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25
نتائج ل
"Bates, Sandra M"
صنف حسب:
Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials
Summary Background Proton-pump inhibitors (PPIs) are often prescribed in combination with thienopyridines. Conflicting data exist as to whether PPIs diminish the efficacy of clopidogrel. We assessed the association between PPI use, measures of platelet function, and clinical outcomes for patients treated with clopidogrel or prasugrel. Methods In the PRINCIPLE-TIMI 44 trial, the primary outcome was inhibition of platelet aggregation at 6 h assessed by light-transmission aggregometry. In the TRITON-TIMI 38 trial, the primary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke. In both studies, PPI use was at physician's discretion. We used a multivariable Cox model with propensity score to assess the association of PPI use with clinical outcomes. Findings In the PRINCIPLE-TIMI 44 trial, 201 patients undergoing elective percutaneous coronary intervention were randomly assigned to prasugrel (n=102) or high-dose clopidogrel (n=99). Mean inhibition of platelet aggregation was significantly lower for patients on a PPI than for those not on a PPI at 6 h after a 600 mg clopidogrel loading dose (23·2±19·5% vs 35·2±20·9%, p=0·02), whereas a more modest difference was seen with and without a PPI after a 60 mg loading dose of prasugrel (69·6±13·5% vs 76·7±12·4%, p=0·054). In the TRITON-TIMI 38 trial, 13 608 patients with an acute coronary syndrome were randomly assigned to prasugrel (n=6813) or clopidogrel (n=6795). In this study, 33% (n=4529) of patients were on a PPI at randomisation. No association existed between PPI use and risk of the primary endpoint for patients treated with clopidogrel (adjusted hazard ratio [HR] 0·94, 95% CI 0·80–1·11) or prasugrel (1·00, 0·84–1·20). Interpretation The current findings do not support the need to avoid concomitant use of PPIs, when clinically indicated, in patients receiving clopidogrel or prasugrel. Funding Daiichi Sankyo Company Limited and Eli Lilly and Company sponsored the trials. This analysis had no funding.
Journal Article
Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations
Polycystic ovary syndrome (PCOS) is a common, highly heritable complex disorder of unknown aetiology characterized by hyperandrogenism, chronic anovulation and defects in glucose homeostasis. Increased luteinizing hormone relative to follicle-stimulating hormone secretion, insulin resistance and developmental exposure to androgens are hypothesized to play a causal role in PCOS. Here we map common genetic susceptibility loci in European ancestry women for the National Institutes of Health PCOS phenotype, which confers the highest risk for metabolic morbidities, as well as reproductive hormone levels. Three loci reach genome-wide significance in the case-control meta-analysis, two novel loci mapping to chr 8p23.1 [Corrected] and chr 11p14.1, and a chr 9q22.32 locus previously found in Chinese PCOS. The same chr 11p14.1 SNP, rs11031006, in the region of the follicle-stimulating hormone B polypeptide (FSHB) gene strongly associates with PCOS diagnosis and luteinizing hormone levels. These findings implicate neuroendocrine changes in disease pathogenesis.
Journal Article
Conservation of trans-acting circuitry during mammalian regulatory evolution
The basic body plan and major physiological axes have been highly conserved during mammalian evolution, yet only a small fraction of the human genome sequence appears to be subject to evolutionary constraint. To quantify cis- versus trans-acting contributions to mammalian regulatory evolution, we performed genomic DNase I footprinting of the mouse genome across 25 cell and tissue types, collectively defining ∼8.6 million transcription factor (TF) occupancy sites at nucleotide resolution. Here we show that mouse TF footprints conjointly encode a regulatory lexicon that is ∼95% similar with that derived from human TF footprints. However, only ∼20% of mouse TF footprints have human orthologues. Despite substantial turnover of the cis-regulatory landscape, nearly half of all pairwise regulatory interactions connecting mouse TF genes have been maintained in orthologous human cell types through evolutionary innovation of TF recognition sequences. Furthermore, the higher-level organization of mouse TF-to-TF connections into cellular network architectures is nearly identical with human. Our results indicate that evolutionary selection on mammalian gene regulation is targeted chiefly at the level of trans-regulatory circuitry, enabling and potentiating cis-regulatory plasticity.
