Human Microglia-Like Cells Differentiated from Monocytes with GM-CSF and IL-34 Show Phagocytosis of α-Synuclein Aggregates and C/EBPß-Dependent Proinflammatory Activation.

Microglia, the main resident immune cells in the central nervous system, are implicated in the pathogenesis of various neurological disorders. Much of our knowledge on microglial biology was obtained using rodent microglial cultures. To understand the role of microglia in human disease, reliable in vitro models of human microglia are necessary. Monocyte-derived microglia-like cells (MDMi) are a promising approach. This study aimed to characterize MDMi cells generated from adult human monocytes using granulocyte-macrophage colony-stimulating factor and interleukin-34. To this end, 49 independent cultures of MDMI were prepared, and various methodological and functional studies were performed. We show that with this protocol, adult human monocytes develop into microglia-like cells, a coating is unnecessary, and high cell density seeding is preferable. When compared to monocytes, MDMi upregulate the expression of many, but not all, microglial markers, indicating that, although these cells display a microglia-like phenotype, they cannot be considered bona fide human microglia. At the functional level, MDMi phagocytose α-synuclein aggregates and responds to lipopolysaccharide (LPS) by nuclear translocation of the transcription factor nuclear factor-kappaB (NFkappaB) and the upregulation of proinflammatory genes. Finally, a long-lasting silencing of the transcription factor CCAAT/enhancer protein ß (C/EBPß) was achieved by small interfering RNA, resulting in the subsequent downregulation of proinflammatory genes. This supports the hypothesis that C/EBPß plays a key role in proinflammatory gene program activation in human microglia. Altogether, this study sheds new light on the properties of MDMi cells and supports these cells as a promising in vitro model for studying adult human microglia-like cells.

Tofacitinib-induced eosinophilia.

Tofacitinib is an oral small molecule JAK inhibitor approved for the treatment of moderate to severe ulcerative colitis (UC). Its efficacy and safety have been demonstrated in phase III clinical trials and supported by real-life data. We report the case of an 18-year-old woman with a 1-year diagnosis of left-sided UC, with multiple admissions due to disease exacerbation or infections, refractory to infliximab (with azathioprine) and currently under treatment with vedolizumab and tacrolimus. She was admitted due to a severe disease exacerbation and, because of a previous history of neuropsychiatric side effects to corticotherapy, tofacitinib was initiated. In the following 6 days, there was no clinical improvement of UC, and serial blood work-up revealed moderate grade persistent peripheral eosinophilia (3000 cells/mm3) and acute kidney injury grade 1 KDIGO. Tofacitinib temporary suspension was decided, with a rapid normalization of renal function/eosinophil levels. Tofacitinib was restarted 2 days after its suspension. However, she developed moderate eosinophilia (2000 cells/mm3) again, which was considered an adverse effect (AE) to tofacitinib, leading to its suspension with eosinophilia resolution. Given the severity of the disease, after a multidisciplinary discussion, it was decided to start high-dose corticotherapy and ustekinumab with maintenance therapy every 4 weeks, and to add tacrolimus. Clinical and biochemical remission were achieved, and the patient was discharged. Three-month follow-up after tofacitinib suspension showed no recrudescence of eosinophilia. Tofacitinib represents a significant advance in the management of UC patients. The drug has a good safety profile with few related AE. This case aims to warn about an adverse reaction to tofacitinib not reported so far, including in a multicenter real-life setting recently published by Hernández et al where eosinophilia is also not described, thus emphasizing the rarity of this AE. To our knowledge this is the first case of tofacitinib-induced eosinophilia in the context of UC. .

Effectiveness and safety of anti-CGRP monoclonal antibodies in patients over 65 years: a real-life multicentre analysis of 162 patients.

