Introduction paper

contribution to session 5 Member States shall establish certificate systems for mutual recognition of the certificates (according article 8/6

Conclusions of session 5

contribution to session 5 Member States shall establish certificate systems for mutual recognition of the certificates (according article 8/6

Review article liver metastases

Liver metastases are a very common site of distant metastases. Detection and accurate characterization of liver metastases is of importance to guide therapy. A variety of imaging modalities such as US (including contrast agents), MDCT, MRI with liver –specific contrast agents and PET/CT are available for this purpose. This review presents imaging techniques and summarizes the current knowledge, how the different imaging modalities should be used

The effect of NOTCH3 pathogenic variant position on CADASIL disease severity: NOTCH3 EGFr 1–6 pathogenic variant are associated with a more severe phenotype and lower survival compared with EGFr 7–34 pathogenic variant

Purpose: CADASIL is a small-vessel disease caused by a cysteine-altering pathogenic variant in one of the 34 epidermal growth factor-like repeat (EGFr) domains of the NOTCH3 protein. We recently found that pathogenic variant in EGFr domains 7\u201334 have an unexpectedly high frequency in the general population (1:300). We hypothesized that EGFr 7\u201334 pathogenic variant more frequently cause a much milder phenotype, thereby explaining an important part of CADASIL disease variability. Methods: Age at first stroke, survival and white matter hyperintensity volume were compared between 664 CADASIL patients with either a NOTCH3 EGFr 1\u20136 pathogenic variant or an EGFr 7\u201334 pathogenic variant. The frequencies of NOTCH3 EGFr 1\u20136 and EGFr 7\u201334 pathogenic variant were compared between individuals in the genome Aggregation Database and CADASIL patients. Results: CADASIL patients with an EGFr 1\u20136 pathogenic variant have a 12-year earlier onset of stroke than those with an EGFr 7\u201334 pathogenic variant, lower survival, and higher white matter hyperintensity volumes. Among diagnosed CADASIL patients, 70% have an EGFr 1\u20136 pathogenic variant, whereas EGFr 7\u201334 pathogenic variant strongly predominate in the population. Conclusion: NOTCH3 pathogenic variant position is the most important determinant of CADASIL disease severity, with EGFr 7\u201334 pathogenic variant predisposing to a later onset of stroke and longer survival

Polarization of Lambda^0 hyperons in nucleus-nucleus collisions at high energies

The measurement of Lambda^0 hyperons polarization in nucleus-nucleus collisions is considered as one of possible tools to study the phase transition. Fixed target and collider experiments are discussed for the case of Lambda^0's production from Au-Au central collisions at \sqrt{s_{NN}} of several GeV.Comment: 15 pages, 6 figure

Hyperon polarization and single spin left-right asymmetry in inclusive production processes at high energies

It is shown that the polarization of hyperons observed in high energy collisions using unpolarized hadron beams and unpolarized nucleon or nuclear targets is closely related to the left-right asymmetries observed in single spin inclusive hadron production processes. The relationship is most obvious for the production of the hyperons which have only one common valence quark with the projectile. Examples of this kind are given. Further implications of the existence of large polarization for hyperon which has two valence quarks in common with the projectile and their consequences are discussed. A comparison with the available data is made. Further tests are suggested.Comment: REVTeX, 12 pages, 2 figures embedde

Adipocyte ATP-binding cassette G1 promotes triglyceride storage, fat mass growth, and human obesity

