Navigating the Link Between Non-alcoholic Fatty Liver Disease/Non-alcoholic Steatohepatitis and Cardiometabolic Syndrome.

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.

Revisión histórica, distribución potencial y estado de conservación de la rata endémica de México Xenomys nelsoni (Rodentia: Cricetidae) / Historical review, potential distribution, and conservation of the Mexican endemic rat Xenomys nelsoni (Rodentia: Cricetidae)

Resumen Introducción: La Rata de Magdalena, Xenomys nelsoni, es un roedor endémico de México, de distribución restringida a las selvas bajas caducifolias densas, en una pequeña región de la costa del Pacífico mexicano. Es una especie poco conocida, catalogada como "En Peligro" de acuerdo con la Unión Internacional para la Conservación de la Naturaleza (IUCN). Este desconocimiento unido a la alta tasa de deforestación de su hábitat hace que su conservación sea prioritaria. Objetivo: Realizar un recuento histórico de los registros depositados en las colecciones científicas, generar mapas de distribución potencial y analizar el estado de conservación de la especie. Método: Los datos de ocurrencia de las especies se obtuvieron de la literatura y bases de datos digitales y se analizaron por décadas. Se utilizaron los programas GARP y MaxEnt para generar los modelos de nicho ecológico. La importancia de las variables en el modelo se estimó mediante un análisis Jackknife. Resultados: A lo largo de 129 años 19 recolectores registraron 69 ejemplares, de los cuales 65 están depositados en siete colecciones internacionales y una nacional. Aunque la especie sólo se ha recolectado en Jalisco y Colima, la distribución potencial de X. nelsoni incluye también el estado de Michoacán. De esta área estimada, sólo el 1.5 % se encuentra dentro de un Área Natural Protegida. Conclusiones: Los resultados de la distribución potencial podrían ser utilizados para verificar la presencia de la especie en lugares donde no ha sido recolectada como el norte de la Reserva de la Biosfera Chamela-Cuixmala y en algunas zonas de la provincia fisiográfica Costas del Sur en el estado de Michoacán. Es necesario incrementar los muestreos en regiones poco estudiadas predichas por el modelo y aumentar el área de protección.

Abstract Introduction: The Magdalena Rat, Xenomys nelsoni, is a rodent endemic to Mexico, whose distribution is restricted to dense tropical dry forests in a small region on the Pacific coast of Mexico. It is a poorly known species categorized as "Endangered" by the International Union for Conservation of Nature (IUCN). This lack of knowledge and the high rates of deforestation of its habitat makes its conservation a priority. Objective: To summarize the historical records deposited in scientific collections, to create potential distribution maps, and to analyze the conservation status of the species. Methods: We obtained species occurrence data from literature and digital databases, analyzing them by the decade. We used GARP and MaxEnt software to generate the ecological niche models. The importance of the variables in the model was estimated using the Jackknife technique. Results: Over 129 years, 19 collectors registered 69 specimens, of which 65 are deposited in one national and seven international collections. Although the species has only been collected in Jalisco and Colima, the potential distribution for X. nelsoni also includes the state of Michoacán. Of this estimated area, only 1.5 % is in a Protected Natural Area. Conclusions: The results of the potential distribution could be used to verify the presence of the species in places where it has not been collected, such as the northern part of the Chamela-Cuixmala Biosphere Reserve and in some areas of the physiographic province Costas del Sur in the state of Michoacán. It is needed to increase samplings in the least studied regions predicted by the model and expand the area of protection.

Hepatosplenic schistosomiasis: an uncommon cause of liver disease in developed countries.

Schistosomiasis is a parasitic infection caused by trematode species of the genus Schistosoma. It is prevalent in tropical regions of Africa, Asia and South America, being rare in Europe, where it is usually diagnosed in immigrants and tourists from endemic areas. It has different clinical forms of presentation. Hepatosplenic schistosomiasis produces periportal fibrosis, which can progress to presinusoidal portal hypertension, with all its associated complications. We present the case of a 43-year-old female patient from the Philippines who was referred to gastroenterology consultation due to liver enzyme alteration with a predominantly cholestatic pattern. An aetiological study was performed, with negative results. An abdominal ultrasound revealed signs of chronic liver disease, with transient elastography of 9.5 kPa. A percutaneous liver biopsy was performed, with histological findings consistent with infestation by schistosome eggs, receiving treatment with praziquantel and subsequently verifying its eradication with a stool test.