BACKGROUND: Anti-CGRP monoclonal antibodies have shown notable effectiveness and tolerability in migraine patients; however, data on their use in elderly patients is still lacking, as clinical trials have implicit age restrictions and real-world evidence is scarce. In this study, we aimed to describe the safety and effectiveness of erenumab, galcanezumab and fremanezumab in migraine patients over 65 years old in real-life. METHODS: In this observational real-life study, a retrospective analysis of prospectively collected data from 18 different headache units in Spain was performed. Migraine patients who started treatment with any anti-CGRP monoclonal antibody after the age of 65 years were included. Primary endpoints were reduction in monthly migraine days after 6 months of treatment and the presence of adverse effects. Secondary endpoints were reductions in headache and medication intake frequencies by months 3 and 6, response rates, changes in patient-reported outcomes and reasons for discontinuation. As a subanalysis, reduction in monthly migraine days and proportion of adverse effects were also compared among the three monoclonal antibodies. RESULTS: A total of 162 patients were included, median age 68 years (range 65-87), 74.1% women. 42% had dyslipidaemia, 40.3% hypertension, 8% diabetes, and 6.2% previous cardiovascular ischaemic disease. The reduction in monthly migraine days at month 6 was 10.1 ± 7.3 days. A total of 25.3% of patients presented adverse effects, all of them mild, with only two cases of blood pressure increase. Headache and medication intake frequencies were significantly reduced, and patient-reported outcomes were improved. The proportions of responders were 68%, 57%, 33% and 9% for reductions in monthly migraine days ≥ 30%, ≥ 50%, ≥ 75% and 100%, respectively. A total of 72.8% of patients continued with the treatment after 6 months. The reduction in migraine days was similar for the different anti-CGRP treatments, but fewer adverse effects were detected with fremanezumab (7.7%). CONCLUSIONS: Anti-CGRP mAbs are safe and effective treatments in migraine patients over 65 years old in real-life clinical practice.

Positioning Aeromonas Infection in Inflammatory Bowel Disease: A Retrospective Analysis.

Background and Aim: Aeromonas are Gram-negative rods known to cause a spectrum of diseases. Inflammatory bowel disease (IBD) is an idiopathic complex condition resulting from interaction of multiple factors. Aeromonas infection in association with IBD is still largely unknown. We aim to look for the significance of Aeromonas infection and for significant differences between IBD and non-IBD patients. Methods: A retrospective observational analysis was performed of all patients positive for Aeromonas in stool cultures, during a 10-year period, from a tertiary and university hospital. Results: Fifty patients were included, 56% male with a mean age of 42.1 years. Thirty-eight (76%) were non-IBD and 12 (24%) IBD patients. IBD patients were more frequently under immunosuppressors. Two patients were asymptomatic and 44% developed mild, 44% moderate, and 16.7% severe infection. The main strains isolated were Aeromonas hydrophila/caviae. Bacterial co-isolation was found in 4 non-IBD and histological findings of cytomegalovirus in 2 IBD patients. Non-IBD patients presented more frequently with fever and IBD patients with bloody diarrhea and abdominal pain. There was higher tendency for severe infection rate in IBD patients with higher antimicrobial therapy use. Steroids were exclusively used in the IBD group. From IBD, 4 patients had the diagnosis of ulcerative colitis and 9 of Crohn's disease with colonic involvement. Of these patients, 5 received IBD diagnosis after the acute episode of Aeromonas infection. Conclusions: Clinical presentation of Aeromonas infection differs between IBD and non-IBD patients. Non-IBD patients had milder severity of infection with less use of antibiotics. Aeromonas infection seems to greatly contribute to IBD manifestation.

