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  • 1
    Keywords: GENE ; VARIANTS ; HEALTH ; HEART-FAILURE ; SOCIETY ; susceptibility loci ; CORONARY-ARTERY-DISEASE ; Myocarditis ; HLA-C ; CARDIOLOGY
    Abstract: Aims Dilated cardiomyopathy (DCM) is one of the leading causes for cardiac transplantations and accounts for up to one-third of all heart failure cases. Since extrinsic and monogenic causes explain only a fraction of all cases, common genetic variants are suspected to contribute to the pathogenesis of DCM, its age of onset, and clinical progression. By a large-scale case-control genome-wide association study we aimed here to identify novel genetic risk loci for DCM. Methods and reuslts Applying a three-staged study design, we analysed more than 4100 DCM cases and 7600 controls. We identified and successfully replicated multiple single nucleotide polymorphism on chromosome 6p21. In the combined analysis, the most significant association signal was obtained for rs9262636 (P = 4.90 x 10(-9)) located in HCG22, which could again be replicated in an independent cohort. Taking advantage of expression quantitative trait loci (eQTL) as molecular phenotypes, we identified rs9262636 as an eQTL for several closely located genes encoding class I and class II major histocompatibility complex heavy chain receptors. Conclusion The present study reveals a novel genetic susceptibility locus that clearly underlines the role of genetically driven, inflammatory processes in the pathogenesis of idiopathic DCM.
    Type of Publication: Journal article published
    PubMed ID: 23853074
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  • 2
    Abstract: OBJECTIVE: Micro-RNAs (miRNAs) play a crucial role in controlling intestinal epithelial barrier function partly by modulating the expression of tight junction (TJ) proteins. We have previously shown differential messenger RNA (mRNA) expression correlated with ultrastructural abnormalities of the epithelial barrier in patients with diarrhoea-predominant IBS (IBS-D). However, the participation of miRNAs in these differential mRNA-associated findings remains to be established. Our aims were (1) to identify miRNAs differentially expressed in the small bowel mucosa of patients with IBS-D and (2) to explore putative target genes specifically involved in epithelial barrier function that are controlled by specific dysregulated IBS-D miRNAs. DESIGN: Healthy controls and patients meeting Rome III IBS-D criteria were studied. Intestinal tissue samples were analysed to identify potential candidates by: (a) miRNA-mRNA profiling; (b) miRNA-mRNA pairing analysis to assess the co-expression profile of miRNA-mRNA pairs; (c) pathway analysis and upstream regulator identification; (d) miRNA and target mRNA validation. Candidate miRNA-mRNA pairs were functionally assessed in intestinal epithelial cells. RESULTS: IBS-D samples showed distinct miRNA and mRNA profiles compared with healthy controls. TJ signalling was associated with the IBS-D transcriptional profile. Further validation of selected genes showed consistent upregulation in 75% of genes involved in epithelial barrier function. Bioinformatic analysis of putative miRNA binding sites identified hsa-miR-125b-5p and hsa-miR-16 as regulating expression of the TJ genes CGN (cingulin) and CLDN2 (claudin-2), respectively. Consistently, protein expression of CGN and CLDN2 was upregulated in IBS-D, while the respective targeting miRNAs were downregulated. In addition, bowel dysfunction, perceived stress and depression and number of mast cells correlated with the expression of hsa-miR-125b-5p and hsa-miR-16 and their respective target proteins. CONCLUSIONS: Modulation of the intestinal epithelial barrier function in IBS-D involves both transcriptional and post-transcriptional mechanisms. These molecular mechanisms include miRNAs as master regulators in controlling the expression of TJ proteins and are associated with major clinical symptoms.
