ENPP1 induces blood-brain barrier dysfunction and promotes brain metastasis formation in HER2-positive breast cancer.

BACKGROUND: Brain metastasis (BrM) is a devastating end-stage neurological complication that occurs in up to 50% of HER2+ breast cancer patients. Understanding how disseminating tumor cells manage to cross the blood-brain barrier (BBB) is essential for developing effective preventive strategies. We identified the ecto-nucleotidase ENPP1 as specifically enriched in the secretome of HER2+ brain metastatic cells, prompting us to explore its impact on BBB dysfunction and BrM formation. METHODS: We used in vitro BBB and in vivo premetastatic mouse models to evaluate the effect of tumor-secreted ENPP1 on brain vascular permeability. BBB integrity was analyzed by real-time fluorescence imaging of 20 kDa Cy7.5-dextran extravasation and immunofluorescence staining of adherens and tight junction proteins. Pro-metastatic effects of ENPP1 were evaluated in an experimental brain metastatic model. RESULTS: Systemically secreted ENPP1 from primary breast tumors impaired the integrity of BBB with loss of tight and adherens junction proteins early before the onset of BrM. Mechanistically, ENPP1 induced endothelial cell dysfunction by impairing insulin signaling and its downstream AKT/GSK3ß/ß-catenin pathway. Genetic ablation of ENPP1 from HER2+ brain metastatic cells prevented endothelial cell dysfunction and reduced metastatic burden while prolonging the overall and metastasis-free survival of mice. Furthermore, plasmatic ENPP1 levels correlate with brain metastatic burden and inversely with overall survival. CONCLUSIONS: We demonstrated that metastatic breast cancer cells exploit the ENPP1 signaling for cell transmigration across the BBB and brain colonization. Our data implicate ENPP1 as a potential biomarker for poor prognosis and early detection of BrM in HER2+ breast cancer.

Nerve growth factor inducible (VGF) is a secreted mediator for metastatic breast cancer tropism to the brain.

Brain metastases are one of the most serious clinical problems in breast cancer (BC) progression, associated with lower survival rates and a lack of effective therapies. Thus, to dissect the early stages of the brain metastatic process, we studied the impact of brain organotropic BC cells' secretomes on the establishment of the brain pre-metastatic niche (PMN). We found that BC cells with specific tropism to the brain caused significant blood-brain barrier (BBB) disruption, as well as microglial activation, in both in vitro and in vivo models. Further, we searched for a brain-organotropic metastatic signature, as a promising source for the discovery of new biomarkers involved in brain metastatic progression. Of relevance, we identified VGF (nerve growth factor inducible) as a key mediator in this process, also impacting the BBB and microglial functions both in vitro and in vivo. In a series of human breast tumors, VGF was found to be expressed in both cancer cells and the adjacent stroma. Importantly, VGF-positive tumors showed a significantly worse prognosis and were associated with HER2 (human epidermal growth factor receptor 2) overexpression and triple-negative molecular signatures. Further clinical validation in primary tumors from metastatic BC cases showed a significant association between VGF and the brain metastatic location, clearly and significantly impacting on the prognosis of BC patients with brain metastasis. In conclusion, our study reveals a unique secretome signature for BC with a tropism for the brain, highlighting VGF as a crucial mediator in this process. Furthermore, its specific impact as a poor prognostic predictor for BC patients with brain metastasis opens new avenues to target VGF to control the progression of brain metastatic disease. © 2024 The Pathological Society of Great Britain and Ireland.

Brain metastasis: An insight into novel molecular targets for theranostic approaches.

Brain metastases (BrM) are common malignant lesions in the central nervous system, and pose a significant threat in advanced-stage malignancies due to delayed diagnosis and limited therapeutic options. Their distinct genomic profiles underscore the need for molecular profiling to tailor effective treatments. Recent advances in cancer biology have uncovered molecular drivers underlying tumor initiation, progression, and metastasis. This, coupled with the advances in molecular imaging technology and radiotracer synthesis, has paved the way for the development of innovative radiopharmaceuticals with enhanced specificity and affinity for BrM specific targets. Despite the challenges posed by the blood-brain barrier to effective drug delivery, several radiolabeled compounds have shown promise in detecting and targeting BrM. This manuscript provides an overview of the recent advances in molecular biomarkers used in nuclear imaging and targeted radionuclide therapy in both clinical and preclinical settings. Additionally, it explores potential theranostic applications addressing the unique challenges posed by BrM.

