The quassinoid derivative NBT-272 targets both the AKT and ERK signaling pathways in embryonal tumors

The quassinoid analogue NBT-272 has been reported to inhibit MYC, thus warranting a further effort 7to better understand its preclinical properties in models of embryonal tumors (ET), a family of childhood malignancies sharing relevant biological and genetic features such as deregulated expression of MYC oncogenes. In our study, NBT-272 displayed a strong antiproliferative activity in vitro that resulted from the combination of diverse biological effects, ranging from G(1)/S arrest of the cell cycle to apoptosis and autophagy. The compound prevented the full activation of both eukaryotic translation initiation factor 4E (eIF4E) and its binding protein 4EBP-1, regulating cap-dependent protein translation. Interestingly, all responses induced by NBT-272 in ET could be attributed to interference with 2 main proproliferative signaling pathways, that is, the AKT and the MEK/extracellular signal-regulated kinase pathways. These findings also suggested that the depleting effect of NBT-272 on MYC protein expression occurred via indirect mechanisms, rather than selective inhibition. Finally, the ability of NBT-272 to arrest tumor growth in a xenograft model of neuroblastoma plays a role in the strong antitumor activity of this compound, both in vitro and in vivo, with its potential to target cell-survival pathways that are relevant for the development and progression of ET.

Meta-analysis of mould and dampness exposure on asthma and allergy in eight European birth cohorts: an ENRIECO initiative

Background:  Several cross-sectional studies during the past 10 years have observed an increased risk of allergic outcomes for children living in damp or mouldy environments. Objective:  The objective of this study was to investigate whether reported mould or dampness exposure in early life is associated with the development of allergic disorders in children from eight European birth cohorts. Methods:  We analysed data from 31 742 children from eight ongoing European birth cohorts. Exposure to mould and allergic health outcomes were assessed by parental questionnaires at different time points. Meta-analyses with fixed- and random-effect models were applied. The number of the studies included in each analysis varied based on the outcome data available for each cohort. Results:  Exposure to visible mould and/or dampness during first 2 years of life was associated with an increased risk of developing asthma: there was a significant association with early asthma symptoms in meta-analyses of four cohorts [0–2 years: adjusted odds ratios (aOR), 1.39 (95%CI, 1.05–1.84)] and with asthma later in childhood in six cohorts [6–8 years: aOR, 1.09(95%CI, 0.90–1.32) and 3–10 years: aOR, 1.10 (95%CI, 0.90–1.34)]. A statistically significant association was observed in six cohorts with symptoms of allergic rhinitis at school age [6–8 years: aOR, 1.12 (1.02–1.23)] and at any time point between 3 and 10 years [aOR, 1.18 (1.09–1.28)]. Conclusion:  These findings suggest that a mouldy home environment in early life is associated with an increased risk of asthma particularly in young children and allergic rhinitis symptoms in school-age children.

A navigation system for open liver surgery: design, workflow and first clinical applications

The surgical treatment of liver tumours relies on precise localization of the lesions and detailed knowledge of the patient-specific vascular and biliary anatomy. Detailed three-dimensional (3D) anatomical information facilitates complete tumour removal while preserving a sufficient amount of functional liver tissue.

Lesion characteristics of patients with chronic critical limb ischemia that determine choice of treatment modality

This paper will review the literature in order to define lesion characteristics that determine decision for surgical or endovascular therapy in patients with chronic critical limb ischemia (CLI). The typical pattern of disease is multilevel, infrainguinal disease. The great majority of patients with CLI can be treated by endovascular means, and the pathoanatomical pattern of disease dictates the choice of treatment modality. Long iliac artery occlusions, in particular, if associated with common femoral artery pathology and long superficial femoral artery occlusions crossing the knee joint so far remain a domain of surgery. However, there is an ongoing shift from surgery to endovascular treatment.

Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians

A recent genome-wide study revealed an association between variation in the PNPLA3 gene and liver fat content. In addition, the PNPLA3 single-nucleotide polymorphism rs738409 (M148I) was reported to be associated with advanced alcoholic liver disease in alcohol-dependent individuals of Mestizo descent. We therefore evaluated the impact of rs738409 on the manifestation of alcoholic liver disease in two independent German cohorts. Genotype and allele frequencies of rs738409 (M148I) were determined in 1,043 alcoholic patients with or without alcoholic liver injury and in 376 at-risk drinkers from a population-based cohort. Relative to alcoholic patients without liver damage (n = 439), rs738409 genotype GG was strongly overrepresented in patients with alcoholic liver cirrhosis (n = 210; OR 2.79; P(genotype) = 1.2 × 10(-5) ; P(allelic) = 1.6 × 10(-6) ) and in alcoholic patients without cirrhosis but with elevated alanine aminotransferase levels (n = 219; OR 2.33; P(genotype) = 0.0085; P(allelic) = 0.0042). The latter, biochemically defined association was confirmed in an independent population-based cohort of at-risk drinkers with a median alcohol intake of 300 g/week (OR 4.75; P(genotype) = 0.040; P(allelic) = 0.022), and for aspartate aminotransferase (AST) levels. Frequencies of allele PNPLA3 rs738409(G) in individuals with steatosis and normal alanine aminotransferase (ALT) and AST levels were lower than in alcoholics without steatosis and normal ALT/AST (P(combined) = 0.03). The population attributable risk of cirrhosis in alcoholic carriers of allele PNPLA3 rs738409(G) was estimated at 26.6%. CONCLUSION: Genotype PNPLA3 rs738409(GG) is associated with alcoholic liver cirrhosis and elevated aminotransferase levels in alcoholic Caucasians.

Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

Standard procedures for adults in accredited sleep medicine centres in Europe

The present paper describes standardized procedures within clinical sleep medicine. As such, it is a continuation of the previously published European guidelines for the accreditation of sleep medicine centres and European guidelines for the certification of professionals in sleep medicine, aimed at creating standards of practice in European sleep medicine. It is also part of a broader action plan of the European Sleep Research Society, including the process of accreditation of sleep medicine centres and certification of sleep medicine experts, as well as publishing the Catalogue of Knowledge and Skills for sleep medicine experts (physicians, non-medical health care providers, nurses and technologists), which will be a basis for the development of relevant educational curricula. In the current paper, the standard operational procedures sleep medicine centres regarding the diagnostic and therapeutic management of patients evaluated at sleep medicine centres, accredited according to the European Guidelines, are based primarily on prevailing evidence-based medicine principles. In addition, parts of the standard operational procedures are based on a formalized consensus procedure applied by a group of Sleep Medicine Experts from the European National Sleep Societies. The final recommendations for standard operational procedures are categorized either as 'standard practice', 'procedure that could be useful', 'procedure that is not useful' or 'procedure with insufficient information available'. Standard operational procedures described here include both subjective and objective testing, as well as recommendations for follow-up visits and for ensuring patients' safety in sleep medicine. The overall goal of the actual standard operational procedures is to further develop excellence in the practice and quality assurance of sleep medicine in Europe.

Scheduler-dependent inter-cell interference and its impact on LTE uplink performance at flow level

The Long Term Evolution (LTE) cellular technology is expected to extend the capacity and improve the performance of current 3G cellular networks. Among the key mechanisms in LTE responsible for traffic management is the packet scheduler, which handles the allocation of resources to active flows in both the frequency and time dimension. This paper investigates for various scheduling scheme how they affect the inter-cell interference characteristics and how the interference in turn affects the user’s performance. A special focus in the analysis is on the impact of flow-level dynamics resulting from the random user behaviour. For this we use a hybrid analytical/simulation approach which enables fast evaluation of flow-level performance measures. Most interestingly, our findings show that the scheduling policy significantly affects the inter-cell interference pattern but that the scheduler specific pattern has little impact on the flow-level performance.