PubMed Health⌕ Search

Biomedical subjects

Norbert Müller

Publications and source records attributed to Norbert Müller.

At least 19 recordsLinked to original sources
PubMed2006

PCR-based diagnosis of Naegleria sp. infection in formalin-fixed and paraffin-embedded brain sections.

We developed a real-time PCR which allowed the highly sensitive detection of Naegleria fowleri in histological brain tissue sections from experimentally infected mice. This genus-specific small-subunit (18S) rRNA gene-based PCR can complement conventional (immuno-) histology for the diagnosis of primary amoebic meningoencephalitis in paraffin-embedded brain necropsy specimens that had been fixed in formalin buffered with phosphate-buffered saline.

Amebiasis↗
PubMed2006

Structure-activity relationships from in vitro efficacies of the thiazolide series against the intracellular apicomplexan protozoan Neospora caninum.

Nitazoxanide (2-acetolyloxy-N-(5-nitro 2-thiazolyl) benzamide; NTZ) represents the parent compound of a novel class of broad-spectrum anti-parasitic compounds named thiazolides. NTZ is active against a wide variety of intestinal and tissue-dwelling helminths, protozoa, enteric bacteria and a number of viruses infecting animals and humans. While potent, this poses a problem in practice, since this obvious non-selectivity can lead to undesired side effects in both humans and animals. In this study, we used real time PCR to determine the in vitro activities of 29 different thiazolides (NTZ-derivatives), which carry distinct modifications on both the thiazole- and the benzene moieties, against the tachyzoite stage of the intracellular protozoan Neospora caninum. The goal was to identify a highly active compound lacking the undesirable nitro group, which would have a more specific applicability, such as in food animals. By applying self-organizing molecular field analysis (SOMFA), these data were used to develop a predictive model for future drug design. SOMFA performs self-alignment of the molecules, and takes into account the steric and electrostatic properties, in order to determine 3D-quantitative structure activity relationship models. The best model was obtained by overlay of the thiazole moieties. Plotting of predicted versus experimentally determined activity produced an r2 value of 0.8052 and cross-validation using the "leave one out" methodology resulted in a q2 value of 0.7987. A master grid map showed that large steric groups at the R2 position, the nitrogen of the amide bond and position Y could greatly reduce activity, and the presence of large steric groups placed at positions X, R4 and surrounding the oxygen atom of the amide bond, may increase the activity of thiazolides against Neospora caninum tachyzoites. The model obtained here will be an important predictive tool for future development of this important class of drugs.

Animals↗
PubMed2006

Investigating disease susceptibility and the negative correlation of schizophrenia and rheumatoid arthritis focusing on MIF and CD14 gene polymorphisms.

Schizophrenia and rheumatoid arthritis (RA) are both chronic diseases with an estimated genetic component of 60%. While RA is a well-known autoimmune inflammatory joint disease, recent data point to an active immune process also being involved in schizophrenia. Several studies confirmed the negative association between schizophrenia and RA, indicating genetic factors that predispose to the one disorder, while protecting from the other. Macrophage migration inhibitory factor (MIF) and the monocytes surface receptor CD14 are involved in the development and maintenance of chronic inflammation. We therefore investigated if the -G173C single nucleotide polymorphism (SNP) and the tetranucleotide repeat CATT (5 - 8) at position -794 of the MIF gene and the CD14 - C159T transition are candidates for genetic liability to schizophrenia and RA or could explain the negative association between them. In our study 157 schizophrenic patients, 119 patients suffering from RA, and 225 healthy individuals were genotyped. All subjects were Caucasians. The CD14- and MIF-genotypes were equally distributed in all three groups. From our results, we cannot confirm the hypothesis that the investigated genetic mutations within the MIF and/or the CD14 gene are involved in the aetiology of either disease or could explain the negative correlation of schizophrenia and RA.

Adolescent↗
PubMed2006

Is there a role of the Thr164Ile-beta(2)-adrenoceptor polymorphism for the outcome of chronic heart failure?

