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Biomedical subjects

R Zimmer

Publications and source records attributed to R Zimmer.

At least 19 recordsLinked to original sources
PubMed2006

IL-1beta, but not BMP-7 leads to a dramatic change in the gene expression pattern of human adult articular chondrocytes--portraying the gene expression pattern in two donors.

Anabolic and catabolic cytokines and growth factors such as BMP-7 and IL-1beta play a central role in controlling the balance between degradation and repair of normal and (osteo)arthritic articular cartilage matrix. In this report, we investigated the response of articular chondrocytes to these factors IL-1beta and BMP-7 in terms of changes in gene expression levels. Large scale analysis was performed on primary human adult articular chondrocytes isolated from two human, independent donors cultured in alginate beads (non-stimulated and stimulated with IL-1beta and BMP-7 for 48 h) using Affymetrix gene chips (oligo-arrays). Biostatistical and bioinformatic evaluation of gene expression pattern was performed using the Resolver software (Rosetta). Part of the results were confirmed using real-time PCR. IL-1beta modulated significantly 909 out of 3459 genes detectable, whereas BMP-7 influenced only 36 out of 3440. BMP-7 induced mainly anabolic activation of chondrocytes including classical target genes such as collagen type II and aggrecan, while IL-1beta, both, significantly modulated the gene expression levels of numerous genes; namely, IL-1beta down-regulated the expression of anabolic genes and induced catabolic genes and mediators. Our data indicate that BMP-7 has only a limited effect on differentiated cells, whereas IL-1beta causes a dramatic change in gene expression pattern, i.e. induced or repressed much more genes. This presumably reflects the fact that BMP-7 signaling is effected via one pathway only (i.e. Smad-pathway) whereas IL-1beta is able to signal via a broad variety of intracellular signaling cascades involving the JNK, p38, NFkB and Erk pathways and even influencing BMP signaling.

Aged↗
PubMed2006

[Transsexuals' life satisfaction after gender transformation operations].

BACKGROUND: More and more frequently, the registration of life satisfaction is being used to evaluate different medical treatments. So far, there have been only few such surveys on transsexuals (TS). Therefore, the aim of this study was to evaluate the general and the health-related life satisfaction of transsexuals after gender transformation operations. PATIENTS AND METHODS: Forty patients took part in this German cross-sectional study. The Questions on Life Satisfaction Module (FLZ) and free questions on different aspects of the new gender identity were used as measuring instruments. RESULTS: Of the TS studied, 85-95% were "very satisfied" or "satisfied" with the results of their gender transformation operation in respect to gender identity. The TS were significantly less satisfied (P>0.001) in overall "general life satisfaction" than the general population. In overall FLZ scores for "health-related life satisfaction", no differences were seen. CONCLUSION: These data indicate a discrepancy between subjective satisfaction with new gender identity and current life situation, and they identify problems with life satisfaction.

Adult↗
PubMed2005

Comparison of the chondrosarcoma cell line SW1353 with primary human adult articular chondrocytes with regard to their gene expression profile and reactivity to IL-1beta.

OBJECTIVE: In this study, the human chondrosarcoma cell line SW1353 was investigated by gene expression analysis in order to validate it as an in vitro model for primary human (adult articular) chondrocytes (PHCs). METHODS: PHCs and SW1353 cells were cultured as high density monolayer cultures with and without 1ng/ml interleukin-1beta (IL-1beta). RNA was isolated and assayed using a custom-made oligonucleotide microarray representing 312 chondrocyte-relevant genes. The expression levels of selected genes were confirmed by real-time polymerase chain reaction and the gene expression profiles of the two cell types, both with and without IL-1beta treatment, were compared. RESULTS: Overall, gene expression profiling showed only very limited similarities between SW1353 cells and PHCs at the transcriptional level. Similarities were predominantly seen with respect to catabolic effects after IL-1beta treatment. In both cell systems matrix metalloproteinase-1 (MMP-1), MMP-3 and MMP-13 were strongly induced by IL-1beta, without significant induction of MMP-2. IL-6 was also found to be up-regulated by IL-1beta in both cellular models. On the other hand, intercellular mediators such as leukemia inhibitory factor (LIF) and bone morphogenetic protein-2 (BMP-2) were not induced by IL-1beta in SW1353 cells, but significantly up-regulated in PHCs. Bioinformatical analysis identified nuclear factor kappa-B (NFkappaB) as a common transcriptional regulator of IL-1beta induced genes in both SW1353 cells and PHCs, whereas other transcription factors were only found to be relevant for individual cell systems. CONCLUSION: Our data characterize SW1353 cells as a cell line with only a very limited potential to mimic PHCs, though SW1353 cells can be of value to study the induction of protease expression within cells, a phenomenon also seen in chondrocytes.

