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  • 1
    Keywords: POPULATION ; GENOME ; ASSOCIATION ; FREQUENCY ; BREAST-CANCER ; GENETIC-VARIATION ; SIGNATURES ; POSITIVE SELECTION ; JEWS ; TAY-SACHS DISEASE
    Abstract: Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews
    Type of Publication: Journal article published
    PubMed ID: 21597964
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  • 2
  • 3
    Abstract: The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (, 40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (lambda) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values, 10 25 and 39 SNPs had p-values〈10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, p = 3: 8 x 10(-5)) and for rs311499 was 0.72 (95% CI 0.61-0.85, p = 6: 6 x 10(-5)). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, p = 1: 2 x 10(-8)). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer
    Type of Publication: Journal article published
    PubMed ID: 21060860
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  • 4
    ISSN: 0920-9964
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-1041
    Keywords: diuretics ; antihypertensive agents ; renal disease ; dispositon ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacodynamic actions and disposition of diuretic and antihypertensive agents may be significantly modified in subjects with renal disease. Most studies on this question have dealt with alterations in the elimination kinetics of these drugs and, while they generate descriptive data, minimal insight about changes in dose-response relationships or mechanisms of drug action are provided by such investigations. Several basic principles which may serve as useful guidelines in determining how renal failure will influence the response to drugs have been considered. They include the following: degree of renal malfunction, intrinsic toxicity of the drug, alternative pathways for drug metabolism and elimination, elimination pharmacokinetics and dose-response characteristics. Several classes of diuretic agents (thiazides, furosemide) and antihypertensive drugs (hydralazine, methyldopa, propranolol, prazosin, and clonidine) have been used as models to define how basic knowledge of renal and non-renal pathways for elimination of drugs and their pharmacodynamic actions may assist in establishing rational therapeutic regimens for these agents in patients with renal failure.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: β-endorphin is an endogenous opioid peptide that has been hypothesized to be involved in the behavioral effects of drugs of abuse including psychostimulants. Using microdialysis, we studied the effect of cocaine on extracellular levels of β-endorphin in the nucleus accumbens, a brain region involved in the reinforcing effects of psychostimulant drugs. Experimenter-delivered cocaine (2 mg/kg, i.v.) increased extracellular β-endorphin immunoreactive levels in the nucleus accumbens, an effect attenuated by 6-hydroxy-dopamine lesions or systemic administration of the D1-like receptor antagonist, SCH-23390 (0.25 mg/kg, i.p.). The effect of cocaine on β-endorphin release in the nucleus accumbens was mimicked by a local perfusion of dopamine (5 µm) and was blocked by coadministration of SCH-23390 (10 µm). Self-administered cocaine (1 mg/kg/infusion, i.v.) also increased extracellular β-endorphin levels in the nucleus accumbens. In addition, using functional magnetic resonance imaging, we found that cocaine (1 mg/kg, i.v.) increases regional brain activity in the nucleus accumbens and arcuate nucleus. We demonstrate an increase in β-endorphin release in the nucleus accumbens following experimenter-delivered and self-administered cocaine mediated by the local dopaminergic system. These findings suggest that activation of the β-endorphin neurons within the arcuate nucleus–nucleus accumbens pathway may be important in the neurobiological mechanisms underlying the behavioral effects of cocaine.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    ISSN: 1365-2230
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    ISSN: 1365-2230
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: A 68-year-old woman presented with a 10-year history of multiple milia on her scalp. Spontaneous eruptive milia are uncommon and the term describes cases that are more extensive in number and distribution than would be expected in primary milia.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    European spine journal 2 (1993), S. 209-214 
    ISSN: 1432-0932
    Keywords: Disque intervertébral ; Fatigue ; Rupture ; Mécanique ; Flexion ; Intervertebral disc ; Fatigue ; Failure ; Mechanics ; Bending
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Part I of this study showed that collagen fibres do need not need to be continuous to reinforce the annulus fibrosus, and that 15-mm-wide samples of annulus retain about 44% of their in situ stiffness and strength when stretched vertically. Part II investigated the ultimate tensile strength (UTS) and fatigue life of such samples. Vertical slices, 5 mm thick and 30 mm wide, were cut from the anterior and posterior margins of the annulus and adjacent vertebral bodies. Each slice was divided sagittally to obtain a matched pair of specimens. The bony ends of each specimen were secured in a materials testing machine so that the annulus could be stretched vertically, as occurs during bending movements of the spine in life. One of each pair of specimens was stretched to failure to obtain its UTS; the other was cyclically loaded at some fraction of the UTS until failure occurred. Tensile failure started with the hyaline cartilage end-plate being stripped off the underlying bone and ended with the most peripheral annular fibres pulling out of the matrix. The estimated in situ strength in the vertical direction was 3.9 MPa for the anterior annulus and 8.6 MPa for the posterior annulus. Fatigue failure could occur in less than 10000 cycles if the tensile force exceeded 45% of the UTS. The results explain why radial fissures often fail to penetrate the peripheral annulus. When compared with in vivo measurements of spinal loading, they suggest that repetitive forward bending movements could cause fatigue failure of the posterior annulus.