Condições de trabalho dos agentes comunitários de saúde em um contexto de saúde digital: velhos e novos desafios / Condiciones de trabajo de las agentes comunitarias de salud en un contexto de salud digital: viejos y nuevos desafíos / Working conditions of community health workers in a digital health context: old and new challenges

O uso de ferramentas da saúde digital tem sido intensificado na Atenção Primária à Saúde (APS) e nas práticas de agentes comunitários de saúde (ACS). Este artigo tem como objetivo analisar os desafios impostos pelas condições de trabalho dos ACS no contexto da saúde digital. Trata-se de uma pesquisa qualitativa com triangulação de métodos envolvendo lideranças sindicais, gestores e profissionais da saúde. Os resultados apontam uma reedição de velhos desafios em torno do trabalho dos ACS, como maior burocratização, controle, divisão social e técnica. Porém, novos desafios emergem em torno da manutenção, da qualidade dos instrumentos e da formação profissional. Conclui-se demarcando a necessidade de uma garantia logística, financeira e política para a implementação da saúde digital no trabalho dos ACS.(AU)

El uso de herramientas de la salud digital se ha intensificado en la Atención Primaria de la Salud (APS) y en las prácticas de Agentes Comunitarias de Salud (ACS). El objetivo de este artículo es analizar los desafíos impuestos por las condiciones de trabajo de las ACS en el contexto de la salud digital. Se trata de una investigación cualitativa, con triangulación de métodos, envolviendo liderazgos sindicales, gestores y profesionales de la salud. Los resultados señalan una reedición de viejos desafíos alrededor del trabajo de las ACS, tales como mayor burocratización, control, división social y técnica. Sin embargo, surgen nuevos desafíos alrededor del mantenimiento, calidad de los instrumentos y formación profesional. Se concluye demarcando la necesidad de una garantía logística, financiera y política para la implementación de la salud digital en el trabajo de las ACS.(AU)

The use of digital health tools has grown in intensity in Primary Health Care (PHC) and in the practices of Community Health Workers (CHWs). This article aims to analyze the challenges imposed by the working conditions of CHWs in the context of digital health. It is a qualitative study, with triangulation of methods involving union leaders, managers and health professionals. The results indicate the re-emergence of old challenges surrounding the work of CHWs, such as greater bureaucratization, control, social and technical division of work. However, new challenges emerge around maintenance, quality of tools and professional training. In conclusion, there is a need for logistical, financial and political safeguards for the implementation of digital health in the work of CHWs.(AU)

Unveiling the role of osteosarcoma-derived secretome in premetastatic lung remodelling.

BACKGROUND: Lung metastasis is the most adverse clinical factor and remains the leading cause of osteosarcoma-related death. Deciphering the mechanisms driving metastatic spread is crucial for finding open therapeutic windows for successful organ-specific interventions that may halt or prevent lung metastasis. METHODS: We employed a mouse premetastatic lung-based multi-omics integrative approach combined with clinical features to uncover the specific changes that precede lung metastasis formation and identify novel molecular targets and biomarker of clinical utility that enable the design of novel therapeutic strategies. RESULTS: We found that osteosarcoma-bearing mice or those preconditioned with the osteosarcoma cell secretome harbour profound lung structural alterations with airway damage, inflammation, neutrophil infiltration, and extracellular matrix remodelling with increased deposition of fibronectin and collagens by resident stromal activated fibroblasts, favouring the adhesion of disseminated tumour cells. Systemic-induced microenvironmental changes, supported by transcriptomic and histological data, promoted and accelerated lung metastasis formation. Comparative proteome profiling of the cell secretome and mouse plasma identified a large number of proteins involved in extracellular-matrix organization, cell-matrix adhesion, neutrophil degranulation, and cytokine-mediated signalling, consistent with the observed lung microenvironmental changes. Moreover, we identified EFEMP1, an extracellular matrix glycoprotein exclusively secreted by metastatic cells, in the plasma of mice bearing a primary tumour and in biopsy specimens from osteosarcoma patients with poorer overall survival. Depletion of EFEMP1 from the secretome prevents the formation of lung metastasis. CONCLUSIONS: Integration of our data uncovers neutrophil infiltration and the functional contribution of stromal-activated fibroblasts in ECM remodelling for tumour cell attachment as early pro-metastatic events, which may hold therapeutic potential in preventing or slowing the metastatic spread. Moreover, we identified EFEMP1, a secreted glycoprotein, as a metastatic driver and a potential candidate prognostic biomarker for lung metastasis in osteosarcoma patients. Osteosarcoma-derived secreted factors systemically reprogrammed the lung microenvironment and fostered a growth-permissive niche for incoming disseminated cells to survive and outgrow into overt metastasis. Daily administration of osteosarcoma cell secretome mimics the systemic release of tumour-secreted factors of a growing tumour in mice during PMN formation; Transcriptomic and histological analysis of premetastatic lungs revealed inflammatory-induced stromal fibroblast activation, neutrophil infiltration, and ECM remodelling as early onset pro-metastatic events; Proteome profiling identified EFEMP1, an extracellular secreted glycoprotein, as a potential predictive biomarker for lung metastasis and poor prognosis in osteosarcoma patients. Osteosarcoma patients with EFEMP1 expressing biopsies have a poorer overall survival.

