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Biomedical subjects

D Walther

Publications and source records attributed to D Walther.

At least 19 recordsLinked to original sources
PubMed2007

Randomised controlled trials of homeopathy in hyperactive children: treatment procedure leads to an unconventional study design. Experience with open-label homeopathic treatment preceding the Swiss ADHD placebo controlled, randomised, double-blind, cross-over trial.

BACKGROUND: Treatment of patients with attention deficit hyperactivity disorder (ADHD) with homeopathy is difficult. The Swiss randomised, placebo controlled, cross-over trial in ADHD patients (Swiss ADHD trial) was designed with an open-label screening phase prior to the randomised controlled phase. During the screening phase, the response of each child to successive homeopathic medications was observed until the optimal medication was identified. Only children who reached a predefined level of improvement participated in the randomised, cross-over phase. Although the randomised phase revealed a significant beneficial effect of homeopathy, the cross-over caused a strong carryover effect diminishing the apparent difference between placebo and verum treatment. METHODS: This retrospective analysis explores the screening phase data with respect to the risk of failure to demonstrate a specific effect of a randomised controlled trial (RCT) with randomisation at the start of the treatment. RESULTS: During the screening phase, 84% (70/83) of the children responded to treatment and reached eligibility for the randomised trial after a median time of 5 months (range 1-18), with a median of 3 different medications (range 1-9). Thirteen children (16%) did not reach eligibility. Five months after treatment start, the difference in Conners Global Index (CGI) rating between responders and non-responders became highly significant (p = 0.0006). Improvement in CGI was much greater following the identification of the optimal medication than in the preceding suboptimal treatment period (p < 0.0001). CONCLUSIONS: Because of the necessity of identifying an optimal medication before response to treatment can be expected, randomisation at the start of treatment in an RCT of homeopathy in ADHD children has a high risk of failure to demonstrate a specific treatment effect, if the observation time is shorter than 12 months.

Adolescent↗
PubMed2006

Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling.

Rejection diagnosis by endomyocardial biopsy (EMB) is invasive, expensive and variable. We investigated gene expression profiling of peripheral blood mononuclear cells (PBMC) to discriminate ISHLT grade 0 rejection (quiescence) from moderate/severe rejection (ISHLT > or = 3A). Patients were followed prospectively with blood sampling at post-transplant visits. Biopsies were graded by ISHLT criteria locally and by three independent pathologists blinded to clinical data. Known alloimmune pathways and leukocyte microarrays identified 252 candidate genes for which real-time PCR assays were developed. An 11 gene real-time PCR test was derived from a training set (n = 145 samples, 107 patients) using linear discriminant analysis (LDA), converted into a score (0-40), and validated prospectively in an independent set (n = 63 samples, 63 patients). The test distinguished biopsy-defined moderate/severe rejection from quiescence (p = 0.0018) in the validation set, and had agreement of 84% (95% CI 66% C94%) with grade ISHLT > or = 3A rejection. Patients >1 year post-transplant with scores below 30 (approximately 68% of the study population) are very unlikely to have grade > or = 3A rejection (NPV = 99.6%). Gene expression testing can detect absence of moderate/severe rejection, thus avoiding biopsy in certain clinical settings. Additional clinical experience is needed to establish the role of molecular testing for clinical event prediction and immunosuppression management.

Adolescent↗
PubMed2005

Observation of in-medium modifications of the omega meson.

The photoproduction of omega mesons on nuclei has been investigated using the Crystal Barrel/TAPS experiment at the ELSA tagged photon facility in Bonn. The aim is to study possible in-medium modifications of the omega meson via the reaction gamma + A --> omega + X --> pi(0)gamma + X('). Results obtained for Nb are compared to a reference measurement on a LH2 target. While for recoiling, long-lived mesons (pi(0), eta, and eta;(')), which decay outside of the nucleus, a difference in the line shape for the two data samples is not observed, we find a significant enhancement towards lower masses for omega mesons produced on the Nb target. For momenta less than 500 MeV/c an in-medium omega meson mass of M(medium) = [722(+4)(-4)(stat)+35-5(syst)] MeV/c(2) has been deduced at an estimated average nuclear density of 0.6rho(0).

