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Purpose: Lack of diagnostic and prognostic biomarkers in hepatocellular carcinoma impedes stratifying patients based on their risk of developing cancer. The aim of this study was to evaluate phenotypic and genetic heterogeneity of circulating epithelial cells (CECs) based on asialoglycoprotein receptor 1 (ASGR1) and miR-122-5p expression as potential diagnostic and prognostic tools in patients with hepatocellular carcinoma (HCC) and liver cirrhosis (LC).Methods: Peripheral blood samples were extracted from LC and HCC patients at different disease stages. CECs were isolated using positive immunomagnetic selection. Genetic and phenotypic characterization was validated by double immunocytochemistry for cytokeratin (CK) and ASGR1 or by in situ hybridization with miR-122-5p and CECs were visualized by confocal microscopy.Results: The presence of CECs increased HCC risk by 2.58-fold, however, this was only significant for patients with previous LC (p = 0.028) and not for those without prior LC (p = 0.23). Furthermore, the number of CECs lacking ASGR1 expression correlated significantly with HCC incidence and absence of miR-122-5p expression (p = 0.014; r = 0.23). Finally, overall survival was significantly greater for patients at earlier cancer stages (p = 0.018), but this difference was only maintained in the group with the presence of CECs (p = 0.021) whereas progression-free survival was influenced by the absence of ASGR1 expression.Conclusion: Identification and characterization of CECs by ASGR1 and/or miR-122-5p expression may be used as a risk-stratification tool in LC patients, as it was shown to be an independent prognostic and risk-stratification marker in LC and early disease stage HCC patients.

RESUMEN Introducción: La insuficiencia cardíaca constituye un problema a nivel mundial y aumentará en los próximos años a consecuencia del envejecimiento poblacional. Se asocia a múltiples comorbilidades que pueden estar implicadas en su desarrollo, contribuir a la progresión de la enfermedad o empeorar el pronóstico. Objetivo: Evaluar la influencia de comorbilidades en la mortalidad de pacientes con insuficiencia cardíaca crónica. Métodos: Se realizó un estudio de cohorte retrospectivo en 242 pacientes, con diagnóstico de insuficiencia cardíaca crónica y una media de seguimiento de 5 años en la consulta de protocolo de insuficiencia cardíaca del Hospital Clínico Quirúrgico “Hermanos Ameijeiras”. Se determinó la magnitud de la asociación de la presencia de comorbilidades y la mortalidad a través del empleo de regresión logística. Resultados: El promedio de la edad fue mayor en los pacientes fallecidos 72,12 ± 12,088 años (p = 0,003). La presencia aislada de comorbilidades no mostró asociación con la mortalidad pero sí cuando coexistían más de dos comorbilidades. (OR: 2,91. IC: .991-8,61). Se encontró asociación lineal entre el número de comorbilidades y la mortalidad (p = 0,044). Conclusión: Las comorbilidades estudiadas no presentaron una asociación independiente con la mortalidad, pero la suma de ellas sí aumentó el riesgo de muerte en los pacientes con insuficiencia cardiaca.

Chronic Hepatitis C infection is associated with a broad spectrum of liver pathologies, ranging from inflammation to fibrosis and liver cancer. Here Thabet et al. identified a polymorphism in the gene MBOAT7 that is associated with increased hepatic inflammation and higher risk of fibrosis development and progression.

The global prevalence of non-alcoholic fatty liver disease (NAFLD) is nearly 25% and is increasing rapidly. The spectrum of liver damage in NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis, characterised by the presence of lobular inflammation and hepatocyte ballooning degeneration, with or without fibrosis, which can further develop into cirrhosis and hepatocellular carcinoma. Not only is NAFLD a progressive liver disease, but numerous pieces of evidence also point to extrahepatic consequences. Accumulating evidence suggests that patients with NAFLD are also at increased risk of cardiovascular disease (CVD); in fact, CVDs are the most common cause of mortality in patients with NAFLD. Obesity, type 2 diabetes and higher levels of LDL are common risk factors in both NAFLD and CVD; however, how NAFLD affects the development and progression of CVD remains elusive. In this review, we comprehensively summarise current data on the key extrahepatic manifestations of NAFLD, emphasising the possible link between NAFLD and CVD, including the role of proprotein convertase substilisin/kenin type 9, extracellular vesicles, microbiota, and genetic factors.

