraction and analysis of a performed study to a data pool of a different medical centre using the same type of Anaesthesia Information Management System (AIMS). For this purpose the objective of a study in cardiac anaesthesia, investigated at the University Hospital Giessen, was applied to the data pool of the Heart Centre Siegburg. RESEARCH DESIGN AND METHODS: The Giessen study evaluated factors related to the use of positive inotropic drugs (PIDs) in adults undergoing elective cardiac surgery with cardiopulmonary bypass (CPB). The same objective and methods were applied to data of 1672 patients of the Heart Centre Siegburg. In both centres anaesthetic procedures were recorded with the AIMS NarkoData. Existing database queries were adapted according to the Siegburg database configuration for detection of patients having received PIDs during or after weaning from CPB. RESULTS: It was revealed that data from the Siegburg database using the same data model and configuration, were identical to the Giessen database except for a few items only. Thus database queries of the Giessen study could be applied to the new data pool requiring no considerable additional input. CONCLUSIONS: We could demonstrate that multicentre data analysis in anaesthesia using AIM systems can be carried out successfully. Once the methods of data extraction and analysis are established they can be transferred to data pools of different centres without requiring additional time, personnel and material resources.

Aged↗
PubMed2003

Porcine 11beta-hydroxysteroid dehydrogenase type 2 isoform: complete coding sequence and polymorphisms.

11Beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) is involved in the regulation of the peripheral glucocorticoid concentrations. Due to the central role of glucocorticoids in protein turnover, 11beta-HSD2 is a candidate gene for optimising production traits in livestock. In addition, mutant 11beta-HSD2 animals may be used as models for human disorders. Here, we present the complete porcine 11beta-HSD2 coding sequence, the RT-PCR strategy for the examination of the coding sequence and the polymorphisms found in the pig.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed2003

Penetration of fosfomycin into inflammatory lesions in patients with cellulitis or diabetic foot syndrome.

We investigated the distribution of the broad-spectrum antibiotic fosfomycin in infected soft tissue of patients with uncomplicated cellulitis of the lower extremities or diabetic foot infection using in vivo microdialysis. Our findings suggest that fosfomycin exhibits good and similar penetration into the fluid in the interstitial space in inflamed and noninflamed soft tissue in patients.

Area Under Curve↗
PubMed2003

Relevance of soft-tissue penetration by levofloxacin for target site bacterial killing in patients with sepsis.

Antimicrobial therapy of soft tissue infections in patients with sepsis sometimes lacks efficiency, despite the documented susceptibility of the causative pathogen to the administered antibiotic. In this context, impaired equilibration between the antibiotic concentrations in plasma and those in tissues in critically ill patients has been discussed. To characterize the impact of tissue penetration of anti-infective agents on antimicrobial killing, we used microdialysis to measure the concentration-versus-time profiles of levofloxacin in the interstitial space fluid of skeletal muscle in patients with sepsis. Subsequently, we applied an established dynamic in vivo pharmacokinetic-in vitro pharmacodynamic approach to simulate bacterial killing at the site of infection. The population mean areas under the concentration-time curves (AUCs) for levofloxacin showed that levofloxacin excellently penetrates soft tissues, as indicated by the ratio of the AUC from time zero to 8 h (AUC(0-8)) for muscle tissue (AUC(0-8 muscle)) to the AUC(0-8) for free drug in plasma (AUC(0-8 plasma free)) (AUC(0-8 muscle)/AUC(0-8 plasma free) ratio) of 0.85. The individual values of tissue penetration and maximum concentration (C(max)) in muscle tissue were highly variable. No difference in bacterial killing of a select Staphylococcus aureus strain for which the MIC was 0.5 microg/ml was found between individuals after exposure to dynamically changing concentrations of levofloxacin in plasma and tissue in vitro. In contrast, the decrease in the bacterial counts of Pseudomonas aeruginosa (MIC = 2 microg/ml) varied extensively when the bacteria were exposed to levofloxacin at the concentrations determined from the individual concentration-versus-time profiles obtained in skeletal muscle. The extent of bacterial killing could be predicted by calculating individual C(max)/MIC and AUC(0-8 muscle)/AUC(0-8 plasma free) ratios (R = 0.96 and 0.93, respectively). We have therefore shown in the present study that individual differences in the tissue penetration of levofloxacin may markedly affect target site killing of bacteria for which MICs are close to 2 microg/ml.

Aged↗
PubMed2003

ATP binding cassette transporter gene expression in rat liver progenitor cells.