Introdução: A etiologia da Doença Inflamatória Intestinal (DII) é complexa e resultante da interação de diversos fatores, nomeadamente microbiológicos. A infeção por Aeromonas caracteriza-se por um espectro alargado de manifestações clínicas. O papel da infeção por Aeromonas na DII não está caracterizado. Objetivos: Avaliar o significado da infeção por Aeromonas na DII e as diferenças com a infeção em doentes não-DII. Métodos: avaliação retrospetiva e observacional de todos os doentes com isolamento microbiológico de Aeromonas em amostras fecais num período de 10 anos, num hospital terciário. Resultados: foram avaliados 50 doentes, 56% do sexo masculino, com idade média de 42.1 anos. Doze (24%) com diagnóstico de DII e trinta e oito (76%) não-DII. Os doentes com DII encontravam-se mais frequentemente sob imunossupressão. Dois doentes foram assintomáticos, 44% desenvolveram doença ligeira, 44% moderada e 16.7% severa, havendo maior tendência para infeção severa nos DII. Os doentes não-DII apresentaram mais frequentemente febre e os DII diarreia sanguinolenta e dor abdominal. O uso de antimicrobianos foi superior no grupo DII e a utilização de corticoesteroides foi exclusiva nestes doentes. Isolamento concomitante de outros agentes microbiológicos ocorreu em 4 doentes não-DII e 2 com DII tinham histologia compatível com infeção por Citomegalovírus. Da população DII, 4 eram Colite Ulcerosa e 9 Doença de Crohn com envolvimento cólico. Destes, 5 receberam o diagnóstico após a infeção por Aeromonas. Conclusão: A apresentação clínica da infeção por Aeromonas foi distinta entre as populações DII e não-DII, sendo que os doentes DII apresentaram doença mais severa e maior utilização de antimicrobianos. A infeção na DII ocorreu essencialmente em doentes com envolvimento cólico.

Setting Requirements for a Dashboard to Inform Portuguese Decision-Makers About Environment Health in an Urban Setting.

Dashboards are being increasingly used in the health field, and literature points out that accurate and efficient dashboards require not only dealing with data issues, but also ensuring that dashboards are user-friendly and that incorporate users' views and needs. The integration of evidence and data into decision aiding tools, such as dashboards, to assess and monitor environmental health (EH) in urban settings requires careful design. Departing from EH evidence and making use of the views of EH stakeholders and experts, this study aimed at defining requirements for a dashboard to help decision-makers analyzing and visualizing EH information in the Lisbon urban context. In order to set those requirements, it was combined a user-centered with a design card approach to engage EH potential end-users so as to collect their visualization preferences and gather information related to dashboard requirements. Specifically, three online group semi-structured interviews, involving 11 potential end-users from different organizations, were conducted; design cards with a set of visualization options regarding 17 indicators of built and natural environment determinants were used in the interviews to capture participants' preferences and their rationale; questions about other dashboard features were also asked; and the results from the interviews were synthesized into four separate, but interrelated features, and operationalized into 11 requirements for a dashboard to monitor EH in Lisbon. This study contributes to EH literature by producing knowledge to inform dashboard construction, by highlighting issues related with the usability, analysis, and visualization of data to inform EH decision-making in urban contexts, and by designing an approach that can be replicated to other EH dashboard contexts.

The Coronavirus Chasm in Inflammatory Bowel Disease: Report of Patient-Centered Care at a Hospital in Northern Portugal.

INTRODUCTION: Although patient-centered care can be found in the mission statement of nearly every hospital, it is not always put into practice, and COVID-19 brings new challenges even to the best-organized hospitals and well-developed health care systems. METHODS: In the current COVID-19 pandemic, inflammatory bowel disease (IBD) patients have a potentially higher risk of complications from this infectious disease due to the use of immunosuppressant and/or biologic treatments and due to flares of this chronic illness, which often require urgent care and sometimes hospitalization. Moreover, patients undergoing biologic intravenous (IV) treatment visit the hospital for scheduled IV infusions. DISCUSSION: In hospitals like ours, where COVID-19 patients are treated, the organization of "clean circuits" is essential to minimize the risks of infection for non-COVID-19 patients, such as patients in IBD infusion units. In our hospital, the IBD infusion unit is located within the gastroenterology department, which, under normal circumstances, is very advantageous for patients but in the current context is not. Our goal was to maximize adherence to biologic IV treatment and clinical safety at a time of profound changes in gastroenterology activity and in a department with daily increases in the number of COVID-19 patients. CONCLUSION: To this end, we initiated proactive COVID-19 testing in IBD patients undergoing biologic IV treatment and changed the location of the infusion unit to a "COVID-free" institution, maintaining the care of these patients by the dedicated IBD team of our department. The purpose of this report is to show that a patient-centered care strategy allowed us to reach very high levels of patient comfort, satisfaction, and compliance with therapeutics.