    Notes: Résumé La première partie de cette étude a montré que les fibres de collagène ne doivent être en continuité pour renforcer l'anneau fibreux et que des échantillons d'annulus de 15 mm de largeur conservent environ 44% de leur rigidité in-situ et de leur résistance lorsqu'ils sont soumis à un étirement vertical. La seconde partie a exploré la limite de résistance à la tension (Ultimate Tensile Strength= UTS) et le comportement à la fatigue de tels échantillons. Des tranches verticales e disque de 5 mm d'épaisseur et de 30 mm de largeur ont été taillées à partir des bords latéraux de l'annulus et des corps vertébraux adjacents. Chaque tranche a été divisée sagittalement pour obtenir une paire d'échantillons identiques. Les extrémités osseuses de chaque tranche ont été fixées dans un appareil destiné à tester les matériaux de manière à ce que l'annulus puisse être étiré verticalement, comme cela se produit lors des mouvements de flexion du rachis dans la vie courante. L'un des deux échantillons de chaque paire a été étiré jusqu'à sa rupture pour déterminer sa limite de résistance à la tension (UTS); l'autre a été soumis à une charge cyclique égale à une fraction de l'UTS jusqu'à obtenir sa rupture. La rupture sous tension a commencé par l'arrachement du cartilage hyalin du plateau de l'os sous-jacent et s'est terminé par l'arrachement des fibres les plus périphériques de l'anneau hors de leur matrice. La résistance in-situ estimée dans le sens vertical était de 3,9 MPa pour la partie antérieure de l'annulus et de 8,6 MPa pour la partie postérieure de l'annulus. La rupture de fatigue pourrait survenir en moins de 10000 cycles si la force de tension venait à dépasser 45% de l'UTS. Ces résultats expliquent pourquoi les fissures radiaires manquent souvent de pénétrer la partie périphérique de l'anneau fibreux. Lorsqu'on les compare aux mesures, in vivo de la mise en charge rachidienne, nos résultats suggèrent que les mouvements répétés de flexion antérieure du rachis pourraient provoquer une rupture de fatigue de la partie postérieure de l'anneau fibreux.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    European spine journal 2 (1993), S. 203-208 
    ISSN: 1432-0932
    Keywords: Disque intervertébral ; Collagène ; Protéoglycans ; Mécanique ; Renforcement fibrillaire ; Intervertebral disc ; Collagen ; Proteoglycans ; Mechanics ; Fibre reinforcement
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary We investigated the tensile properties of samples of human lumbar annulus fibrosus. Here we consider the effect of sample size, and hence collagen disruption, on the results obtained. Vertical slices, 5 mm thick and 30 mm wide, were cut from the lateral margins of the annulus and adjacent vertebral bodies. The bony ends of each slice were secured in a materials testing machine so that the annulus could be stretched vertically, as occurs during bending movements of the spine in life. Tensile stiffness was measured repeatedly after successive vertical cuts in the annulus had reduced the effective size of the sample. Stiffness (per unit cross-sectional area) decreased as the specimen size decreased. The mean length of collagen fibre bundles in the specimens was calculated from a geometrical model and shown to be proportional to the tensile stiffness. Extrapolation of the results suggested that the vertical stiffness and strength of 15-mm-wide specimens of annulus would be about 44% of their values in situ. We conclude that collagen fibres need not be continous to reinforce the annulus and that fibre-matrix interactions make a large contribution to the tensile stiffness and strength.
    Notes: Résumé Nous avons étudié les propriétés mécaniques d'échantillons d'anneau fibreux de disques lombaires humains soumis à la tension. La première partie de ce travail étudie l'effet de la taille de l'échantillon et de la rupture du collagène sur le résultat obtenu. Des tranches verticales de disque de 5 mm d'épaisseur et de 30 mm de largeur ont été taillées à partir des bords latéraux de l'annulus et des corps vertébraux adjacents. Les extrémités osseuses de chaque tranche ont été fixées dans un appareil destiné à tester les matériaux de manière à ce que l'annulus puisse être étiré verticalement, comme cela se produit lors des mouvements de flexion du rachis dans la vie courante. La raideur sous tension a été mesurée de manière répétitive après réduction de la taille effective de l'échantillon par des sections verticales successives de l'annulus. La raideur (par unité de surface) a diminué avec la taille du spécimen. La longueur moyenne des faisceaux de fibres de collagène dans les échantillons étudiés a été calculée à partir d'un modèle géométrique et il apparaît qu'elle est proportionnelle à la raideur sous tension. L'extrapolation des résultats a suggéré que la rigidité verticale et la solidité d'échantillons d'annulus de 15 mm de largeur devrait se situer autour de 44% de leur valeur in-situ. En conclusion, les fibres de collagène doivent être en continuité pour renforcer l'annulus, et les interactions fibresmatrice contribuent largement à la rigidité sous tension et à la résistance.
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