Susceptibility factors in paracetamol-induced acute liver failure

Paracetamol is a popular antipyretic and analgesic medication. It is a known hepatotoxin in overdose and is the commonest cause of acute liver failure in the UK. There is significant variability in inter-individual susceptibility to the hepatotoxic effects of paracetamol, which is incompletely understood. This thesis describes work done in murine models of paracetamol-induced acute liver failure with the aim of identifying causes of variable susceptibility and understanding the immune response to liver injury. A quantitative trait locus (QTL) mapping approach was taken using a murine strain susceptible to paracetamol hepatotoxicity (C3H/HeH) crossed with a relatively resistant strain (C57BL/6). Novel QTLs on murine chromosome 17 and 18 were identified that associated with response to paracetamol. Within the loci a number of candidate genes were identified. A survey of 10 inbred mouse strains for their response to paracetamol was conducted and highlighted the large variability within each strain. It was hypothesised that this variability might be due to differences in intestinal microbiota. A study of the role of intestinal microbiota in paracetamol-induced liver failure was conducted, by comparing response in germ free (GF) mice and conventional (CV) controls. This demonstrated that the presence of intestinal microbiota influenced the sulphonation:glucuronidation ratio during paracetamol metabolism. Although the extent of liver injury as assessed by necrosis and liver enzyme elevation was the same in GF and CV mice, there was evidence of a protective effect of a sterile intestine. Finally a reverse genetics approach was taken to study the influence of the gene Slpi in the secondary immune response to liver injury. It was shown that absence of SLPI protected mice against peak liver injury. The work presented in this thesis highlights some potential sources of variability in response to paracetamol and a number of targets that with further research could have therapeutic potential.Open Acces

Suicide risk: a psychophysiological perspective

openCon il termine suicidio ci si riferisce alla morte causata da un atto autolesionistico intenzionale e progettato per essere letale. Il numero di morti annue per atti suicidari è tornato a crescere lungo il periodo della pandemia del COVID-19, rendendo il suicidio un problema sociale sempre più pressante, soprattutto per quanto riguarda le fasce più giovani della popolazione. Il modello biopsicosociale permette di indagare non solo quali elementi contribuiscono alla formazione di pensieri suicidari ma anche perché solo alcuni individui passano dall’ideazione alla messa in atto di tentativi di suicidio concreti. Alla fragilità dell’individuo, determinata dall’ereditarietà genetica dei disturbi psicologici, dalle inclinazioni del carattere o dalle esperienze di vita traumatiche, si sommano i sentimenti di disperazione e di sconfitta che creano le basi per la formazione di pensieri suicidi. Il suicidio può quindi essere descritto come un fenomeno complesso determinato da una combinazione di fattori di rischio ambientali, psicologici, genetici e psicofisiologici che interagiscono tra loro in modo sempre differente. Tra i diversi fattori di rischio presi in considerazione si è deciso di porre l’accento su quelli esaminati tramite tecniche psicofisiologiche. Un esempio sono gli studi condotti tramite elettroencefalografia che hanno identificato una correlazione tra tentato suicidio e deficit nella distinzione tra stimoli di ricompensa e stimoli neutrali e dimostrato il fatto che soggetti a rischio di condotte suicidarie elaborino in modo differente gli stimoli negativi. Altri studi esaminati hanno preso in considerazione tecniche quali la polisonnografia, l’elettrocardiogramma, la conduttanza cutanea e l'analisi delle componenti neuroendocrine. Dagli studi emerge che il prosieguo degli studi in ambito psicofisiologico potrebbe risultare particolarmente importante per la ricerca futura in quanto, non solo è in grado di fornire nuovi spunti e dettagli sull’eziologia del suicidio ma, al contempo, permette di stabilire punteggi di rischio per identificare i soggetti con tendenze suicide. L’incremento delle nostre conoscenze in questo ambito fornirà poi le basi per la creazione di programmi di prevenzione e di trattamento potenzialmente sempre più efficaci.Suicide is described as death caused by intentional self-harm, designed to be lethal. The number of deaths per year from suicide has risen again throughout the COVID-19 pandemic, making suicide an increasingly pressing social problem, especially among the younger population. The biopsychosocial model allows us to investigate not only which elements contribute to the formation of suicidal thoughts but also why only some people turn suicidal ideation into a suicidal attempt. To the fragility of the individual, determined by the genetic heredity of psychological disorders, the inclinations of character or traumatic life experiences, are added to the feelings of despair and defeat that create the basis for the formation of suicidal thoughts. Suicide can therefore be described as a complex phenomenon determined by a combination of environmental, psychological, genetic and psychophysiological risk factors that interact with each other in an ever-changing way. Among the different risk factors considered, it was decided to focus on those examined using psychophysiological techniques. Examples are electroencephalography studies that have identified a correlation between attempted suicide and deficits in the ability to distinguish between reward-predicting and non–reward-predicting stimuli and demonstrated the fact that individuals at risk of suicidal behavior have a different way of processing negative stimuli. Other studies examined used techniques such as polysomnography, electrocardiogram, skin conductance and neuroendocrine tests. From this it emerges that the continuation of psychophysiological studies could be particularly important for future research as, it is not only able to provide new insights and details on the etiology of suicide but, at the same time, it allows to establish risk scores to identify individuals with suicidal tendencies. The increase in our knowledge in this area will then provide the basis for the creation of potentially more effective prevention and treatment programs

