Untargeted lipidomics uncovers lipid signatures distinguishing severe versus moderate forms of acutely decompensated cirrhosis

BACKGROUND AND AIM: Acutely decompensated of cirrhosis is a heterogeneous clinical entity associated with moderate mortality. In some patients, this condition develops quickly into a more often deadly acute-on-chronic liver failure (ACLF), in which other organs such as the kidneys or brain fail. The aim of this study was to characterize the blood lipidome in a large series of patients with cirrhosis and identify specific signatures associated with acute decompensation and ACLF development. METHODS: Serum untargeted lipidomics was performed in 561 patients with acutely decompensated (AD) cirrhosis (518 without and 43 with ACLF) (discovery cohort) and in 265 AD patients (128 without and 137 with ACLF) in whom serum samples were available to perform repeated measurements during the 28-day follow-up (validation cohort). Analyses were also performed in 78 AD patients included in a therapeutic albumin trial, 43 patients with compensated cirrhosis and 29 healthy subjects. RESULTS: The circulating lipid landscape associated with cirrhosis was characterized by a generalized suppression, which was more manifest during acute decompensation and in non-surviving patients. By computing discriminating accuracy and the variable importance projection score for each of the 223 annotated lipids, we identified a sphingomyelin fingerprint specific for AD cirrhosis and a distinct cholesteryl ester and lysophosphatidylcholine fingerprint for ACLF. Liver dysfunction, mainly, and infections were the principal net contributors to these fingerprints, which were dynamic and interchangeable between AD patients whose condition worsened to ACLF and those who improved. Notably, blood lysophosphatidylcholine levels increased in these patients after albumin therapy. CONCLUSIONS: Our findings provide insights into the lipid landscape associated with decompensation of cirrhosis and ACLF progression and identify unique noninvasive diagnostic biomarkers of advanced cirrhosis. LAY SUMMARY: Analysis of lipids in blood from patients with advanced cirrhosis reveals a general suppression of their levels in the circulation of these patients. A specific group of lipids known as sphingomyelins are useful to distinguish compensated from decompensated patients with cirrhosis. Another group of lipids designated cholesteryl esters further distinguish patients with decompensated patients who are at risk of developing organ failures

SoxD genes are required for adult neural stem cell activation

19 páginas, 6 figuras. Supplemental information can be found online at https://doi.org/10.1016/j. celrep.2022.110313.The adult neurogenic niche in the hippocampus is maintained through activation of reversibly quiescent neural stem cells (NSCs) with radial glia-like morphology (RGLs). Here, we show that the expression of SoxD transcription factors Sox5 and Sox6 is enriched in activated RGLs. Using inducible deletion of Sox5 or Sox6 in the adult mouse brain, we show that both genes are required for RGL activation and the generation of new neurons. Conversely, Sox5 overexpression in cultured NSCs interferes with entry in quiescence. Mechanistically, expression of the proneural protein Ascl1 (a key RGL regulator) is severely downregulated in SoxD-deficient RGLs, and Ascl1 transcription relies on conserved Sox motifs. Additionally, loss of Sox5 hinders the RGL activation driven by neurogenic stimuli such as environmental enrichment. Altogether, our data suggest that SoxD genes are key mediators in the transition of adult RGLs from quiescence to an activated mitotic state under physiological situations.This work was funded by grants to A.V.M. from the Spanish MICINN (SAF2017-85717-R, PID2020-112989RB-I00) and F. Alicia Koplowitz (2018) and to H.M. from the Spanish MICINN (SAF2015-70433-R, PID2019- 111225RB-I00) and PROMETEO/2018/055 from Generalitat ValencianaPeer reviewe

Artrodesis cervical con cajas de tantalio

Debida a su baja morbilidad y tasa de complicaciones, la discectomía cervical y fusión anterior ha ganado gran aceptación en los últimos 30 años en los que ha evolucionado desde su primera descripción. La esponja de tantalio se ha mostrado como un material ideal para fabricar cajas intersomáticas cervicales y lumbares debido a su alta porosidad, estabilidad y elasticidad parecida a la del hueso. Presentamos la técnica quirúrgica y nuestros resultados en los 12 primeros pacientes intervenidos en nuestra institución con un seguimiento mínimo de seis meses. No se ha recogido ninguna complicación intraoperatoria significativa. En ningún caso se empleó injerto óseo asociado a la caja. Los resultados clínicos han sido evaluados con los criterios de Odom y con las escalas de Oswestry y de Zung. La consolidación radiológica se ha considerado teniendo en cuenta los criterios de Cannada et al., y se han medido las diferencias del ángulo de Cobb y de la distancia interespinosas entre los espacios artrodesados en las radiografías dinámicas. No se ha observado ningún caso de pseudoartrosis. El implante ha mostrado una fácil y reproducible implantación quirúrgica y una rápida integración radiológica. La caja de tantalio para la artrodesis cervical representa un avance real, sin embargo, aún es perfectible desde el punto de vista técnico

Long-chain acylcarnitines promote leukocyte mitochondrial dysfunction: role in patients with acutely decompensated cirrhosis

Resumen del trabajo presentado en el International Liver Congress 2022: Savour science together again, celebrado en Londres (Gran Bretaña), del 22 al 26 de junio de 2022Background and aims: Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation (AD) of cirrhosis, organ failure (s) and high short-term mortality. The cytokinome of these patients revealed that exaggerated systemic inflammatory response is an important driver of disease progression. Recently, it has been demonstrated that the elevated circulating levels of acylcarnitines predict mortality in patients with AD and ACLF. Therefore, inflammation-associated mitochondrial dysfunction can be regarded as another major contributor to disease progression. Here, we hypothesize that acylcarnitines not only function as biomarkers of mitochondrial dysfunction but also exert biological effects on mitochondria of circulating immune cells. In addition, as organ donors are scarce, we explore whether existing treatments such as human serum albumin (HSA) might modulate the effect of acylcarnitines on mitochondrial function. Method: Peripheral blood mononuclear leukocytes from healthy subjects were isolated by Ficoll gradient and in vitro experiments were performed to assess mitochondrial function under treatment with long- and medium-chain acylcarnitines, in the presence or absence of HSA. We assessed mitochondrial membrane potential (MMP) with the cationic dye JC-1 and mitochondrial respiration using Agilent Seahorse XF technology. This was complemented by electron microscopic evaluation of mitochondrial ultrastructure of immune cells treated with acylcarnitines and expression analysis of genes involved in mitochondrial function and biogenesis. Results: Palmitoyl- and hexanoylcarnitine were increased in blood of patients with AD cirrhosis. In contrast to hexanoylcarnitine, the longchain palmitoylcarnitine impaired maximal respiration of leukocyte mitochondria and reduced MMP in peripheral mononuclear leukocytes without affecting cell viability. Palmitoylcarnitine also downregulated HMOX-1 gene expression in a concentration-dependent manner, indicating impairment of cell antioxidant responses. The effect of palmitoylcarnitine on HMOX-1 expression was reversed by etomoxir, an inhibitor of the carnitine palmitoyltransferase 1A located at the outer mitochondrial membrane. Finally, HSA partially reversed the MMP-reducing effect, without being physically localized to mitochondria. Conclusion: Our results indicate that elevated circulating long-chain acylcarnitines in patients with AD are not only an epiphenomenon but have the potential to actively promote mitochondrial dysfunction in immune cells, thereby contributing to immune dysbalance in these patients