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The concept of liver fibrosis and cirrhosis being static and therefore irreversible is outdated. Indeed, both human and animal studies have shown that fibrogenesis is a dynamic and potentially reversible process that can be modulated either by stopping its progression and/or by promoting its resolution. Therefore, the study of the molecular mechanisms involved in the pathogenesis of liver fibrosis is critical for the development of future antifibrotic therapies. The fibrogenesis process, common to all forms of liver injury, is characterized by the increased deposition of extracellular matrix components (EMCs), including collagen, proteoglycans, and glycoproteins (laminin and fibronectin 2). These changes in the composition of the extracellular matrix components alter their interaction with cell adhesion molecules, influencing the modulation of cell functions (growth, migration, and gene expression). Hepatic stellate cells and Kupffer cells (liver macrophages) are the key fibrogenic effectors. The antifibrogenic mechanism starts with the activation of Ly6Chigh macrophages, which can differentiate into macrophages with antifibrogenic action. The research of biochemical changes affecting fibrosis irreversibility has identified lysyl oxidase-like 2 (LOXL2), an enzyme that promotes the network of collagen fibers of the extracellular matrix. LOXL2 inhibition can decrease cell numbers, proliferation, colony formations, and cell growth, and it can induce cell cycle arrest and increase apoptosis. The development of a new humanized IgG4 monoclonal antibody against LOXL2 could open the window of a new antifibrogenic treatment. The current therapeutic target in patients with liver cirrhosis should focus (after the eradication of the causal agent) on the development of new antifibrogenic drugs. The development of these drugs must meet three premises: Patient safety, in non-cirrhotic phases, down-staging or at least stabilization and slowing the progression to cirrhosis must be achieved; whereas in the cirrhotic stage, the objective should be to reduce fibrosis and portal pressure.

Background & Aims: Growing evidence suggests an increased prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in the context of immune-mediated inflammatory diseases (IMIDs). We aimed to clinically and mechanistically characterize steatotic liver disease (SLD) in a prospective cohort of patients with IMID compared to controls. Methods: Cross-sectional, case-control study including a subset of patients with IMID. Controls from the general population were age-, sex-, type 2 diabetes-, and BMI-matched at a 1:2 ratio. SLD was established using controlled attenuation parameter. Liver biopsies were obtained when significant liver fibrosis was suspected. Total RNA was extracted from freshly frozen cases and analyzed by RNA-seq. Differential gene expression was performed with ‘limma-voom’. Gene set-enrichment analysis was performed using the fgsea R package with a preranked “limma t-statistic” gene list. Results: A total of 1,456 patients with IMID and 2,945 controls were included. Advanced SLD (liver stiffness measurement ≥9.7 kPa) (13.46% vs. 3.79%; p

Abstract Different reports have shown the clinical and serologic response to the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) messenger RNA (mRNA) vaccines in preventing coronavirus disease 2019 (COVID‐19) in the general population, but few studies have examined these responses in transplant recipients. We assessed the vaccine immunogenicity of two doses (100 μg) of the mRNA‐1273 vaccine (Moderna) administered with a 28‐day interval in liver transplant recipients (LTRs) at follow‐up at the Marques de Valdecilla University Hospital. LTRs without a history of COVID‐19 infection were tested for SARS‐CoV‐2 immunoglobulin G (IgG) antibodies directed against the spike protein (S) a median of 43 days after receiving the second Moderna vaccine dose. Clinical data, including immunosuppressive regimen and routine laboratory data, were obtained from the medical record of each patient up to 3 months before the date of the first vaccination. Factors associated with serologic response were evaluated through logistic regression. In total, 129 LTRs who had anti‐S results were included. Most patients were men (n = 99; 76.7%) with a median age of 63 years (interquartile range, 56–68). Alcohol (43.4%) and chronic hepatitis C (18.6%) were the most frequent causes of liver transplantation. A positive anti‐S IgG response was observed in 113 LTRs (87.6%; 95% confidence interval [CI], 80.8–92.2). A strong inverse relationship between mycophenolate mofetil use and serologic response was found (odds ratio, 0.07; 95% CI, 0.02–0.26; p = 0.001). Conclusion: Most LTRs develop an immunological response to the Moderna SARS‐CoV‐2 mRNA‐based vaccine. An immunosuppressive regimen that includes mycophenolate predicts a weak serologic response.