Motivação para prática de exercício físico na pandemia COVID-19 de idosos ativos

Objective: To verify the association between the motivation to practice physical exercise and the level of physical activity during the COVID-19 pandemic. Methods: A descriptive cross-sectional study was carried out. The sample consisted of 98 older adults from a university extension program. A questionnaire with closed questions about motivation to practice physical exercise and the level of physical activity during the pandemic was applied; through an online form sent to the participants by the whatsapp application during the first semester of 2020. For statistical analysis, the chi-square test for independence was used by the IBM-SPSS Statistics Base v.20 software. (Ethics Committee-University No. 39.373). Results: The sample consisted of 93% (n=91) female and 7% (n=7) male, with a mean age of 72.19±6.30. The results show that 10% (n=10) consider themselves sedentary, 35% (n=35) little active and 54% (n=53) active. Regarding the motivation to practice physical exercise, 45% (n=45) considered that their motivation decreased, 32% (n=32) remained and 21% (n=21) increased. It was observed that there was an association between the decrease in motivation to practice physical activity and the low level of physical activity in the pandemic [X² (2)= 33.201; (p<0.000)], showing an association of 0.582 (58%) between these variables. Conclusion: Older adults with physical activity level considered sedentary were less motivated to perform physical activity during the COVID-19 pandemic. In this sample, active and less active elderly people oscillate their motivation regarding the practice of physical activity, which may limit their engagement to remain in the activity in the long term.Objetivo: Verificar la asociación entre la motivación para practicar ejercicio físico y el nivel de actividad física durante la pandemia de COVID-19. Métodos: se realizó un estudio descriptivo transversal. En el estudio participaron 98 adultos mayores de un programa de extensión universitaria. Se aplicó un cuestionario con preguntas cerradas sobre la motivación para practicar ejercicio físico y el nivel de actividad física durante la pandemia; a través de un formulario en línea, enviado a los participantes a través de la aplicación de whatsapp durante el primer semestre de 2020. Para el análisis estadístico se utilizó la prueba chi-cuadrado de independencia, utilizando el software IBM-SPSS Statistics Base v.20. (Comité de Ética-Universidad No. 39.373). Resultados: La muestra estuvo conformada por 93% (n = 91) mujeres y 7% (n = 7) hombres, con una edad media de 72,19 ± 6,30. Los resultados muestran que el 10% (n = 10) se considera sedentario, el 35% (n = 35) poco activo y el 54% (n = 53) activo. En cuanto a la motivación para practicar ejercicio físico, el 45% (n = 45) consideró que su motivación disminuyó, el 32% (n = 32) permaneció y el 21% (n = 21) aumentó. Se observó que hubo asociación entre la disminución de la motivación para la práctica de actividad física y el bajo nivel de actividad física en la pandemia [X² (2) = 33.201; (p <0,000)], mostrando una asociación de 0,582 (58%) entre estas variables. Conclusión: Los adultos mayores con nivel de actividad física considerada sedentaria estuvieron menos motivados para realizar actividad física durante la pandemia de COVID-19. En esta muestra, los adultos mayores activas y menos activas oscilan su motivación con respecto a la práctica de actividad física, lo que puede limitar su compromiso para permanecer en la actividad a largo plazo.Objetivo: Verificar associação entre a motivação para prática de exercício físico e o nível de atividade física durante a pandemia de COVID-19. Método: Foi realizado um estudo transversal descritivo. Participaram do estudo 98 idosos de um programa de extensão universitária. Foi aplicado questionário com questões fechadas sobre motivação à prática de exercício físico e o nível de atividade física durante a pandemia; através de um formulário on-line enviado aos participantes pelo aplicativo WhatsApp durante o primeiro semestre de 2020. Para análise estatística, foi utilizado o teste de qui-quadrado para independência pelo software IBM-SPSS Statistics Base v.20. (Comitê de Ética-Universidade nº39.373). Resultados: A amostra foi composta por 93% (n=91) do sexo feminino e 7% (n=7) sexo masculino, com média de idade de 72,19±6,30. Os resultados apontam que  10% (n=10) consideram-se sedentários, 35%  (n=35) pouco ativos e 54% (n=53) ativos. Sobre a motivação para a prática de exercício físico 45% (n=45) consideraram que a sua motivação diminuiu, 32% (n=32) se manteve e 21% (n=21) aumentou. Observou-se que houve associação entre a diminuição da motivação para a prática de atividade física e o baixo de nível de atividade física na pandemia [X² (2)= 33,201; (p<0,000)], apresentando uma associação de 0,582 (58%) entre estas variáveis. Conclusão: Idosos com nível de atividade física considerados sedentários apresentaram-se menos motivados a realizar atividade física durante a pandemia de COVID-19. Nesta amostra, idosos ativos e pouco ativos oscilam sua motivação quanto a prática de atividade física, podendo limitar o seu engajamento a permanecer na atividade a longo prazo

