Formação para enfrentar a morte na perspectiva de futuros médicos / Training to cope with death from the perspective of future physicians / Formación para afrontar la muerte en la perspectiva de los futuros médicos

Resumo Ocasionalmente, a morte é considerada falha ou insucesso da medicina e a inabilidade em enfrentá-la pode gerar medo e frustração, interferindo nas decisões clínicas. Este estudo avaliou a percepção de estudantes de medicina quanto ao enfrentamento da morte, analisando seu preparo para lidar com essas situações e comparando seus perfis sociodemográfico, religioso e acadêmico. Realizou-se estudo transversal, quantitativo e qualitativo, com 294 estudantes de medicina da Bahia. Demonstrou-se que o estudante de medicina considera a morte um processo natural, mas não se sente totalmente preparado para lidar com a terminalidade da vida durante a prática clínica, possivelmente em razão das escassas discussões acadêmicas e da oferta insuficiente de conteúdo teórico-prático durante a formação. Homens com formação prévia e que tiveram contato pessoal e acadêmico com a morte foram associados à maior percepção de preparo para lidar com a terminalidade da vida, sem interferência de ciclo acadêmico e religião.

Abstract Occasionally, death is considered a medical failure and the inability to cope with it can generate fear and frustration, interfering with clinical decisions. This study assessed how medical students perceived coping with death, analyzing their preparedness to tackle these situations and comparing their sociodemographic, religious and academic profiles. This cross-sectional, quantitative and qualitative study was conducted with 294 medical students from Bahia. Results showed that medical students consider death to be a natural process, but do not feel fully prepared to address end of life during clinical practice, possibly due to the scarcity of academic discussions and the insufficient theoretical and practical content during training. Men with previous training and who had personal and academic contact with death were associated with a greater perceived preparedness to cope with death, without interference from academic level and religion.

Resumen En ocasiones, se percibe la muerte como un fracaso de la medicina, y la incapacidad de afrontarla puede generar miedo y frustración, interfiriendo en las decisiones clínicas. Este estudio evaluó la percepción de los estudiantes de medicina sobre el enfrentamiento a la muerte, analizando su preparación para lidiar con esta situación y comparando sus perfiles sociodemográficos, religiosos y académicos. En este estudio transversal, cuantitativo y cualitativo participaron 294 estudiantes de medicina de Bahía (Brasil). Los estudiantes de medicina perciben la muerte como algo natural, pero no se sienten totalmente preparados para afrontar el final de la vida durante la práctica clínica, posiblemente debido a escasas discusiones académicas y a insuficientes contenidos en la formación teórico-práctica. Los hombres con formación previa y que tuvieron contacto personal y académico con la muerte tuvieron una mayor percepción de preparación para afrontar el final de la vida, sin interferencia académica y de la religión.

Mentoria científica na graduação em Medicina: repercussões na satisfação, engajamento e produção discente / Scientific mentoring in undergraduate medical school: impacts on student satisfaction, engagement and production

Resumo: Introdução: A mentoria é uma estratégia acadêmica que está cada vez mais presente no curso de Medicina por promover benefícios, como a criação de ambientes de acolhimento e afetividade, e discussão de conteúdos médicos e de temas relacionados à formação profissional. Entretanto, pouco se discute acerca dessa estratégia com finalidades científicas. Objetivo: Este estudo teve como objetivos descrever a implementação do programa de mentorias científicas, investigar a percepção dos estudantes sobre a sua implantação e execução, além de mensurar indicadores de êxito. Método: Trata-se de estudo seccional descritivo, realizado em um curso de graduação em Medicina, localizado em Salvador/Bahia. Foram incluídos estudantes do terceiro ao quarto ano da graduação. Aplicou-se um questionário virtual, estruturado, anônimo, com perguntas objetivas relacionadas ao perfil discente, às percepções sobre o programa de mentorias científicas e à publicação dos trabalhos de conclusão de curso (TCC). Resultado: Dos 143 estudantes participantes, houve predominância de solteiros (90,9%), pardos (46,2%), do sexo feminino (72,0%), com idade de 25,3 ± 5,54 anos, que não participaram de programas de iniciação científica (88,8%). Dentre aqueles que participaram das mentorias (n = 101), 97,1% afirmaram que elas contribuíram para o desenvolvimento do TCC, 98,0% se mostraram favoráveis à manutenção de sua oferta e 85,0% consideraram a estratégia inovadora. No recorte temporal de dois semestres letivos, apresentaram-se 131 TCC, dos quais 27,5% foram publicados contando com a participação de 19 professores, com média de 1,89 produção/professor. Conclusão: Os estudantes de Medicina são favoráveis à implementação do sistema de mentorias científicas, tendo essa estratégia se mostrado factível e eficaz.