OBJECTIVE: The Thr164Ile-beta(2)-adrenoceptor (AR) polymorphism exhibits lower affinities for catecholamines and reduced basal and agonist-stimulated adenylyl cyclase activity in vitro. It has been suggested that patients with chronic heart failure (CHF) due to ischemic or dilated cardiomyopathy carrying the Thr164Ile-beta(2)AR polymorphism exhibit much more rapid progression to death or heart transplantation (HTX) than CHF-patients carrying the homozygous Thr164-beta(2)AR. This study aimed to further evaluate the role of the Thr164Ile-beta(2)AR in CHF. For this we hypothesized that the Thr164Ile-beta(2)AR variant should be more abundant in HTX-patients than in patients with stable CHF or healthy controls. METHODS AND RESULTS: We genotyped 309 HTX-patients, 520 stable CHF-patients and 328 healthy controls for the three beta(2)AR variants Arg16Gly, Gln27Glu and Thr164Ile. The prevalence of the Thr164Ile-beta(2)AR variant was not considerably different in HTX-patients (2.3%) from that in CHF-patients (1.9%) or healthy controls (2.1%). Similarly, the frequency of the minor Ile164-allele was f(-)=0.0106 in HTX-patients, f(-)=0.0096 in CHF-patients and f(-)=0.0113 in healthy controls. CONCLUSIONS: The prevalence of the hypofunctional Thr164Ile-beta(2)AR variant and the frequency of the Ile164-allele were almost identical in CHF-patients, who had undergone HTX, with those in patients with stable CHF or in healthy controls. Thus, the role of the Thr164Ile-beta(2)AR in CHF remains questionable.

Adolescent↗
PubMed2006

Cogwheel phase cycling in common triple resonance NMR experiments for the liquid phase.

We demonstrate that cogwheel phase cycling, which was previously only used in solid state NMR, can be applied to optimize the efficiency of commonly used pulse sequences in multiple resonance liquid-state biomolecular NMR. In favorable cases the required minimum number of scans can be reduced by more than 80% as compared to a corresponding sequence with nested phase cycles. Since cogwheel phase cycling procedures can be designed for a range of scan numbers, and can be combined with pulsed field gradients, the total experiment time can be adjusted closely to the required signal-to-noise ratio with minimal overhead. Examples are shown for 3D-TROSY-HNCO, 3D-TROSY-HNCACO, and 3D-HACACO experiments on diamagnetic and paramagnetic proteins.

Algorithms↗
PubMed2006

Nuclear spin noise imaging.

NMR images were obtained from the proton spin noise signals of a water-containing phantom, which was placed in the highly tuned, low-noise resonant circuit of a cryogenically cooled NMR probe in the presence of systematically varied magnetic field gradients. The spatially resolved proton spin density was obtained from the raw signal by a modified projection-reconstruction protocol. Although spin noise imaging is inherently less sensitive than conventional magnetic resonance imaging, it affords an entirely noninvasive visualization of the interior of opaque objects or subjects. Thus, tomography becomes possible even when neither x-ray nor radio frequency radiation can be applied for technical or safety reasons.

Humans↗
PubMed2006

Apparatus for rapid adjustment of the degree of alignment of NMR samples in aqueous media: verification with residual quadrupolar splittings in (23)Na and (133)Cs spectra.

NMR spectra of (23)Na(+) and (133)Cs(+) in gelatine in a silicone rubber tube that was stretched to various extents showed remarkably reproducible resonance multiplicity. The relative intensities of the components of the split peaks had ratios, 3:4:3, and 7:12:15:16:15:12:7, respectively, that conformed with those predicted using a Mathematica program. The silicone-rubber tube was sealed at its lower end by a small rubber stopper and placed inside a thick-walled glass tube. Gelatine was injected in solution into the silicone tube and 'set' by cooling below 30 degrees C. A plastic thumb-screw held the silicone tube at various degrees of extension, up to approximately 2-fold. After constituting the gel in buffers containing NaCl and CsCl, both (23)Na and (133)Cs NMR spectroscopy revealed that after stretching the initial single Lorentzian line was split into a well-resolved triplet and a heptet, respectively. This was interpreted as being due to coupling between the electric quadrupoles of the nuclei and the average electric field gradient tensor of the collagen molecules of gelatine; these molecules became progressively more aligned in the direction of the main magnetic field, B(0), of the vertical bore magnet, as the gel was stretched. This apparatus provides a simple way of demonstrating fundamental physical characteristics of quadrupolar cations, some characteristics of gelatine under stretching, and a way to invoke static distortion of red blood cells. It should be useful with these and other cell types, for studies of metabolic and membrane transport characteristics that may change when the cells are distorted, and possibly for structural studies of macromolecules.