INTRODUÇÃO: Os cuidados centrados no doente são uma intenção de quase todas as declarações de missão de um hospital. No entanto, nem sempre são colocados em prática. A doença por COVID-19 trouxe novos desafios, mesmo para os hospitais mais bem organizados e com sistemas de saúde desenvolvidos. MÉTODOS: Na atual pandemia COVID-19, os doentes com doença intestinal inflamatória (DII), têm um risco potencialmente maior de complicações desta doença infeciosa, quer pelo uso de tratamentos imunossupressores e/ou biológicos, quer pela natureza crónica da doença, que evolui com agudizações, que frequentemente requerem cuidados urgentes e, às vezes, hospitalização. Os doentes sob biológicos intravenosos (IV) necessitam de recorrer ao hospital para infusão programada. DISCUSSÃO: Em hospitais como o nosso, onde doentes com COVID-19 são recebidos e tratados, a organização de "circuitos limpos" é essencial para minimizar os riscos de infeção em doentes não-COVID-19, nomeadamente nas unidades de infusão de biológicos. No nosso Hospital, a unidade de infusão localiza-se dentro do Departamento de Gastrenterologia, o que em circunstâncias normais é muito vantajoso para os doentes, mas não o foi no contexto da atual pandemia. O nosso objetivo, num momento de profunda mudança da atividade da Gastrenterologia e num Departamento com aumento diário do número de doentes COVID-19, foi o de maximizar a adesão aos tratamentos biológicos IV e a sua segurança clínica. CONCLUSÃO: Para isso iniciamos um programa proactivo de teste a COVID-19, nos doentes com DII, sob biológicos IV, e mudamos a unidade de infusão para uma Instituição "COVID free," mantendo a habitual orientação destes doentes pela equipe diferenciada de DII do nosso Serviço. O objetivo deste trabalho é mostrar que, com uma estratégia de cuidados centrados no doente, foi possível atingir níveis elevados de adesão à terapêutica, de conforto e satisfação.

Bringing Policymakers to Science Through Communication: A Perspective From Latin America.

Scientific knowledge should be shared beyond academic circles in order to promote science in policymaking. Science communication increases the understanding of how the natural world works and the capacity to make informed decisions. However, not every researcher has the ability to master the art of communicating, and even less in a clear, concise, and easy to understand language that society representatives appreciate. Within the huge and extraordinarily diverse Latin American region, science communication has been going on for at least 200 years, when the first science stories appeared in the newspapers, as well as the first science museums and botanical gardens were founded. Nevertheless, resources are limited, and notably time, which researchers spend mostly in mentoring, ensuring funding, publication of their results and laboratory work, while science journalists are an endangered species. This perspective article aims at providing some recommendations to build bridges between science and decision-making parties through communication, by exploring how Latin American diplomats and policymakers engage with scientific knowledge.

Selecting Indicators to Monitor and Assess Environmental Health in a Portuguese Urban Setting: A Participatory Approach.