Anti-tumor necrosis factor therapy is associated with attenuated humoral response to SARS-COV-2 vaccines in patients with inflammatory bowel disease.

BACKGROUND: Immunosuppressive therapy used in the treatment of inflammatory bowel disease (IBD) is known to reduce vaccine immunogenicity. AIMS: This study aimed to 1) predict the humoral response elicited by SARS-CoV-2 vaccination in IBD patients based on their ongoing treatment and other relevant patient and vaccine characteristics and 2) assess the humoral response to a booster dose of mRNA vaccine. METHODS: We conducted a prospective study in adult IBD patients. Anti-spike (S) IgG antibodies were measured after initial vaccination and again after one booster dose. A multiple linear regression model was created to predict anti-S antibody titer following initial complete vaccination in different therapeutic groups (no immunosuppression, anti-TNF, immunomodulators and combination therapy). A two-tailed Wilcoxon test for two dependent groups was performed to compare anti-S values before and after the booster dose. RESULTS: Our study included 198 IBD patients. The multiple linear regression identified anti-TNF and combination therapy (versus no immunosuppression), current smoking, viral vector (versus mRNA) vaccine and interval between vaccination and anti-S measurement as statistically significant predictors of the log anti-S antibody levels (p < 0.001). No statistically significant differences were found between no immunosuppression and immunomodulators (p = 0.349) and between anti-TNF and combination therapy (p = 0.997). Statistically significant differences for anti-S antibody titer before and after the booster dose of mRNA SARS-CoV-2 vaccine were found, both for non-anti-TNF and anti-TNF groups. CONCLUSIONS: Anti-TNF treatment (either alone or in combination therapy) is associated with lower anti-S antibody levels. Booster mRNA doses seem to increase anti-S both in non-anti-TNF and anti-TNF treated patients. Special attention should be paid to this group of patients when planning vaccination schemes.

O uso de tecnologias digitais nas práticas de trabalhadores comunitários de saúde: uma revisão internacional de escopo / El uso de las tecnologías digitales en las prácticas de los trabajadores comunitarios de la salud: una revisión internacional del alcance / The use of digital technologies in the practices of community health workers: an international scoping review

RESUMO Este artigo objetiva mapear a literatura sobre as aplicações e percepções acerca do uso de tecnologias digitais nas práticas de trabalhadores comunitários de saúde. Trata-se de uma revisão de escopo realizada na PubMed, Bireme, SciELO, Web of Science, Embase e Scopus. Foram incluídos 63 artigos que relatam o uso de tecnologias digitais por esses trabalhadores em 24 países. Como resultados, identificou-se que o suporte à saúde materno-infantil é a condição com maior predomínio das práticas. Os benefícios identificados envolvem ampliação do acesso, melhoria da gestão do trabalho, qualificação, diversificação, ampliação da formação e ganho de legitimidade da categoria. Os desafios se traduzem nas limitações em relação ao vínculo com a comunidade, longitudinalidade do cuidado, acesso à internet, energia elétrica e alfabetização digital. Como conclusão, corrobora-se com análises acerca da irreversibilidade do uso de tecnologias de informação e comunicação no mundo do trabalho, destacando-se a necessidade do seu uso racional dessas com a garantia do acesso de forma integral, universal e equitativa.

RESUMEN Este artículo tiene por objeto mapear la literatura sobre las aplicaciones y percepciones acerca del uso de tecnologías digitales en las prácticas de los trabajadores comunitarios de la salud. Se trata de una revisión del alcance realizada en PubMed, Bireme, SciELO, Web of Science, Embase y Scopus. Se han incluido 63 artículos sobre el uso de tecnologías digitales por parte de estos trabajadores en 24 países. Como resultado, se ha identificado que el apoyo a la salud maternoinfantil es la condición con mayor predominio de las prácticas. Los beneficios identificados implican la ampliación del acceso, mejora de la gestión del trabajo, calificación, diversificación, ampliación de la formación y aumento de la legitimidad de la categoría. Los desafíos se traducen en limitaciones en relación con el vínculo con la comunidad, la longitudinalidad de la atención, el acceso a Internet, la energía eléctrica y la alfabetización digital. En conclusión, se corrobora con análisis sobre la irreversibilidad del uso de las tecnologías de la información y la comunicación en el mundo del trabajo, y se destaca la necesidad de su uso racional con la garantía del acceso de manera integral, universal y equitativa.