Abstract: Introduction: Mentoring is an academic strategy that is increasingly present in the medical course, as it promotes benefits such as the creation of welcoming and affective environments, discussion of medical content and topics related to professional training. However, little is discussed about this strategy for scientific purposes. Objectives: To describe the implementation of the scientific mentoring program, investigate the students' perception of its implementation and performance, in addition to measuring success indicators. Methods: This was a cross-sectional, descriptive study carried out in an undergraduate medical course, located in Salvador/Bahia. Students from the 3rd to the 4th year of undergraduate school were included. A virtual, structured, anonymous questionnaire was applied, with objective questions related to the students' profile, their perceptions in relation to the scientific mentorship program and the publication of the Term Paper (TP). Results: Of the 143 participating students, there was a predominance of single (90.9%), brown (46.2%), female individuals (72.0%), aged 25.3±5.54 years, those who did not participate in Undergraduate Research programs (88.8%). Among those who participated in mentorships (n=101), 97.1% considered that they contributed to the development of the TP, 98.0% are in favor of maintaining its offer and 85.0% consider the strategy to be innovative. In the time frame of two academic semesters, 131 TPs were presented, of which 27.5% were published with the participation of 19 teachers, with an average of 1.89 productions/teacher. Conclusion: Medical students are in favor of implementing the scientific mentoring system, and this strategy has shown to be feasible and effective.

Ensino da Língua Brasileira de Sinais durante a graduação em Medicina: a percepção dos futuros médicos / Teaching Brazilian Sign Language during medical students' training: the perception of future physicians

RESUMO Objetivo Avaliar a percepção dos estudantes de Medicina em relação à oferta da disciplina Língua Brasileira de Sinais (Libras) durante a sua formação acadêmica. Métodos Estudo transversal, descritivo e analítico, incluindo estudantes de Medicina da cidade de Salvador, Bahia, maiores de 18 anos. Aplicou-se um questionário virtual, semiestruturado, contendo aspectos sociodemográficos, acadêmicos e sobre a Libras (comunicação, aprendizado, importância na formação médica e oferta curricular). Resultados Dos 240 estudantes avaliados, 82,9% não sabe se comunicar através de Libras, entretanto 95,8% acreditam que a disciplina é necessária no currículo médico. Quanto à oferta curricular, os estudantes consideram que esta deveria ser obrigatória (55,2%) e na modalidade presencial (75,7%). Os principais motivos para não cursar a disciplina foram por esta ser optativa (41,7%) e por falta de tempo (33,3%). Identificou-se que as mulheres dão mais importância a esta formação (p=0,0013) e essa percepção independe de idade, natureza administrativa da instituição e ciclo acadêmico em curso. Conclusão Os estudantes de Medicina têm uma percepção favorável ao ensino de Libras na educação médica. Entretanto, a maioria desses estudantes não cursou a disciplina em seus percursos acadêmicos e acredita ser desafiador o atendimento a este público.

ABSTRACT Purpose To assess the perception of medical students regarding the discipline Brazilian Sign Language (Libras) during their academic training. Methods Cross-sectional, descriptive and analytical study, including medical students from the city of Salvador, Bahia, over 18 years old. A virtual, semi-structured questionnaire was applied, containing sociodemographic, academic and Libras (communication, learning, importance in medical training and curriculum offer) aspects. Results Of the 240 students evaluated, 82.9% do not know how to communicate through Libras, however 95.8% believe that the discipline is necessary in the medical curriculum. As for the curricular offer, students consider that it should be mandatory (55.2%) and in the face-to-face modality (75.7%). The main reasons for not taking the course were because it was optional (41.7%) and lack of time (33.3%). It was identified that women give more importance to this training (p=0.0013) and this perception is independent of age, administrative nature of the institution and ongoing academic cycle. Conclusion Medical students have a favorable perception of the teaching of Libras in medical education. However, most of these students did not attend the discipline in their academic careers and believe that serving this public is challenging.

Prevalence of common mental disorders among medical students during the Covid-19 pandemic / Prevalência de transtornos mentais comuns entre estudantes de Medicina durante a pandemia de Covid-19

Abstract: Introduction: Common mental disorders (CMD) have been frequently identified among university students in the health area, especially in Medicine. It is believed that characteristics inherent to the course have a potential influence on the student's mental health. When adding the pandemic context, with its inherent social restrictions, the psychological determinants related to the unknown pathology and the fear of the rapid spread of the new coronavirus, there is the possibility of increasing the risk factors for psychological distress in this population. Objective: To estimate the prevalence of CMD among medical students during the COVID-19 pandemic, analyzing its main determinants in the academic, social and economic spheres. Method: Cross-sectional study, carried out with 388 medical students in Salvador/BA., Data on sociodemographic and academic aspects, life habits, comorbidities and symptoms of non-psychotic disorders were collected using the Google Forms platform, measured by the Self-Reporting Questionnaire (SRQ-20). Results: The prevalence of CMD was 39.7% among medical students, with 47.4% in the basic cycle, 40.3% in the clinical cycle and 12.3% in the internship period. Among the factors associated with the emergence of CMD are sedentary lifestyle, smoking, use of substances that enhance academic performance, dissatisfaction with one's academic performance, poor sleep quality, lack of appetite, frequent headaches, poor digestion, suicidal ideation and sadness. There was a higher rate of non-psychotic mental disorders among women, with no difference regarding the academic cycle and the administrative type of the educational institution. Conclusion: During the COVID-19 pandemic, a significant prevalence of CMD was demonstrated among female, white, single medical students who live with family members and do not have their own income. Although studies suggest an increase in the prevalence among university students at the present time, the data from the present study remain in agreement with the literature data prior to the pandemic, showing that the medical course itself is the main risk factor for higher rates of CMD in this population. However, further studies on the long-term impact of the pandemic on the mental health of university students are still necessary.

