Stiripentol fails to lower plasma oxalate in a dialysis-dependent PH1 patient

Background: Primary hyperoxaluria type 1 (PH1) is a multisystemic metabolic disorder caused by an excessive production of oxalate by the liver. The majority of patients presenting in early infancy have end-stage renal disease (ESRD). While awaiting the results of sRNAi trials, the current standard treatment is combined liver-kidney transplantation. Recently, Stiripentol has been reported as a promising drug in the treatment of primary hyperoxaluria by reducing urinary oxalate (UOx). Stiripentol is an anti-convulsive drug used in the treatment of children suffering from Dravet syndrome. It causes blockage of the last step in oxalate production by inhibition of hepatic lactate dehydrogenase 5 (LDH5). Case: We administered Stiripentol as compassionate use in an anuric infant with dialysis-dependent PH1 over a period of 4 months. Although achieving plasma concentrations of Stiripentol that were recently reported to lower UOx excretion, we did not observe significant reduction to plasma oxalate concentrations (POx). Conclusion: We conclude that Stiripentol may not be useful to reduce POx in PH patients with advanced chronic kidney disease (CKD), but larger studies are needed to confirm this finding

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Sedimentation rates and geochemical analysis of surface sediments from the South Atlantic

Extensive investigations of sedimentary barium were performed in the southern South Atlantic in order to assess the reliability of the barium signal in Antarctic sediments as a proxy for paleoproductivity. Maximum accumulation rates of excess barium were calculated for the Antarctic zone south of the polar front where silica accumulates at high rates. The correspondence between barium and opal supports the applicability of barium as a proxy for productivity. Within the Antarctic zone north of today's average sea ice maximum, interglacial vertical rain rates of excess barium are high, with a maximum occurring during the last deglaciation and early Holocene and during oxygen isotope chronozone 5.5. During these periods, the maximum silica accumulation was supposedly located south of the polar front. Glacial paleoproductivity, instead, was low within the Antarctic zone. North of the polar front, significantly higher barium accumulation occurs during glacial times. The vertical rain rates, however, are as high as in the glacial Antarctic zone. Therefore there was no evidence for an increased productivity in the glacial Southern Ocean

Neurite density imaging in amygdala nuclei reveals interindividual differences in neuroticism

Neuroticism is known to have significant health implications. While previous research revealed that interindividual differences in the amygdala function are associated with interindividual differences in neuroticism, the impact of the amygdala's structure and especially microstructure on variations in neuroticism remains unclear. Here, we present the first study using NODDI to examine the association between the in vivo microstructural architecture of the amygdala and neuroticism at the level of neurites. We, therefore, acquired brain images from 221 healthy participants using advanced multi-shell diffusion-weighted imaging. Because the amygdala comprises several nuclei, we, moreover, used a high-resolution T1 image to automatically segment the amygdala into eight different nuclei. Neuroticism and its facets have been assessed using the NEO-PI-R. Finally, we associated neuroticism and its facets with the volume and microstructure of the amygdala nuclei. Statistical analysis revealed that lower neurite density in the lateral amygdala nucleus (La) was significantly associated with higher scores in depression, one of the six neuroticism facets. The La is the sensory relay of the amygdala, filtering incoming information based on previous experiences. Reduced neurite density and related changes in the dendritic structure of the La could impair its filtering function. This again might cause harmless sensory information to be misevaluated as threatening and lead to the altered amygdala responsivity as reported in previous studies investigating the functional correlates of neuroticism and neuroticism-related disorders like depression

Cooperation Is Not Enough—Exploring Social-Ecological Micro-Foundations for Sustainable Common-Pool Resource Use

<div><p>Cooperation amongst resource users holds the key to overcoming the social dilemma that characterizes community-based common-pool resource management. But is cooperation alone enough to achieve sustainable resource use? The short answer is no. Developing management strategies in a complex social-ecological environment also requires ecological knowledge and approaches to deal with perceived environmental uncertainty. Recent behavioral experimental research indicates variation in the degree to which a group of users can identify a sustainable exploitation level. In this paper, we identify social-ecological micro-foundations that facilitate cooperative sustainable common-pool resource use. We do so by using an agent-based model (ABM) that is informed by behavioral common-pool resource experiments. In these experiments, groups that cooperate do not necessarily manage the resource sustainably, but also over- or underexploit. By reproducing the patterns of the behavioral experiments in a qualitative way, the ABM represents a social-ecological explanation for the experimental observations. We find that the ecological knowledge of each group member cannot sufficiently explain the relationship between cooperation and sustainable resource use. Instead, the development of a sustainable exploitation level depends on the distribution of ecological knowledge among the group members, their influence on each other’s knowledge, and the environmental uncertainty the individuals perceive. The study provides insights about critical social-ecological micro-foundations underpinning collective action and sustainable resource management. These insights may inform policy-making, but also point to future research needs regarding the mechanisms of social learning, the development of shared management strategies and the interplay of social and ecological uncertainty.</p></div