935-38 Restenosis After Coronary Angioplasty is Associated with the Activation Status of Circulating Phagocytes Before Treatment

BackgroundThe purpose of this study was to identify biological risk factors for restenosis after PTCA, in order to predict the long-term outcome of PTCA before treatment.Methods and ResultsTo investigate whether blood granulocytes and monocytes could determine luminal renarrowing after PTCA, several characteristics of these phagocytes were assessed before angioplasty in 32 patients who underwent PTCA of one coronary artery and who had repeat angiograms at six months follow-up. The plasma levels 1L-1β, TNF-α, IL-6, fibrinogen, C-reactive protein and LP(a) before angioplasty were assessed as well. We found that the expression of the membrane antigens CD64, CD66 and CD67 by granulocytes was inversely associated with the luminal renarrowing normalized for vessel size (relative loss) at six months after PTCA. while the production of IL-1β by stimulated monocytes was positively associated with the relative loss. Next. these univariate predictors were corrected for the established clinical risk factors, dilation of the LAD, current smoking and angina class.Multiple linear regression analysis showed that luminal renarrowing could be predicted reliably (R2=0.65; P<0.0001) in this patients group on the basis of the vessel dilated and only two biological risk factors that reflect the activation status of blood phagocytes, i.e., the expression of CD66 by granulocytes and the production of IL-lβ by stimulated monocytes.ConclusionsThe results of the present study indicate that activated blood granulocytes prevent luminal renarrowing after PTCA, while activated blood monocytes promote restenosis. To validate this new finding further study in an independent patients group is required

The effect of desferrioxamine on iron metabolism and lipid peroxidation in hepatocytes of C57BL/10 mice in experimental uroporphyria

The effects of the iron chelator desferrioxamine (DFx) on liver iron accumulation, malondialdehyde (MDA) production, porphyrin accumulation and uroporphyrinogen decarboxylase (URO-D; EC 4.1.1.37) activity were investigated over a period of 14 weeks in C57BL/10 mice, made porphyric by the administration of hexachlorobenzene (HCB) and iron-dextran (Imferon, IMF) or IMF alone. In addition, we measured the amount of low molecular weight (LMW) iron in liver tissue to determine a possible correlation with MDA production. These experiments showed that combined treatment with HCB + IMF, as well as IMF alone, resulted in porphyrin accumulation, increased MDA production and reduced URO-D activity, whereas HCB alone had no effect. DFx caused a reduction in hepatic porphyrins, this reduction being more distinct in the IMF group than in the HCB + IMF group. The effect of DFx on MDA production and URO-D activity was in agreement with the results on porphyrin accumulation. LMW iron pool measurements at 11 weeks correlated well with data on MDA production in all treated groups in that period (r2 = 0.84), suggesting both variables are interdependent. In conclusion, these results suggest an important role for iron in porphyrin accumulation, probably through its catalytic role in the generation of oxygen-related free radicals, resulting in direct damage to URO-D. The effectiveness of DFx in reducing porphyrin accumulation is probably the result of a reduction in LMW iron, thus diminishing the amount of iron available for a catalytic role in the generation of oxygen-related free radicals

Impacts of meeting minimum access on critical earth systems amidst the Great Inequality

The Sustainable Development Goals aim to improve access to resources and services, reduce environmental degradation, eradicate poverty and reduce inequality. However, the magnitude of the environmental burden that would arise from meeting the needs of the poorest is under debate—especially when compared to much larger burdens from the rich. We show that the ‘Great Acceleration’ of human impacts was characterized by a ‘Great Inequality’ in using and damaging the environment. We then operationalize ‘just access’ to minimum energy, water, food and infrastructure. We show that achieving just access in 2018, with existing inequalities, technologies and behaviours, would have produced 2–26% additional impacts on the Earth’s natural systems of climate, water, land and nutrients—thus further crossing planetary boundaries. These hypothetical impacts, caused by about a third of humanity, equalled those caused by the wealthiest 1–4%. Technological and behavioural changes thus far, while important, did not deliver just access within a stable Earth system. Achieving these goals therefore calls for a radical redistribution of resources

Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes

Neuroblastoma is a childhood tumour of the peripheral sympathetic nervous system. The pathogenesis has for a long time been quite enigmatic, as only very few gene defects were identified in this often lethal tumour. Frequently detected gene alterations are limited to MYCN amplification (20%) and ALK activations (7%). Here we present a whole-genome sequence analysis of 87 neuroblastoma of all stages. Few recurrent amino-acid-changing mutations were found. In contrast, analysis of structural defects identified a local shredding of chromosomes, known as chromothripsis, in 18% of high-stage neuroblastoma. These tumours are associated with a poor outcome. Structural alterations recurrently affected ODZ3, PTPRD and CSMD1, which are involved in neuronal growth cone stabilization. In addition, ATRX, TIAM1 and a series of regulators of the Rac/Rho pathway were mutated, further implicating defects in neuritogenesis in neuroblastoma. Most tumours with defects in these genes were aggressive high-stage neuroblastomas, but did not carry MYCN amplifications. The genomic landscape of neuroblastoma therefore reveals two novel molecular defects, chromothripsis and neuritogenesis gene alterations, which frequently occur in high-risk tumours