The role of ATP-binding Cassette G1 (ABCG1) transporter in human pathophysiology is still largely unknown. Indeed, beyond its role in mediating free cholesterol efflux to HDL, ABCG1 transporter equally promotes lipid accumulation in a triglyceride (TG)-rich environment through regulation of the bioavailability of Lipoprotein Lipase (LPL).As both ABCG1 and LPL are expressed in adipose tissue, we hypothesize that ABCG1 is implicated in adipocyte TG storage and could be then a major actor in adipose tissue fat accumulation.Silencing of Abcg1 expression by RNAi in 3T3-L1 preadipocytes compromised LPL-dependent TG accumulation during initial phase of differentiation. Generation of stable Abcg1 Knockdown 3T3-L1 adipocytes revealed that Abcg1 deficiency reduces TG storage and diminishes lipid droplet size through inhibition of Pparγ expression. Strikingly, local inhibition of adipocyte Abcg1 in adipose tissue from mice fed a high fat diet led to a rapid decrease of adiposity and weight gain. Analysis of two frequent ABCG1 SNPs (rs1893590 (A/C) and rs1378577 (T/G)) in morbidly obese individuals indicated that elevated ABCG1 expression in adipose tissue was associated with an increased PPARγ expression and adiposity concomitant to an increased fat mass and BMI (haplotype AT>GC). The critical role of ABCG1 regarding obesity was further confirmed in independent populations of severe obese and diabetic obese individuals.For the first time, this study identifies a major role of adipocyte ABCG1 in adiposity and fat mass growth and suggests that adipose ABCG1 might represent a potential therapeutic target in obesity

Genome-wide genotyping demonstrates a polygenic risk score associated with white matter hyperintensity volume in CADASIL

Background and Purpose—White matter hyperintensities (WMH) on MRI are a quantitative marker for sporadic cerebral small vessel disease and are highly heritable. To date, large-scale genetic studies have identified only a single locus influencing WMH burden. This might in part relate to biological heterogeneity of sporadic WMH. The current study searched for genetic modifiers of WMH volume in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a monogenic small vessel disease. Methods—We performed a genome-wide association study to identify quantitative trait loci for WMH volume by combining data from 517 CADASIL patients collected through 7 centers across Europe. WMH volumes were centrally analyzed and quantified on fluid attenuated inversion recovery images. Genotyping was performed using the Affymetrix 6.0 platform. Individuals were assigned to 2 distinct genetic clusters (cluster 1 and cluster 2) based on their genetic background. Results—Four hundred sixty-six patients entered the final genome-wide association study analysis. The phenotypic variance of WMH burden in CADASIL explained by all single nucleotide polymorphisms in cluster 1 was 0.85 (SE=0.21), suggesting a substantial genetic contribution. Using cluster 1 as derivation and cluster 2 as a validation sample, a polygenic score was significantly associated with WMH burden (P=0.001) after correction for age, sex, and vascular risk factors. No single nucleotide polymorphism reached genome-wide significance. Conclusions—We found a polygenic score to be associated with WMH volume in CADASIL subjects. Our findings suggest that multiple variants with small effects influence WMH burden in CADASIL. The identification of these variants and the biological pathways involved will provide insights into the pathophysiology of white matter disease in CADASIL and possibly small vessel disease in general

Breakpoint mapping of 13 large parkin deletions/duplications reveals an exon 4 deletion and an exon 7 duplication as founder mutations

Early-onset Parkinson’s disease (EOPD) has been associated with recessive mutations in parkin (PARK2). About half of the mutations found in parkin are genomic rearrangements, i.e., large deletions or duplications. Although many different rearrangements have been found in parkin before, the exact breakpoints involving these rearrangements are rarely mapped. In the present study, the exact breakpoints of 13 different parkin deletions/duplications, detected in 13 patients out of a total screened sample of 116 EOPD patients using Multiple Ligation Probe Amplification (MLPA) analysis, were mapped using real time quantitative polymerase chain reaction (PCR), long-range PCR and sequence analysis. Deletion/duplication-specific PCR tests were developed as a rapid and low cost tool to confirm MLPA results and to test family members or patients with similar parkin deletions/duplications. Besides several different deletions, an exon 3 deletion, an exon 4 deletion and an exon 7 duplication were found in multiple families. Haplotype analysis in four families showed that a common haplotype of 1.2 Mb could be distinguished for the exon 7 duplication and a common haplotype of 6.3 Mb for the deletion of exon 4. These findings suggest common founder effects for distinct large rearrangements in parkin