Increased Expression of Cytotoxic T-Lymphocyte-Associated Protein 4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure.

BACKGROUND & AIMS: Patients with acute liver failure (ALF) have defects in innate immune responses to microbes (immune paresis) and are susceptible to sepsis. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4), which interacts with the membrane receptor B7 (also called CD80 and CD86), is a negative regulator of T-cell activation. We collected T cells from patients with ALF and investigated whether inhibitory signals down-regulate adaptive immune responses in patients with ALF. METHODS: We collected peripheral blood mononuclear cells from patients with ALF and controls from September 2013 through September 2015 (45 patients with ALF, 20 patients with acute-on-chronic liver failure, 15 patients with cirrhosis with no evidence of acute decompensation, 20 patients with septic shock but no cirrhosis or liver disease, and 20 healthy individuals). Circulating CD4+ T cells were isolated and analyzed by flow cytometry. CD4+ T cells were incubated with antigen, or agonist to CD3 and dendritic cells, with or without antibody against CTLA4; T-cell proliferation and protein expression were quantified. We measured levels of soluble B7 molecules in supernatants of isolated primary hepatocytes, hepatic sinusoidal endothelial cells, and biliary epithelial cells from healthy or diseased liver tissues. We also measured levels of soluble B7 serum samples from patients and controls, and mice with acetaminophen-induced liver injury using enzyme-linked immunosorbent assays. RESULTS: Peripheral blood samples from patients with ALF had a higher proportion of CD4+ CTLA4+ T cells than controls; patients with infections had the highest proportions. CD4+ T cells from patients with ALF had a reduced proliferative response to antigen or CD3 stimulation compared to cells from controls; incubation of CD4+ T cells from patients with ALF with an antibody against CTLA4 increased their proliferative response to antigen and to CD3 stimulation, to the same levels as cells from controls. CD4+ T cells from controls up-regulated expression of CTLA4 after 24-48 hours culture with sera from patients with ALF; these sera were found to have increased concentrations of soluble B7 compared to sera from controls. Necrotic human primary hepatocytes exposed to acetaminophen, but not hepatic sinusoidal endothelial cells and biliary epithelial cells from patients with ALF, secreted high levels of soluble B7. Sera from mice with acetaminophen-induced liver injury contained high levels of soluble B7 compared to sera from mice without liver injury. Plasma exchange reduced circulating levels of soluble B7 in patients with ALF and expression of CTLA4 on T cells. CONCLUSIONS: Peripheral CD4+ T cells from patients with ALF have increased expression of CTLA4 compared to individuals without ALF; these cells have a reduced response to antigen and CD3 stimulation. We found sera of patients with ALF and from mice with liver injury to have high concentrations of soluble B7, which up-regulates CTLA4 expression by T cells and reduces their response to antigen. Plasma exchange reduces levels of B7 in sera from patients with ALF and might be used to restore antimicrobial responses to patients

Multidisciplinary recommendations for essential baseline functional and laboratory tests to facilitate early diagnosis and management of immune-related adverse events among cancer patients.