Journal Article↗
PubMed2005

Neutral-pion photoproduction off protons in the energy range 0.3 GeV<E(gamma)<3 GeV.

Single pi(0) photoproduction has been studied with the CB-ELSA experiment at Bonn using tagged photon energies between 0.3 and 3.0 GeV. The experimental setup covers a very large solid angle of approximately 98% of 4pi. Differential cross sections dsigma/dOmega have been measured. Complicated structures in the angular distributions indicate a variety of different resonances being produced in the s channel intermediate state gammap-->N(*)(Delta(*))-->ppi(0). A combined analysis including the data presented in this letter along with other data sets reveals contributions from known resonances and evidence for a new resonance N(2070)D15.

Journal Article↗
PubMed2005

Photoproduction of eta mesons off protons for 0.75 GeV<E(gamma)<3 GeV.

Total and differential cross sections for the reaction p(gamma,eta)p have been measured for photon energies in the range from 750 MeV to 3 GeV. The low-energy data are dominated by the S11 wave which has two poles in the energy region below 2 GeV. Eleven nucleon resonances are observed in their decay into peta. At medium energies we find evidence for a new resonance N(2070)D15 with (M,Gamma)=(2068+/-22, 295+/-40) MeV. At gamma energies above 1.5 GeV, a strong peak in the forward direction develops, signaling the exchange of vector mesons in the t channel.

Journal Article↗
PubMed2004

Human cannabinoid receptor 1: 5' exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse.

A number of lines of evidence make the gene that encodes the G-protein-coupled CB1/Cnr1 receptor a strong candidate to harbor variants that might contribute to individual differences in human addiction vulnerability. The CB1/Cnr1 receptor is the major brain site at which cannabinoid marijuana constituents are psychoactive as well as the principal brain receptor for endogenous anandamide ligands. It is densely expressed in brain circuits likely to be important for both the reward and mnemonic processes important for addiction. Altered drug effects in CB1/Cnr1 knockout mice and initial association studies also make variants at the CB1/Cnr1 locus candidates for roles in human vulnerabilities to addictions. However, many features of this gene's structure, regulation and variation remain poorly defined. This poor definition has limited the ability of previous association studies to adequately sample variation at this locus. We now report improved definition of the human CB1/Cnr1 locus and its variants. Novel exons 1-3, splice variant and candidate promoter region sequences add to the richness of the CB1/Cnr1 locus. Candidate promoter region sequences confer reporter gene expression in cells that express CB1/Cnr1. Common polymorphisms reveal patterns of linkage disequilibrium in European- and in African-American individuals. A 5' CB1/Cnr1 "TAG" haplotype displays significant allelic frequency differences between substance abusers and controls in European-American, African-American and Japanese samples. Post-mortem brain samples of heterozygous individuals contain less mRNA transcribed from the TAG alleles than from other CB1/Cnr1 haplotypes. CB1/ Cnr1 genomic variation thus appears to play roles in human addiction vulnerability.

Black or African American↗
PubMed2001

Reversible fixation of carbon dioxide at nickel(0) centers: a route for large organometallic rings, dimers, and tetramers.

The reaction between bis(cycloocta-1,5-diene)nickel(0), carbon dioxide and benzaldehyde-N-furfurylideneimine (A) in 1,4-dioxane or THF results in the formation of the 24-membered organometallic macrocycles of the type [(A)Ni(-CH(R1)-N(R2)-COO-)]6(solv)n (R1: phenyl, R2: furfurylidene, solv: 1,4-dioxane in 1a, THF in 1b). According to the X-ray analyses, six monomeric nickelacyclic units are connected through six Ni-mu2-OCO-Ni bridges in these macrocycles. The cavities of the metallomacrocycles (diameter: 9.410(1) A in 1a, 9.250(1) A in 1b) each contain one solvent molecule. Reaction of 1b with Me3P results in the displacement of the peripheral ligands A by the phosphine to form the 24-membered organometallic macrocycle 1c. Both 1a and 1b isomerize in benzene to form the dimeric complex [(A)Ni(-CH(R1)-N(R2)-COO-)]2(solv)n (2). The X-ray crystal structure reveals that 2 consists of the same monomeric units as found in 1a and 1b. However two Ni-mu2-O-Ni bonds link the carboxylato groups. The solvent-dependent isomerization of 1b yielding 2 is a reversible reaction. Furthermore, the macrocycle 1b partially eliminates carbon dioxide above 20 degrees C, followed by elimination of half of the monodentately coordinated Schiff base ligands to form the planar tetrameric complex 6. This is also a reversible process.