    Type of Publication: Journal article published
    PubMed ID: 28082316
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  • 3
    Keywords: CANCER ; GENE ; GENES ; SIMULATION ; BREAST ; breast cancer ; BREAST-CANCER ; BRCA1 ; DATABASE ; HEREDITARY ; FAMILY-CANCER DATABASE ; BRCA2 ; CHEK2
    Type of Publication: Journal article published
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  • 4
    Keywords: CANCER ; CELL ; Germany ; human ; COMMON ; LUNG-CANCER ; SYSTEM ; COHORT ; DISEASE ; RISK ; GENE ; GENES ; INFECTION ; ANTIGEN ; cell cycle ; CELL-CYCLE ; CYCLE ; papillomavirus ; ASSOCIATION ; CANDIDATE GENE ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; VARIANTS ; smoking ; cervical cancer ; CERVICAL-CANCER ; PCR ; RISK FACTOR ; human papillomavirus ; HIGH-RISK ; HPV ; CLASS-I ; HUMAN-PAPILLOMAVIRUS ; SQUAMOUS-CELL CARCINOMA ; case-control studies ; INDIVIDUALS ; intraepithelial neoplasia ; HLA ; NESTED CASE-CONTROL ; CYCLIN D1 ; case control study ; case-control study ; POPULATION-BASED COHORT ; VARIANT ; CLASS-II ; development ; INTERLEUKIN-6 ; IMMUNE-SYSTEM ; ALLELES ; LOCUS ; TECHNOLOGY ; USA ; GENETIC SUSCEPTIBILITY ; INCREASED RISK ; RISK-FACTOR ; population-based ; FAMILIAL RISKS ; nested case-control study ; HUMAN-PAPILLOMAVIRUS INFECTION ; immune system ; CONFIDENCE-INTERVALS ; SWEDISH ; CCND1 ; Genetic ; CONFIDENCE ; genetic study ; HLA-B ; host factors ; HUMAN-LEUKOCYTE ANTIGEN ; LYMPHOTOXIN-ALPHA GENE
    Abstract: High-risk human papillomavirus (hrHPV) infection is the major risk factor for cervical cancer (CxCa). The role of genetic susceptibility in the disease has been suggested, but the existing data lack consistency. We conducted a nested case-control study on 973 CxCa cases and 1,763 matched controls, from two Swedish population-based cohorts to examine the association of common genetic variants with CxCa risk. Human leukocyte antigen (HLA) alleles and 24 other polymorphisms in 14 genes were selected on the basis of reported association or mechanistic plausibility with an HPV infection or cervical cancer development. Genotyping was conducted using multiplex PCR and Luminex technology. A significant association of CxCa with various polymorphisms was observed: rs1800797 in the IL-6 gene (odds ratio [OR] = 0.88, 95% confidence intervals [CI]: 0.79-0.99); rs1041981 in the LTA gene (OR = 0.87, 95% CI: 0.78-0.98), and rs9344 in the CCND1 gene (OR = 1.14, 95% CI: 1.02-1.27), for those individuals carrying the rare allele. Additionally, the alleles 0401 and 1501 of the HLA class II DRB1 locus were associated with an increased risk (OR = 1.23, 95% CI: 1.04-1.45 and OR = 1.29, 95% CI: 1.11-1.50, respectively), and allele 1301 was associated with decreased risk (OR = 0.59, 95% CI: 0.47-0.73). The effects of CCND1 and the HLA*DRB1 alleles were independent of the effect of smoking. We did not find any association of risk with polymorphisms in genes related to the innate immune system. In conclusion, our study provides evidence for genetic susceptibility to CxCa due to variations in genes involved in the immune system and in cell cycle. (C) 2009 UICC
    Type of Publication: Journal article published
    PubMed ID: 19585495
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  • 5
    ISSN: 1365-2036
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The effectiveness and tolerability of combination therapy for 12 months have not been evaluated sufficiently in chronic hepatitis C relapsers to interferon.〈section xml:id="abs1-2"〉〈title type="main"〉Aims:To evaluate the sustained response to interferon plus ribavirin for 12 months in chronic hepatitis C relapsers.〈section xml:id="abs1-3"〉〈title type="main"〉Methods:We included 55 chronic hepatitis C relapsers in a 12-month treatment protocol with interferon (3 MU thrice weekly) plus ribavirin (1–1.2 g/day). The effectiveness was evaluated using serum aminotransferase and hepatitis C virus RNA levels, alanine aminotransferase normalization and viraemia clearance after 12 months, defining the end-of-treatment response, and 6 months after completion of therapy, defining the sustained response. Adverse effects were recorded.〈section xml:id="abs1-4"〉〈title type="main"〉Results:End-of-treatment response and sustained response were achieved in 47 (85%) and 37 (67%) patients, respectively; there were 10 (21%) relapsers after combination therapy. Predictive factors of sustained response included the genotype (non-1 95% vs. 1 48%; P 〈 0.001), lower viraemia (503 917 ± 553 230 vs. 901 393 ± 548 267 copies/mL; P 〈 0.005), higher alanine aminotransferase levels (137 ± 75 vs. 103 ± 41 IU/L; P 〈 0.05) and a lower γ-glutamyl transpeptidase/alanine aminotransferase ratio (0.30 ± 0.23 vs. 0.49 ± 0.39; P 〈 0.05). Tolerance to therapy was good, with no withdrawals.〈section xml:id="abs1-5"〉〈title type="main"〉Conclusions:Interferon plus ribavirin treatment for 12 months in chronic hepatitis C relapsers yields high sustained response rates and is well tolerated. The sustained response is related to a non-1 genotype, lower baseline viraemia, higher alanine aminotransferase level and a lower γ-glutamyl transpeptidase/alanine aminotransferase ratio.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1434-6036
