Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic-ischemic brain injury on neurocognitive outcome (ALBINO): Study protocol of a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III)

Background: Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia. Methods: This study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age 65 36 weeks and a birth weight 65 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion. Discussion: This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia. Trial registration: NCT03162653, www.ClinicalTrials.gov, May 22, 2017

Breast cancer risk genes: association analysis in more than 113,000 women

BACKGROUNDGenetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.METHODSWe used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity.RESULTSProtein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants.CONCLUSIONSThe results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.)Molecular tumour pathology - and tumour geneticsMTG1 - Moleculaire genetica en pathologie van borstkanke

Recruitment processes in Baltic sprat - A re-evaluation of GLOBEC Germany hypotheses

The GLOBEC Germany program (2002–2007) had the ambitious goal to resolve the processes impacting the recruitment dynamics of Baltic sprat (Sprattus sprattus L.) by examining various factors affecting early life history stages. At the start of the research program, a number of general recruitment hypotheses were formulated, i.e. focusing on (1) predation, (2) food availability, (3) physical parameters, (4) the impact of current systems, and finally (5) the importance of top-down vs bottom-up effects. The present study synthesizes the results of field sampling (2002 and 2003), laboratory experiments, and modeling studies to re-evaluate these hypotheses for the Baltic sprat stock. Recruitment success was quite different in the 2 years investigated. Despite a lower spawning stock biomass in 2003, the total number of recruits was almost 2-fold higher that year compared to 2002. The higher recruitment success in 2003 could be attributed to enhanced survival success during the post-larval/juvenile stage, a life phase that appears to be critical for recruitment dynamics. In the state of the Baltic ecosystem during the period of investigation, we consider bottom-up control (e.g. temperature, prey abundance) to be more important than top-down control (predation mortality). This ranking in importance does not vary seasonally. Prevailing water circulation patterns and the transport dynamics of larval cohorts have a strong influence on sprat recruitment success. Pronounced transport to coastal areas is detrimental for year-class strength particularly at high sprat stock sizes. A suggested mechanism is density-dependant regulation of survival via intra- and inter-specific competition for prey in coastal areas. A documented change in larval vertical migration behavior between the early 1990s and early 2000s increased the transport potential to the coast, strengthening the coupling between inter-annual differences in the magnitude and direction of wind-driven surface currents and year-to-year changes in reproductive success. However, due to the strong linkages and feed-back loops in the Baltic Sea food web, the most robust projections of the future strength of the Baltic sprat stock will need to take into account climate-driven changes in both abiotic (e.g., drift trajectories) and biotic (trophodynamic) factors. Although our understanding of processes affecting pre-recruit (larval) growth and survival has been advanced by the integrated research conducted within the GLOBEC Germany program, key mechanisms potentially affecting life stages outside of the spawning basins remain to be explored including the dynamics of coastal habitats of juveniles and the feeding and overwintering grounds of adults. Highlights: ► Food limitation may contribute to the formation of seasonal ‘windows of survival’. ► Change in larval migration exalted the importance of transport. ► Temperature is the most important physical factor influencing sprat recruitment. ► Bottom-up control is more important than top-down control. ► Projected Baltic water temperature increase suggests higher sprat recruitment potential

The GEO600 gravitational wave detector

The GEO600 Gravitational Wave Detector is currently under construction near Hannover / Germany as a collaboration of scientists from Germany and Great Britain. Although only intermediate in size, the GEO600 detector has a good chance to achieve a sensitivity comparable to the first version of the large baseline detectors. This is due to the fact that GEO600 uses signal recycling, an advanced optical technique to shape the coupling of the optical read-out noise into the detector strain sensitivity, and a low-loss suspension system to reduce thermal noise. This talk will describe the different subsystems of the GEO600 and the current status of the construction will be outlined

The GEO 600 gravitational wave detector

The GEO 600 laser interferometer with 600 m armlength is part of a worldwide network of gravitational wave detectors. Due to the use of advanced technologies like multiple pendulum suspensions with a monolithic last stage and signal recycling, the anticipated sensitivity of GEO 600 is close to the initial sensitivity of detectors with several kilometres armlength. This paper describes the subsystems of GEO 600, the status of the detector by September 2001 and the plans towards the first science run