Effect of Conservative Rehabilitation Interventions on Health-Related Quality of Life in Women with Upper Limb Lymphedema Secondary to Breast Cancer: A Systematic Review.

Breast cancer-related lymphedema (BCRL) of the upper limb is a very common condition in women undergoing breast cancer treatment; it can cause considerable alterations in the daily life of patients and a decrease in their health-related quality of life (HRQoL). Currently, there are many conservative therapies that try to palliate the symptoms, but the results are still controversial and there are still no globally accepted treatments. The purpose of this article is to determine the effect, according to the current available evidence, on HRQoL of different conservative interventions in the rehabilitation of BCRL in the upper limb in women. Eighteen articles that compared the effects of standard treatments, such as manual lymphatic drainage-based decongestive therapy or compression measures, and other newer treatments, including new technologies and other types of treatment programs, were reviewed. According to the results of this review, the most recommended modality for the improvement of HRQoL would be a complex decongestive technique without manual lymphatic drainage. Although there are clinical trials that have demonstrated the effectiveness of various treatments, the results of the positive effects on HRQoL remain highly controversial. There is a need to continue to develop studies to help guide therapeutic decisions that can promote HRQoL in women affected by upper limb BCRL.

Treatment and Improvement of Healing after Surgical Intervention.

The development of abnormal scars has a great impact on people's well-being, and improving scarring outcomes after surgery is a field that currently lacks consensus. This review aims to identify newly researched approaches to improving the quality of surgical scars. A systematic search of PubMed, Scopus, Web of Science, and ScienceDirect was conducted between 13 May 2023 and 17 May 2023, in accordance with the recommendations of the PRISMA Statement. Study selection and analysis of methodological quality were performed in parts, independently and blindly, based on eligibility criteria. The 21 prospective, comparative, and randomized studies reviewed included 1057 subjects and studied approaches such as topical applications of creams with herbal extracts and silicone gels, growth factors, negative pressure dressings, oligonucleotides, intralesional injection of compounds such as botulinum toxin, skin closure techniques such as suturing and tissue adhesive, and laser treatments. There are recent research techniques that generate good results and are really promising to improve the results of surgical scars; however, the available evidence is extremely limited in some cases, and it is necessary to deepen its analysis to obtain reliable action protocols in each type of surgery.

Role of EpCAM+ CD133+ extracellular vesicles in steatosis to steatohepatitis transition in NAFLD.

BACKGROUND AND AIMS: Extracellular vesicles (EVs) have emerged as a potential source of circulating biomarkers in liver disease. We evaluated circulating AV+ EpCAM+ CD133+ EVs as a potential biomarker of the transition from simple steatosis to steatohepatitis. METHODS: EpCAM and CD133 liver proteins and EpCAM+ CD133+ EVs levels were analysed in 31 C57BL/6J mice fed with a chow or high fat, high cholesterol and carbohydrates diet (HFHCC) for 52 weeks. The hepatic origin of MVs was addressed using AlbCrexmT/mG mice fed a Western (WD) or Dual diet for 23 weeks. Besides, we assessed plasma MVs in 130 biopsy-proven NAFLD patients. RESULTS: Hepatic expression of EpCAM and CD133 and EpCAM+ CD133+ EVs increased during disease progression in HFHCC mice. GFP+ MVs were higher in AlbCrexmT/mG mice fed a WD (5.2% vs 12.1%) or a Dual diet (0.5% vs 7.3%). Most GFP+ MVs were also positive for EpCAM and CD133 (98.3% and 92.9% respectively), suggesting their hepatic origin. In 71 biopsy-proven NAFLD patients, EpCAM+ CD133+ EVs were significantly higher in those with steatohepatitis compare to those with simple steatosis (286.4 ± 61.9 vs 758.4 ± 82.3; p < 0.001). Patients with ballooning 367 ± 40.6 vs 532.0 ± 45.1; p = 0.01 and lobular inflammation (321.1 ± 74.1 vs 721.4 ± 80.1; p = 0.001), showed higher levels of these EVs. These findings were replicated in an independent cohort. CONCLUSIONS: Circulating levels of EpCAM+ CD133+ MVs in clinical and experimental NAFLD were increased in the presence of steatohepatitis, showing high potential as a non-invasive biomarker for the evaluation and management of these patients.