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract. The lattice dynamics of crystalline L-alanine shows unusual features tentatively assigned to a localization of vibrational energy. However, other properties alternatively suggest the existence of a second order phase transition undetected in previous crystallographic work. In this paper, we present the results of a high resolution X-ray diffraction study down to 10 K, together with new structure determinations at intermediate temperatures. The data rule out the hypothesis of a conventional structural phase transition. No change in the space group symmetry is observed and an anomalous decrease of the lattice parameter c in discrete steps is discovered when heating the crystal from 10 K to room temperature. It could be ascribed to a progressive conformational change of the NH3 + group of the zwitterionic molecule. An analysis of the physical properties of crystalline L-alanine suggests the existence of a strong dynamic Jahn-Teller-like effect owing to the NH3 + charge-lattice coupling. This would explain both the splitting of some vibrational states and properties related to a microscopic lattice instability like the onset of depolarization in the transmitted light below ~250 K.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1434-6036
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract. We have carried out high resolution neutron powder diffraction experiments aiming at a determination of the magnetic structure of the S=1/2 layer compound NaNiO2. The magnetic moments are ferromagnetically aligned in the NiO2 layers and antiparallel between layers. The direction of the magnetic moment has a small component along the a-direction.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1573-904X
    Keywords: diltiazem ; deacetyldiltiazem ; metabolism ; extrahepatic tissues
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Diltiazem (DTZ) undergoes extensive metabolism yielding several metabolites, some of which retain a certain degree of pharmacological activity. N-demethylating activity has been detected mainly in the liver. Nevertheless, the organs involved in the formation of the deacetylated metabolite of DTZ (Ml) have not been fully elucidated. In order to address this issue, we have carried out in vitro studies using the blood, lung, brain, small intestine, and liver as enzyme sources. Methods. DTZ (1,000 ng/ml) was incubated in 10,000 × g supernatant homogenates of selected tissues or in whole blood for 240 minutes at 37°C. Multiple samples were withdrawn, and DTZ and its metabolite Ml were assayed by HPLC. Results. The apparent degradation rate constant of DTZ was in the rank order blood 〉 lung 〉 brain 〉 liver 〉 small intestine. This trend can also be observed for the AUC and for the percentage of DTZ metabolized. In all the tissue homogenates examined there was a net production of the deacetylated metabolite. The Ml metabolite was also detected in the blood (500 ng/ml after 240 minutes of incubation). Conclusions. The widespread distribution of the DTZ deacetylase activity described in this study suggests that extrahepatic metabolism of DTZ to Ml may play a relevant role in the overall pharmacokinetics of DTZ.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1600-5767
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Geosciences , Physics
    Notes: The development of the energy/angular dispersive diffraction setup, which can be used for anomalous diffraction, allows the collection of diffracted intensities around an absorption edge, either over a continuous energy range [for DAFS (diffraction anomalous fine structure) studies], or at discrete energies [for simultaneous MAD (multiwavelength anomalous diffraction) studies]. Used with a large two-dimensional detector and an oscillating single crystal, this setup allows simultaneous collection of many reflections for a given energy range. An integration procedure has been developed along with a program, DAD (dispersive anomalous diffraction), for the collection and analysis of the raw images, to yield finally data in the form I(h, k, l, λ) for all reflections. Wavelength calibration and intensity corrections are made during the integration process, and parameters that may be needed in later stages of the analysis are extracted and referenced within the integrated data. A general procedure to calculate the positions of diffracted reflections, for a monochromatic oscillation scan with a two-dimensional detector, when the incident beam is not perpendicular to the oscillation axis, is also described.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1600-5767
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Geosciences , Physics
    Notes: A low-absorption ionization chamber has been developed to monitor the incident beam in X-ray diffraction experiments. The chamber current is digitized by means of an ultra-stable linear charge integrator. The digital signal is used to control the measuring time for each point of the desired scattering curve. In our application, fluctuations in the scattering curve resulting from instability of the incident beam have been reduced by a factor of 5.
    Type of Medium: Electronic Resource
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