Artifacts↗
PubMed2006

The GNAS1 T393C polymorphism predicts survival in patients with clear cell renal cell carcinoma.

PURPOSE: G proteins mediate signaling from cell surface receptors to specific intracellular proteins. In vitro cancer cell line studies revealed a link between the Galphas protein and proapoptotic processes. We have recently shown that TT genotypes of the GNAS1 T393C polymorphism display increased transcription of Galphas and a more favorable clinical course in bladder and colorectal cancer patients compared both with TC or CC genotypes. EXPERIMENTAL DESIGN: In the present study, 150 patients with clear cell renal cell carcinoma surgically treated by nephrectomy with curative intent were retrospectively genotyped to elucidate a potential association between T393C genotypes and clinical outcome. RESULTS: The C-allele frequency in the renal cell carcinoma patient group was 0.51, which is not significantly different from that of a healthy blood donor group. Kaplan-Meier curves for tumor progression, development of metastasis, and tumor-related death showed a significant association of the T393C polymorphism with outcome (5-year cancer-specific survival rates: TT, 91%; TC, 81%; CC, 69%; P = 0.015). Multivariate Cox proportional analysis of a 10-year follow-up confirmed the T393C polymorphism as an independent prognostic factor in clear cell renal cell carcinoma. Homozygous CC patients were at highest risk for progression (hazard ratio, 2.48; P = 0.009) or tumor-related death (hazard ratio, 3.15; P = 0.018) compared with T-allele carriers. CONCLUSION: Our results show that besides tumor stage, lymph node status, and tumor grade, the GNAS1 T393C status is a novel independent host factor for disease progression in patients with clear cell renal cell carcinoma and provides further evidence for the T393C polymorphism as a general prognostic tumor marker.

Carcinoma, Renal Cell↗
PubMed2006

Decreased T cellular immune response in schizophrenic patients.

The involvement of an alteration of the immune system in the pathogenesis of schizophrenia is discussed since many years. In particular, in vitro studies give evidence that the T helper-1 (Th1) mediated cellular immune response is deficient in schizophrenia. We therefore hypothesized that the type-IV delayed skin hypersensitivity reaction, which is effected by the Th1 immune response, is attenuated in schizophrenia patients. A prospective case-control study was performed to assess skin reactivity of 30 patients vs. 30 age and sex matched healthy controls. A standardized device with seven different antigens (Multitest Immignost) was applied intracutaneously; after 48h, the skin reactions were quantified. In general, the mean skin reaction of the schizophrenic patients were significantly smaller as compared to the healthy control group. Moreover, significantly more schizophrenic patients showed a diminished skin reaction to distinct antigens. Our findings demonstrate a markedly attenuated in vivo type-1 mediated cellular immune response in schizophrenic patients, further confirming the hypothesis of a relative Th2 shift in schizophrenia.

Adult↗
PubMed2006

In vitro effects of thiazolides on Giardia lamblia WB clone C6 cultured axenically and in coculture with Caco2 cells.

The thiazolides represent a novel class of anti-infective drugs, with the nitrothiazole nitazoxanide [2-acetolyloxy-N-(5-nitro 2-thiazolyl) benzamide] (NTZ) as the parent compound. NTZ exhibits a broad spectrum of activities against a wide variety of helminths, protozoa, and enteric bacteria infecting animals and humans. In vivo, NTZ is rapidly deacetylated to tizoxanide (TIZ), which exhibits similar activities. We have here comparatively investigated the in vitro effects of NTZ, TIZ, a number of other modified thiazolides, and metronidazole (MTZ) on Giardia lamblia trophozoites grown under axenic culture conditions and in coculture with the human cancer colon cell line Caco2. The modifications of the thiazolides included, on one hand, the replacement of the nitro group on the thiazole ring with a bromide, and, on the other hand, the differential positioning of methyl groups on the benzene ring. Of seven compounds with a bromo instead of a nitro group, only one, RM4820, showed moderate inhibition of Giardia proliferation in axenic culture, but not in coculture with Caco2 cells, with a 50% inhibitory concentration (IC50) of 18.8 microM; in comparison, NTZ and tizoxanide had IC50s of 2.4 microM, and MTZ had an IC50 of 7.8 microM. Moreover, the methylation or carboxylation of the benzene ring at position 3 resulted in a significant decrease of activity, and methylation at position 5 completely abrogated the antiparasitic effect of the nitrothiazole compound. Trophozoites treated with NTZ showed distinct lesions on the ventral disk as soon as 2 to 3 h after treatment, whereas treatment with metronidazole resulted in severe damage to the dorsal surface membrane at later time points.