Aged↗
PubMed2004

The Helmholtz Network for Bioinformatics: an integrative web portal for bioinformatics resources.

SUMMARY: The Helmholtz Network for Bioinformatics (HNB) is a joint venture of eleven German bioinformatics research groups that offers convenient access to numerous bioinformatics resources through a single web portal. The 'Guided Solution Finder' which is available through the HNB portal helps users to locate the appropriate resources to answer their queries by employing a detailed, tree-like questionnaire. Furthermore, automated complex tool cascades ('tasks'), involving resources located on different servers, have been implemented, allowing users to perform comprehensive data analyses without the requirement of further manual intervention for data transfer and re-formatting. Currently, automated cascades for the analysis of regulatory DNA segments as well as for the prediction of protein functional properties are provided. AVAILABILITY: The HNB portal is available at http://www.hnbioinfo.de

Algorithms↗
PubMed2003

Secondary ion and laser ablation mass spectrometry for the quantitative characterization of styrene-butadiene copolymers.

Styrene-butadiene copolymers were analyzed by static secondary ion mass spectrometry (S-SIMS) and laser ablation Fourier transform ion cyclotron resonance mass spectrometry (LA-FTICRMS) to obtain quantitative information based on specific ions. Silver deposition was performed on polystyrene, butadiene rubber and styrene-butadiene rubber. Under these experimental conditions, new secondary ions were detected, in particular silver-cationized butadiene [M(butadiene) - Ag](+) and styrene [M(styrene) - Ag](+) monomers. In contrast, LA-FTICRMS experiments did not require pretreatment. At high laser power density, UV photons (193, 266 and 355 nm) allowed the detection of styrene and butadiene monomers at m/z 104 and 54, respectively. The use of the observed ions by SIMS or LA-FTICRMS ensures that quantitative information on the relative distribution of each monomer is obtained. However, the silver coating thickness in the SIMS experiment seems to have an important influence on the quantitative information obtained. For LA-FTICRMS experiments, the best results are obtained at a wavelength of 355 nm.

Journal Article↗
PubMed2001

Heterogeneous RNA-binding protein M4 is a receptor for carcinoembryonic antigen in Kupffer cells.

Here we report the isolation of the recombinant cDNA clone from rat macrophages, Kupffer cells (KC) that encodes a protein interacting with carcinoembryonic antigen (CEA). To isolate and identify the CEA receptor gene we used two approaches: screening of a KC cDNA library with a specific antibody and the yeast two-hybrid system for protein interaction using as a bait the N-terminal part of the CEA encoding the binding site. Both techniques resulted in the identification of the rat heterogeneous RNA-binding protein (hnRNP) M4 gene. The rat ortholog cDNA sequence has not been previously described. The open reading frame for this gene contains a 2351-base pair sequence with the polyadenylation signal AATAAA and a termination poly(A) tail. The mRNA shows ubiquitous tissue expression as a 2.4-kilobase transcript. The deduced amino acid sequence comprised a 78-kDa membrane protein with 3 putative RNA-binding domains, arginine/methionine/glutamine-rich C terminus and 3 potential membrane spanning regions. When hnRNP M4 protein is expressed in pGEX4T-3 vector system in Escherichia coli it binds (125)I-labeled CEA in a Ca(2+)-dependent fashion. Transfection of rat hnRNP M4 cDNA into a non-CEA binding mouse macrophage cell line p388D1 resulted in CEA binding. These data provide evidence for a new function of hnRNP M4 protein as a CEA-binding protein in Kupffer cells.