Carbon Dioxide↗
PubMed2001

Polysubstance abuse-vulnerability genes: genome scans for association, using 1,004 subjects and 1,494 single-nucleotide polymorphisms.

Strong genetic contributions to drug abuse vulnerability are well documented, but few chromosomal locations for human drug-abuse vulnerability alleles have been confirmed. We now identify chromosomal markers whose alleles distinguish drug abusers from control individuals in each of two samples, on the basis of pooled-sample microarray and association analyses. Reproducibly positive chromosomal regions defined by these markers in conjunction with previous results were especially unlikely to have been identified by chance. Positive markers identify the alcohol dehydrogenase (ADH) locus, flank the brain-derived neurotropic factor (BDNF) locus, and mark seven other regions previously linked to vulnerability to nicotine or alcohol abuse. These data support polygenic contributions of common allelic variants to polysubstance abuse vulnerability.

Adult↗
PubMed2001

Dopaminergic mRNA expression in the intact substantia nigra of unilaterally 6-OHDA-lesioned and grafted rats: an in situ hybridization study.

The present study was performed to investigate the influence of intrastriatal fetal mesencephalic grafts on dopaminergic mRNA expression in the non-lesioned substantia nigra pars compacta of unilaterally 6-hydroxydopamine-lesioned rats. The expression of dopamine transporter mRNA, synaptic vesicular monoamine transporter mRNA and tyrosine hydroxylase mRNA was assessed in adjacent cryostat sections using in situ hybridization. Rotational behavior induced by apomorphine and amphetamine as well as hybridization of striatal sections cut at the grafting coordinates were used to prove the functional recovery and the presence of grafted cells, respectively. After grafting, the number of rotations was decreased and hybridization signals overlying cells in the grafted striatum were detected. Mean grain densities overlying labeled neurons in the substantia nigra pars compacta of grafted rats were compared to those of shamgrafted rats and revealed differential expression of dopamine transporter mRNA, whereas synaptic vesicular monoamine transporter mRNA and tyrosine hydroxylase mRNA expression showed no difference. The results will be discussed in relation to previous in vitro and in vivo studies suggesting a reduction of functional dopamine transporter molecules in the contralateral striatum.

Animals↗
PubMed2001

Basecalling with LifeTrace.

A pivotal step in electrophoresis sequencing is the conversion of the raw, continuous chromatogram data into the actual sequence of discrete nucleotides, a process referred to as basecalling. We describe a novel algorithm for basecalling implemented in the program LifeTrace. Like Phred, currently the most widely used basecalling software program, LifeTrace takes processed trace data as input. It was designed to be tolerant to variable peak spacing by means of an improved peak-detection algorithm that emphasizes local chromatogram information over global properties. LifeTrace is shown to generate high-quality basecalls and reliable quality scores. It proved particularly effective when applied to MegaBACE capillary sequencing machines. In a benchmark test of 8372 dye-primer MegaBACE chromatograms, LifeTrace generated 17% fewer substitution errors, 16% fewer insertion/deletion errors, and 2.4% more aligned bases to the finished sequence than did Phred. For two sets totaling 6624 dye-terminator chromatograms, the performance improvement was 15% fewer substitution errors, 10% fewer insertion/deletion errors, and 2.1% more aligned bases. The processing time required by LifeTrace is comparable to that of Phred. The predicted quality scores were in line with observed quality scores, permitting direct use for quality clipping and in silico single nucleotide polymorphism (SNP) detection. Furthermore, we introduce a new type of quality score associated with every basecall: the gap-quality. It estimates the probability of a deletion error between the current and the following basecall. This additional quality score improves detection of single basepair deletions when used for locating potential basecalling errors during the alignment. We also describe a new protocol for benchmarking that we believe better discerns basecaller performance differences than methods previously published.