Environmental health (EH) is influenced by complex interactions between health and the built and natural environments, there being little research on its specificities in urban settings. The use of suitable indicators to monitor and assess EH is fundamental in informing evidence-based interventions at the local level. A participatory approach to selecting indicators to inform the monitoring and assessment of EH in Lisbon is herein considered. Evidence derived from a systematic review of literature and data from Lisbon and Portuguese databases were analyzed by 12 Portuguese experts in individual semi-structured interviews. The interviews aimed at identifying relevant indicators and important emerging issues in the Lisbon urban setting. The outputs from the interviews were validated by a two-round Web-Delphi process in which panelists (22 experts) from different areas of expertise expressed their views regarding the relevance of the indicators for the analysis of EH in urban settings. Seventeen indicators were validated in the Web-Delphi process. High participation achieved along this process supports the view that this participatory approach was useful for validation. Results from the adopted participatory approach point out gaps in the collection of noise and mobility indicators data and raise emerging issues on housing indicators that require further research. The results also suggest the need for local action to improve indicators and tools in order to help the monitorization of EH in urban contexts. The adopted participatory approach can be replicated for other Portuguese and European urban settings.

Environmental determinants of population health in urban settings. A systematic review.

BACKGROUND: Population health is influenced by interactions between environmental determinants, which are captured by dimensions and indicators. This study aims to systematically review key environmental determinants and respective dimensions and indicators, relevant to evaluate population health in urban settings, and to understand their potential implications into policies. METHODS: A search of literature published between 2008 and 2018 was conducted in PubMed, Web of Science, Scopus and SciELO Portugal databases, on studies with evidence on association between an environmental determinant and a health outcome in urban contexts. Health determinants, dimensions and indicators researched in the selected studies were synthetized, and associations analyzed. An independent assessment of quality of the studies was performed. Key conclusions and policy recommendations were extracted to build a framework to analyze environment related population health and policies in urban settings. RESULTS: Ninety four studies of varied methodological approaches and quality met the inclusion criteria. The review identified positive associations between all environmental determinants -socioeconomic, built environment, natural environment, healthcare, behaviors, and health outcomes - overall mortality and morbidity, in urban settings. Improvements in income, education, air quality, occupation status, mobility and smoking habits indicators have positive impact in overall mortality and chronic diseases morbidity indicators. Initiatives to improve population health in which policymakers can be more evidence-informed include socioeconomic, natural environment and built environment determinants. CONCLUSIONS: There is scope and need to further explore which environmental determinants and dimensions most contribute to population health to create a series of robust evidence-based measures to better inform urban planning policies.

Pneumatosis cystoides intestinalis - an incidental finding with unpredictable evolution / Pneumatose cistoide intestinal - um achado incidental com evolução imprevisível

Abstract Pneumatosis cystoides intestinalis is an uncommon disease with unknown etiology characterized by the presence of multiple gas-filled cysts within the submucosa or subserosa of the intestinal wall. Pneumoperitoneum and/or intestinal perforation are complications that may be associated with pneumatosis cystoides intestinalis. The patients are often prone to misdiagnosis or mistreatment.We are presenting a case of pneumatosis cystoides intestinalis in a 42 year-old woman affected by peritoneal free air and numerous, diffuse, bubble-like intramural gas collections into the jejunum and ileum, showed in CT-enterography images. The woman had a carcinoid tumor located in jejunum two years ago, treated with enterectomy. Recent complaints of nonspecific symptoms of abdominal discomfort and diarrhea motivated the realization of CT scan, serum chromogranin and urine 5-hidroxindolacetic acid for hypothesis of tumor carcinoid recurrence withdraw. The only change found was the presence of pneumatosis cystoides intestinalis in CT-enterography images without intestinal necrosis, bleeding or evident obstruction. For that reason no surgical procedure was realized and the patient stayed on surveillance. Actually, the patient complaints are sporadic abdominal discomfort, without pneumatosis cystoides intestinalis clinical evidence. Conclusion: The treatment plan of patient with PCI depends on underlying cause and clinical condition severity. When conservative treatment is adopted the clinical evolution of pneumatosis cystoides intestinalis is unpredictable and can even disappear in an indeterminate number of patients.