The selection of the anesthetic regime is a crucial component in many experimental animal studies. In rodent models of liver disease, the combination of ketamine and diazepam (KD), generally by the intramuscular (i.m.) route, has traditionally been the anesthesia of choice for the evaluation of systemic and hepatic hemodynamics but it presents several problems. Here, we compared the performance of inhalational sevoflurane (Sevo) against the KD combination as the anesthesia used for hemodynamic studies involving the measurement of portal pressure in normal rats (Ctrl) and rats with non-cirrhotic portal hypertension induced by partial portal vein ligation (PPVL). Compared with Ctrl rats, rats with PPVL presented characteristic alterations that were not influenced by the anesthetic regime, which included liver atrophy, splenomegaly, increased plasma fibrinogen, decreased alkaline phosphatase and glycemia, and frequent ascites. The use of the KD combination presented several disadvantages compared with the inhalational anesthesia with sevoflurane, including considerable mortality, a higher need of dose adjustments to maintain an optimal depth of anesthesia, increases of heart rate, and alteration of blood biochemical parameters such as the concentration of aspartate aminotransferase, lactate, and lactic dehydrogenase. Rats anesthetized with sevoflurane, on the other hand, presented lower respiratory rates. Importantly, the anesthetic regime did not influence the measurement of portal pressure either in Ctrl or PPVL rats, with the increase of portal pressure being similar in Sevo- and KD- anesthetized groups of PPVL rats compared with their respective control groups. Overall, our results suggest that anesthesia with sevoflurane is preferable to the combination of KD for performing systemic and hepatic hemodynamic studies in rats with non-cirrhotic portal hypertension.

Liver disease resulting from heart failure (HF) has generally been referred as “cardiac hepatopathy”. One of its main forms is congestive hepatopathy (CH), which results from passive venous congestion in the setting of chronic right-sided HF. The current spectrum of CH differs from earlier reports with HF, due to ischemic cardiomyopathy and congenital heart disease having surpassed rheumatic valvular disease. The chronic passive congestion leads to sinusoidal hypertension, centrilobular fibrosis, and ultimately, cirrhosis (“cardiac cirrhosis”) and hepatocellular carcinoma after several decades of ongoing injury. Contrary to primary liver diseases, in CH, inflammation seems to play no role in the progression of liver fibrosis, bridging fibrosis occurs between central veins to produce a “reversed lobulation” pattern and the performance of non-invasive diagnostic tests of liver fibrosis is poor. Although the clinical picture and prognosis is usually dominated by the underlying heart condition, the improved long-term survival of cardiac patients due to advances in medical and surgical treatments are responsible for the increased number of liver complications in this setting. Eventually, liver disease could become as clinically relevant as cardiac disease and further complicate its management.

Mixed cryoglobulinemia (MC) is a small-vessel systemic vasculitis characterized by the presence of cryoglobulins, immunoglobulin complexes that precipitate at low temperatures (< 37 ºC) inducing the inflammatory process. The most frequent etiology is hepatitis C infection (HCV) (1). Rituximab (RTX), an anti-CD20 monoclonal antibody, has recently emerged as the treatment of choice for severe MC (2). We present a case of severe hepatitis C virus-induced MC that was controlled and maintained in remission with RTX for 26 months, a remarkable prolonged period of time.

Este artículo trata de hacer un análisis prosopográfico de los corregidores castellanos en el periodo 1588-1633. El autor traza un esbozo general del origen de los corregidores, de su perfil social, de las trayectorias vitales y profesionales de los candidatos y de las razones que determinaron su nombramiento. Este fue el resultado de un proceso de decisión complejo en el que el origen social, la capacitación profesional y la experiencia previa en oficios de gobierno y de justicia de los candidatos se combinaron con sus conexiones familiares y políticas, la gracia real y el servicio a la Corona para producir un tipo de corregidor socialmente homogéneo en el que la condición de caballero acabó convirtiéndose en su rasgo más característico.This article tries to make a prosopographical analysis of the Castilian corregidores appointed by the Crown in the period 1588-1633. It draws a general draft about their origin, their social profile and their professional and political activities, concluding with an analysis of the reasons that led to their appointment by the Crown. This was the result of a complex decision process in which social background, professional training and previous experience of the candidates were combined with their family and political connections, the royal grace and the service to the Crown in order to produce a socially homogeneous type of corregidor in which his hidalgo condition eventually became its most characteristic feature.

This article tries to make a prosopographical analysis of the Castilian corregidores appointed by the Crown in the period 1588-1633. It draws a general draft about their origin, their social profile and their professional and political activities, concluding with an analysis of the reasons that led to their appointment by the Crown. This was the result of a complex decision process in which social background, professional training and previous experience of the candidates were combined with their family and political connections, the royal grace and the service to the Crown in order to produce a socially homogeneous type of corregidor in which his hidalgo condition eventually became its most characteristic feature.