Algorithms↗
PubMed2000

Solution structural studies and low-resolution model of the Schizosaccharomyces pombe sap1 protein.

Sap1 is a DNA-binding protein involved in controlling the mating type switch in fission yeast Schizosaccharomyces pombe. In the absence of any significant sequence similarity with any structurally known protein, a variety of biophysical techniques has been used to probe the solution low-resolution structure of the sap1 protein. First, sap1 is demonstrated to be an unusually elongated dimer in solution by measuring the translational diffusion coefficient with two independent techniques: dynamic light-scattering and ultracentrifugation. Second, sequence analysis revealed the existence of a long coiled-coil region, which is responsible for dimerization. The length of the predicted coiled-coil matches estimates drawn from the hydrodynamic experimental behaviour of the molecule. In addition, the same measurements done on a shorter construct with a coiled-coil region shortened by roughly one-half confirmed the localization of the long coiled-coil region. A crude T-shape model incorporating all these information was built. Third, small-angle X-ray scattering (SAXS) of the free molecule provided additional evidence for the model. In particular, the P(r) curve strikingly demonstrates the existence of long intramolecular distances. Using a novel 3D reconstruction algorithm, a low resolution 3D model of the protein has been independently constructed that matches the SAXS experimental data. It also fits the translation diffusion coefficients measurements and agrees with the first T-shaped model. This low-resolution model has clearly biologically relevant new functional implications, suggesting that sap1 is a bifunctional protein, with the two active sites being separated by as much as 120 A; a tetrapeptide repeated four times at the C terminus of the molecule is postulated to be of utmost functional importance.

Algorithms↗
PubMed2000

Co-evolution of proteins with their interaction partners.

The divergent evolution of proteins in cellular signaling pathways requires ligands and their receptors to co-evolve, creating new pathways when a new receptor is activated by a new ligand. However, information about the evolution of binding specificity in ligand-receptor systems is difficult to glean from sequences alone. We have used phosphoglycerate kinase (PGK), an enzyme that forms its active site between its two domains, to develop a standard for measuring the co-evolution of interacting proteins. The N-terminal and C-terminal domains of PGK form the active site at their interface and are covalently linked. Therefore, they must have co-evolved to preserve enzyme function. By building two phylogenetic trees from multiple sequence alignments of each of the two domains of PGK, we have calculated a correlation coefficient for the two trees that quantifies the co-evolution of the two domains. The correlation coefficient for the trees of the two domains of PGK is 0. 79, which establishes an upper bound for the co-evolution of a protein domain with its binding partner. The analysis is extended to ligands and their receptors, using the chemokines as a model. We show that the correlation between the chemokine ligand and receptor trees' distances is 0.57. The chemokine family of protein ligands and their G-protein coupled receptors have co-evolved so that each subgroup of chemokine ligands has a matching subgroup of chemokine receptors. The matching subfamilies of ligands and their receptors create a framework within which the ligands of orphan chemokine receptors can be more easily determined. This approach can be applied to a variety of ligand and receptor systems.

Chemokines↗
PubMed2000

Detection of C-type natriuretic peptide in fetal circulation.

C-type natriuretic peptide (CNP) belongs to the natriuretic peptide family that plays an important role in the control of blood pressure, renal function and volume homeostasis. In contrast to the atrial natriuretic peptide and brain natriuretic peptide, CNP acts in an autocrine/paracrine fashion and is considered to be the endothelial component of the natriuretic peptide system. CNP has a high expression and tissue-specific regulation in reproductive organs. Using a radio-immunoassy for CNP-22 we measured for the first time CNP in fetal blood. Samples were taken by cordocentesis in a group of fetuses with rhesus isoimmunisation (10.74 +/- 2.81 pg/ml), fetuses with rhesus isoimmunisation after intravascular transfusion (10.03 +/- 4.01 pg/ml) and a group with structural anomalies (12.9 +/- 5.67 pg/ml). A group of healthy fetuses was used as controls (11.64 +/- 4.32 pg/ml). In contrast to ANP, the fetal CNP-plasma concentrations remain stable in the investigated fetal diseases and after volume load during intravascular transfusion. Moreover, fetal CNP-plasma levels are higher than previously measured maternal concentrations in normal pregnancies. Therefore, the fetus expresses CNP independently of the maternal circulation.