ABSTRACT This article aims to map the literature on the applications and perceptions regarding the use of digital technologies in the practices of community health workers. This is a scoping review conducted on PubMed, Bireme, SciELO, Web of Science, Embase, and Scopus. A total of 63 articles reporting the use of digital technologies by these workers in 24 countries were included. As a result, it was identified that support for maternal and child health is the most prevalent condition in these practices. The identified benefits involve increased access, improved work management, qualification, diversification, expanded training, and increased legitimacy of the profession. The challenges are reflected in limitations regarding community engagement, continuity of care, internet access, electricity, and digital literacy. In conclusion, it supports analyses regarding the irreversibility of the use of information and communication technologies in the world of work, emphasizing the need for their rational use while ensuring comprehensive, universal, and equitable access.

Desastres com petróleo e ações governamentais ante os impactos socioambientais e na saúde: scoping review / Oil disasters and government actions in the face of social, environmental, and health-related impacts: A scoping review

RESUMO Este artigo teve por objetivo analisar as ações desenvolvidas pelos governos para o enfrentamento dos impactos socioambientais e na saúde em decorrência dos desastres envolvendo petróleo no mundo. Trata-se de uma revisão de escopo realizada na Bireme, Lilacs, SciELO, PubMed, Cochrane Library e Embase, considerando artigos publicados entre 1973 e 2021. As buscas efetuadas nas bases de dados resultaram em 22 artigos sobre 10 desastres de petróleo ao redor do mundo em três continentes (Ásia, América e Europa), cujas causas dos desastres foram encalhe (3), naufrágio (1), colisão (2), derrame (3) e explosão (1). As ações desenvolvidas foram caracterizadas como intersetoriais, econômicas, ambientais e na saúde, sendo que as mais frequentes foram ações ambientais e econômicas. Nas ações desenvolvidas, observaram-se críticas ao controle, mitigação ou prevenção dos danos instantâneos ou futuros decorrentes dos desastres por petróleo, sendo essa uma agenda ainda em aberto para os movimentos sociais na luta pela garantia de um ambiente saudável, promotor de saúde e com preservação de toda a sua biodiversidade. Conclui-se que as ações para o enfrentamento dos desastres por petróleo nos diferentes países parecem ter sido incipientes, revelando uma incapacidade governamental de orientar o enfrentamento dos impactos desse evento inusitado.

ABSTRACT This article aims to analyze the actions taken by governments to face the social, environmental, and health impacts of oil spill disasters worldwide. This scoping review was conducted in Bireme, Lilacs, SciELO, PubMed, Cochrane Library, and Embase databases, considering articles published between 1973 and 2021. The database search returned 22 articles on ten global oil disasters in three continents (Asia, the Americas, and Europe), whose causes were grounding (03), shipwreck (01), collision (02), spill (03), and explosion (01). The actions developed were characterized as intersectoral, economic, environmental, and health-related, and the most frequent were environmental and economic actions. In the actions developed, we observed criticisms of controlling, mitigating, or preventing instantaneous or future damages resulting from oil disasters, which is still an open agenda for social movements in the struggle to ensure a healthy, health-promoting environment that preserves all its biodiversity. The actions to face oil disasters in different countries seem incipient, revealing a governmental inability to guide the confrontation of the impacts of this unusual event.

Nanobody-Based Theranostic Agents for HER2-Positive Breast Cancer: Radiolabeling Strategies.

The overexpression of human epidermal growth factor 2 (HER2) in breast cancer (BC) has been associated with a more aggressive tumor subtype, poorer prognosis and shorter overall survival. In this context, the development of HER2-targeted radiotracers is crucial to provide a non-invasive assessment of HER2 expression to select patients for HER2-targeted therapies, monitor response and identify those who become resistant. Antibodies represent ideal candidates for this purpose, as they provide high contrast images for diagnosis and low toxicity in the therapeutic setting. Of those, nanobodies (Nb) are of particular interest considering their favorable kinetics, crossing of relevant biological membranes and intratumoral distribution. The purpose of this review is to highlight the unique characteristics and advantages of Nb-based radiotracers in BC imaging and therapy. Additionally, radiolabeling methods for Nb including direct labeling, indirect labeling via prosthetic group and indirect labeling via complexation will be discussed, reporting advantages and drawbacks. Furthermore, the preclinical to clinical translation of radiolabeled Nbs as promising theranostic agents will be reported.