Abstract The main aim was to evaluate changes in urea cycle enzymes in NAFLD patients and in two preclinical animal models mimicking this entity. Seventeen liver specimens from NAFLD patients were included for immunohistochemistry and gene expression analyses. Three-hundred-and-eighty-two biopsy-proven NAFLD patients were genotyped for rs1047891, a functional variant located in carbamoyl phosphate synthetase-1 (CPS1) gene. Two preclinical models were employed to analyse CPS1 by immunohistochemistry, a choline deficient high-fat diet model (CDA-HFD) and a high fat diet LDLr knockout model (LDLr −/−). A significant downregulation in mRNA was observed in CPS1 and ornithine transcarbamylase (OTC1) in simple steatosis and NASH-fibrosis patients versus controls. Further, age, obesity (BMI > 30 kg/m2), diabetes mellitus and ALT were found to be risk factors whereas A-allele from CPS1 was a protective factor from liver fibrosis. CPS1 hepatic expression was diminished in parallel with the increase of fibrosis, and its levels reverted up to normality after changing diet in CDA-HFD mice. In conclusion, liver fibrosis and steatosis were associated with a reduction in both gene and protein expression patterns of mitochondrial urea cycle enzymes. A-allele from a variant on CPS1 may protect from fibrosis development. CPS1 expression is restored in a preclinical model when the main trigger of the liver damage disappears.

Metabolic dysfunction–associated fatty liver disease (MAFLD) prevalence and incidence is rising globally. It is associated with metabolic comorbidities, obesity, overweight, type 2 diabetes mellitus, and at least two metabolic risk factors, such as hypertension, hypertriglyceridemia, hypercholesterolemia, insulin resistance, and cardiovascular risk, increasing the risk of mortality. The excessive accumulation of fat comprises apoptosis, necrosis, inflammation and ballooning degeneration progressing to fibrosis, cirrhosis, and liver decompensations including hepatocellular carcinoma development. The limitation of approved drugs to prevent MAFLD progression is a paradigm. This review focuses on recent pathways and targets with evidence results in phase II/III clinical trials.

La investigación tuvo por objetivo analizar las percepciones que posee un grupo de 15 docentes en formación inicial respecto de los servicios ecosistémicos culturales asociados al bosque nativo. Los sujetos participantes fueron estudiantes de las carreras de Pedagogía en Educación General Básica, ingresos 2013, 2014, 2015, 2016 y Pedagogía en Educación General Básica con Mención, ingreso 2017, de la Universidad Católica del Maule-Chile. En el estudio se emplearon dos técnicas de trabajo cualitativas, el grupo focal y el dibujo identitario revisado. Los resultados arrojan que en docentes en formación coexisten una serie de visiones alternativas respecto de los servicios ecosistémicos, que relacionan con temáticas de reciclaje e instituciones gubernamentales, pero también se evidencia la importancia que los sujetos participantes asignan a los innumerables beneficios y aportes que entregan los servicios ecosistémicos al ser humano, así como también, la trascendencia que tienen los bosques nativos y sus servicios ecosistémicos culturales, como espacios pedagógicos al servicio de aprendizajes transversales en la formación del alumnado de enseñanza básica.

Background & aims. G-allele of PNPLA3 (rs738409) favours triglycerides accumulation and steatosis. In this study, we examined the effect of quercetin and natural extracts from mushroom and artichoke on reducing lipid accumulation in hepatic cells.Material and methods. Huh7.5 cells were exposed to oleic acid (OA) and treated with quercetin and extracts to observe the lipid accumulation, the intracellular-TG concentration and the LD size. Sterol regulatory element binding proteins-1 (SREBP-1), peroxisome proliferator-activated receptor (PPARα-γ) and cholesterol acyltransferase (ACAT) gene expression levels were analysed.Results. Quercetin decreased the intracellular lipids, LD size and the levels of intracellular-TG through the down-regulation of SREBP-1c, PPARγand ACAT1 increasing PPARα. The natural-extracts suppressed OA-induced lipid accumulation and the intracellular-TG. They down-regulate the hepatic lipogenesis through SREBP-1c, besides the activation of lipolysis through the increasing of PPARα expression.Conclusions. Quercetin and the aqueous extracts decrease intracellular lipid accumulation by down-regulation of lipogenesis and up-regulation of lipolysis.