Resumo: Introdução: Transtornos mentais comuns (TMC) têm sido frequentemente identificados entre universitários na área de saúde, especialmente em Medicina. Acredita-se que características inerentes ao curso exerçam potencial influência na saúde mental do estudante. Quando se adiciona o contexto de pandemia com as restrições sociais inerentes, os determinantes psicológicos relacionados à desconhecida patologia e o temor do rápido alastramento do novo coronavírus, existe a possibilidade de potencialização dos fatores de riscos para o sofrimento psíquico nessa população. Objetivo: Este estudo teve como objetivo estimar a prevalência de TMC entre estudantes de Medicina durante a pandemia da Covid-19, analisando seus principais determinantes nos âmbitos acadêmico, social e econômico. Método: Trata-se de estudo transversal, realizado com 388 estudantes de Medicina em Salvador, na Bahia. Por meio da plataforma Google Forms, coletaram-se dados sociodemográficos e acadêmicos, sobre hábitos de vida, comorbidades e sintomas de transtornos não psicóticos mensurados pelo Self-Reporting Questionnaire (SRQ-20). Resultado: A prevalência de TMC foi de 39,7% entre os estudantes de Medicina, sendo de 47,4% no ciclo básico, 40,3% no ciclo clínico e 12,3% no internato. Entre os fatores associados ao surgimento de TMC, estão sedentarismo, tabagismo, uso de substâncias que favoreçam o desempenho acadêmico, insatisfação com o próprio rendimento acadêmico, má qualidade de sono, falta de apetite, cefaleia frequente, má digestão, ideação suicida e tristeza. Observou-se maior índice de transtornos mentais não psicóticos entre as mulheres, não havendo diferença quanto ao ciclo acadêmico e à natureza administrativa da instituição de ensino. Conclusão: Durante a pandemia de Covid-19, demonstrou-se uma expressiva prevalência de TMC entre estudantes de Medicina do sexo feminino, brancos, solteiros, que residem com familiares e não possuem renda própria. Apesar de estudos sugerirem aumento da prevalência nos universitários no momento atual, os dados deste estudo permaneceram concordantes com a literatura anterior à pandemia, configurando o próprio curso de Medicina como principal fator de risco para taxas superiores de TMC nessa população. Entretanto, novos estudos acerca do impacto em longo prazo da pandemia na saúde mental dos universitários ainda são necessários.

Simulação realística como estratégia de ensino na graduação médica: uma revisão sistemática / Realistic simulation as a teaching strategy in medical undergraduation: a systematic review

Objetivo: avaliar a eficácia da simulação realística (SR) na graduação em medicina com base no conhecimento adquirido e na melhoria do desempenho clínico e analisar a percepção dos estudantes quanto à aplicabilidade do método como ferramenta de ensino. Métodos: foi realizada uma revisão sistemática de artigos científicos nas bases de dados PubMed, Lilacs e SciELO, em inglês e português, publicados no período de 2015 a 2020, utilizando a seguinte estratégia de busca: (simulation training OR simulation patient) AND (students medical AND education, medical, undergraduate). Resultados: dos 261 artigos identificados, apenas sete atenderam aos critérios de inclusão e exclusão estabelecidos, 57,2% deles com baixo ou moderado nível de evidência. Todos demonstraram que a SR promove modificações positivas no processo de construção acadêmica dos estudantes, contribuindo para o desenvolvimento de habilidades e competências essenciais para a formação médica. Além disso, houve majoritária percepção positiva dos estudantes quanto à utilização da SR como método de ensino durante a formação médica. Conclusão: houve evidências de eficácia da SR na aprendizagem e favorável percepção dos estudantes de medicina quanto à sua utilização. Todavia, os desafios relativos à sua implantação e execução, bem como o restrito número de artigos de alto rigor metodológico, limitam a inferência inequívoca de sua eficácia na educação médica.

Aims: to evaluate the effectiveness of realistic simulation (RS) in medical graduation based on the knowledge acquired and on the improvement of clinical performance, and to analyze the students' perception regarding the applicability of the method as a teaching tool. Methods: a systematic review of scientific articles was carried out in the PubMed, Lilacs and SciELO databases, in English and Portuguese, published from 2015 to 2020, using the following search strategy: (simulation training OR simulation patient) AND (students medical AND education, medical, undergraduate). Results: of 261 identified, only seven met the inclusion and exclusion criteria (57.2% with a low or moderate level of scientific quality). All of them demonstrated that RS promotes positive changes in the students' academic construction process, contributing to the development of essential skills and competences for medical education. In addition, there was a majority positive perception of students regarding the use of RS as a teaching method during medical training. Conclusion: there was evidence of the effectiveness of RS in learning and favorable perception of medical students regarding its use. However, the challenges related to its implementation and execution, as well as the limited number of articles of high methodological rigor, limit the unequivocal inference of its effectiveness in medical education.