This article is intended as a comparative study of the course of institutional, social and political development in the regimes of municipal government in the Crown of Castile and the Crown of Aragon throughout the Modern Age. The obvious differences between the models of institutional organisation of urban government typical of either kingdom are clearly identified, but the study also highlights the similarities of the principles underlying either model, and the convergence of the objectives that they pursued. The study also analyses the processes, having their own specific forms in either territory, that brought about the formation of a municipal oligarchy which was socially heterogeneous in origin but progressively achieve cohesion around common values, properties and ways of life. Finally, the article examines the principles inspiring the Crown and the objectives that it pursued in its relations with local power elites in the municipalities of the two Crowns.

Independientemente del hecho de que todavía quede mucho camino por recorrer, es indudable que en los últimos años el uso de documentación fiscal ha permitido progresar de forma apreciable en el conocimiento del volumen demográfico, el perfil socioprofesional, las actividades económicas o las estructuras agrarias de determinadas poblaciones o comarcas. También se ha avanzado de forma apreciable en los planteamientos propiamente políticos del hecho fiscal. No obstante, apenas si se ha abordado con carácter monográfico el problema de las actitudes sociales ante el fisco. La cuestión, sin embargo, tiene su importancia. Como es bien sabido, la progresión de la fiscalidad real se convirtió en un hecho constitutivo del Estado Moderno que por la magnitud de las demandas de la Monarquía alteraba el marco consuetudinario de relaciones en el que hasta entonces se habían movido monarcas y subditos a este respecto. Indudablemente, la cuestión no está sólo en que las necesidades de las Monarquías obligarán a extraer más recursos de sus subditos, o, al menos, a intentarlo, con ser esto de por sí una novedad, sino también en las vías y formas por las que se canalizaron las nuevas demandas del Estado.

RESUMEN: A fines del reinado de Felipe II se acumularon diversos memoriales que pretendían solucionar los problemas financieros, económicos y políticos con los que se enfrentaba por entonces la Monarquía. Eran tres los puntos fundamentales que aquéllos se planteaban: cómo sanear la hacienda regia, qué papel había de jugar el Reino a este respecto y cómo podía lograrse una más equitativa distribución de los costes de su defensa. El artículo analiza diversas propuestas de sentido contradictorio nacidas en el seno del Consejo de Hacienda y trata de exponer las razones por la que acabó imponiéndose la vía de los servicios sobre la de los arbitrios o la de los impuestos como la más idónea para solucionar los problemas planteados, valorando las implicaciones políticas de la opción escogida.ABSTRACT: At the end of the reign of king Philip II many memorials were written in an attempt to solve the financial, economic and political difficulties faced by the Monarchy. The problem consisted of three main points: increasing the revenue of the Royal Treasury; defining the role to be played by the Kingdom in this respect; determining how its defence costs could be more equitably shared. This article studies different contradictory proposals drawn up by members of the Council of Finance and puts forward the reasons why subsidies were finally prefered over arbitrios or taxes. The political implications of this decision are also discussed.

Background and aims: The regression of liver fibrosis and portal hypertension (PH) and their influence on the natural history of compensated hepatitis C virus (HCV)-related cirrhosis has not been studied previously. Our objective was to evaluate the influence of sustained virologic response (SVR) on the portal pressure gradient (HVPG) and non-invasive parameters of PH and prognostic factors of response. Methods: Sixteen patients with compensated HCV genotype 1-related cirrhosis with PH (HVPG > 6 mmHg) without beta-blocker therapy were considered as candidates for PEGα2a + RBV + BOC (48 weeks; lead-in and accepted stopping rules). A hemodynamic study and Fibroscan® were performed at baseline, at eight weeks and, in the case of SVR, 24 weeks after treatment. In each hemodynamic study, serum samples were analyzed for inflammatory biomarkers associated with PH. Results: In eight cases, SVR was obtained; five patients relapsed, and treatment was stopped early for non-response to lead in (one case) and a decrease of < 3 log at week 8 (two patients). Compared to baseline, there was a significant decrease in HVPG and Fibroscan® at weeks 8 and 72 (10.31 ± 4.3 vs 9.4 ± 5.04 vs 6.1 ± 3.61 mmHg, p < 0.0001 and 21.3 ± 14.5 vs 16.2 ± 9.5 vs 6.4 ± 4.5 kPa, p < 0.0001, respectively). The average HVPG decrease in SVR was 40.8 ± 17.53%, achieving an HVPG < 6 mmHg in five patients (62.5%) and a Fibroscan® < 7.1 kPa in three patients (37.5%). Conclusions: Complete hemodynamic response (HVPG < 6 mmHg) and fibrosis regression (Fibroscan® < 7.1 kPa) occur in more than half and one-third of patients achieving SVR, respectively, and must be another target in cirrhotic patients with SVR.