Immunosuppression Therapy in Acquired Hemophilia A: Pursuing an Optimal Regimen.

Acquired hemophilia A (AHA) is a rare bleeding disorder occurring mostly in elderly persons, caused by inhibition of factor VIII (FVIII). It is generally detected prior to surgery by an isolated prolonged activated partial thromboplastin time (aPTT) not correcting on mixing studies, with subsequent identification of reduced FVIII levels and presence of FVIII inhibitor. It is treated with hemostatics and immunosuppressants, which may increase the risk for life-threatening opportunistic infections. A 79-year-old woman with idiopathic acquired FVIII inhibition and severe bleeding presented with anemia, isolated and prolonged aPTT, low FVIII activity (<1%), and elevated FVIII inhibitor titer (471 Bethesda units per milliliter [BU/mL]). Initially, she was treated with recombinant activated factor VII and steroids. However, several hematomas appeared, one of which caused airway compression that required orotracheal intubation. Cyclophosphamide, rituximab (RTX), and activated prothrombin complex concentrate were initiated, resulting in clinical and laboratory resolution after five weeks. Cyclophosphamide and RTX were maintained for six and four weeks more, respectively. After 12 weeks of oral immunosuppression, the patient was readmitted due to antibiotic-resistant Pseudomonas aeruginosa sepsis, which resulted in death. Infection secondary to immunosuppression is the leading cause of death of patients with AHA. In AHA, combination therapy was shown to be more effective than monotherapy, but it was also identified to increase the risk of infection. Age, FVIII activity <1%, and FVIII inhibitor titers >20 BU are predictors of adverse events and poor prognosis in AHA patients. Additional studies are needed to clarify the ideal drug regimens and the need for prophylactic antibiotics in this population.

S616-p-DRP1 associates with locally invasive behavior of follicular cell-derived thyroid carcinoma.

PURPOSE: Dynamin-related protein 1 (DRP1), a mitochondrial fission protein, and its active form phosphorylated at Serine 616 (S616-p-DRP1) have been increasingly associated with tumorigenesis and invasion in various tumor models, including oncocytic thyroid cancer (TC). In this study, the expression of DRP1 and S616-p-DRP1 and its relationship with patients' clinicopathological characteristics, tumor genetic profiles, and clinical outcomes were assessed in a large series of follicular cell-derived TC (FCDTC). METHODS: Retrospective biomarker study characterizing the clinicopathological and immunochemistry DRP1 and S616-p-DRP1 expression of a series of 259 patients with FCDTC followed in two University Hospitals. RESULTS: DRP1 expression was positive in 65.3% (169/259) of the cases, while the expression of the S616-p-DRP1 was positive in only 17.3% (17/98). DRP1-positive expression was significantly associated with differentiated tumors (67.7 vs. 48.0%; P = 0.049), non-encapsulated tumors (73.8 vs. 57.4%; P = 0.011) and thyroid capsule invasion (73.4 vs. 57.5%; P = 0.013). S616-p-DRP1-positive expression was significantly associated with tumor infiltrative margins (88.9 vs. 11.1%; P = 0.033), thyroid capsule invasion (29.8 vs. 3.1%; P = 0.043), lymph node metastases (23.3 vs. 8.1%; P = 0.012), and higher mean cumulative radioiodine dosage (317.4 ± 265.0 mCi vs. 202.5 ± 217.7 mCi; P = 0.038). S616-p-DRP1 expression was negatively associated with oncocytic phenotype (0.0 vs. 26.2%; P = 0.028). CONCLUSIONS: S616-p-DRP1 is a better candidate than DRP1 to identify tumors with locally invasive behavior. Prospective studies should be pursued to assess S616-p-DRP1 role as a molecular marker of malignancy in TC and in patients' risk assessment.

Response to lower dose TNF inhibitors in axial spondyloarthritis; a real-world multicentre observational study.