Maternidade, paternidade e vida acadêmica: impactos e percepções de mães e pais estudantes de medicina / Maternity, paternity and academic life: impacts and views of parents who are studying medicine

Resumo: Introdução: Aspectos pessoais, como a maternidade e a paternidade podem representar grandes desafios acadêmicos e profissionais, uma vez que requerem tempo, envolvimento afetivo, atenção e cuidado. Principalmente no curso de Medicina, caracterizado pela extensa rotina de estudos e carga horária, essa conjuntura pode ser ainda mais impactante. Objetivo: Este estudo teve como objetivos avaliar o impacto da maternidade/paternidade no rendimento acadêmico de estudantes de Medicina, e analisar as principais percepções, motivações e desafios deles durante a formação médica. Método: Trata-se de um estudo transversal, quanti-qualitativo de abordagem descritiva e analítica que avaliou o perfil e as percepções de 85 mães/pais estudantes de Medicina em todo o país. Como instrumento de coleta, foi empregado um formulário virtual, semiestruturado, contendo questões sociodemográficas de única escolha e de percepções utilizando a escala Likert. A fim de avaliar o impacto da maternidade/paternidade no rendimento acadêmico, parte dos respondentes de uma das instituições avaliadas teve seus rendimentos acadêmicos obtidos para a comparação com amostras aleatórias e não identificadas de estudantes sem filhos da mesma instituição. Resultado: Os estudantes possuem clareza e não se arrependem de suas escolhas pessoais (93%), têm orgulho de ser mãe/pai universitários (93%) e ressaltam a importância e essencialidade da rede de apoio (88%). Ao serem questionados quanto ao rendimento acadêmico, as mães e os pais estudantes de Medicina expressaram limitação na compatibilidade dos afazeres e responsabilidades pessoais e profissionais (42%) e relataram que as obrigações parentais comprometem o rendimento no curso de Medicina (53%). Neste âmbito, porém, nossos dados apontam para um rendimento acadêmico de mães e pais similar aos de estudantes sem filhos. Conclusão: Os estudantes de Medicina com filhos, apesar de relatarem limitação na capacidade de associar os afazeres e as responsabilidades pessoais e acadêmicas, não se arrependem das suas escolhas e têm orgulho de exercer a dupla função. Além disso, eles apresentam rendimento acadêmico semelhante ao de estudantes sem filhos, apesar de acreditarem que as obrigações da maternidade/paternidade comprometem o seu rendimento acadêmico. Destacam-se a essencialidade da rede de apoio para realização das atividades acadêmicas e a uniformidade dessas percepções entre variáveis como sexo, estado civil e ciclo acadêmico.

Abstract: Introduction: Personal aspects such as maternity and paternity can represent major academic and professional challenges, as they require time, emotional involvement, attention and care. Mainly in the medical schools, characterized by the extensive study routine and workload, this situation can be even more impactful. Objective: To assess the impact of parenthood on the academic performance of medical students, as well as to analyze their main views, motivations and challenges during medical training. Method: Cross-sectional, quantitative-qualitative study with a descriptive and analytical approach that evaluated the profile and perceptions of 85 parents who are studying medicine in Brazil. A semi-structured virtual questionnaire was used containing single-choice sociodemographic questions and evaluation of views using the Likert scale. In order to assess the impact of parenthood on academic performance, the academic performance of some of the respondents from one of the institutions evaluated was considered for comparison with random and unidentified samples of childless students from the same institution. Result: Students are clear and do not regret their personal choices (93%), are proud to be parent students (93%) and emphasize the importance and essentiality of the support network (88%). When asked about academic performance, the parents who are medical students express limitations in the compatibility of personal and professional responsibilities (42%) and report that parental duties compromise their performance at medical school (53%). In this context, however, our data indicate that the academic performance of mothers and fathers is similar to that of childless students. Conclusion: Medical students with children, despite reporting limitations in the ability to combine personal and academic responsibilities, do not regret their choices and are proud to exercise both roles. Furthermore, their academic performance is similar to that of childless students, despite believing that parental duties compromise their academic performance. They highlight the essential role played by the support network for performing academic activities and these perceptions between variables such as gender, marital status and academic cycle are distinctively uniform.

Longitudinal profiling of the vaccination coverage in Brazil reveals a recent change in the patterns hallmarked by differential reduction across regions.

