Liver Transplantation in Acute Liver Failure: Indications and Outcome

The term acute liver failure (ALF) refers to the acute (<26 weeks) and severe worsening in liver function associated with encephalopathy in a person with no underlying chronic liver disease. ALF constitutes a critical clinical syndrome that is potentially reversible but has a very variable prognosis. No specific treatment is available, and liver transplantation (LT) is the treatment of choice in many cases. However, the challenge remains of identifying those patients with a poor likelihood of spontaneous recovery of liver function and for whom the indication and time of LT in order to guarantee survival (based on identification of prognostic factors) need to be established. In Europe, 8% of LT are due to ALF. Although the results of LT due to ALF have improved over recent years, they are still far from those seen after elective LT

Magnetic phase diagram of nanostructured zinc ferrite as a function of inversion degree delta

Magnetic properties of spinel zinc ferrites are strongly linked to the synthesis method and the processing route since they control the microstructure of the resulting material. In this work, ZnFe_2O_4 nanoparticles were synthesized by the mechanochemical reaction of stoichiometric ZnO and alpha-Fe2O3, and single-phase ZnFe_2O_4 was obtained after 150 h of milling. The as-milled samples, with a high inversion degree, were subjected to different thermal annealings up to 600 ºC to control the inversion degree and, consequently, the magnetic properties. The as-milled samples, with a crystallite size of 11 nm and inversion degree delta = 0.57, showed ferrimagnetic behavior even above room temperature, as shown by Rietveld refinements of the X-ray diffraction pattern and superconducting quantum interference device magnetometry. The successive thermal treatments at 300, 400, 500, and 600 degrees C decrease delta from 0.15 to 0.18, affecting the magnetic properties. A magnetic phase diagram as a function of delta can be inferred from the results: for delta 0.5, a new antiferromagnetic order appeared due to the overpopulation of nonmagnetic Zn on octahedral sites that leads to equally distributed magnetic cations in octahedral and tetrahedral sites

Comparative and functional genomics of the protozoan parasite Babesia divergens highlighting the invasion and egress processes

Babesiosis is considered an emerging disease because its incidence has significantly increased in the last 30 years, providing evidence of the expanding range of this rare but potentially life-threatening zoonotic disease. Babesia divergens is a causative agent of babesiosis in humans and cattle in Europe. The recently sequenced genome of B. divergens revealed over 3,741 protein coding-genes and the 10.7-Mb high-quality draft become the first reference tool to study the genome structure of B. divergens. Now, by exploiting this sequence data and using new computational tools and assembly strategies, we have significantly improved the quality of the B. divergens genome. The new assembly shows better continuity and has a higher correspondence to B. bovis chromosomes. Moreover, we present a differential expression analysis using RNA sequencing of the two different stages of the asexual lifecycle of B. divergens: the free merozoite capable of invading erythrocytes and the intraerythrocytic parasite stage that remains within the erythrocyte until egress. Comparison of mRNA levels of both stages identified 1,441 differentially expressed genes. From these, around half were upregulated and the other half downregulated in the intraerythrocytic stage. Orthogonal validation by real-time quantitative reverse transcription PCR confirmed the differential expression. A moderately increased expression level of genes, putatively involved in the invasion and egress processes, were revealed in the intraerythrocytic stage compared with the free merozoite. On the basis of these results and in the absence of molecular models of invasion and egress for B. divergens, we have proposed the identified genes as putative molecular players in the invasion and egress processes. Our results contribute to an understanding of key parasitic strategies and pathogenesis and could be a valuable genomic resource to exploit for the design of diagnostic methods, drugs and vaccines to improve the control of babesiosis.This work was funded by grants from Ministerio de Economía y Competitividad from Spain (AGL2010-21774 and AGL2014-56193 R to EM and LMG). ES was awarded a research fellowship from Plan Estatal de Investigación Científica y Técnica y de Innovación, Ministerio de Economía y Competitividad, Spain (http://www.mineco.gob.es/portal/site/mineco/). Work in CL’s laboratory is funded by a grant from the National Institutes of Health (https://www.nih.gov/) NIH- 1R01HL140625-01. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscriptS

Ferrimagnetic clusters as the origin of anomalous Curie-Weiss behavior in ZnFe_2O_4 antiferromagnetic susceptibility

Different studies carried out in the last three decades on the magnetic susceptibility of the spinel ZnFe_2O_4 ferrite have revealed the positive character of its Curie-Weiss temperature, contradicting its observed antiferromagnetic behavior which is characterized by a well-defined susceptibility peak centered around the Neel temperature (10 K). Some approaches based on ab initio calculations and mixture of interactions have been attempted to explain this anomaly. This work shows how for very low values of the inversion parameter, the small percentage of Fe atoms located in tetrahedral sites gives rise to the appearance of ferrimagnetic clusters around them. Superparamagnetism of these clusters is the main cause of the anomalous Curie-Weiss behavior. This finding is supported experimentally from the thermal dependence of the inverse susceptibility and its evolution with the degree of inversion

Incidence and prevalence of acute hepatitis E virus infection in patients with suspected Drug-Induced Liver Injury in the Spanish DILI Registry

Background and Aims: Drug-induced liver injury (DILI) presents with a wide phenotypic spectrum requiring an extensive differential diagnosis. Hepatitis E virus (HEV) is not systematically ruled out during acute hepatitis assessment in Spain. The aims of this study were to establish the role of HEV infection and its phenotypic presentation in patients initially suspected of DILI and to determine the anti-HEV seroprevalence rate. Methods: An analysis of 265 patients with suspected DILI and considered for enrolment in the Spanish DILI Registry and 108 controls with normal liver profiles was undertaken. Anti-HEV Immunoglobulin (Ig) G antibodies were analyzed in serum from all subjects. In those with serum samples extracted within 6 months from liver damage onset (n=144), HEV antigen (Ag) and anti- HEV IgM antibodies were tested in duplicate by ELISA. In addition, RT-PCR was performed externally in 8 patients. Results: Out of 144 patients, 12 (8%) were positive for anti-HEV IgM, mean age 61 years. Underlying hepatic diseases (OR=23.4, p20 folds upper limit of normal (OR=10.9, p=0.002) were associated with the diagnosis of acute hepatitis E. The overall anti-HEV IgG seroprevalence rate was 35%, evenly distributed between patients with suspected DILI (34%), and controls (39%). Conclusions: HEV seroprevalence and acute hepatitis E rates are relatively high in Spain. A search for active HEV infection is therefore advised in patients assessed for suspicion of DILI, particularly in patients with underlying liver diseases and high transaminase levels.The present study has been supported by grants of the Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional FEDER (contract numbers: FIS PI0274-2016, PI-0285- 2016, PI 18-01804, PI 18-00901, PT17/0017/0020, CM17/00243, JR16/00015, B-0002-2019, UMA-18-FEDERJA-193 and by the Agencia Española del Medicamento. SCReN and CIBERehd are funded by Instituto de Salud Carlos III. European Cooperation in Science & Technology (COST) ACTION CA17112 Prospective European Drug-Induced Liver Injury Network, IMI2-Translational Safety Biomarker Pipeline (TransBioLine). The funding sources had no involvement in the study design, in the collection, analysis, and interpretation of data, in the writing of the report or in the decision to submit the manuscript for publicatio

Unveiling the hidden entropy in ZnFe_2O_4

The antiferromagnetic (AFM) transition of the normal ZnFe_2O_4 has been intensively investigated with results showing a lack of long-range order, spin frustrations, and a "hidden" entropy in the calorimetric properties for inversion degrees delta approximate to 0 or delta = 0. As delta drastically impacts the magnetic properties, it is logical to question how a delta value slightly different from zero can affect the magnetic properties. In this work, (Zn_(1-delta)Fe_delta)[Zn_delta Fe_(2-delta)]O_4 with delta = 0.05 and delta = 0.27 have been investigated with calorimetry at different applied fields. It is shown that a delta value as small as 0.05 may affect 40% of the unit cells, which become locally ferrimagnetic (FiM) and coexists with AFM and spin disordered regions. The spin disorder disappears under an applied field of 1 T. Mossbauer spectroscopy confirms the presence of a volume fraction with a low hyperfine field that can be ascribed to these spin disordered regions. The volume fractions of the three magnetic phases estimated from entropy and hyperfine measurements are roughly coincident and correspond to approximately 1/3 for each of them. The "hidden" entropy is the zero point entropy different from 0. Consequently, the so-called "hidden" entropy can be ascribed to the frustrations of the spins at the interphase between the AFM-FiM phases due to having delta approximate to 0 instead of ideal delta = 0