Resumo A pneumatose cistoide intestinal é uma doença incomum, de etiologia desconhecida, caracterizada pela presença de múltiplos cistos preenchidos com gás na submucosa ou subserosa da parede intestinal. O pneumoperitoneu e/ou a perfuração intestinal são complicações que podem estar associadas à pneumatose cistoide intestinal. Os pacientes geralmente estão sujeitos a erros de diagnóstico ou de tratamento.Apresentamos um caso de pneumatose cistoide intestinal em paciente do sexo feminino, 42 anos de idade, com ar livre peritoneal e numerosas coleções gasosas intramurais, difusas e semelhantes a bolhas no jejuno e íleo, visualizados em imagens de enterografia por tomografia computadorizada (TC). Há dois anos, a paciente teve um tumor carcinoide localizado no jejuno que foi tratado com enterectomia. As queixas recentes de sintomas inespecíficos, desconforto abdominal e diarreia motivaram a realização da TC e exame de cromogranina sérica e ácido 5-hidroxindolacético na urina para excluir a hipótese de recorrência do tumor carcinoide. A única alteração encontrada foi a presença de pneumatose cistoide intestinal em imagens de enterografia por TC sem necrose intestinal, sangramento ou obstrução evidente. Por esse motivo, nenhum procedimento cirúrgico foi realizado, e a paciente permaneceu em observação. Atualmente, a queixa da paciente é de desconforto abdominal esporádico, sem evidência clínica de pneumatose cistoide intestinal. Conclusão: O plano de tratamento de pacientes com PCI depende da causa subjacente e da gravidade da condição clínica. Quando o tratamento conservador é adotado, a evolução clínica da pneumatose cistoide intestinal é imprevisível e pode até desaparecer em alguns pacientes.

Comparing the Continuous Geboes Score With the Robarts Histopathology Index: Definitions of Histological Remission and Response and their Relation to Faecal Calprotectin Levels.

BACKGROUND AND AIMS: The histological status of ulcerative colitis [UC] patients in clinical and endoscopic remission has gained space as an important prognostic marker and a key component of disease monitoring. Our main aims were to compare two histological indexes-the continuous Geboes score [GS] and the Robarts Histopathology index [RHI]-regarding their definitions of histological remission and response, and the ability of faecal calprotectin [FC] levels to discriminate between these statuses. METHODS: This was an analysis of three prospective cohorts including 422 patients previously enrolled in other studies. RESULTS: The two continuous scores [GS and RHI] were shown to be significantly correlated [correlation coefficient of 0.806, p < 0.001] and particularly close regarding their definition of histological response: 95% and 88% of all patients classified as having/not having [respectively] histological response according to RHI also did so according to GS. Moreover, median FC levels in patients with histological response were lower than those in patients without histological response [GS: 73.00 vs 525.00, p < 0.001; RHI: 73.50 vs 510.00, p < 0.001]; a similar trend was observed when FC levels of patients in histological remission were compared to those of patients with histological activity [GS: 76.00 vs 228.00, p < 0.001; RHI: 73.50 vs 467.00, p < 0.001]. FC levels allowed us to exclude the absence of histological remission [according to RHI] and absence of histological response [according to RHI and GS], with negative predictive values varying from 82% to 96%. However, optimization of the FC cut-off to exclude the absence of histological remission, as for the continuous GS, falls within values that resemble those of the healthy population. CONCLUSION: The continuous GS and RHI histological scores are strongly correlated in their definitions of histological response. An absence of histological remission could only be excluded at physiological levels of FC.

Treating Untreatable Rectal Varices.