BACKGROUND AND AIM: Liver regeneration after severe liver damage depends in part on proliferation and differentiation of hepatic progenitor cells (HPCs). Under these conditions they must be able to withstand the toxic milieu of the damaged liver. ATP binding cassette (ABC) transporters are cytoprotective efflux pumps that may contribute to the preservation of these cells. The aim of this study was to determine the ABC transporter phenotype of HPCs. METHODS: HPC activation was studied in rats treated with 2- acetylaminofluorene (2-AAF) followed by partial hepatectomy (PHx). ABC transporter gene expression was determined by real time detection reverse transcription-polymerase chain reaction in isolated HPCs, hepatocytes, cholangiocytes, and cultured progenitor cell-like RLF phi 13 cells and by immunohistochemistry of total liver samples. ABC transporter efflux activity was studied in RLF phi 13 cells by flow cytometry. RESULTS: 2-AAF/PHx treated animals showed increased hepatic mRNA levels of the genes encoding multidrug resistance proteins Mdr1b, Mrp1, and Mrp3. Immunohistochemistry demonstrated expression of Mrp1 and Mrp3 proteins in periportal progenitor cells and of the Mdr1b protein in periportal hepatocytes. Freshly isolated Thy-1 positive cells and cultured RLF phi 13 progenitor cells highly expressed Mrp1 and Mrp3 mRNA while the hepatocyte specific transporters Mdr2, Bsep, Mrp2, and Mrp6 were only minimally expressed. Blocking Mrp activity by MK-571 resulted in accumulation of the Mrp specific substrate carboxyfluorescein in RLF phi 13 cells. CONCLUSION: HPCs express high levels of active Mrp1 and Mrp3. These may have a cytoprotective role in conditions of severe hepatotoxicity.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2003

Ragaglitazar: the pharmacokinetics, pharmacodynamics, and tolerability of a novel dual PPAR alpha and gamma agonist in healthy subjects and patients with type 2 diabetes.

Ragaglitazar is a novel dual peroxisome proliferator-activated receptor (PPAR) alpha and gamma agonist intended to restore insulin sensitivity and correct diabetic dyslipidemia. These studies assessed single-dose pharmacokinetics and tolerability of ragaglitazar in healthy subjects, as well as multiple-dose pharmacokinetics, pharmacodynamics, and tolerability of ragaglitazar in healthy subjects and in patients with type 2 diabetes. Healthy subjects received a single oral dose (1-120 mg), and healthy subjects and type 2 diabetic patients received a loading dose and thereafter once-daily doses (0.5-16 mg) of ragaglitazar for 6 and 20 days, respectively. Ragaglitazar was rapidly absorbed (tmax: 1.5-1.7 h), with mean AUC0-24 h and Cmax proportional to dose after single and multiple dosing; t1/2 was 80 hours following a single dose and 104 hours in healthy subjects and 122 hours in patients after multiple dosing. Administration of 4 mg ragaglitazar to patients (n = 4) for 21 days resulted in mean decreases from baseline in fasting levels of plasma glucose (18%), C-peptide (18%), fructosamine (6%), triglycerides (36%), free fatty acids (49%), total cholesterol (11%), low-density lipoprotein (LDL) cholesterol (21%), and very low-density lipoprotein (VLDL) cholesterol (15%), as well as an increase in high-density lipoprotein (HDL) cholesterol (33%). Overall, ragaglitazar was well tolerated; with multiple dosing, there was a higher incidence of adverse events for patients that, at the highest dose level (16 mg), included peripheral edema and anemia.

Adolescent↗
PubMed2003

The role of membrane-bound LBP, endotoxin aggregates, and the MaxiK channel in LPS-induced cell activation.

