Plasma Chemokine Levels Are Associated with the Presence and Extent of Angiographic Coronary Collaterals in Chronic Ischemic Heart Disease

In patients with chronic ischemic heart disease (IHD), the presence and extent of spontaneously visible coronary collaterals are powerful determinants of clinical outcome. There is marked heterogeneity in the recruitment of coronary collaterals amongst patients with similar degrees of coronary artery stenoses, but the biological basis of this heterogeneity is not known. Chemokines are potent mediators of vascular remodeling in diverse biological settings. Their role in coronary collateralization has not been investigated. We sought to determine whether plasma levels of angiogenic and angiostatic chemokines are associated with of the presence and extent of coronary collaterals in patients with chronic IHD.We measured plasma concentrations of angiogenic and angiostatic chemokine ligands in 156 consecutive subjects undergoing coronary angiography with at least one ≥90% coronary stenosis and determined the presence and extent of spontaneously visible coronary collaterals using the Rentrop scoring system. Eighty-eight subjects (56%) had evidence of coronary collaterals. In a multivariable regression model, the concentration of the angiogenic ligands CXCL5, CXCL8 and CXCL12, hyperlipidemia, and an occluded artery were associated with the presence of collaterals; conversely, the concentration of the angiostatic ligand CXCL11, interferon-γ, hypertension and diabetes were associated with the absence of collaterals (ROC area 0.91). When analyzed according to extent of collateralization, higher Rentrop scores were significantly associated with increased concentration of the angiogenic ligand CXCL1 (p<0.0001), and decreased concentrations of angiostatic ligands CXCL9 (p<0.0001), CXCL10 (p = 0.002), and CXCL11 (p = 0.0002), and interferon-γ (p = 0.0004).Plasma chemokine concentrations are associated with the presence and extent of spontaneously visible coronary artery collaterals and may be mechanistically involved in their recruitment

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Hafting and « Retooling » at Verberie

The results of a microwear analysis of approximately 1000 artifacts from the magdalenian site of Verberie (Oise) are summarized. The correlations between hafting traces and data on tool use, refitting, spatial distribution, raw materials, the microchronology of the occupation, etc. are discussed. It is argued that tools made of some types of raw material were not used on the site but merely « retooled » there.Les résultats d'une analyse des traces d’utilisation d’environ 1000 outils magdaléniens du site de Verberie (Oise) sont résumés. Les corrélations entre les traces d’emmanchement et les données sur l’utilisation des outils, le remontage, les matériaux bruts, etc. sont décrits. On démontre que les outils de certains types de matériaux n’étaient pas utilisés in situ mais y étaient seulement réemmanchés.Keeley Lawrence H. Hafting and « Retooling » at Verberie. In: La Main et l’Outil. Manches et emmanchements préhistoriques. Table Ronde C.N.R.S. tenue à lyon du 26 au 29 novembre 1984, sous la direction de D. Stordeur. Lyon : Maison de l'Orient et de la Méditerranée Jean Pouilloux, 1987. pp. 89-96. (Travaux de la Maison de l'Orient, 15

Hafting and « Retooling » at Verberie

The results of a microwear analysis of approximately 1000 artifacts from the magdalenian site of Verberie (Oise) are summarized. The correlations between hafting traces and data on tool use, refitting, spatial distribution, raw materials, the microchronology of the occupation, etc. are discussed. It is argued that tools made of some types of raw material were not used on the site but merely « retooled » there.Les résultats d'une analyse des traces d’utilisation d’environ 1000 outils magdaléniens du site de Verberie (Oise) sont résumés. Les corrélations entre les traces d’emmanchement et les données sur l’utilisation des outils, le remontage, les matériaux bruts, etc. sont décrits. On démontre que les outils de certains types de matériaux n’étaient pas utilisés in situ mais y étaient seulement réemmanchés.Keeley Lawrence H. Hafting and « Retooling » at Verberie. In: La Main et l’Outil. Manches et emmanchements préhistoriques. Table Ronde C.N.R.S. tenue à lyon du 26 au 29 novembre 1984, sous la direction de D. Stordeur. Lyon : Maison de l'Orient et de la Méditerranée Jean Pouilloux, 1987. pp. 89-96. (Travaux de la Maison de l'Orient, 15

Neolithic novelties : the view from ethnography and microwear analysis

Le temps libéré par un mode de vie plus sédentaire et un nouveau style d'économie ont influencé les technologies du Néolithique. Les outils en pierre sont alors utilisés différemment pour des opérations plus complexes qu'au Paléolithique : ainsi les mèches d'Abu Hureyra pour creuser des trous cylindriques afin d'y placer des chevilles en bois, et d'autres outils pour un travail des fibres végétales lié aux activités textiles, et non plus simplement alimentaires.Keeley Lawrence H. Neolithic novelties : the view from ethnography and microwear analysis. In: Traces d’utilisation sur les outils néolithiques du Proche Orient. Table ronde CNRS tenue à Lyon du 8 au 10 juin 1982. Lyon : Maison de l'Orient et de la Méditerranée Jean Pouilloux, 1983. pp. 251-256. (Travaux de la Maison de l'Orient, 5

Neolithic novelties : the view from ethnography and microwear analysis

Le temps libéré par un mode de vie plus sédentaire et un nouveau style d'économie ont influencé les technologies du Néolithique. Les outils en pierre sont alors utilisés différemment pour des opérations plus complexes qu'au Paléolithique : ainsi les mèches d'Abu Hureyra pour creuser des trous cylindriques afin d'y placer des chevilles en bois, et d'autres outils pour un travail des fibres végétales lié aux activités textiles, et non plus simplement alimentaires.Keeley Lawrence H. Neolithic novelties : the view from ethnography and microwear analysis. In: Traces d’utilisation sur les outils néolithiques du Proche Orient. Table ronde CNRS tenue à Lyon du 8 au 10 juin 1982. Lyon : Maison de l'Orient et de la Méditerranée Jean Pouilloux, 1983. pp. 251-256. (Travaux de la Maison de l'Orient, 5