OBJECTIVE: Dose optimization of TNF inhibitors in axial spondyloarthritis (axSpA) is attractive, but it is unclear for which patients this approach might be appropriate. METHODS: Seventy-one patients with axSpA, from six UK centres, were identified who had reduced their dose of TNF inhibitor after being considered to be stable responders. All completed a questionnaire concerning their approach to and experience of dose reduction. Data on patient characteristics, metrology and CRP were retrieved retrospectively from patient records. RESULTS: Over 2 years of observation, 60 (84.5%) remained (REM) on reduced-dose medication and 11 (15.5%) reverted (REV) to the original dose. The overall mean dose reduction was 39% for REM patients and 44% for REV patients. Both groups initially responded in a similar manner to treatment, but the data showed a trend that younger women were more likely to revert. Neither BMI nor smoking was associated with continued low-dose responsiveness. Eight of the 11 REV patients reverted by 6 months. None reached criteria of secondary drug failure, and all regained control after increasing back to the original dose. Most patients in both groups reached the decision to reduce the dose jointly with clinicians. A preference for taking the reduced dose was not associated with low-dose drug survival. CONCLUSION: Many patients with axSpA remain well symptomatically after stepping down the dose of TNF inhibitor, but young women are less likely to do well on a reduced dose. Dose reduction should be one element of the management of patients with axSpA.

Vitamin D Deficiency in a Portuguese Cohort of Patients with Inflammatory Bowel Disease: Prevalence and Relation to Disease Activity.

BACKGROUND AND AIMS: Vitamin D deficiency is more common in inflammatory bowel disease (IBD) patients than in the general population. However, there are conflicting data about predictive factors of vitamin D deficiency and its potential association with disease activity. The aims of this study were to determine the prevalence and predictive factors of vitamin D deficiency and to evaluate a possible association with disease activity. METHODS: A prospective observational study was conducted, including patients with IBD from January to July 2016. The Endocrine Society guidelines were considered for defining levels of serum 25-hydroxyvitamin D (25-OH-D) as follows: deficient (< 20 ng/mL, < 10 ng/mL being severe deficiency), insufficient (21-29 ng/mL), and adequate (> 30 ng/mL). RESULTS: A total of 152 patients (52% men; 47.2 ± 17.3 years) were included, of whom 70% had Crohn's disease (CD). Thirty-seven percent of patients were on immunosuppressors and 17% were on biologics. The majority were outpatients (88.2%). Mean 25-OH-D levels were 17.1 ± 8 ng/mL (CD: 16.7 ± 8 ng/mL vs. ulcerative colitis: 17.6 ± 7 ng/mL, p = 0.1). Inadequate levels were present in 90.8% of patients (deficiency: 68.4%; insufficiency: 22.4%). A significant negative correlation between 25-OH-D levels and age (r = -0.2, p = 0.04), C-reactive protein (CRP) levels (r = -0.22, p = 0.004), and Harvey-Bradshaw index (HBi) (r = -0.32, p = 0.001) was found. Patients with severe deficiency showed a higher CRP (0.6 vs. 1.4 mg/dL, p = 0.03), erythrocyte sedimentation rate (ESR) (22 vs. 31 mm/h, p = 0.03), and HBi (2 vs. 5, p < 0.001) and lower hemoglobin (13.6 vs. 12.7 g/dL, p = 0.02). There was no association between vitamin D deficiency and gender, type, extent, and duration of disease, surgery, and other measures of disease activity, such as ESR, hemoglobin (these 2 items except for severe deficiency), fecal calprotectin, or Truelove and Witts classification. CONCLUSIONS: There is a high prevalence of inadequate levels of vitamin D in IBD patients, particularly deficiency (68.4%). There seems to exist an association between lower levels of vitamin D and higher disease activity, especially in CD.