We have previously shown in patch-clamp experiments on excised outside-out cytoplasmic membrane patches from human macrophages that the activation of a high-conductance Ca(2+)- and voltage-dependent potassium channel, the MaxiK channel, is an early step in LPS-induced transmembrane signal transduction in macrophages. MaxiK can be activated by agonistically active LPS, and activation can be completely inhibited by LPS antagonists (e.g. synthetic compound 406) and by anti-CD14 antibodies. Furthermore, by inhibiting MaxiK with the specific MaxiK blocker paxilline, we could show that activation of MaxiK is essential for LPS-induced cytokine production. As shown by RT-PCR, blockade of MaxiK by paxilline also inhibits induction of the mRNA of TNF-alpha and IL-6. This observation together with the fact that all patch-clamp experiments were done on excised outside-out patches reveal that MaxiK activation is an early step in cell activation by endotoxins. Thus, since cells lacking TLR4 on their surface can also not be activated to produce cytokines, these data allow the conclusion that TLR4 and MaxiK are both essential for activation by LPS and may form a co-operative signaling complex. We have also shown that LBP not only exists as a soluble acute-phase serum protein, but is also incorporated as a transmembrane protein (mLBP) in the cytoplasmic membrane of MNC; in this configuration, it is obviously involved in the binding of endotoxin and its transfer to the transmembrane signaling proteins finally triggering cell activation. Complexation of soluble LBP and LPS in the serum prior to binding of LPS to mLBP, in contrast, leads to neutralization of LPS. Here, we provide evidence from fluorescence resonance energy transfer spectroscopy that endotoxin aggregates are intercalated into reconstituted membranes by mLBP. In addition, cell culture assays and patch-clamp experiments demonstrate that endotoxin activates macrophages and the MaxiK channel in the aggregated, but not in the monomeric, state at similar concentrations.

Acute-Phase Proteins↗
PubMed2003

Pharmacogenomics and drug response.

Following pioneer work in the early 20th century, the era of molecular pharmacogenomics started with the cloning of a polymorphic gene encoding the drug-metabolizing enzyme cytochrome P450-2D6. Today, recent conceptual and methodological advances in genomics allow a much broader approach to elucidating inheritance patterns in drug response and identification of functional polymorphisms, that affect drug response, has become a key issue. Despite recent euphoria about potential applications of pharmacogenomic principles, currently available pharmacogenomic data have had modest overall impact on the routine of drug therapy. Most data were derived from single gene approaches for select drug metabolizing enzymes with extreme phenotypes. Data on genetic determinants of drug distribution, absorption and response, however, are scarce and it seems that most events in the dose-response cascade follow a complex interplay of environmental factors with several genes encoding proteins in multiple pathways. Thus, there is great need for clinical studies on genotype-phenotype and gene environment interactions, based on multiple gene approaches. Major challenges also relate to practical aspects of clinical pharmacogenomic studies, e.g. appropriate data handling, selection of appropriate study designs and control groups and issues of prediction accuracy. To move to a clinically useful and predictive level in pharmacogenomics, much work remains to be completed. Nevertheless, it can be anticipated that for select drugs, pharmacogenomics may lead to a shift from the current strategy of developing medications for a statistically optimized fraction of patients to a strategy that aims to provide tailored medications for genetically diverse patients.

Dose-Response Relationship, Drug↗
PubMed2003

Less invasive stabilization system (LISS) in the treatment of distal femoral fractures.

The treatment of distal femoral fractures has been associated with a high rate of complications for a long time. Although implants and surgical techniques have improved, plate osteosynthesis and intramedullary nailing have been accompanied by a high occurrence of infection, non-union and malalignment. The treatment of soft tissue envelopes using "biological" osteosynthesis and minimally invasive approaches has resulted in a decrease in complication rates and ultimately led to the concept of the less invasive stabilization system (LISS). This is an extramedullary-applied, internal fixator shaped according to the implantation site anatomy, with minimal invasiveness. The purpose of this study was to present this new surgical technique and draw attention to its advantages and importance. Although this is not a scientific paper, we hope to provide enough evidence of the LISS usefulness. The main LISS components include multiple-fixed angle screws and an insertion handle for submuscular sliding of a fixator and placement of percutaneous, self-drilling, unicortical screws for fixation of the diaphyseal fracture fragments. The LISS has been designed to preserve periosteal perfusion and to facilitate a minimally invasive application. Since the first implantation of the LISS, only a few studies have been published on its use in treatment of distal femoral fractures. The rate of infection has been low, ranging from 0 to 4%. The rate of delayed union has been between 2.4 and 6.1%, but delayed unions do not necessarily lead to secondary bone grafting or repeat osteosynthesis as the LISS has a high and lasting stability. When the LISS is used, bone grafting is rarely necessary (0 to 1.6% in primary and 0 to 5% in secondary grafting). Also implant failure differs from the failure of plate osteosynthesis because, with the use of LISS, no screw loosening or secondary malalignment occurs. Implant failures (up to 7.4%) were recorded particularly at the time of LISS introduction in surgical practice and were attributed to the technique of implantation rather than to the implant itself. Good treatment outcomes have been reported. The average knee flexion has been 103 degrees and 107 degrees. In 72.5% of the patients, flexion has been more than 90 degrees and an extension lag of > or = 10 degrees has been found in only 7.5% of all cases. The average Neer score has ranged from 73.9 to 77.2 points. In conclusion, the LISS is a useful implant for treatment of distal femoral fractures, especially when bone quality is poor. Infection, delayed union and non-union rates are low, as shown by yet unpublished data from our clinic. Primary bone grafting, which is rarely necessary with this system, is carried out only when there is a great bone loss. Implant failure, such as screw loosening or secondary malalignment, is not seen.