OBJECTIVE: Vaccination coverage is decreasing worldwide, favoring the potential reemergence of vaccine-preventable diseases. In this study, we performed a longitudinal characterization of vaccination coverage in Brazil and compared the profiles between the distinct regions in the country to test whether there has been a substantial change over the last 5 years. METHODS: De-identified publicly available data were retrieved from the repository of the Brazilian Ministry of Health, comprising detailed information on vaccination coverage in all age groups between 1994 and 2019. The vaccination coverage for the whole country and for each Brazilian region, by year, was examined, and a time-series pattern analysis was performed. RESULTS: A significant decrease in overall vaccination coverage across the country regions was observed between 2017 and 2019, especially in childhood immunization. A reduction in BCG, hepatitis B, influenza, and rotavirus vaccine coverage was observed. Conversely, vaccines against measles, mumps, rubella, varicella, and meningococcus showed an increase in coverage. Region-specific changes in vaccination patterns within the study period were observed. CONCLUSIONS: A substantial reduction in vaccination coverage was detected in Brazil, a country already highly susceptible to the emergence of epidemic infectious diseases. Continuing evaluation of the immunization program actions may help to improve vaccination coverage and prevent new epidemics.

The impact of cancer campaigns in Brazil: a Google Trends analysis.

It is estimated that more than 600,000 new cases of cancer will be reported in Brazil during the 2018-2019 biennium, especially with regard to prostate, breast, lung and colorectal cancers. Due to the high prevalence, incidence and mortality rates of these diseases, cancer campaigns such as 'Pink October' and 'Blue November' were strongly promoted in the past decade throughout the country to raise awareness of breast and prostate cancer, respectively. Nevertheless, whether the implementation of these campaigns has been proven efficient is still unknown. In the present study, we analysed the effectiveness of these campaigns on eliciting population online interest for cancer information. The Google Trends database was evaluated for the relative Internet search popularity for the terms 'breast cancer' and 'prostate cancer' from 2014 to 2019. Aside from some regional differences, we found that there was a high demand for 'breast cancer' and, to a lesser extent, 'prostate cancer' searches in a seasonal fashion (during October and November, respectively). Despite the worldwide high incidence of lung and colorectal cancers, searches including these keywords did not show increases in any specific period of the year, demonstrating the efficiency of the 'Pink October' and 'Blue November' campaigns in engaging the interest of the Brazilian population on the subject. These results allow us to infer that campaigns are effective in mobilising the attention of the Brazilian population with regard to breast and prostate cancers, but the practical aspects in reducing incidence and mortality should still be discussed.

Advances in Hepatic Tissue Bioengineering with Decellularized Liver Bioscaffold.

The burden of liver diseases continues to grow worldwide, and liver transplantation is the only option for patients with end-stage liver disease. This procedure is limited by critical issues, including the low availability of donor organs; thus, novel therapeutic strategies are greatly needed. Recently, bioengineering approaches using decellularized liver scaffolds have been proposed as a novel strategy to overcome these challenges. The aim of this systematic literature review was to identify the major advances in the field of bioengineering using decellularized liver scaffolds and to identify obstacles and challenges for clinical application. The main findings of the articles and each contribution for technique optimization were highlighted, including the protocols of perfusion and decellularization, duration, demonstration of quality control-scaffold acellularity, matrix composition, and preservation of growth factors-and tissue functionality after recellularization. In previous years, many advances have been made as this technique has evolved from studies in animal models to human livers. As the field develops and this promising technique has become much more feasible, many challenges remain, including the selection of appropriate cell types for recellularization, route of cell administration, cell-seeding protocol, and scalability that must be standardized prior to clinical application.

Medical student perceptions about active methodologies in the study of physiology in medical schools in Salvador, Brazil.

In the field of medical education, it is possible to consider that the acquisition of professional competences can gain new contours when considering the use of active methodologies. It is important to analyze the perception of the students about the use of them in medical courses, as well as to reflect on their challenges and potentials. In the present study, a semistructured questionnaire of student perception was applied immediately after the execution of different types of active methodologies in the discipline of physiology in two medical courses. The results suggest a highly positive evaluation of the use of active methodologies by the student body of the two institutions. The students evaluated positively the application of the method (94.6%) and the perception about the learning (84.1%). On the other hand, when questioned about the substitution of the traditional expository method by the active methodologies, there was a tendency to the centrality of the answers, with 84.0% of the responses concentrated at positions 2, 3, and 4 on a scale of 1 (minimum) to 5 (maximum) on the Likert scale. There were no statistically significant differences when comparing variables of age, sex, and previous graduation. Although there was no consensus regarding the full replacement of traditional for active methodologies, one can conclude that the students' perception about the introduction of said methodologies in the teaching of physiology in medical courses is positive, regardless of the subgroups evaluated. These results encourage the insertion of these and other methodologies into medical courses.

Células tronco mesenquimais derivadas de tecido adiposo no tratamento de cirrose hepática / Adipose derived mesenchymal stem cells in the treatment of liver cirrhosis