INTRODUÇÃO: A deficiáncia de vitamina D é mais comum na doença inflamatória intestinal (DII) que na população geral. Contudo, existem dados controversos sobre fatores preditivos da deficiáncia de vitamina D e a potencial associação com a atividade da doença. Os objetivos deste estudo foram determinar a prevaláncia e fatores preditivos da deficiáncia de vitamina D e aferir possível associação à atividade da doença. MÉTODOS: Desenhou-se um estudo observacional prospetivo incluindo doentes com DII entre janeiro e julho/2016. Foram consideradas as orientações da The Endocrine Society para definir níveis de 25-hidroxivitamina D (25-OH-D) sérica como: deficientes (< 20 ng/mL, sendo <10 ng/mL deficiáncia grave [DG]), insuficientes (21­29 ng/ mL) e adequados (> 30 ng/mL). RESULTADOS: Foram incluídos 152 doentes (52% homens; 47.2 ± 17.3 anos), dos quais 70% com Doença de Crohn (DC). Do total, 37% estavam medicados com immunossupressores e 17% com biológicos. A maioria (88.2%) estava em ambulatório. O nível sérico de 25-OH-D foi 17.1 ± 8 ng/mL (DC: 16.7 ± 8 ng/mL vs. Colite ulcerosa: 17.6 ± 7 ng/mL, p = 0.1). Verificaram-se níveis inadequados em 90.8% (deficiáncia: 68.4%; insuficiáncia: 22.4%). Registou-se correlação negativa significativa entre níveis de 25-OH-D e idade (r = −0.2, p = 0.04), proteína C-reativa (PCR) (r = −0.22, p = 0.004) e índice Harvey-Bradshaw (iHB) (r = −0.32, p = 0.001). Doentes com DG apresentaram níveis mais elevados de PCR (0.6 vs. 1.4 mg/dL, p = 0.03), velocidade de sedimentação (VS) (22 vs. 31 mm/h, p = 0.03) e iHB (2 vs. 5, p < 0.001), e mais baixos de hemoglobina (13.6 vs. 12.7 g/dL, p = 0.02). Não se verificou associação entre deficiáncia de vitamina D e sexo, tipo, extensão e duração da doença, cirurgia, e outras medidas de atividade da doença como VS, hemoglobina (estas duas exceto para DG), calprotectina fecal ou classificação Truelove e Witts. CONCLUSÕES: Registou-se prevaláncia alta de níveis inadequados de vitamina D na DII, particularmente de deficiáncia (68.4%). Parece existir associação entre níveis mais baixos de vitamina D e maior atividade da doença, nomeadamente na DC.

Recurrent Gastrointestinal Bleeding from Dieulafoy's Lesions in a Patient with Type 1 von Willebrand Disease: A Rare Association.

Von Willebrand disease (vWD) is the most prevalent hereditary bleeding disorder, affecting 0.6-1.3% of the population. While gastrointestinal bleeding from angiodysplasia is a well-known complication of vWD, the same is not true for Dieulafoy's lesions (DLs). We report the case of a 21-year-old black male with type 1 vWD and 2 previous hospital admissions for severe anemia with no visible blood loss. In both episodes, DLs were identified and treated endoscopically, one in the stomach and another in the duodenum. The patient presented to the emergency department in September 2016 with dizziness, fatigue, and again no visible blood loss. He was hemodynamically stable, and laboratory workup showed a hemoglobin level of 3.4 g/dL. After transfusion of packed red blood cells, intravenous iron, and von Willebrand factor/factor VIII concentrate infusions, the patient underwent upper endoscopy and colonoscopy, which were normal. Small-bowel capsule endoscopy showed dark blood and a fresh clot in the proximal jejunum. At this site, push enteroscopy identified a pulsatile vessel with an overlying minimal mucosal defect, consistent with a DL, type 2b of the Yano-Yamamoto classification, which was successfully treated with adrenaline and 2 hemoclips. The patient remains stable after 18 months of follow-up, with a hemoglobin level of 13.2 g/dL. This is a case of recurrent severe occult gastrointestinal bleeding from multiple DL in a young patient with vWD who is otherwise healthy. Three other cases of DL bleeding in the setting of vWD have been reported in the literature, suggesting a possible association between these 2 entities.

A doença de von Willebrand é a perturbação hemorrágica hereditária mais frequente, afetando 0.6 a 1.3% da população. A hemorragia por angiectasias do tubo digestivo é uma complicação bem estabelecida desta doença. Contudo, o mesmo não é verdade para as lesões de Dieulafoy. Apresentamos o caso de um doente de 21 anos, melanodérmico, com doença de von Willebrand tipo 1 e dois internamentos prévios por anemia grave sem perdas hemáticas visíveis. Em ambos os episódios foram identificadas lesões de Dieulafoy que foram tratadas endoscopicamente, uma das quais no estômago e outra no duodeno. O doente foi admitido no serviço de urgáncia em Setembro de 2016 por quadro de tonturas e cansaço, novamente sem perdas visíveis. Apresentava-se hemodinamicamente estável e a avaliação laboratorial mostrou hemoglobina de 3.4 g/dL. Após transfusão de concentrados eritrocitários, terapáutica com ferro endovenoso e concentrados de fator de von Willebrand/fator VIII, foram realizadas endoscopia digestiva alta e colonoscopia, sem alterações. A enteroscopia por cápsula detetou a presença de sangue digerido e um coágulo fresco no jejuno proximal. A enteroscopia de pulsão identificou nessa topografia uma solução de continuidade da mucosa milimétrica sobre lesão vascular pulsátil procidente, compatível com lesão de Dieulafoy tipo 2b da Classificação de Yano-Yamamoto, que foi tratada eficazmente com adrenalina e dois hemoclips. Após 18 meses, o doente mantém-se clinicamente estável e com Hb 13.2 g/dL. Este é um caso particular de hemorragia gastrointestinal oculta recorrente por múltiplas lesões de Dieulafoy num jovem com doença de von Willebrand, sem outras patologias. Há trás casos semelhantes descritos na literatura, sugerindo uma possível associação entre estas duas entidades.