Adult↗
PubMed2003

Morphological assessment of preimplantation embryo quality in cattle.

The extensive use of embryo technologies has emphasized the need for assessing embryo quality by morphological techniques, such as transmission electron microscopy, immunocytochemistry for confocal laser scanning microscopy and fluorescence in situ hybridization. By a combination of these techniques, it has been possible to demonstrate: (i) that rRNA gene activation, as monitored by embryonic nucleolar development, is comparable in bovine embryos developed in vivo and produced in vitro, whereas reconstructed nuclear transfer embryos may be deviant, (ii) that generating embryos by both in vitro production and reconstruction by nuclear transfer is associated with increased occurrence of apoptosis, in particular in the inner cell mass of blastocysts, and (iii) that these two embryo production techniques are associated with increased occurrence of mixoploidy that is, embryos presenting a large population of normal diploid cells and a small population of abnormal haploid or polyploid cells. It is clear that blastocysts that appear healthy at stereomicroscopy may have subcellular defects. Therefore, the possibility of long-term evaluation in vitro of embryos after hatching has been examined. However, whereas embryos developing in vivo after hatching present a number of well defined developmental milestones, such as elongation of the trophoblast, formation of hypoblast and epiblast followed by differentiation of endoderm, mesoderm and ectoderm, in vitro culture systems for development beyond the blastocyst stage currently allow the embryo to complete only a single milestone, namely hypoblast formation.

Animals↗
PubMed2002

Signal recognition particle-dependent protein targeting, universal to all kingdoms of life.

The signal recognition particle (SRP) and its membrane-bound receptor represent a ubiquitous protein-targeting device utilized by organisms as different as bacteria and humans, archaea and plants. The unifying concept of SRP-dependent protein targeting is that SRP binds to signal sequences of newly synthesized proteins as they emerge from the ribosome. In eukaryotes this interaction arrests or retards translation elongation until SRP targets the ribosome-nascent chain complexes via the SRP receptor to the translocation channel. Such channels are present in the endoplasmic reticulum of eukaryotic cells, the thylakoids of chloroplasts, or the plasma membrane of prokaryotes. The minimal functional unit of SRP consists of a signal sequence-recognizing protein and a small RNA. The as yet most complex version is the mammalian SRP whose RNA, together with six proteinaceous subunits, undergo an intricate assembly process. The preferential substrates of SRP possess especially hydrophobic signal sequences. Interactions between SRP and its receptor, the ribosome, the signal sequence, and the target membrane are regulated by GTP hydrolysis. SRP-dependent protein targeting in bacteria and chloroplasts slightly deviate from the canonical mechanism found in eukaryotes. Pro- and eukaryotic cells harbour regulatory mechanisms to prevent a malfunction of the SRP pathway.

Animals↗
PubMed2002

Elastic properties of polymer interfaces: aggregation of pure diblock, mixed diblock, and triblock copolymers.

Block copolymers adsorbing to an interface between two immiscible homopolymers modify the elastic constants of this interface. Within self-consistent field calculations for Gaussian chains, we determine how the bending constants vary in dependence on the block copolymer concentration and architecture. Four phenomena are discussed. (i) When a tricritical or isotropic Lifshitz critical point is approached in a ternary mixture by varying the concentration of diblock copolymers or changing temperature, the elastic constants vanish. We determine the corresponding power laws, and show that the de Gennes-Taupin criterium for the stability of lamellar phases against undulations and the Ginzburg-Landau criterium for bulk fluctuations yield identical predictions for the validity of the mean-field approximation. (ii) Addition of a small amount of diblock copolymers modifies the bending rigidity. If the diblock copolymers are comparable in length to the homopolymers, adsorption of the diblocks reduces the bending rigidity. If the diblocks are much longer, they increase the bending rigidity. Only for an extreme ratio of chain lengths (>100), the predictions for polymers tethered to an infinitely thin, impenetrable sheet become accurate. (iii) Mixtures of short and long symmetric diblock copolymers are studied, as well as mixtures of two asymmetric diblocks, which are obtained by exchanging the long and short ends. The saddle-splay modulus is found to be the same in both mixtures, while the bending rigidity is significantly smaller in the latter case. (iv) The role of the block copolymer architecture is studied by comparing the effect of triblock copolymers with the effect of diblocks with the same overall length and composition. We propose that triblock copolymers are a very efficient way to control the spontaneous curvature of an interface.