Introdução: hepatopatias crônicas figuram entre as principais causas de morte no mundo e o transplante hepático permanece como a única alternativa terapêutica curativa disponível. A terapia celular utilizando células tronco tem sido demonstrada como uma alternativa potencial, porém os mecanismos envolvidos na resolução da doença permanecem em debate. Metodologia: trata-se de uma revisão de literatura, na qual foi realizada uma consulta por artigos científicos selecionados através de busca no banco de dados do PubMed e Scielo no período de agosto de 2016 a junho de 2017. Objetivo: este estudo tem como objetivo descrever os mecanismos envolvidos na regeneração/reparo da cirrose hepática através do tratamento com células tronco mesenquimais derivadas do tecido adiposo (AD-MSCs). Resultados e discussão: os estudos utilizando terapia celular apontam como principais mecanismos a fibrinólise, imunomodulação e atividade antioxidante. Com relação a atividade fibrinolítica, o aumento proeminente na expressão de enzimas como MMP2, MMP3 e MMP9 explica a redução da fibrose normalmente observada. A atividade imunomodulatória das ADMSCs parece estar relacionada com a secreção de agentes imunossupressores e fatores que promovem a hematopoiese. Finalmente, as AD-MSCS são capazes de aumentar a atividade do NF-E2-related fator (Nrf2), um fator de transcrição crucial na expressão de diversas enzimas relacionadas à resolução do estresse oxidativo. Conclusão: os estudos utilizando a terapia celular evidenciaram que fibrinólise, imunomodulação e efeito antioxidante podem, de forma associada, contribuir para os bons resultados apresentados. Apesar dos principais mecanismos propostos terem sido apresentados neste presente trabalho, mais estudos são necessários a fim de determinar a precisa contribuição de cada um deles.

Introduction: chronic liver diseases are among the leading causes of death in the world and liver transplantation remains the only curative alternative available. Cell therapy using stem cells has been demonstrated as a potential alternative, but the mechanisms involved in this proccess remain unclear. Methodology: we performed a review of the literature, in which a query was made for scientific articles selected through a search in the PubMed and Scielo database from August 2016 to June 2017. Objectives: this study aims to describe the mechanisms involved in the regeneration/repair of liver cirrhosis by treatment with adipose tissue-derived mesenchymal stem cells (AT-MSCs). Results and discussion: studies using cellular therapy point out as main mechanisms fibrinolysis, immunomodulation and antioxidant activity. With regard to fibrinolytic activity, the prominent increase in the expression of enzymes such as MMP2, MMP3 and MMP9 explains the reduction in fibrosis normally observed. The immunomodulatory activity of AT-MSCs appears to be related to the secretion of immunosuppressive agents and factors that promote hematopoiesis. Finally, AT-MSCS are able to increase the activity of the NF-E2-related factor (Nrf2), a crucial transcription factor in the expression of several enzymes related to the resolution of oxidative stress. Conclusion: studies using cell therapy have shown that fibrinolysis, immunomodulation and antioxidant effect may, in an associated way, contribute to the good results presented. Although the main proposed mechanisms have been presented in this present study, more studies are necessary in order to determine the precise contribution of each of them.

Evaluating effects of L-carnitine on human bone-marrow-derived mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are multipotent cells showing potential for use in regenerative medicine. Culture techniques that are more stable and methods for the more efficient production of MSCs with therapeutic efficacy are needed. We evaluate the effects of growing bone marrow (Bm)-derived MSCs in the presence of L-carnitine, which is believed to promote lipid metabolism and to suppress apoptosis. The presence of L-carnitine decreased the degree of drug-induced apoptosis and suppressed adipogenic differentiation. Metabolomic analysis by means of the exhaustive investigation of metabolic products showed that, in addition to increased ß-oxidation and the expression of all carnitine derivatives other than deoxycarnitine (an intermediate in carnitine synthesis), polysaturated and polyunsaturated acids were down-regulated. An integrated analysis incorporating both serial analysis of gene expression and metabolomics revealed increases in cell survival, suggesting the utility of carnitine. The addition of carnitine elevated the oxygen consumption rate by BmMSCs that had been cultured for only a few generations and those that had become senescent following repeated replication indicating that mitochondrial activation occurred. Our exhaustive analysis of the effects of various carnitine metabolites thus suggests that the addition of L-carnitine to BmMSCs during expansion enables efficient cell production.

A canine liver fibrosis model to develop a therapy for liver cirrhosis using cultured bone marrow-derived cells.

We have been developing a therapy for liver cirrhosis using cultured autologous bone marrow-derived mesenchymal stem cells (BMSCs). Before human clinical trials can be considered, the safety and efficacy of BMSC infusion in medium to large animals must be confirmed; thus, we developed a canine liver fibrosis model. A small amount of bone marrow fluid was aspirated from the canine humerus to assess the characteristics of BMSCs. We implanted a venous catheter in the stomach and a subcutaneous infusion port in the back of the neck of each canine. Repeated injection of CCl4 through the catheter was performed to induce liver cirrhosis. After 10 weeks of CCl4 injection, eight canines were equally divided into two groups: no cell infusion (control group) and autologous BMSC infusion through the peripheral vein (BMSC group). A variety of assays were carried out before and 4 weeks after the infusion. The area of liver fibrosis stained with sirius red was significantly reduced in the BMSC group 4 weeks after BMSC infusion, consistent with a significantly shortened half-life of indocyanine green and improved liver function. Conclusion: We established a useful canine liver fibrosis model and confirmed that cultured autologous BMSC infusion improved liver fibrosis without adverse effects. (Hepatology Communications 2017;1:691-703).

Enhanced survival of mice infused with bone marrow-derived as compared with adipose-derived mesenchymal stem cells.