Immune checkpoint inhibitors (ICIs) have fundamentally changed the treatment landscape of various cancers. While ICI treatments result in improved survival, quality of life and are cost-effective, the majority of patients experience at least one immune-related adverse event (irAE). Many of these side effects cause little discomfort or are asymptomatic; however, irAEs can affect any organ and are potentially life-threatening. Consequently, early diagnosis and appropriate treatment of irAEs are critical for optimizing long-term outcomes and quality of life in affected patients. Some irAEs are diagnosed according to typical symptoms, others by abnormal findings from diagnostic tests. While there are various guidelines addressing the management of irAEs, recommendations for the early recognition of irAEs as well as the optimal extent and frequency of laboratory tests are mostly lacking. In clinical practice, blood sampling is usually performed before each ICI administration (i.e., every 2-3 weeks), often for several months, representing a burden for patients as well as health care systems. In this report, we propose essential laboratory and functional tests to improve the early detection and management of irAEs and in cancer patients treated with ICIs. These multidisciplinary expert recommendations regarding essential laboratory and functional tests can be used to identify possible irAEs at an early time point, initiate appropriate interventions to improve patient outcomes, and reduce the burden of blood sampling during ICI treatment

MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure.

OBJECTIVE: Acute liver failure (ALF) is characterised by overwhelming hepatocyte death and liver inflammation with massive infiltration of myeloid cells in necrotic areas. The mechanisms underlying resolution of acute hepatic inflammation are largely unknown. Here, we aimed to investigate the impact of Mer tyrosine kinase (MerTK) during ALF and also examine how the microenvironmental mediator, secretory leucocyte protease inhibitor (SLPI), governs this response. DESIGN: Flow cytometry, immunohistochemistry, confocal imaging and gene expression analyses determined the phenotype, functional/transcriptomic profile and tissue topography of MerTK+ monocytes/macrophages in ALF, healthy and disease controls. The temporal evolution of macrophage MerTK expression and its impact on resolution was examined in APAP-induced acute liver injury using wild-type (WT) and Mer-deficient (Mer-/-) mice. SLPI effects on hepatic myeloid cells were determined in vitro and in vivo using APAP-treated WT mice. RESULTS: We demonstrate a significant expansion of resolution-like MerTK+HLA-DRhigh cells in circulatory and tissue compartments of patients with ALF. Compared with WT mice which show an increase of MerTK+MHCIIhigh macrophages during the resolution phase in ALF, APAP-treated Mer-/- mice exhibit persistent liver injury and inflammation, characterised by a decreased proportion of resident Kupffer cells and increased number of neutrophils. Both in vitro and in APAP-treated mice, SLPI reprogrammes myeloid cells towards resolution responses through induction of a MerTK+HLA-DRhigh phenotype which promotes neutrophil apoptosis and their subsequent clearance. CONCLUSIONS: We identify a hepatoprotective, MerTK+, macrophage phenotype that evolves during the resolution phase following ALF and represents a novel immunotherapeutic target to promote resolution responses following acute liver injury

The Role of Myeloid Cells in Hepatotoxicity Related to Cancer Immunotherapy

Drug-related hepatotoxicity is an emerging clinical challenge with the widening use of immunotherapeutic agents in the field of oncology. This is an important complication to consider as more immune oncological targets are being identified to show promising results in clinical trials. The application of these therapeutics may be complicated by the development of immune-related adverse events (irAEs), a serious limitation often requiring high-dose immunosuppression and discontinuation of cancer therapy. Hepatoxicity presents one of the most frequently encountered irAEs and a better understanding of the underlying mechanism is crucial for the development of alternative therapeutic interventions. As a novel drug side effect, the immunopathogenesis of the condition is not completely understood. In the liver, myeloid cells play a central role in the maintenance of homeostasis and promotion of inflammation. Recent research has identified myeloid cells to be associated with hepatic adverse events of various immune modulatory monoclonal antibodies. In this review article, we provide an overview of the role of myeloid cells in the immune pathogenesis during hepatoxicity related to cancer immunotherapies and highlight potential treatment options