Journal Article↗
PubMed2002

Universal relationship between a quantum phase transition and instability points of classical systems.

The direct and universal relationship between the accumulation of exceptional points in the quantum spectrum at a phase transition and the singularity of the classical action at a homoclinic point of the separatrix is investigated. The particular common features are the analytic structure and, related to it, instability and high sensitivity leading generically to the onset of chaos in both cases under perturbation.

Journal Article↗
PubMed2002

Transition from Gaussian-orthogonal to Gaussian-unitary ensemble in a microwave billiard with threefold symmetry.

Recently it has been shown that time-reversal invariant systems with discrete symmetries may display, in certain irreducible subspaces, spectral statistics corresponding to the Gaussian-unitary ensemble (GUE) rather than to the expected orthogonal one (GOE). A Kramers-type degeneracy is predicted in such situations. We present results for a microwave billiard with a threefold rotational symmetry and with the option to display or break a reflection symmetry. This allows us to observe the change from GOE to GUE statistics for one subset of levels. Since it was not possible to separate the three subspectra reliably, the number variances for the superimposed spectra were studied. The experimental results are compared with a theoretical and numerical study considering the effects of level splitting and level loss.

Journal Article↗
PubMed2002

[Improving resistance profile, simplifying administration mode. New antiretroviral drugs].

We had some good news in the last year: Tenofovir received its FDA approval, a new class of antiretrovirals, the fusion-inhibitors, entered phase III trials and there are some promising agents in the pipeline of the pharmaceutical laboratories. The major issue in the development of new drugs is the antiretroviral activity. One of the "winners" here is TMC-125, a new NNRTI. But people focus also on the side-effects of the HAART, especially on long-term toxicity. One example is Atazanavir, a protease inhibitor which doesn't show any increase in cholesterin or triglycerides. But all the exciting news drugs have to prove their real potential in large phase III trials.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Phase diagram of a mixed polymer brush.

We investigate the structure and phase behavior of a two-component (binary) polymer brush in a solvent within self-consistent field theory as a function of the chains' stretching, the composition, and the incompatibility. Grafting the chains irreversibly prevents macrophase separation and the chains assemble into three-dimensional structures with lateral periodicity. At small incompatibilities a "ripple" phase is formed where different species aggregate into an array of parallel cylinders. At larger incompatibilities or asymmetric composition two "dimple" phases become stable, where different species form clusters which arrange on a quadratic (checkerboard structure) or hexagonal lattice.

Journal Article↗
PubMed2002

Molecular arrangements and reorientation behavior in a dibenzopyrene-derivative ferroelectric columnar liquid crystal as studied by time-resolved Fourier-transform ir spectroscopy.

Polarized, time-resolved Fourier-transform infrared spectroscopy was employed to study the orientational order and the reorientation dynamics of a diskotic ferroelectric liquid crystal. In the shear oriented cell the dibenzopyrene derivative forms two different field-dependent columnar phases that show a tripling in the spontaneous polarization. These field-dependent phases are analyzed with respect to the dependence of the infrared absorbance from the polarization plane. In this way it was confirmed that the high-field phase is characterized by a homogeneous orientation of the tilt-plane formed by the core normals n and the column axis N. In contrast, in the low-field phase the columns exhibit several different tilt-planes. The orientational order parameter of the columns is determined. It was also detected that the average orientation of the alkyl tails of the molecules is not lying in the plane of the disklike core. By monitoring the evolution of the infrared bands in the course of the electric-field-induced reorientation, we found that the reorientation process is divided into three steps: A fast initial response followed by a slowing down of the reorientation is observed, which then is followed by an acceleration of the reorientation. In the high-field phase the fast initial electrical induced process can be assigned to a rotation of the molecules around the column axis by a few degrees. During the subsequent ferroelectriclike response the molecules rotate around the column axis by approximately 180 degrees. Other models for this switching mechanisms could be excluded.

Journal Article↗