Objective: This study aimed to determine the prevalence of successful aging (SA) and identify its predictive factors in a cohort of older people in the Colombian Andes Mountain. Method: Data were drawn from a prospective longitudinal study of community-dwelling elderly people in Manizales. SA encompassed indicators in four domains: physical, cognitive, emotional, and social functioning. Results: The prevalence of SA was 24.4%. The independent predictors were good and very good self-rated health, middle–high/high-income level, absence of chronic conditions, married status, high educational level, and very high spirituality. Discussion: The prevalence of SA was low: One of 10 people older than 65 years showed SA when presence of diseases was included in the criteria, compared with one of four when such an item was excluded. The identification of predictive factors allows distinguishing this population in primary care services and promoting strategies that ensure high functionality levels for as long as possible.

Hepatitis C virus (HCV) infection has been related to increased risk of development of hepatocellular carcinoma (HCC) while metformin (M) and statins treatment seemed to protect against HCC development. In this work, we aim to identify the mechanisms by which metformin and simvastatin (S) could protect from liver cancer. Huh7.5 cells were infected with HCV particles and treated with M+S. Human primary hepatocytes were treated with M+S. Treatment with both drugs inhibited Huh7.5 cell growth and HCV infection. In non-infected cells S increased translational controlled tumor protein (TCTP) and phosphatase and tensin homolog (PTEN) proteins while M inhibited mammalian target of rapamycin (mTOR) and TCTP. Simvastatin and metformin co-administered down-regulated mTOR and TCTP, while PTEN was increased. In cells infected by HCV, mTOR, TCTP, p62 and light chain 3B II (LC3BII) were increased and PTEN was decreased. S+M treatment increased PTEN, p62 and LC3BII in Huh7.5 cells. In human primary hepatocytes, metformin treatment inhibited mTOR and PTEN, but up-regulated p62, LC3BII and Caspase 3. In conclusion, simvastatin and metformin inhibited cell growth and HCV infection in vitro. In human hepatocytes, metformin increased cell-death markers. These findings suggest that M+S treatment could be useful in therapeutic prevention of HCV-related hepatocellular carcinoma.

A partir de los soportes papel (manual, bond, periódico), fotografías con gelatina como aglutinante y planos con soporte en fibra textil del Archivo General de la Nación (AGN), se realizaron diferentes pruebas de aislamiento e identificación de hongos, determinando los géneros de mayor frecuencia de aparición, y el efecto de los desinfectantes Tego51®, Timsen® a 4000 ppm (1.6 g principio activo n-alquil dimetil bencil amonio), etanol 70% y New ger® 0.7% (solución de N-duopropenida mezcla completa de yoduros de amonio cuaternario al 2.5%), sobre papel afectado y su forma de aplicación nebulización y aspersión.Igualmente a 231 fotografías con gelatina como aglutinante, tomadas del fondo del Ministerio de Obras Publicas (MOP) que presentaron indicadores de biodeterioro, se realizó, aislamiento e identificación de 48 géneros siendo los más frecuentes Penicillium sp. y Cladosporium sp. y los más agresivos frente al soporte Rhizopus sp., Cladosporium sp., Aspergillus sp1, y Fusarium sp., con efecto de biodeterioro en 25 días.A partir de este estudio, se tomaron los géneros Penicillium sp., Cladosporium sp., Aspergillus sp., Rhizopus sp y se realizaron pruebas con desinfectantes (Timsen®, etanol, New ger®) para determinar el efecto fungicida y su acción sobre el soporte fotográfico, evaluando 4 formas de aplicación de los desinfectantes (aspersión, inmersión, aplicación puntual y directa) sobre muestras de fotografías inoculadas, determinando que la inmersión en los desinfectantes evaluados, fue el mejor método de aplicación ya que no afecta las características físicas de la imagen.Finalmente también se evaluaron 66 planos con soporte en fibra textil a partir de los cuales se aislaron e identificaron 37 géneros siendo los más frecuentes Penicillium sp. y Cladosporium sp., los cuales también demostraron alta agresividad junto con Bipolaris sp.