Amino Acid Sequence↗
PubMed2001

Mutations in the carcinoembryonic antigen gene in colorectal cancer patients: implications on liver metastasis.

Carcinoembryonic antigen (CEA) expression is used clinically to monitor patients with colorectal and other cancers. A subset of patients have extraordinarily high CEA levels that cannot be attributed solely to tumor load. We have shown mutations in the region of CEA (PELPK motif) responsible for its hepatic clearance in three of eight patients with high CEA levels. We used denaturing high-performance liquid chromatography to provide evidence of polymorphism in these patients. These mutations were scored by DNA cycle sequencing and shown to be heterozygous. The patients with mutations in the PELPK motif showed remarkably reduced circulatory clearance rates in an animal model. A patient without mutation in the region showed normal clearance rates. Mutations in PELPK may affect structural stability and binding affinity to the Kupffer cell receptor in the liver. These studies have implications for the role of CEA as a facilitator of hepatic metastasis.

Amino Acid Sequence↗
PubMed2001

Noninvasive drug delivery.

Advances in biopharmaceutical technology have spawned new drug delivery devices and mechanisms. Noninvasive methods, including iontophoresis and transmucosal drug delivery, have improved treatment of certain patient population. Their use is discussed in the following paper.

Administration, Buccal↗
PubMed2001

Centralization: a new method for the normalization of gene expression data.

Microarrays measure values that are approximately proportional to the numbers of copies of different mRNA molecules in samples. Due to technical difficulties, the constant of proportionality between the measured intensities and the numbers of mRNA copies per cell is unknown and may vary for different arrays. Usually, the data are normalized (i.e., array-wise multiplied by appropriate factors) in order to compensate for this effect and to enable informative comparisons between different experiments. Centralization is a new two-step method for the computation of such normalization factors that is both biologically better motivated and more robust than standard approaches. First, for each pair of arrays the quotient of the constants of proportionality is estimated. Second, from the resulting matrix of pairwise quotients an optimally consistent scaling of the samples is computed.

Computational Biology↗
PubMed2000

Association of an interleukin 1 alpha polymorphism with Alzheimer's disease.

BACKGROUND: Retrospective epidemiologic studies suggest that individuals exposed to anti-inflammatory agents such as nonsteroidal anti-inflammatory drugs have a lower probability of developing AD as well as an older age at onset for the illness. Neuroinflammation may play an important role in the pathogenesis of AD. Interleukin 1 (IL-1), a potent proinflammatory cytokine, is colocalized immunohistochemically to neuritic plaques, a requisite neuropathologic feature for AD. A polymorphism in the 5'-flanking regulatory region at -889 of the IL-1 alpha gene (a C-to-T transition designated as IL-1A[-889] allele 2) may cause an overexpression of IL-1 alpha, a finding shown to be associated with inflammatory diseases. The IL-1A(-889) allele 2 polymorphism may be associated with AD pathogenesis. METHODS: A total of 259 patients with AD and 192 nondemented control subjects were included from two different centers (Indianapolis, IN, and Munich, Germany). Genotyping for APOE alleles and IL-1A(-889) allele 2 was performed by PCR-based amplification followed by restrictive endonuclease digestion. Statistical analyses were conducted by center-, gender group-, and age group-stratified Mantel-Haenszel odds ratios, CI, and p values. RESULTS: The allele frequency of IL-1A(-889) allele 2 was 46% in clinically diagnosed patients with probable AD versus 34% in control subjects from the combined centers. CONCLUSION: The authors found an increased risk for AD with an estimated Mantel-Haenszel odds ratio of 1.68 (95% CI 1.1 to 2.6; p = 0.022) for heterozygous carriers and 7.2 (95% CI 2.0 to 24.5; p = 0.003) for individuals homozygous for IL-1A(-889) allele 2. They found no evidence for an interaction between the IL-1A and the apoE epsilon 4 polymorphisms (carriers and homozygotes), age, or gender with regard to conferred risk. The data strongly support an association between the IL-1A(-889) allele 2, especially in homozygotes, and later-onset AD.