Uncommon etiology of Cullen´s sign and Grey Turner sign.

Cullen´s sign and Grey Turner sign are, respectively, the cutaneous ecchymoses located in periumbilical region and tissues flanks along the lower portion of the abdomen. Both have been observed in <1% of individuals with acute pancreatitis, suggesting poor prognosis in terms of gravity and mortality. However, these signs are not exclusive for acute pancreatitis, as they can appear in other identities such as: ruptured ectopic pregnancy, aortic aneurysm, rectus abdominis muscle hematoma, perforated duodenal ulcer, common bile duct rupture and biliary peritonitis, idiopathic perirenal hemorrhage, infectious mononucleosis with splenic rupture, metastatic esophageal and thyroid cancer, non-Hodgkin lymphoma, amoebic liver abscess, portal hypertension, and liver tumor disease. Based on the review of the literature, it is patent that Cullen´s sign and Grey Turner sign are neither sensitive nor specific for acute pancreatitis, therefore it may be best to relate these findings in the physical examination to conditions associated with abdominal pathology and retroperitoneal hemorrhage. We report the case of a 60-year-old Spanish female, with previous history of squamous small cell neuroendocrine lung carcinoma with hepatic extension in follow-up by palliative care services. Due to disease progression after two palliative chemotherapy sessions, the patient came to the emergency room with jaundice and abdominal pain in superior regions. On physical examination, notable findings included ecchymoses in the right flank and periumbilical region. Laboratory findings showed elevated bilirubin and transaminase levels, as well as a small increase in the serum amylase and lipase levels. Cholangioresonance was performed to discard acute biliary pancreatitis. The imaging revealed no enlargement of the pancreas, dilatation of the common bile duct without visible stone, and a liver full of new cancerous liver implants. These findings were consistent with diffuse distribution metastases lesions, concluding the progression of liver disease.

Pancreas fat content, insulin homeostasis and circulating endothelial microparticles in male essential hypertensive patients.

The pancreas fat content has been poorly investigated in essential hypertension. The authors aim to relate pancreas and liver fat content with parameters measuring insulin resistance, beta-cell function and also with markers of endothelial dysfunction and platelet or endothelial cell destruction. The authors studied a group of 40 male hypertensive patients with well-controlled blood pressure, maintaining a stable weight, and having not changed their medication during the last year. Pancreas fat content was correlated with HOMA-IR (r = .616, p < .001), HOMA-S (r = -.439, p < .005), beta cell function parameter (r = .457, p < .005), and QUICKI (r = .412, p < .01), whereas liver fat was not patients in the highest quartile of pancreas fat content had more circulating endothelial microparticles than patients in the other quartiles (median 129 [94.3-200] vs. 60.9 [49.4-88.8], p = .002). However, patients in the highest quartile of the pancreas fat content distribution did not differ from the lowest in hyperemic response after ischemia nor circulating platelet microparticles count. Liver fat content was not related to any of the parameters studied. In a multivariate stepwise binary logistic regression analysis (Wald Method) circulating endothelial microparticles remain significantly associated with pancreas fat content after adjusting for confounding factors, such as tobacco, diabetes mellitus, hypercholesterolemia, or metabolic syndrome. Our results reflect that in essential hypertension, pancreas fat content is superior to liver fat to study beta-cell functionality and insulin resistance. Moreover, the authors described for the first time that pancreas fat content is related to endothelial cell destruction. Further studies are needed to confirm this point.