BACKGROUND: Rectal varices are portosystemic collaterals that arise as a complication of portal hypertension. Despite their significant prevalence among cirrhotic patients, clinically important bleeding occurs only in a minority. Various treatment options are available, with endoscopic therapies being widely used, and both interventional radiology and surgery being considered for refractory bleeding rectal varices. CASE: We report the case of a 61-year-old male with hepatic cirrhosis and bleedingrectal varices refractory to endoscopic therapy, successfully managed with a combination of transjugular intrahepatic portosystemic shunt (TIPS) and selective variceal embolization. CONCLUSIONS: Radiological techniques are effective options for refractory bleeding. Adding embolization to TIPS implantation could represent a valid adjunctive measure for haemostasis of recurrent rectal variceal bleeding.

Management of Gastrointestinal Toxicity from Immune Checkpoint Inhibitor.

Immune checkpoint inhibitors have shown anti-tumour activity in cancers such as melanoma, renal cell carcinoma, non-small-cell lung cancer, urothelial carcinoma, colorectal cancer, and Hodgkin's lymphoma. Though immune checkpoint inhibitors have revolutionized the treatment and prognosis of some advanced malignancies, they are also associated with a significant risk of immune-related adverse events. These adverse events can occur in any organ system, but gastrointestinal side effects are among the most commonly reported, with manifestations ranging from mild diarrhoea to severe colitis, sharing some features with inflammatory bowel disease. Anticipating a greater use of these drugs in the future, gastroenterologists should expect to be increasingly faced with gastrointestinal immune-related adverse events. Knowledge of these toxicities, as well as effective management algorithms, is essential to enable early diagnosis and treatment, decreasing morbidity and mortality. We reviewed the currently available literature on gastrointestinal toxicity induced by immune checkpoint inhibitors, namely the clinical features, diagnosis, and management.

Os inibidores dos checkpoint imunológicos demonstraram atividade antitumoral em neoplasias como o melanoma, o carcinoma de células renais, o carcinoma pulmonar de não pequenas células, o carcinoma urotelial, o carcinoma colorretal e o linfoma de Hodgkin. Estes fármacos, embora tenham revolucionado o tratamento e o prognóstico de algumas neoplasias avançadas, também se associam a um risco considerável de efeitos adversos associadosao sistema imunitário. Qualquer órgão pode ser afetado, mas os efeitos adversos gastrointestinais estão entre os mais comumente relatados. As manifestações gastrointestinais variam desde diarreia ligeira a colite grave, a qual pode evidenciar características idênticas às da doença inflamatória intestinal. Antecipando uma maior utilização destes fármacos no futuro, os gastroenterologistas devem esperar confrontar-se cada vez mais com este tipo de efeitos adversos. O conhecimento dessas toxicidades, bem como dos algoritmos de abordagem destes doentes é fundamental para um diagnóstico e tratamento precoces, diminuindo desta forma a morbilidade e a mortalidade. Os autores pretenderam rever a literatura mais atual sobre a toxicidade gastrointestinal induzida pelos inibidores dos checkpoint imunológicos, nomeadamente apresentação clínica, abordagem diagnóstica e terapêutica.

Cerebrospinal fluid cytokines in multiple system atrophy: A cross-sectional Catalan MSA registry study.