Aged↗
PubMed2000

Alpha2 macroglobulin and the risk of Alzheimer's disease.

BACKGROUND: alpha2 Macroglobulin is a panproteinase inhibitor that is found immunohistochemically in neuritic plaques, a requisite neuropathologic feature of AD. Recently, a pentanucleotide deletion near the 5' end of the "bait region" of the alpha2 macroglobulin (A2M) gene was reported to be associated with AD in a large cohort of sibpairs, in which the mutation conferred a similar odds ratio with AD as the APOE-epsilon4 allele for carriers of at least one copy of the A2M gene (Mantel-Haenszel odds ratio, 3.56). METHODS: We studied three independent association samples of AD patients (n = 309) with an age range of 50 to 94 years and representative controls (n = 281) to characterize the allele frequency of the pentanucleotide deletion in this cohort. We detected the mutation near the 5' splice site of exon 18 using standard PCR and restriction fragment length polymorphism methods. The results were adjusted for age, gender, education, and APOE polymorphism. RESULTS: We found that the A2M gene polymorphism conferred an increased risk for AD, with an estimated Mantel-Haenszel ratio of 1.5 (95% CI 1.1 to 2.2; p = 0.025). There was no age- or gender-dependent increase in A2M gene allele frequencies in AD patients compared with controls. The combined sample showed the expected association between AD and APOE-epsilon 4. In one of our three samples there was an interaction between the A2M and APOE-epsilon4 genes, but the other two samples showed no interaction between the two risk factors. CONCLUSIONS: Our data support an association between the A2M gene and AD. This association is less pronounced, however, in our cohort than in the previously reported sample of sibpairs.

Aged↗
PubMed2000

Effect of adjunctive paroxetine on serum levels and side-effects of tricyclic antidepressants in depressive inpatients.

RATIONALE: Previous studies showed that adjunctive paroxetine increases tricyclic antidepressant (TCA) serum levels by inhibiting cytochrome P4502D6. This effect has, however, been examined only in experimental studies using low doses of TCAs in healthy volunteers. OBJECTIVE: The present study investigated TCA serum level changes and side-effects after the addition of paroxetine in depressed patients treated with doses customarily used for inpatients. METHODS: 14 patients who had a moderate or severe depressive episode according to ICD-10 and who had not sufficiently responded (< or = 25% reduction of the Hamilton depression scale) to 3-week monotherapy with amitriptyline (n = 9) or imipramine (n = 5) with daily doses between 125 and 200 mg/day, received 20 mg/day paroxetine additionally under steady state conditions. RESULTS: After 2 weeks the serum levels of the metabolites nortriptyline (from 88 +/- 49 ng/ml to 176 +/- 57 ng/ml) and desipramine (from 152 +/- 78 ng/ml to 338 +/- 104 ng/ml) had risen to a significantly greater extent than those of the parent compounds amitriptyline (123 +/- 50 ng/ml to 195 +/- 128 ng/ml) and imipramine (from 75 +/- 36 ng/ml to 98 +/- 51 ng/ml). It is noteworthy that, with the exception of one case of incipient delirium, the combination therapy was well tolerated despite high TCA serum level rises. CONCLUSION: The higher increase of the metabolites as compared with the parent compounds can be explained by a paroxetine-induced inhibition of the liver enzyme cytochrome P4502D6, which catalyses the second step of the TCA metabolism, i.e. the hydroxylation of the metabolites. Blood levels should be meticulously monitored, if TCAs are combined with paroxetine.

Antidepressive Agents, Second-Generation↗
PubMed2000

A simple iterative approach to parameter optimization.