Innovations in surgical training: exploring the role of artificial intelligence and large language models (LLM) / Inovações no treinamento cirúrgico: explorando o papel da inteligência artificial e dos grandes modelos de linguagem (LLM)

ABSTRACT The landscape of surgical training is rapidly evolving with the advent of artificial intelligence (AI) and its integration into education and simulation. This manuscript aims to explore the potential applications and benefits of AI-assisted surgical training, particularly the use of large language models (LLMs), in enhancing communication, personalizing feedback, and promoting skill development. We discuss the advancements in simulation-based training, AI-driven assessment tools, video-based assessment systems, virtual reality (VR) and augmented reality (AR) platforms, and the potential role of LLMs in the transcription, translation, and summarization of feedback. Despite the promising opportunities presented by AI integration, several challenges must be addressed, including accuracy and reliability, ethical and privacy concerns, bias in AI models, integration with existing training systems, and training and adoption of AI-assisted tools. By proactively addressing these challenges and harnessing the potential of AI, the future of surgical training may be reshaped to provide a more comprehensive, safe, and effective learning experience for trainees, ultimately leading to better patient outcomes. .

RESUMO O cenário do treinamento cirúrgico está evoluindo rapidamente com o surgimento da inteligência artificial (IA) e sua integração na educação e simulação. Este artigo explora as aplicações e benefícios potenciais do treinamento cirúrgico assistido por IA, em particular o uso de modelos de linguagem avançados (MLAs), para aprimorar a comunicação, personalizar o feedback e promover o desenvolvimento de habilidades. Discutimos os avanços no treinamento baseado em simulação, ferramentas de avaliação impulsionadas por IA, sistemas de avaliação baseados em vídeo, plataformas de realidade virtual (RV) e realidade aumentada (RA), e o papel potencial dos MLAs na transcrição, tradução e resumo do feedback. Apesar das oportunidades promissoras apresentadas pela integração da IA, vários desafios devem ser abordados, incluindo precisão e confiabilidade, preocupações éticas e de privacidade, viés nos modelos de IA, integração com os sistemas de treinamento existentes, e treinamento e adoção de ferramentas assistidas por IA. Ao abordar proativamente esses desafios e aproveitar o potencial da IA, o futuro do treinamento cirúrgico pode ser remodelado para proporcionar uma experiência de aprendizado mais abrangente, segura e eficaz para os aprendizes, resultando em melhores resultados para os pacientes.

Emerging pharmacological treatment options for MAFLD.

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.

Extracellular Vesicles as Biomarkers in Liver Disease.

Extracellular vesicles (EVs) are membrane-derived vesicles released by a variety of cell types, including hepatocytes, hepatic stellate cells, and immune cells in normal and pathological conditions. Depending on their biogenesis, there is a complex repertoire of EVs that differ in size and origin. EVs can carry lipids, proteins, coding and non-coding RNAs, and mitochondrial DNA causing alterations to the recipient cells, functioning as intercellular mediators of cell-cell communication (auto-, para-, juxta-, or even endocrine). Nevertheless, many questions remain unanswered in relation to the function of EVs under physiological and pathological conditions. The development and optimization of methods for EV isolation are crucial for characterizing their biological functions, as well as their potential as a treatment option in the clinic. In this manuscript, we will comprehensively review the results from different studies that investigated the role of hepatic EVs during liver diseases, including non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic liver disease, fibrosis, and hepatocellular carcinoma. In general, the identification of patients with early-stage liver disease leads to better therapeutic interventions and optimal management. Although more light needs to be shed on the mechanisms of EVs, their use for early diagnosis, follow-up, and prognosis has come into the focus of research as a high-potential source of 'liquid biopsies', since they can be found in almost all biological fluids. The use of EVs as new targets or nanovectors in drug delivery systems for liver disease therapy is also summarized.

Multiple eruptive delay as a variant of primary eruption failure. A preliminary case report.