Blood Transfusion, Intrauterine↗
PubMed1999

A molecular scanner to automate proteomic research and to display proteome images.

Identification and characterization of all proteins expressed by a genome in biological samples represent major challenges in proteomics. Today's commonly used high-throughput approaches combine two-dimensional electrophoresis (2-DE) with peptide mass fingerprinting (PMF) analysis. Although automation is often possible, a number of limitations still adversely affect the rate of protein identification and annotation in 2-DE databases: the sequential excision process of pieces of gel containing protein; the enzymatic digestion step; the interpretation of mass spectra (reliability of identifications); and the manual updating of 2-DE databases. We present a highly automated method that generates a fully annoated 2-DE map. Using a parallel process, all proteins of a 2-DE are first simultaneously digested proteolytically and electro-transferred onto a poly(vinylidene difluoride) membrane. The membrane is then directly scanned by MALDI-TOF MS. After automated protein identification from the obtained peptide mass fingerprints using PeptIdent software (http://www.expasy.ch/tools/peptident.html + ++), a fully annotated 2-D map is created on-line. It is a multidimensional representation of a proteome that contains interpreted PMF data in addition to protein identification results. This "MS-imaging" method represents a major step toward the development of a clinical molecular scanner.

Automation↗
PubMed1999

An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3.

Steroid hormones may enter cells by diffusion through the plasma membrane. However, we demonstrate here that some steroid hormones are taken up by receptor-mediated endocytosis of steroid-carrier complexes. We show that 25-(OH) vitamin D3 in complex with its plasma carrier, the vitamin D-binding protein, is filtered through the glomerulus and reabsorbed in the proximal tubules by the endocytic receptor megalin. Endocytosis is required to preserve 25-(OH) vitamin D3 and to deliver to the cells the precursor for generation of 1,25-(OH)2 vitamin D3, a regulator of the calcium metabolism. Megalin-/- mice are unable to retrieve the steroid from the glomerular filtrate and develop vitamin D deficiency and bone disease.

Animals↗
PubMed1999

Two-dimensional electrophoresis resources available from ExPASy.

This paper describes the set of two-dimensional electrophoresis (2-DE) resources currently available from the ExPASy proteomics Web server. These resources include the SWISS-2DPAGE database, 2-DE software packages, 2-DE technical and educational services, as well as indexes and search engines for 2-DE related sites over the Internet.

Databases, Factual↗
PubMed1999

C-type natriuretic peptide levels in women with gestational hypertension and preeclampsia.

OBJECTIVE: To measure plasma levels of C-type natriuretic peptide in women with normal pregnancies and those complicated by gestational hypertension and preeclampsia. METHODS: We collected venous plasma samples from 20 women with normal pregnancies, 15 with gestational hypertension, and nine with preeclampsia. Gestational ages ranged from 26-39 weeks. We measured C-type natriuretic peptide concentrations by radioimmunoassay. Statistical comparisons were made by one-way analysis of variance and Tukey test. RESULTS: The mean plasma concentration of C-type natriuretic peptide in the women with normal pregnancy was 7.1 +/-2.5 pg/mL, in those with gestational hypertension 9.6+/-4.2 pg/mL, and in those with preeclampsia 8.1+/-2.4 pg/mL. There were no statistically significant differences between groups. The statistical power to detect a difference of 3 pg/mL at the 5% significance level was 78% for the group with gestational hypertension and 64% for the preeclamptic group. CONCLUSION: Our results suggest that C-type natriuretic peptide plasma levels are not significantly different in normal pregnancies and those complicated by gestational hypertension or preeclampsia. In hypertensive pregnancy disorders, C-type natriuretic peptide showed a distinct course compared with atrial natriuretic peptide and brain natriuretic peptide.

Adult↗