Various bioinformatics problems require optimizing several different properties simultaneously. For example, in the protein threading problem, a scoring function combines the values for different parameters of possible sequence-to-structure alignments into a single score to allow for unambiguous optimization. In this context, an essential question is how each property should be weighted. As the native structures are known for some sequences, a partial ordering on optimal alignments to other structures, e.g., derived from structural comparisons, may be used to adjust the weights. To resolve the arising interdependence of weights and computed solutions, we propose a heuristic approach: iterating the computation of solutions (here, threading alignments) given the weights and the estimation of optimal weights of the scoring function given these solutions via systematic calibration methods. For our application (i.e., threading), this iterative approach results in structurally meaningful weights that significantly improve performance on both the training and the test data sets. In addition, the optimized parameters show significant improvements on the recognition rate for a grossly enlarged comprehensive benchmark, a modified recognition protocol as well as modified alignment types (local instead of global and profiles instead of single sequences). These results show the general validity of the optimized weights for the given threading program and the associated scoring contributions.

Algorithms↗
PubMed2000

Protein structure prediction methods for drug design.

Along the long path from genomic data to a new drug, the knowledge of three-dimensional protein structure can be of significant help in several places. This paper points out such places, discusses the virtues of protein structure knowledge and reviews bioinformatics methods for gaining such knowledge on the protein structure.

Computational Biology↗
PubMed2000

Pathway analysis in metabolic databases via differential metabolic display (DMD).

MOTIVATION: A number of metabolic databases are available electronically, some with features for querying and visualizing metabolic pathways and regulatory networks. We present a unifying, systematic approach based on PETRI nets for storing, displaying, comparing, searching and simulating such nets from a number of different sources. RESULTS: Information from each data source is extracted and compiled into a PETRI net. Such PETRI nets then allow to investigate the (differential) content in metabolic databases, to map and integrate genomic information and functional annotations, to compare sequence and metabolic databases with respect to their functional annotations, and to define, generate and search paths and pathways in nets. We present an algorithm to systematically generate all pathways satisfying additional constraints in such PETRI nets. Finally, based on the set of valid pathways, so-called differential metabolic displays (DMDs) are introduced to exhibit specific differences between biological systems, i.e. different developmental states, disease states, or different organisms, on the level of paths and pathways. DMDs will be useful for target finding and function prediction, especially in the context of the interpretation of expression data.

Algorithms↗
PubMed2000

Analysis of gene expression data with pathway scores.

We present a new approach for the evaluation of gene expression data. The basic idea is to generate biologically possible pathways and to score them with respect to gene expression measurements. We suggest sample scoring functions for different problem specifications. We assess the significance of the scores for the investigated pathways by comparison to a number of scores for random pathways. We show that simple scoring functions can assign statistically significant scores to biologically relevant pathways. This suggests that the combination of appropriate scoring functions with the systematic generation of pathways can be used in order to select the most interesting pathways based on gene expression measurements.

Animals↗
PubMed2000

Velocities, shear stresses and blood damage potential of the leakage jets of the Medtronic Parallel bileaflet valve.

Even nowadays, the essential problem of mechanical heart valve prostheses is the risk of thromboembolic events mainly caused by unnatural hemodynamics, e.g. just a few years ago the Medtronic Parallel (MP) showed unsatisfactory clinical results caused by thrombi. Therefore, in vitro investigations of the whole leakage jets were performed at the MP in mitral position by means of a pulse duplicator using a two channel laser Doppler anemometer. From the measured data, mean velocity profiles and the distribution of Reynolds shear stresses, as a function of the location within the jet, were calculated. From this data the potential of blood damage is evaluated computing a Blood Damage Index (BDI) of hemolysis and platelet damage. Four regurgitant free jets right above the hinges were observed during systole at the inflow side of the MP. The peak velocities at the origin of the jets were in the order of 1.6-2.1 m/s. Two jets experienced maximum turbulent shear stresses around 100 N/m2 within this area. The BDI for platelets of the MP is around ten times higher than the BDI of the St.-Jude-Medical. The study shows that besides the flow structure within the hinges of a mechanical heart valve, the whole regurgitant jet has a large blood damage potential. This potential is measurable, respectively calculable and seems to be (on account of it's support of the clinical outcome) one piece of the puzzle that explains the negative trials of the MP.

Blood Flow Velocity↗