Primary failure of eruption (PFE) is an autosomal disease that occurs in approximately 0.06% of the population and is defined as the malfunction of dental eruptive mechanisms with delay and absence of these processes in a non-ankylosed tooth. Treatment options for patients with eruptive delays range from prosthetic to surgical interventions. Although this condition is relatively rare, the occurrence of eruptive disorders in clinical dental practice is becoming more frequent. Correct diagnosis of this eruptive anomaly plays an essential role in treatment planning. The aim of this case report was to describe the treatment of a case of multiple PFE with a biomechanical approach to extrusive traction using NiTi closed coil springs and a customized rigid anchorage. In conclusion, complex orthodontic cases with eruptive delay and variants of PFE can be successfully intervened to make morphologically and functionally compromised dental organs viable, if diagnosed and treated in a timely and preventive manner by a multidisciplinary approach using alternative biomechanics for efficient osteogenic traction.

Tropical wetlands and land use changes: The case of oil palm in neotropical riverine floodplains.

Oil palm plantations are expanding in Latin America due to the global demand for food and biofuels, and much of this expansion has occurred at expense of important tropical ecosystems. Nevertheless, there is limited knowledge about effects on aquatic ecosystems near to oil palm-dominated landscapes. In this study, we used Landsat 7 ETM+, Landsat 8 OLI imagery and high-resolution images in Google Earth to map the current extent of oil palm plantations and determined prior land use land cover (LULC) in the Usumacinta River Basin as a case-study site. In addition, we assess the proximity of the crop with aquatic ecosystems distributed in the Usumacinta floodplains and their potential effects. Based on our findings, the most significant change was characterized by the expansion of oil palm crop areas mainly at expenses of regional rainforest and previously intervened lands (e.g. secondary vegetation and agriculture). Although aquatic ecosystem class (e.g. rivers, lagoons and channels) decreased in surface around 3% during the study period (2001-2017), the change was not due to the expansion of oil palm lands. However, we find that more than 50% of oil palm cultivations are near (between 500 and 3000 m) to aquatic ecosystems and this could have significant environmental impacts on sediment and water quality. Oil palm crops tend to spatially concentrate in the Upper Usumacinta ecoregion (Guatemala), which is recognized as an area of important fish endemism. We argue that the basic information generated in this study is essential to have better land use decision-making in a region that is relative newcomer to oil palm boom.

Los receptores acoplados a proteínas G como blanco terapéutico / G protein-coupled receptors as therapeutic target

Resumen Los receptores son proteínas codificadas por el ADN, algunos de los cuales ya han sido cristalizados, lo que permite conocer los detalles de su estructura a nivel atómico y algunos aspectos de su función. Esta revisión se enfoca en los más diversos y abundantes, los receptores acoplados a la proteína G. Esta familia de receptores reconoce y media la acción de varios ligandos endógenos (hormonas, neurotransmisores, factores de crecimiento y hormonas locales) y también interviene en la patogenia de diversas enfermedades, por lo que son el blanco terapéutico de aproximadamente 30 a 40 % de los medicamentos que se emplean en la práctica clínica cotidiana y de diversas drogas ilegales. La cristalografía de rayos X es una de las herramientas clave que ha permitido observar la estructura de estos receptores en los aminoácidos que participan en esta interacción, lo que posibilita conocer el sitio de unión del ligando endógeno y de moléculas sintéticas que actúan sobre ellos para modular su acción. El modelado molecular es también una herramienta bioinformática computacional que apoya la investigación sobre la unión receptor-ligando, que hace posible el diseño y desarrollo de fármacos cada vez más específicos. A estos desarrollos se suman importantes cambios en los conceptos farmacodinámicos fundamentales.

Abstract Receptors are proteins coded by DNA, some of which have already been crystalized, thus allowing the details of their structure at the atomic level and some aspects of their function to be known. This review focuses on the most diverse and abundant family of receptors, G protein-coupled receptors. This family of receptors recognizes and mediates the action of several endogenous ligands (hormones, neurotransmitters, growth factors and local hormones) and also intervenes in the pathogenesis of various diseases, which is why they are targeted by approximately 30 to 40% of medications that are used in daily clinical practice and of various illegal drugs as well. X-ray crystallography is one of the essential tools that has allowed to observe the structure of these receptors in the amino acids that participate in this interaction, which allows to know the binding site of the endogenous ligand and of synthetic molecules that act on them to modulate their action. Molecular modeling or "docking" is also a computational bioinformatics tool that supports research on receptor-ligand binding, which allows the design and development of increasingly specific drugs. These developments have brought along significant changes in fundamental pharmacodynamic concepts.