The interplay between glioblastoma and microglia cells leads to endothelial cell monolayer dysfunction via the interleukin-6-induced JAK2/STAT3 pathway.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor, with an average life expectancy of 12-15 months. GBM is highly infiltrated by microglial cells (MG) promoting tumor growth and invasiveness. Moreover, microglia activation and subsequent neuroinflammation seem to be involved in blood-brain barrier (BBB) dysfunction commonly observed in several central nervous system diseases, including brain tumors. Nevertheless, how the crosstalk between microglia and tumor cells interferes with BBB function is far from being clarified. Herein, we evaluated the effects of reciprocal interactions between MG and GBM cells in the barrier properties of brain endothelial cells (ECs), using an in vitro approach. The exposure of ECs to the inflammatory microenvironment mediated by MG-GBM crosstalk induced a decrease in the transendothelial electric resistance and an increase in permeability across the ECs (macromolecular flux of 4 kDa-fluorescein isothiocyanate and 70 kDa-Rhodamine B isothiocyanate-Dextran). These effects were accompanied by a downregulation of the intercellular junction proteins, ß-catenin and zonula occludens. Moreover, the dynamic interaction between microglia and tumor cells triggered the release of interleukin-6 (IL-6) by microglia and subsequent activation of the downstream Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway. Interestingly, the depletion of IL-6 or the blockade of the JAK/STAT3 signaling with AG490 were able to prevent the EC hyperpermeability. Overall, we demonstrated that IL-6 released during MG-GBM crosstalk leads to barrier dysfunction through the activation of the JAK/STAT3 pathway in ECs and downregulation of intercellular junction proteins. These results provide new insights into the mechanisms underlying the disruption of BBB permeability in GBM.

Azoro y silencio. La huella en los afectos del sujeto de la experiencia de violencia escolar / Astonishment and silence. The imprint on the subject affections of the experience of school violence

Resumen El estudio analiza las consecuencias en los afectos de estudiantes de 5° y 6° grado de primaria víctimas de violencia escolar. El trabajo es de tipo cualitativo interpretativo, realizado a partir de entrevistas individuales y grupos focales. Su análisis permitió la construcción de cuatro bloques categoriales: "Afectos ante la vivencia de violencia", "Consecuencias académicas y malestar al ser víctima de violencia", "Tipología de la violencia de la que el menor es víctima", y "Características generales de la víctima de violencia". En estos se detalla la respuesta afectiva de los escolares, sus dificultades de desempeño académico e interaccional, las características de las situaciones de agresividad de los que son objeto y los elementos del cuerpo o psicosociales en que se focaliza la expresión de violencia.

Abstract The study analyzes the consequences in the students' affections of 5° and 6° grades of primary victims of school violence. The work is of qualitative interpretive type realized from individual interviews and to focal groups. His analysis allowed the construction of four thematic blocks: Affections before the experience of violence, Academic consequences and discomfort on having been a victim of violence, Typology of the violence of which the child is victim and Characteristic personal of the victim of violence, in which it is detailed from the affective response of the students, his difficulties of academic performance and interactional, the characteristics of the situations of aggressiveness of which they are an object and body or psycho social elements in that the expression of violence is focused.

Oesophageal atresia with tracheo-oesophageal fistula, ileal atresia and Hirschsprung's disease: outcome of a rare phenotype.

Oesophageal atresia with or without tracheo-oesophageal fistula, ileal atresia and Hirschsprung's disease are surgical malformations of the gastrointestinal tract typically diagnosed early in the neonatal period and varying in severity and prognosis. This report describes a full-term male newborn presenting simultaneous oesophageal atresia with distal tracheo-oesophageal fistula, ileal atresia and Hirschsprung's disease. In addition to the complex types of gastrointestinal malformations involved, the combination of ileal atresia and Hirschsprung's disease, as well as ganglion cells distal to intestinal atresia, resulted in a challenging diagnosis. Despite a successful outcome, the patient presented increased morbidity and prolonged hospitalisation. We highlight some important findings that may aid the early diagnosis of Hirschsprung's disease in this clinical setting. To our knowledge, the association of oesophageal atresia/tracheo-oesophageal fistula, ileal atresia and Hirschsprung's disease has not been previously reported.