Animals↗
PubMed2006

Neuroimmune-endocrine crosstalk in schizophrenia and mood disorders.

This review focuses on possible causes and the impact of different immune states in schizophrenia and major depression. It discusses the fact that, in schizophrenia, an over-activation of the type 2 immune response may dominate, while the type 1 and the pro-inflammatory immune responses are over-activated in major depression. The consequence of these diverse immune states is the activation and, respectively, inhibition of different enzymes in tryptophan/kynurenine metabolism, which may lead to an overemphasis of N-methyl-D-aspartate (NMDA) receptor antagonism in schizophrenia and of NMDA-receptor agonism in depression, resulting in glutamatergic hypofunction in schizophrenia and glutamatergic hyperfunction in major depression. In addition, the activation of the type 1 and the pro-inflammatory immune responses in major depression result in increased serotonin degradation and a serotonergic deficit. While antipsychotics and antidepressants today mainly act on the dopaminergic-glutamatergic and the noradrenergic-serotonergic neurotransmission, anti-inflammatory and immune-modulating therapies might act more basically at the pathophysiological mechanism. The limitations of this concept, however, are critically discussed.

Animals↗
PubMed2005

Quetiapine has equivalent efficacy and superior tolerability to risperidone in the treatment of schizophrenia with predominantly negative symptoms.

Atypical antipsychotics are generally thought to be more effective than conventional agents in treating the negative symptoms of schizophrenia; however, there have been few direct comparisons among atypicals. We therefore investigated risperidone and quetiapine with respect to their efficacy against negative symptoms in a 12-week,double-blind, comparative pilot study involving 44 patients with schizophrenia with predominantly negative symptoms, as defined by Positive and Negative Syndrome Scale (PANSS) scores. Other efficacy measures included the Scale for the Assessment of Negative Symptoms (SANS) and the Clinical Global Impression (CGI) rating scale. Antipsychotic tolerability was assessed using the Simpson-Angus Scale (SAS) and various laboratory measures. Mean doses were 589.7 mg/ day quetiapine and 4.9 mg/day risperidone (observed cases). Both antipsychotics produced significant decreases in PANSS total, positive and negative scores, and SANS scores. Patients receiving risperidone were significantly more likely to experience extrapyramidal symptoms (EPS) [p <0.05], or to require anticholinergic medication (p <0.05), and had significantly higher prolactin levels (p <0.001) than quetiapine-treated patients. In conclusion, there is no significant difference in efficacy between quetiapine and risperidone in alleviating the negative symptoms of schizophrenia. Quetiapine is also well tolerated, with a lower incidence of EPS and prolactin increase than risperidone.

Adult↗
PubMed2005

Sugar pucker modulates the cross-correlated relaxation rates across the glycosidic bond in DNA.

The dependence of N1/9 and C1' chemical shielding (CS) tensors on the glycosidic bond orientation (chi) and sugar pucker (P) in the DNA nucleosides 2'-deoxyadenosine, 2'-deoxyguanosine, 2'-deoxycytidine, and 2'-deoxythymidine was studied using the calculation methods of quantum chemistry. The results indicate that these CS-tensors exhibit a significant degree of conformational dependence on chi and P structural parameters. The presented data test underlying assumptions of currently established methods for interpretation of cross-correlated relaxation rates between the N1/9 chemical shielding tensor and C1'-H1' dipole-dipole (Ravindranathan et al. J. Biomol. NMR 2003, 27, 365-75. Duchardt et al. J. Am. Chem. Soc. 2004, 126, 1962-70) and highlight possible limitations of these methods when applied to DNA.

Computer Simulation↗
PubMed2005

The secondary cell wall polymer of Geobacillus tepidamans GS5-97T: structure of different glycoforms.