Long non-coding RNA H19 as a biomarker for hepatocellular carcinoma.

BACKGROUND AND AIMS: Liver cancer stem cells (CSCs) could be involved in the carcinogenesis, recurrence, metastasis and chemoresistance of hepatocellular carcinoma (HCC). The aim of this study was to explore the role of lncRNA-H19 as a biomarker for liver cancer. METHODS: LncRNA-H19 expression levels and the functional assays were conducted in EpCAM+ CD133+ CSCs and C57BL/6J mice fed with a high-fat high-cholesterol carbohydrate (HFHCC) or standard diet for 52 weeks. Liver tissue and plasma samples from patients with cirrhosis, with or without HCC, were used for the analyses of gene expression and circulating lncRNA-H19 levels in an estimation and validation cohort. RESULTS: EpCAM+ CD133+ cells showed a stem cell-like phenotype, self-renewal capacity, upregulation of pluripotent gene expression and overexpressed lncRNA-H19 (p < .001). Suppression of lncRNA-H19 by antisense oligonucleotide treatment significantly reduced the self-renewal capacity (p < .001). EpCAM, CD133 and lncRNA-h19 expression increased accordingly with disease progression in HFHCC-fed mice (p < .05) and also in liver tissue from HCC patients (p = .0082). Circulating lncRNA-H19 levels were significantly increased in HCC patients in both cohorts (p = .013; p < .0001). In addition, lncRNA-H19 levels increased accordingly with BCLC staging (p < .0001) and decreased after a partial and complete therapeutic response (p < .05). In addition, patients with cirrhosis who developed HCC during follow-up showed higher lncRNA-H19 levels (p = .0025). CONCLUSION: LncRNA-H19 expression was increased in CSCs, in liver tissue and plasma of patients with HCC and decreased after partial/complete therapeutic response. Those patients who developed HCC during the follow-up showed higher levels of lncRNA-H19. LncRNA-H19 could constitute a new biomarker of HCC.

Liver injury in non-alcoholic fatty liver disease is associated with urea cycle enzyme dysregulation.

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.

Comparative matrix metalloproteinase-2 and -9 expression and activity during endotheliochorial and hemochorial trophoblastic invasiveness.

To establish a functional placenta, its development needs adequate trophoblastic invasiveness. The intricate and complex morphological and molecular aspects regulating trophoblastic invasion during endotheliochorial placentation of domestic carnivores and their similarities and differences with the hemochorial placenta are still poorly understood. During placentation processes, from the time of implantation, trophoblast cells invade the uterine endometrium where they achieve extensive degradation and remodeling of extracellular matrix components; in this process, matrix metalloproteinases (MMPs), particularly MMP-2 and 9, have an essential role in rebuilding, cell migration, and invasiveness. This review provides an overview of comparative trophoblast invasive events and the expression and activity of MMP-2 and 9 during endotheliochorial and hemochorial placentation, emphasizing dog and mouse placental models. Understanding of trophoblastic invasiveness in two models of placentation, the intermediately invasive domestic carnivore endotheliochorial placenta, and the more highly invasive mouse hemochorial placenta, contributes to deepen knowledge of the trophoblast invasive processes and their diverse and complex human placental alterations, such as preeclampsia.

A proteomic platform to identify off-target proteins associated with therapeutic modalities that induce protein degradation or gene silencing.

Novel modalities such as PROTAC and RNAi have the ability to inadvertently alter the abundance of endogenous proteins. Currently available in vitro secondary pharmacology assays, which evaluate off-target binding or activity of small molecules, do not fully assess the off-target effects of PROTAC and are not applicable to RNAi. To address this gap, we developed a proteomics-based platform to comprehensively evaluate the abundance of off-target proteins. First, we selected off-target proteins using genetics and pharmacology evidence. This process yielded 2813 proteins, which we refer to as the "selected off-target proteome" (SOTP). An iterative algorithm was then used to identify four human cell lines out of 932. The 4 cell lines collectively expressed ~ 80% of the SOTP based on transcriptome data. Second, we used mass spectrometry to quantify the intracellular and extracellular proteins from the selected cell lines. Among over 10,000 quantifiable proteins identified, 1828 were part of the predefined SOTP. The SOTP was designed to be easily modified or expanded, owing to the rational selection process developed and the label free LC-MS/MS approach chosen. This versatility inherent to our platform is essential to design fit-for-purpose studies that can address the dynamic questions faced in investigative toxicology.