AIM: To investigate the influence of metformin use on liver dysfunction and hepatic encephalopathy in a retrospective cohort of diabetic cirrhotic patients. To analyze the impact of metformin on glutaminase activity and ammonia production in vitro. METHODS: Eighty-two cirrhotic patients with type 2 diabetes were included. Forty-one patients were classified as insulin sensitizers experienced (metformin) and 41 as controls (cirrhotic patients with type 2 diabetes mellitus without metformin treatment). Baseline analysis included: insulin, glucose, glucagon, leptin, adiponectin, TNFr2, AST, ALT. HOMA-IR was calculated. Baseline HE risk was calculated according to minimal hepatic encephalopathy, oral glutamine challenge and mutations in glutaminase gene. We performed an experimental study in vitro including an enzymatic activity assay where glutaminase inhibition was measured according to different metformin concentrations. In Caco2 cells, glutaminase activity inhibition was evaluated by ammonia production at 24, 48 and 72 hours after metformina treatment. RESULTS: Hepatic encephalopathy was diagnosed during follow-up in 23.2% (19/82): 4.9% (2/41) in patients receiving metformin and 41.5% (17/41) in patients without metformin treatment (logRank 9.81; p=0.002). In multivariate analysis, metformin use [H.R.11.4 (95% CI: 1.2-108.8); p=0.034], age at diagnosis [H.R.1.12 (95% CI: 1.04-1.2); p=0.002], female sex [H.R.10.4 (95% CI: 1.5-71.6); p=0.017] and HE risk [H.R.21.3 (95% CI: 2.8-163.4); p=0.003] were found independently associated with hepatic encephalopathy. In the enzymatic assay, glutaminase activity inhibition reached 68% with metformin 100 mM. In Caco2 cells, metformin (20 mM) decreased glutaminase activity up to 24% at 72 hours post-treatment (p

Insulin is critical for controlling energy functions including glucose and lipid metabolism. Insulin resistance seems to interact with hepatitis C promoting fibrosis progression and impairing sustained virological response to peginterferon and ribavirin. The main aim was to elucidate the direct effect of hepatitis C virus (HCV) infection on insulin signaling both in vitro analyzing gene expression and protein abundance. Huh7.5 cells and JFH-1 viral particles were used for in vitro studies. Experiments were conducted by triplicate in control cells and infected cells. Genes and proteins involved in insulin signaling pathway were modified by HCV infection. Moreover, metformin treatment increased gene expression of PI3K, IRS1, MAP3K, AKT and PTEN more than >1.5 fold. PTP1B, encoding a tyrosin phosphatase, was found highly induced (>3 fold) in infected cells treated with metformin. However, PTP1B protein expression was reduced in metformin treated cells after JFH1 infection. Other proteins related to insulin pathway like Akt, PTEN and phosphorylated MTOR were also found down-regulated. Viral replication was inhibited in vitro by metformin. A strong effect of HCV infection on insulin pathway-related gene and protein expression was found in vitro. These results could lead to the identification of new therapeutic targets in HCV infection and its co-morbidities.

Un tema que debe interesar al profesorado de Matemáticas de todos los niveles educativos es cómo hacer comprender a nuestros alumnos la utilidad de los conceptos matemáticos que están estudiando en nuestras asignaturas. Si se les presenta aplicaciones de las Matemáticas en temas atractivos e interesantes conseguiremos motivar a nuestros alumnos. Una de estas aplicaciones es el cifrado de la información. La Criptografía es un tema de gran actualidad debido al auge de Internet, la telefonía móvil, etc. y el correspondiente aumento de intercambio de información: comercio electrónico, transacciones bancarias, etc. Es imprescindible poder intercambiar información de manera segura a salvo de intrusos malintencionados. No sólo se producen intercambios de mensajes de texto sino que también se producen intercambios de otro tipo de ficheros digitales como imágenes, ficheros de audio, etc. Este trabajo se va a dedicar a presentar una experiencia docente realizada con alumnos de una asignatura de Matemáticas de primer curso de Ingeniería Técnica Informática sobre técnicas de cifrado de imágenes digitales. Los métodos de cifrado han sido muy variados: un par de métodos basados en cálculo matricial, un método basado en el Teorema Chino de los Restos y un método basado en secuencias caóticas. De esta forma conseguimos relacionar las Matemáticas que se estudian en clase con temas de interés para nuestros alumnos. Así conseguimos que valoren más los conocimientos que están adquiriendo.