AIM: Less invasive therapies using mesenchymal stem cells (MSC) are being developed to treat patients with severe liver cirrhosis. MSC constitute a promising cell source for regenerative therapy and are frequently isolated from bone marrow (BMSC) or adipose tissue (ASC). Therefore, this study assessed the characteristics of these two cell types and their safety for cell infusion. METHODS: In vitro, exhaustive genetic analysis was performed using human (h)BMSC and hASC. Subsequently, the expression of mRNA and protein was evaluated. In vivo, mouse (m)BMSC or mASC was infused into serial mice via the peripheral vein, and 24-h survival rate, prothrombin time and cause of death were analyzed. RESULTS: On polymerase chain reaction, western blotting, enzyme-linked immunoassay and fluorescence-activated cell sorting, tissue factor was found to be expressed at higher levels in hASC than in hBMSC. Prothrombin time in mice infused with mASC (>120 s) was markedly longer than that of untreated mice (6.5 ± 1.7 s) and that of mice infused with BMSC (6.7 ± 0.8 s) (P < 0.001), indicating that pro-coagulation activity was potently enhanced after ASC infusion. The 24-h survival rates in the mASC- and mBMSC-infused groups were 46.4% (13/28) and 95.5% (21/22), respectively; in the former, the rate decreased with increasing number of infused mASC. This cell number-dependent effect was not observed with mBMSC. A histopathological analysis of mice that died immediately following mASC infusion revealed multiple thrombi in the blood vessels of the lungs. CONCLUSION: These results indicate that BMSC are a superior and safer cell source for regenerative therapy.

Canine bone marrow stromal cells promote functional recovery in mice with spinal cord injury.

Regenerative therapy has begun to be clinically applied in humans and dogs to treat neurological disorders, such as spinal cord injury (SCI). Here, we show the therapeutic potential of transplantation of cultured canine bone marrow stromal cells (BMSCs) into mice with SCI. Canine BMSC transplantation therapy was performed, immediately after the spinal cord was injured. Canine BMSC therapy enhanced functional recovery of the hind limbs in mice with SCI. Nestin-positive cells were observed only in the lesion of mice with SCI that received BMSCs. These results suggest that canine BMSCs promote functional recovery in mice with SCI and that migration of nestin-positive cells may contribute to the efficacy of the BMSC treatment.

Canine mesenchymal stem cells show antioxidant properties against thioacetamide-induced liver injury in vitro and in vivo.

AIM: To overcome current limitations of therapy for liver diseases, cell-based therapies using mesenchymal stem cells (MSC) have been attempted through basic and clinical approaches. Oxidative stress is a crucial factor in hepatology, and reactive oxygen species (ROS) are well-established molecules responsible for its deleterious effects. The antioxidant properties of MSC were recently demonstrated, and therefore we examined the antioxidant activity of canine MSC (cMSC), their effects on isolated hepatocytes in vitro and their curative potential against thioacetamide (TAA)-induced liver injury in vivo. METHODS: To evaluate the ability of cMSC to challenge oxidative stress, cell viability, cytotoxicity and ROS were measured in cultured cMSC treated with TAA. Also, cMSC were co-cultured with hepatocytes in the same injury condition, and the ROS level was measured exclusively in hepatocytes. Finally, to verify the curative potential of cMSC, 2.0 × 10(6) cells or phosphate-buffered saline were injected systemically in non-obese diabetic/severe combined immunodeficiency mice that received TAA injections twice a week for 13 weeks. We then evaluated histological parameters, serum injury markers and redox homeostasis. RESULTS: cMSC overcame TAA-induced oxidative stress in vitro, as shown by increased viability and lower cytotoxicity and ROS levels. Moreover, hepatocytes co-cultured with cMSC also showed decreased cellular ROS. The in vivo study showed that mice treated with cMSC presented with an ameliorated histological pattern, suppressed fibrosis, lower serum injury marker levels and better oxidative parameters. CONCLUSION: We concluded that cMSC injection reduce TAA-induced liver injury through antioxidant activities and hepatoprotective effects, showing a curative potential in liver diseases.

Bone marrow progenitor cells do not contribute to liver fibrogenic cells.