Wilson's disease: Revisiting an old friend.

Wilson's disease (WD) is a rare condition caused by copper accumulation primarily in the liver and secondly in other organs, such as the central nervous system. It is a hereditary autosomal recessive disease caused by a deficiency in the ATP7B transporter. This protein facilitates the incorporation of copper into ceruloplasmin. More than 800 mutations associated with WD have been described. The onset of the disease frequently includes manifestations related to the liver (as chronic liver disease or acute liver failure) and neurological symptoms, although it can sometimes be asymptomatic. Despite it being more frequent in young people, WD has been described in all life stages. Due to its fatal prognosis, WD should be suspected in all patients with unexplained biochemical liver abnormalities or neurological or psychiatric symptoms. The diagnosis is established with a combination of clinical signs and tests, including the measurement of ceruloplasmin, urinary copper excretion, copper quantification in liver biopsy, or genetic assessment. The pharmacological therapies include chelating drugs, such as D-penicillamine or trientine, and zinc salts, which are able to change the natural history of the disease, increasing the survival of these patients. In some cases of end-stage liver disease or acute liver failure, liver transplantation must be an option to increase survival. In this narrative review, we offer an overview of WD, focusing on the importance of clinical suspicion, the correct diagnosis, and treatment.

Endocarditis infecciosa en hospital clínico Herminda Martín de Chillán: experiencia de los últimos cinco años / Infective endocarditis at Herminda Martin clinical hospital of Chillan: last five years experience

Introducción: la endocarditis infecciosa es una afección con elevada morbilidad y mortalidad, con una incidencia en Chile de 2-3 casos por 100.000 habitantes al año, con una edad de presentación en ascenso y una clínica diversa e inespecífica que requiere un manejo multidisciplinario para el manejo de estos pacientes. Materiales y métodos: estudio observacional descriptivo, se consideró el número total de fichas clínicas del hospital clínico Herminda Martín de Chillán durante los años 2015 al 2019, con diagnóstico confirmado de endocarditis infecciosa. Los datos se registraron en la hoja de recolección de datos elaborada, realizándose los análisis estadísticos pertinentes. Resultados:la muestra (n=17) que pudo ser analizada tenía una edad promedio de 53,5 años; 70,5% (DE 14,50) fueron hombres y el agente más común identificado fue Staphylococcus aureus sensible a meticilina. En promedio los pacientes recibieron 28,8 días de antibióticos y la válvula más afectada fue la aórtica. Conclusiones: la endocarditis infecciosa es una patología con una gran morbimortalidad, que presenta un cuadro clínico inespecífico capaz de simular cualquier enfermedad. Se requieren aún de más estudios que reflejen la realidad nacional.

Introduction: Infective endocarditis is a condition with high morbidity and mortality, with an incidence in Chile of 2-3 cases per 100,000 inhabitants per year, with increasing age of presentation and a diverse and nonspecific clinic that requires multidisciplinary management for treatment of these patients. Materials and methods: Descriptive observational study, the total number of clinical records of the Herminda Martín de Chillán clinical hospital during the years 2015 to 2019, with a confirmed diagnosis of infective endocarditis, was considered. The data were recorded in the data collection sheet prepared, performing the relevant statistical analyses. Results: The sample (n = 17) that could be analysed had an average age of 53.5 years (DS 14.50), 70.5% were men, and the most common agent identified was methicillin-sensitive Staphylococcus aureus. On average, patients received 28.8 days of antibiotics, and the most affected valve was the aortic valve. Conclusions: Infective endocarditis is a pathology with high morbidity and mortality, which presents a nonspecific clinical spectrum, capable of simulating any disease. Still, more studies are required that reflect the national reality