IntroductionAlmost 2 years and five infection waves after the COVID-19 pandemic started, healthcare workers continued dealing with the pandemic situation and facing the health consequences and the mental health disorders it caused. This study aimed to evaluate the onset and progression of psychopathology as well as the role of predictor variables such as purpose in life and moral courage among healthcare workers during this time.Materials and methodsThis was a longitudinal prospective study carried out with 45 Spanish healthcare workers who answered two questionnaires, the first questionnaire in April–May 2020 (T1) and the second questionnaire in September–October 2021 (T2).ResultsAlthough 29.5% of the sample considered that their mental health had improved over this time, almost half of them (47.7%) said it had not changed, while 22.7% reported a decline in their mental health from the first time they were asked. Specifically, 46.8% presented anxiety, 23.4% depression, and 42.6% acute stress at T1, and 38.3% had anxiety, 17% depression, and 27.7% post-traumatic stress disorder at T2. Despite this, there were no differences between T1 and T2 anxiety scores (p = 0.53), although there was a decrease in depression (p = 0.03) and acute stress (p = 0.02) scores. Predictor variable outcomes such as purpose in life (p = 0.88) and moral courage (p = 0.86; p = 0.38) did not change over time, but when modelling the data, purpose in life predicted psychopathology at T1, which in turn affected the psychopathology results at T2.ConclusionThis study showed that, although psychopathology decreased over the months, its prevalence remained high. Even though the purpose in life predicted psychopathology at T1, it seems that once the psychopathology is established (T2), the factors that would improve it would be different from the protective factors that prevented its establishment, which become secondary.

ABSTRACT Aim: to analyze the effect of metformin on ammonia production derived from glutamine metabolism in vitro and in vivo. Methods: twenty male Wistar rats were studied for 28 days after a porto-caval anastomosis (n = 16) or a sham operation (n = 4). Porto-caval shunted animals were randomized into two groups (n = 8) and either received 30 mg/kg/day of metformin for two weeks or were control animals. Plasma ammonia concentration, Gls gene expression and K-type glutaminase activity were measured in the small intestine, muscle and kidney. Furthermore, Caco2 were grown in different culture media containing glucose/glutamine as the main carbon source and exposed to different concentrations of the drug. The expression of genes implicated in glutamine metabolism were analyzed. Results: metformin was associated with a significant inhibition of glutaminase activity levels in the small intestine of porto-caval shunted rats (0.277 ± 0.07 IU/mg vs 0.142 ± 0.04 IU/mg) and a significant decrease in plasma ammonia (204.3 ± 24.4 µg/dl vs 129.6 ± 16.1 µg/dl). Glucose withdrawal induced the expression of the glutamine transporter SLC1A5 (2.54 ± 0.33 fold change; p < 0.05). Metformin use reduced MYC levels in Caco2 and consequently, SLC1A5 and GLS expression, with a greater effect in cells dependent on glutaminolytic metabolism. Conclusion: metformin regulates ammonia homeostasis by modulating glutamine metabolism in the enterocyte, exerting an indirect control of both the uptake and degradation of glutamine. This entails a reduction in the production of metabolites and energy through this pathway and indirectly causes a decrease in ammonia production that could be related to a decreased risk of HE development.

BackgroundThe COVID-19 pandemic has led to a significant increase in the workload of healthcare workers that, together with the risks associated with exposure to this new virus, has affected their mental health.ObjectivesThe objective of the current study was to determine the prevalence of psychopathology and burnout syndrome in healthcare workers and the predictive role of purpose in life and moral courage in this relationship.MethodsA cross-sectional study was carried out in 115 Spanish healthcare workers.ResultsParticipants with burnout had higher anxiety (p = 0.001), depression (p < 0.001), post-traumatic stress (p = 0.01) and alcohol consumption (p = 0.03) levels. The different components of burnout (emotional fatigue and despersonalization) were associated with the occurrence of anxiety (OR = 0.31) and depression (OR = 0.26), respectively. A strong purpose in life decreased emotional fatigue (OR = −0.39) depersonalization (OR = −0.23) scores, increased personal accomplishment (OR = 0.52), subsequently reducing burnout levels (OR = −0.45).ConclusionsPurpose in life was most strongly related to decreased levels of burnout. Furthermore, an association between anxiety, depression and the components of burnout was found.