INTRODUCTION: Neuroinflammation is a potential player in neurodegenerative conditions, particularly the aggressive ones, such as multiple system atrophy (MSA). Previous reports on cytokine levels in MSA using serum or cerebrospinal fluid (CSF) have been inconsistent, including small samples and a limited number of cytokines, often without comparison to Parkinson's disease (PD), a main MSA differential diagnosis. METHODS: Cross-sectional study of CSF levels of 38 cytokines using a multiplex assay in 73 participants: 39 MSA patients (19 with parkinsonian type [MSAp], 20 with cerebellar type [MSAc]; 31 probable, 8 possible), 19 PD patients and 15 neurologically unimpaired controls. None of the participants was under non-steroidal anti-inflammatory drugs at the time of the lumbar puncture. RESULTS: There were not significant differences in sex and age among participants. In global non-parametric comparisons FDR-corrected for multiple comparisons, CSF levels of 5 cytokines (FGF-2, IL-10, MCP-3, IL-12p40, MDC) differed among the three groups. In pair-wise FDR-corrected non-parametric comparisons 12 cytokines (FGF-2, eotaxin, fractalkine, IFN-α2, IL-10, MCP-3, IL-12p40, MDC, IL-17, IL-7, MIP-1ß, TNF-α) were significantly higher in MSA vs. non-MSA cases (PD + controls pooled together). Of these, MCP-3 and MDC were the most significant ones, also differed in MSA vs. PD, and were significant MSA-predictors in binary logistic regression models and ROC curves adjusted for age. CSF levels of fractalkine and MIP-1α showed a strong and significant positive correlation with UMSARS-2 scores. CONCLUSION: Increased CSF levels of cytokines such as MCP-3, MDC, fractalkine and MIP-1α deserve consideration as potential diagnostic or severity biomarkers of MSA.

Comparison of different histological indexes in the assessment of UC activity and their accuracy regarding endoscopic outcomes and faecal calprotectin levels.

OBJECTIVE: Histological remission is being increasingly acknowledged as a therapeutic endpoint in patients with UC. The work hereafter described aimed to evaluate the concordance between three histological classification systems-Geboes Score (GS), Nancy Index (NI) and RobartsHistopathologyIndex (RHI), as well as to evaluate their association with the endoscopic outcomes and the faecal calprotectin (FC) levels. DESIGN: Biopsy samples from 377 patients with UC were blindly evaluated using GS, NI and RHI. The results were compared with the patients' Mayo Endoscopic Score and FC levels. RESULT: GS, NI and RHI have a good concordance concerning the distinction between patients in histological remission or activity. RHI was particularly close to NI, with 100% of all patients classified as being in remission with NI being identified as such with RHI and 100% of all patients classified as having activity with RHI being identified as such with NI. These scores could also predict the Mayo Endoscopic Score and the FC levels, with their sensitivity and specificity levels depending on the chosen cut-offs. Moreover, higher FC levels were statistically associated with the presence of neutrophils in the epithelium, as well as with ulceration or erosion of the intestinal mucosa. CONCLUSIONS: GS, NI and RHI histopathological scoring systems are comparable in what concerns patients' stratification into histological remission/activity. Additionally, FC levels are increased when neutrophils are present in the epithelium and the intestinal mucosa has erosions or ulcers. The presence of neutrophils in the epithelium is, indeed, the main marker of histological activity.

RNA-Seq transcriptomic profiling of primary murine microglia treated with LPS or LPS + IFNγ.

Microglia, the main resident immune cells in the CNS, are thought to participate in the pathogenesis of various neurological disorders. LPS and LPS + IFNγ are stimuli that are widely used to activate microglia. However, the transcriptomic profiles of microglia treated with LPS and LPS + IFNγ have not been properly compared. Here, we treated murine primary microglial cultures with LPS or LPS + IFNγ for 6 hours and then performed RNA-Sequencing. Gene expression patterns induced by the treatments were obtained by WGCNA and 11 different expression profiles were found, showing differential responses to LPS and LPS + IFNγ in many genes. Interestingly, a subset of genes involved in Parkinson's, Alzheimer's and Huntington's disease were downregulated by both treatments. By DESeq analysis we found differentially upregulated and downregulated genes that confirmed LPS and LPS + IFNγ as inducers of microglial pro-inflammatory responses, but also highlighted their involvement in specific cell functions. In response to LPS, microglia tended to be more proliferative, pro-inflammatory and phagocytic; whereas LPS + IFNγ inhibited genes were involved in pain, cell division and, unexpectedly, production of some inflammatory mediators. In summary, this study provides a detailed description of the transcriptome of LPS- and LPS + IFNγ treated primary microglial cultures. It may be useful to determine whether these in vitro phenotypes resemble microglia in in vivo pathological conditions.