Nuclear magnetic resonance spectroscopic studies of the strain-specific secondary cell wall polymer (SCWP) of the Gram-positive, moderately thermophilic organism Geobacillus tepidamans GS5-97T reveal two glycoforms consisting of identical tetrasaccharide repeating units with different chemical modifications of the amide moieties. On the basis of sugar analyses along with 1D and 2D 1H, 13C, 15N, and 31P NMR spectroscopy at natural isotope abundance, the basic backbone structure of the SCWP was established to be [beta-D-Manp-2,3-diNAcANH2-(1-->6)-alpha-D-Glcp-(1-->4)-beta-D-Manp-2,3-diNAcANH2-(1-->3)-alpha-D-GlcpNAc-(1-->]6-(1-->O)-PO2-(O-->6)-MurNAc-, with modifications of the amide groups. In one glycoform, all beta-D-Manp-2,3-diNAcANH2 (2,3-diacetamido-2,3-dideoxy-beta-D-mannopyranuronamide, ManpANH2) residues are substituted with two acetyl groups (glycoform I) at the amide group at C-6; in the other glycoform (glycoform II), only one proton of this amide group is substituted by an acetyl group. The ratio between both the glycoforms approximates 1:1.

Bacillaceae↗
PubMed2005

An extended association screen in multiple sclerosis using 202 microsatellite markers targeting apoptosis-related genes does not reveal new predisposing factors.

Apoptosis, the programmed death of cells, plays a distinct role in the etiopathogenesis of Multiple sclerosis (MS), a common disease of the central nervous system with complex genetic background. Yet, it is not clear whether the impact of apoptosis is due to altered apoptotic behaviour caused by variations of apoptosis-related genes. Instead, apoptosis in MS may also represent a secondary response to cellular stress during acute inflammation in the central nervous system. Here, we screened 202 apoptosis-related genes for association by genotyping 202 microsatellite markers in initially 160 MS patients and 160 controls, both divided in 4 sets of pooled DNA samples, respectively. When applying Bonferroni correction, no significant differences in allele frequencies were detected between MS patients and controls. Nevertheless, we chose 7 markers for retyping in individual DNA samples, thereby eliminating 6 markers from the list of candidates. The remaining candidate, the ERBB3 gene microsatellite, was genotyped in additional 245 MS patients and controls. No association of the ERBB3 marker with the disease was detected in these additional cohorts. In consequence, we did not find further evidence for apoptosis-related genes as predisposition factors in MS.

Apoptosis↗
PubMed2005

IL-2 and IL-4 polymorphisms as candidate genes in schizophrenia.

An immune process, characterized by a relative predominance of the T helper-2 (Th2) system and possibly induced by a viral infection,may be involved in the pathophysiology of schizophrenia. In this context, functional polymorphisms in the Interleukin-2 (IL-2) and Interleukin-4 (IL-4) genes appear to be principal candidates for genetic schizophrenia research. Further evidence for these candidate genes comes from several linkage analyses, pointing to susceptibility gene loci on chromosomes 4q and 5q, where the genes coding for IL- 2 and IL-4 are located. We carried out a case-control study including 230 schizophrenic patients and 251 healthy persons, investigating the IL-2 -330 T/G single nucleotide polymorphism (SNP) and the IL-4 -590 C/T SNP. A significant association of the IL-2 -330 TT genotype and of the IL-4 -590 CC genotype with schizophrenia could be identified. Our findings may partly account for the relative predominance of the Th2 system in schizophrenia, although they cannot directly explain this immunological imbalance, but may be related to an altered antiviral immune response in patients with schizophrenia.

Adolescent↗
PubMed2005

Association of the HLA region with multiple sclerosis as confirmed by a genome screen using >10,000 SNPs on DNA chips.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, with a complex genetic background. Here, we present a genome screen for association in small scale, employing 11,555 single nucleotide polymorphisms (SNPs) on DNA chips for genotyping 100 MS patients stratified for HLA-DR2+ and 100 controls. More than 500 SNPs revealed significant differences between cases and controls before Bonferroni correction. A fraction of these SNPs was reanalysed in two additional cohorts of patients and controls, using high-throughput genotyping methods. A marker on chromosome 6p21.32 (rs2395182) yielded the highest significance level, validating the established HLA-DR association.

Genetic Linkage↗