Journal Article
Model analysis of multiple breath nitrogen washout data: robustness to variations in breathing pattern
We recently developed a model-based method for analyzing multiple breath nitrogen washout data that does not require identification of Phase-III. In the present study, we assessed the effect of irregular breathing patterns on the intra-subject variabilities of the model parameters. Nitrogen fraction at the mouth was measured in 18 healthy and 20 asthmatic subjects during triplicate performances of multiple breath nitrogen washout, during controlled (target tidal volume 1 L at 8–12 breaths per minute) and free (unrestricted) breathing. The parameters S
cond
, S
acin
and functional residual capacity (FRC) were obtained by conventional analysis of the slope of Phase-III. Fitting the model to the washout data provided functional residual capacity (FRC
M
), dead space volume (V
D
), the coefficient of variation of regional specific ventilation (
C
V
,
V
˙
e
), and the model equivalent of S
acin
(S
acin-M
). Intra-participant coefficients of variation for the model parameters for both health and asthma were FRC
M
< 5.2%, V
D
< 5.4%,
C
V
,
V
˙
e
< 9.0%, and S
acin-M
< 45.6% for controlled breathing, and FRC
M
< 4.6%, V
D
< 5.3%,
C
V
,
V
˙
e
< 13.2%, and S
acin-M
< 103.2% for free breathing. The coefficients of variation limits for conventional parameters were FRC < 6.1%, with S
cond
< 73.6% and S
acin
< 49.2% for controlled breathing and S
cond
< 35.0% and S
acin
< 74.4% for free breathing. The model-fitting approach to multiple breath nitrogen washout analysis provides a measure of regional ventilation heterogeneity in
C
V
,
V
˙
e
that is less affected by irregularities in the breathing pattern than its corresponding Phase-III slope analysis parameter S
cond
.
Journal Article
Relationship between the morphology of the foveal avascular zone, retinal structure, and macular circulation in patients with diabetes mellitus
Diabetic Retinopathy (DR) is an extremely severe and common degenerative disease. The purpose of this study was to quantify the relationship between various parameters including the Foveal Avascular Zone (FAZ) morphology, retinal layer thickness, and retinal hemodynamic properties in healthy controls and patients with diabetes mellitus (DM) with and with no mild DR (MDR) using Spectral-Domain Optical Coherence Tomography (Spectralis SDOCT, Heidelberg Engineering GmbH, Germany) and the Retinal Function Imager (Optical Imaging, Ltd., Rehovot, Israel). Our results showed a higher FAZ area and diameter in MDR patients. Blood flow analysis also showed that there is a significantly smaller venous blood flow velocity in MDR patients. Also, a significant difference in roundness was observed between DM and MDR groups supporting the development of asymmetrical FAZ expansion with worsening DR. Our results suggest a potential anisotropy in the mechanical properties of the diabetic retina with no retinopathy that may trigger the FAZ elongation in a preferred direction resulting in either thinning or thickening of intraretinal layers in the inner and outer segments of the retina as a result of autoregulation. A detailed understanding of these relationships may facilitate earlier detection of DR, allowing for preservation of vision and better clinical outcomes.
Journal Article
Mouse regulatory DNA landscapes reveal global principles of cis-regulatory evolution
To study the evolutionary dynamics of regulatory DNA, we mapped >1.3 million deoxyribonuclease I–hypersensitive sites (DHSs) in 45 mouse cell and tissue types, and systematically compared these with human DHS maps from orthologous compartments. We found that the mouse and human genomes have undergone extensive cis-regulatory rewiring that combines branch-specific evolutionary innovation and loss with widespread repurposing of conserved DHSs to alternative cell fates, and that this process is mediated by turnover of transcription factor (TF) recognition elements. Despite pervasive evolutionary remodeling of the location and content of individual cis-regulatory regions, within orthologous mouse and human cell types the global fraction of regulatory DNA bases encoding recognition sites for each TF has been strictly conserved. Our findings provide new insights into the evolutionary forces shaping mammalian regulatory DNA landscapes.
Journal Article
A03 Alternative processing of human HTT MRNA in YAC128 mice: implications for Huntington’s disease therapeutics
BackgroundYAC128 transgenic mice carry human HTT with an expanded CAG repeat. This model is particularly useful for evaluating therapies targeting the human HTT gene and/or protein.AimsTo better understand the molecular phenotype of YAC128 mice at the RNA and protein level.MethodsA QuantiGene assay was designed to gain insights into incomplete splicing in the context of human HTT, and to evaluate the lowering efficiency of therapeutic compounds. RNAscope was implemented to visualize HTT transcripts and immunohistochemistry to characterise HTT aggregation spatiotemporally. HTRF measured the levels of the total HTT protein and the pathogenic exon 1 HTT. Mouse embryonic fibroblasts (MEFs) from YAC128 mice were used for screening agents targeting human HTT transcript.ResultsMicroscopic analysis revealed that the full-length HTT mRNA (FL-HTT) was retained in RNA nuclear clusters together with the incompletely spliced HTT1a transcript. These clusters were not observed in zQ175 HD mouse model where, instead, FL-Htt and Htt1a mRNAs were detected as mostly cytoplasmic molecules. Immunohistochemistry showed a progressive appearance of aggregated HTT in nuclei in the cortex, striatum, hippocampus and cerebellum. HTRF indicated that the level of exon 1 HTT was highest in the cerebellum. Soluble mutant exon 1 HTT decreased with age, with concomitant increase in aggregated HTT. In YAC128 MEFs, HTT1a was detected and ASOs targeting HTT were efficient in lowering HTT levels in this model system.ConclusionsHuman HTTundergoes incomplete splicing in brains of YAC128 mice. The RNA clusters detected may have direct therapeutic implications, with pathogenic or protective consequences
Journal Article