The Role of Myeloid Cells in Hepatotoxicity Related to Cancer Immunotherapy

Drug-related hepatotoxicity is an emerging clinical challenge with the widening use of immunotherapeutic agents in the field of oncology. This is an important complication to consider as more immune oncological targets are being identified to show promising results in clinical trials. The application of these therapeutics may be complicated by the development of immune-related adverse events (irAEs), a serious limitation often requiring high-dose immunosuppression and discontinuation of cancer therapy. Hepatoxicity presents one of the most frequently encountered irAEs and a better understanding of the underlying mechanism is crucial for the development of alternative therapeutic interventions. As a novel drug side effect, the immunopathogenesis of the condition is not completely understood. In the liver, myeloid cells play a central role in the maintenance of homeostasis and promotion of inflammation. Recent research has identified myeloid cells to be associated with hepatic adverse events of various immune modulatory monoclonal antibodies. In this review article, we provide an overview of the role of myeloid cells in the immune pathogenesis during hepatoxicity related to cancer immunotherapies and highlight potential treatment options

Programa Future-se: impactos sobre a autonomia das Instituições Federais de Ensino e sobre o direito à educação

This article aims to reflect the implications of Future-se Program on the autonomy of Federal Education Institutions and the right to higher education. To reach this purpose, we present aspects of the political scenario of attacks on Brazilians; social rights and analyze possible outcomes such as: the use of the Bill as an instrument of the current government to further strengthen relations with productive and business sector; the restriction of university autonomy and the alteration of main characteristics and purposes of Universities and Federal Institutes. The research technique used was document analysis and bibliographic review, with a qualitative approach. The reflections start from the understanding that social relations are historically determined by the mode of production, obstinating destruction of pseudo-concrete (KOSIK, 1976). The analysis carried out allows us to affirm that Future-se is unrelated to the improvement of quality of Brazilian education, but comes from capital’s needs, in order to comply with private demands that, in short term, intend to make Federal Education Institutions into a locus of research development and knowledge production committed to the logic of the commodification of education, and therefore, unconnected to the integral development of students and the full enjoyment of the Right to education.Este artículo tiene como objetivo mostrar las implicaciones del ‘Programa Future-se’ sobre la autonomía de las instituciones federales de educación y el derecho a la educación superior. Para tal propósito presentamos aspectos del escenario de los brasileños y analizamos posibles desdobramientos como: el uso del proyecto de ley como instrumento del gobierno actual para fortalecer aún más las relaciones con el sector productivo y empresarial; la restricción de la autonomía universitaria y la alteración de los principales principios y propósitos de las universidades e institutos federales. La metodología de investigación fue el análisis de documentos y la revisión bibliográfica, con enfoque cualitativo. Las reflexiones parten de la comprensión de que las relaciones sociales están históricamente determinadas por el modo de producción, obstinando la destrucción de la pseudoconcreción (KOSIK, 1976). El análisis realizado nos permite establecer que Future-se no está relacionado con la mejora de la calidad de la educación brasileña, sino que va acompañado de las necesidades del capital para cumplir con demandas privadas que, en el corto plazo, pretende hacer que las instituciones federales de educación en el lugar de desarrollo de la investigación y producción de conocimiento comprometido con la lógica de la mercantilización de la educación y, por lo tanto, ajeno al desarrollo integral de los estudiantes y al pleno disfrute del derecho a la educación.Este artigo possui como propósito refletir as implicações do Programa Future-se sobre a autonomia das Instituições Federais de Ensino e o direito à educação, neste caso, à educação superior. Para tanto, serão apresentados aspectos do cenário político de ataques aos direitos sociais dos brasileiros, a fim de analisar possíveis desdobramentos, tais como: o uso do Projeto de Lei como instrumento do atual governo para estreitar ainda mais as relações com o setor produtivo e empresarial, restrição da autonomia universitária e alteração das características precípuas e finalidades das universidades e institutos federais. A técnica de pesquisa utilizada foi a análise documental e bibliográfica, de abordagem qualitativa, e parte da compreensão de que as relações sociais são determinadas, historicamente, pelo modo de produção, obstinando a destruição da pseudoconcreticidade (KOSIK, 1976). A análise realizada nos permite afirmar que o Future-se não possui relação com a melhoria da qualidade da educação brasileira, mas vem à reboque das necessidades do capital a fim de obedecer demandas privadas que, em curto prazo, pretendem tornar as Instituições Federais de Ensino lócus de desenvolvimento de pesquisas e produção de conhecimentos comprometidos com a lógica da mercadorização da educação, e, portanto, alheia ao desenvolvimento integral dos estudantes e ao pleno gozo do direito à educação