A metagenomic portrait of the microbial community responsible for two decades of bioremediation of poly-contaminated groundwater

Biodegradation of pollutants is a sustainable and cost-effective solution to groundwater pollution. Here, we investigate microbial populations involved in biodegradation of poly-contaminants in a pipeline for heavily contaminated groundwater. Groundwater moves from a polluted park to a treatment plant, where an aerated bioreactor effectively removes the contaminants. While the biomass does not settle in the reactor, sediment is collected afterwards and used to seed the new polluted groundwater via a backwash cycle. The pipeline has successfully operated since 1999, but the biological components in the reactor and the contaminated park groundwater have never been described. We sampled seven points along the pipeline, representing the entire remediation process, and characterized the changing microbial communities using genome-resolved metagenomic analysis. We assembled 297 medium- and high-quality metagenome-assembled genome sequences representing on average 46.3% of the total DNA per sample. We found that the communities cluster into two distinct groups, separating the anaerobic communities in the park groundwater from the aerobic communities inside the plant. In the park, the community is dominated by members of the genus Sulfuricurvum, while the plant is dominated by generalists from the order Burkholderiales. Known aromatic compound biodegradation pathways are four times more abundant in the plant-side communities compared to the park-side. Our findings provide a genome-resolved portrait of the microbial community in a highly effective groundwater treatment system that has treated groundwater with a complex contamination profile for two decades

Achieving a nature- and people-positive future

Despite decades of increasing investment in conservation, we have not succeeded in “bending the curve” of biodiversity decline. Efforts to meet new targets and goals for the next three decades risk repeating this outcome due to three factors: neglect of increasing drivers of decline; unrealistic expectations and time frames of biodiversity recovery; and insufficient attention to justice within and between generations and across countries. Our Earth system justice approach identifies six sets of actions that when tackled simultaneously address these failings: (1) reduce and reverse direct and indirect drivers causing decline; (2) halt and reverse biodiversity loss; (3) restore and regenerate biodiversity to a safe state; (4) raise minimum wellbeing for all; (5) eliminate over-consumption and excesses associated with accumulation of capital; and (6) uphold and respect the rights and responsibilities of all communities, present and future. Current conservation campaigns primarily address actions 2 and 3, with urgent upscaling of actions 1, 4, 5, and 6 needed to help deliver the post-2020 global biodiversity framework

Safe and just Earth system boundaries

The stability and resilience of the Earth system and human well-being are inseparably linked 1-3, yet their interdependencies are generally under-recognized; consequently, they are often treated independently 4,5. Here, we use modelling and literature assessment to quantify safe and just Earth system boundaries (ESBs) for climate, the biosphere, water and nutrient cycles, and aerosols at global and subglobal scales. We propose ESBs for maintaining the resilience and stability of the Earth system (safe ESBs) and minimizing exposure to significant harm to humans from Earth system change (a necessary but not sufficient condition for justice) 4. The stricter of the safe or just boundaries sets the integrated safe and just ESB. Our findings show that justice considerations constrain the integrated ESBs more than safety considerations for climate and atmospheric aerosol loading. Seven of eight globally quantified safe and just ESBs and at least two regional safe and just ESBs in over half of global land area are already exceeded. We propose that our assessment provides a quantitative foundation for safeguarding the global commons for all people now and into the future

Safe and just Earth system boundaries

The stability and resilience of the Earth system and human well-being are inseparably linked1-3, yet their interdependencies are generally under-recognized; consequently, they are often treated independently4,5. Here, we use modelling and literature assessment to quantify safe and just Earth system boundaries (ESBs) for climate, the biosphere, water and nutrient cycles, and aerosols at global and subglobal scales. We propose ESBs for maintaining the resilience and stability of the Earth system (safe ESBs) and minimizing exposure to significant harm to humans from Earth system change (a necessary but not sufficient condition for justice)4. The stricter of the safe or just boundaries sets the integrated safe and just ESB. Our findings show that justice considerations constrain the integrated ESBs more than safety considerations for climate and atmospheric aerosol loading. Seven of eight globally quantified safe and just ESBs and at least two regional safe and just ESBs in over half of global land area are already exceeded. We propose that our assessment provides a quantitative foundation for safeguarding the global commons for all people now and into the future