AIM: To investigate the contribution of bone marrow (BM) cells to hepatic fibrosis. METHODS: To establish a model of chimerism, C57Bl/6 female mice were subjected to full-body irradiation (7 Gy) resulting in BM myeloablation. BM mononuclear cells obtained from male transgenic mice expressing enhanced green fluorescent protein (GFP) were used for reconstitution. Engraftment was confirmed by flow cytometry. To induce liver injury, chimeric animals received carbon tetrachloride (CCl(4)) 0.5 mL/kg intraperitoneally twice a week for 30 d (CCl(4) 30 d) and age-matched controls received saline (Saline 30 d). At the end of this period, animals were sacrificed for post mortem analysis. Liver samples were stained with hematoxylin and eosin to observe liver architectural changes and with Sirius red for collagen quantification by morphometric analysis. α-smooth muscle actin (α-SMA) was analyzed by confocal microscopy to identify GFP+ cells with myofibroblast (MF) characteristics. Liver tissue, BM and peripheral blood were collected and prepared for flow cytometric analysis using specific markers for detection of hepatic stellate cells (HSCs) and precursors from the BM. RESULTS: Injury to the liver induced changes in the hepatic parenchymal architecture, as reflected by the presence of inflammatory infiltrate and an increase in collagen deposition (Saline 30 d = 11.10% ± 1.12% vs CCl(4) 30 d = 12.60% ± 0.73%, P = 0.0329). Confocal microscopy revealed increased reactivity against α-SMA in CCl(4) 30 d compared to Saline 30 d, but there was no co-localization with GFP+ cells, suggesting that cells from BM do not differentiate to MFs. Liver flow cytometric analysis showed a significant increase of CD45+/GFP+ cells in liver tissue (Saline 30 d = 3.2% ± 2.2% vs CCl(4) 30 d = 5.8% ± 1.3%, P = 0.0458), suggesting that this increase was due to inflammatory cell infiltration (neutrophils and monocytes). There was also a significant increase of common myeloid progenitor cells (CD117+/CD45+) in the livers of CCl(4)-treated animals (Saline 30 d = 2.16% ± 1.80% vs CCl(4) 30 d = 5.60% ± 1.30%, P = 0.0142). In addition the GFP-/CD38+/CD45- subpopulation was significantly increased in the CCl(4) 30 d group compared to the Saline 30 d group (17.5% ± 3.9% vs 9.3% ± 2.4%, P = 0.004), indicating that the increase in the activated HSC subpopulation was not of BM origin. CONCLUSION: BM progenitor cells do not contribute to fibrosis, but there is a high recruitment of inflammatory cells that stimulates HSCs and MFs of liver origin.

Bone marrow cells obtained from cirrhotic rats do not improve function or reduce fibrosis in a chronic liver disease model.

BACKGROUND: The objective of this study was to evaluate the therapeutic potential of bone marrow cells (BMCs) obtained from cirrhotic donors in a model of chronic liver disease. METHODS: Chronic liver injury was induced in female Wistar rats by the association of an alcoholic diet with intraperitoneal injections of carbon tetrachloride. BMCs obtained from cirrhotic donors or placebo were injected through the portal vein. Blood analysis of alanine aminotransferase (ALT) and albumin levels, ultrasound assessment including the measurement of the portal vein diameter (PVD) and liver echogenicity, histologic evaluation with hematoxylin and eosin and Sirius red staining, and quantification of collagen deposition were performed. RESULTS: ALT and albumin blood levels showed no significant differences between the experimental groups two months after injection. Additionally, no significant variation in PVD and liver echogenicity was found. Histological analysis also showed no significant variation in collagen deposition two months after placebo or BMC injection. CONCLUSION: This study suggests that, even though BMC therapy using cells from healthy donors has previously shown to be effective, this is not the case when BMCs are obtained from cirrhotic animals. This result has major clinical implications when considering the use of autologous BMCs from patients with chronic liver diseases.

Ultrasound imaging in an experimental model of fatty liver disease and cirrhosis in rats.

BACKGROUND: Domestic dogs and cats are very well known to develop chronic hepatic diseases, including hepatic lipidosis and cirrhosis. Ultrasonographic examination is extensively used to detect them. However, there are still few reports on the use of the ultrasound B-mode scan in correlation with histological findings to evaluate diffuse hepatic changes in rodents, which represent the most important animal group used in experimental models of liver diseases. The purpose of this study was to determine the reliability of ultrasound findings in the assessment of fatty liver disease and cirrhosis when compared to histological results in Wistar rats by following up a murine model of chronic hepatic disease. RESULTS: Forty Wistar rats (30 treated, 10 controls) were included. Liver injury was induced by dual exposure to CCl4 and ethanol for 4, 8 and 15 weeks. Liver echogenicity, its correlation to the right renal cortex echogenicity, measurement of portal vein diameter (PVD) and the presence of ascites were evaluated and compared to histological findings of hepatic steatosis and cirrhosis. Liver echogenicity correlated to hepatic steatosis when it was greater or equal to the right renal cortex echogenicity, with a sensitivity of 90%, specificity of 100%, positive and negative predictive values of 100% and 76.9% respectively, and accuracy of 92.5%. Findings of heterogeneous liver echogenicity and irregular surface correlated to liver cirrhosis with a sensitivity of 70.6%, specificity of 100%, positive and negative predictive values of 100% and 82.1% respectively, and accuracy of 87.5%. PVD was significantly increased in both steatotic and cirrhotic rats; however, the later had greater diameters. PVD cut-off point separating steatosis from cirrhosis was 2.1 mm (sensitivity of 100% and specificity of 90.5%). One third of cirrhotic rats presented with ascites. CONCLUSION: The use of ultrasound imaging in the follow-up of murine diffuse liver disease models is feasible and efficient, especially when the studied parameters are used in combination. The potential implication of this study is to provide a non-invasive method that allows follow-up studies of fatty liver disease and cirrhosis of individual rats for pre-clinical drug or cell based therapies.