Biomarkers and polymorphisms in pancreatic neuroendocrine tumors treated with sunitinib

Several circulating biomarkers and single nucleotide polymorphisms (SNPs) have been correlated with efficacy and tolerability to antiangiogenic agents. These associations remain unexplored in well-differentiated, metastatic pancreatic neuroendocrine tumors treated with the multitargeted tyrosine kinase inhibitor sunitinib. We have assessed the effect on tumor response at 6 months, overall survival, progression-free survival and safety of 14 SNPs, and 6 soluble proteins. Forty-three patients were recruited. Two SNPs in the vascular endothelial growth factor receptor 3 (VEGFR-3) gene predicted lower overall survival: rs307826 with hazard ratio (HR) 3.67 (confidence interval [CI] 95%, 1.35-10.00) and rs307821 with HR 3.84 (CI 95%, 1.47-10.0). Interleukin-6 was associated with increased mortality: HR 1.06 (CI 95%, 1.01-1.12), and osteopontin was associated with shorter PFS: HR 1.087 (1.01-1.16), independently of Ki-67. Furthermore, levels of osteopontin remained higher at the end of the study in patients considered non-responders: 38.5 ng/mL vs. responders: 18.7 ng/mL, p-value=0.039. Dynamic upward variations were also observed with respect to IL-8 levels in sunitinib-refractory individuals: 28.5 pg/mL at baseline vs. 38.3 pg/mL at 3 months, p-value=0.024. In conclusion, two VEGFR-3 SNPs as well as various serum biomarkers were associated with diverse clinical outcomes in patients with well-differentiated pancreatic neuroendocrine tumors treated with sunitinib

Comprehensive analysis and insights gained from long-term experience of the Spanish DILI Registry

Background & aims: Prospective drug-induced liver injury (DILI) registries are important sources of information on idiosyncratic DILI. We aimed to present a comprehensive analysis of 843 patients with DILI enrolled into the Spanish DILI Registry over a 20-year time period. Methods: Cases were identified, diagnosed and followed prospectively. Clinical features, drug information and outcome data were collected. Results: A total of 843 patients, with a mean age of 54 years (48% females), were enrolled up to 2018. Hepatocellular injury was associated with younger age (adjusted odds ratio [aOR] per year 0.983; 95% CI 0.974-0.991) and lower platelet count (aOR per unit 0.996; 95% CI 0.994-0.998). Anti-infectives were the most common causative drug class (40%). Liver-related mortality was more frequent in patients with hepatocellular damage aged ≥65 years (p = 0.0083) and in patients with underlying liver disease (p = 0.0221). Independent predictors of liver-related death/transplantation included nR-based hepatocellular injury, female sex, higher onset aspartate aminotransferase (AST) and bilirubin values. nR-based hepatocellular injury was not associated with 6-month overall mortality, for which comorbidity burden played a more important role. The prognostic capacity of Hy's law varied between causative agents. Empirical therapy (corticosteroids, ursodeoxycholic acid and MARS) was prescribed to 20% of patients. Drug-induced autoimmune hepatitis patients (26 cases) were mainly females (62%) with hepatocellular damage (92%), who more frequently received immunosuppressive therapy (58%).The present study has been supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional – FEDER (contract numbers: PI19/00883, PI16/01748, PI18/00901, PI18/01804, PI-0285-2016, PI-0274-2016, PI-0310- 2018, PT17/0017/0020) and Agencia Española del Medicamento. CIBERehd and Plataforma ISCIII Ensayos Clinicos are funded by Instituto de Salud Carlos III. MRD holds a Joan Rodes (JR16/ 00015)/Acción B clinicos investigadores (B-0002-2019) and JSC a Rio Hortega (CM17/00243) research contract from ISCIII and Consejería de Salud de Andalucía. The funding sources had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the report or in the de- cision to submit the manuscript for publication