CCL21-CCR7 signaling promotes microglia/macrophage recruitment and chemotherapy resistance in glioblastoma.

Glioblastoma (GBM) is the most common and fatal primary tumor of the central nervous system (CNS) and current treatments have limited success. Chemokine signaling regulates both malignant cells and stromal cells of the tumor microenvironment (TME), constituting a potential therapeutic target against brain cancers. Here, we investigated the C-C chemokine receptor type 7 (CCR7) and the chemokine (C-C-motif) ligand 21 (CCL21) for their expression and function in human GBM and then assessed their therapeutic potential in preclinical mouse GBM models. In GBM patients, CCR7 expression positively associated with a poor survival. CCL21-CCR7 signaling was shown to regulate tumor cell migration and proliferation while also controlling tumor associated microglia/macrophage recruitment and VEGF-A production, thereby controlling vascular dysmorphia. Inhibition of CCL21-CCR7 signaling led to an increased sensitivity to temozolomide-induced tumor cell death. Collectively, our data indicate that drug targeting of CCL21-CCR7 signaling in tumor and TME cells is a therapeutic option against GBM.

Adiponectin, the adiponectin paradox, and Alzheimer's Disease: Is this association biologically plausible?

Dementia, especially Alzheimer's Disease (AD) and vascular dementia, is a major public health problem that continues to expand in both economically emerging and hegemonic countries. In 2017, the World Alzheimer Report estimated that over 50 million people were living with dementia globally. Metabolic dysfunctions of brain structures such as the hippocampus and cerebral cortex have been implicated as risk factors for dementia. Several well-defined metabolic risk factors for AD include visceral obesity, chronic inflammation, peripheral and brain insulin resistance, type 2 diabetes mellitus (T2DM), hypercholesterolemia, and others. In this review, we describe the relationship between the dysmetabolic mechanisms, although still unknown, and dementia, particularly AD. Adiponectin (ADPN), the most abundant circulating adipocytokine, acts as a protagonist in the metabolic dysfunction associated with AD, with unexpected and intriguing dual biological functions. This contradictory role of ADPN has been termed the adiponectin paradox. Some evidence suggests that the adiponectin paradox is important in amyloidogenic evolvability in AD. We present cumulative evidence showing that AD and T2DM share many common features. We also review the mechanistic pathways involving brain insulin resistance. We discuss the importance of the evolvability of amyloidogenic proteins (APs), defined as the capacity of a system for adaptive evolution. Finally, we describe potential therapeutic strategies in AD, based on the adiponectin paradox.

GANT-61 Induces Autophagy and Apoptosis in Glioblastoma Cells despite their heterogeneity.

Glioblastoma (GBM) is the most common adult primary tumor of the CNS characterized by rapid growth and diffuse invasiveness into the brain parenchyma. The GBM resistance to chemotherapeutic drugs may be due to the presence of cancer stem cells (CSCs). The CSCs activate the same molecular pathways as healthy stem cells such as WNT, Sonic hedgehog (SHH), and Notch. Mutations or deregulations of those pathways play a key role in the proliferation and differentiation of their surrounding environment, leading to tumorigenesis. Here we investigated the effect of SHH signaling pathway inhibition in human GBM cells by using GANT-61, considering stem cell phenotype, cell proliferation, and cell death. Our results demonstrated that GANT-61 induces apoptosis and autophagy in GBM cells, by increasing the expression of LC3 II and cleaved caspase 3 and 9. Moreover, we observed that SHH signaling plays a crucial role in CSC phenotype maintenance, being also involved in the epithelial-mesenchymal transition (EMT) phenotype. We also noted that SHH pathway modulation can regulate cell proliferation as revealed through the analysis of Ki-67 and c-MYC expressions. We concluded that SHH signaling pathway inhibition may be a promising therapeutic approach to treat patients suffering from GBM refractory to traditional treatments.

Saliva NMR-Based Metabolomics in the War Against COVID-19.

COVID-19 is an emergent, worldwide public health concern. Joint efforts have been made by scientific communities of various fields to better understand the mechanisms of action of SARS-CoV-2. The need to understand the pathophysiological fingerprint and pathways of this disease make metabolomics-related approaches an indispensable tool for properly answering concerns relating to disease course. Determination of the metabolomic profile may help to explain the heterogeneous spectra of COVID-19 clinical phenotypes and be useful in monitoring disease progression as well as therapeutic treatments. In this sense, saliva has proven to be a strategic biofluid, owing not only to its appeal as a noninvasive sampling method but also due to the capacity of the virus to invade epithelial cells of the oral mucosa and salivary gland ducts via ACE2 receptors. Accordingly, important changes in metabolism have been described relating to COVID-19, indicating that metabolomics may open new avenues for understanding the pathophysiology of this disease, especially via longitudinal study designs. Thus, we discuss the importance of comprehending the SARS-CoV-2 salivary metabolomic fingerprint and also highlight the situation of Brazil on the frontlines of the war against COVID-19.

Insights Into the Controversial Aspects of Adiponectin in Cardiometabolic Disorders.

In 2016, the World Health Organization estimated that more than 1.9 billion adults were overweight or obese. This impressive number shows that weight excess is pandemic. Overweight and obesity are closely associated with a high risk of comorbidities, such as insulin resistance and its most important outcomes, including metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. Adiponectin has emerged as a salutary adipocytokine, with insulin-sensitizing, anti-inflammatory, and cardiovascular protective properties. However, under metabolically unfavorable conditions, visceral adipose tissue-derived inflammatory cytokines might reduce the transcription of the adiponectin gene and consequently its circulating levels. Low circulating levels of adiponectin are negatively associated with various conditions, such as insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular disease. In contrast, several recent clinical trials and meta-analyses have reported high circulating adiponectin levels positively associated with cardiovascular mortality and all-cause mortality. These results are biologically intriguing and counterintuitive, and came to be termed "the adiponectin paradox". Adiponectin paradox is frequently associated with adiponectin resistance, a concept related with the downregulation of adiponectin receptors in insulin-resistant states. We review this contradiction between the apparent role of adiponectin as a health promoter and the recent evidence from Mendelian randomization studies indicating that circulating adiponectin levels are an unexpected predictor of increased morbidity and mortality rates in several clinical conditions. We also critically review the therapeutic perspective of synthetic peptide adiponectin receptors agonist that has been postulated as a promising alternative for the treatment of metabolic syndrome and type 2 diabetes mellitus.

Evaluation of oral care protocols practice by dentists in Rio de Janeiro towards HIV/AIDS individuals.

BACKGROUND: The aim of this study was to evaluate the dentists' knowledge and practice regarding HIV positive individuals' oral care in Rio de Janeiro State. METHODS: Dentists from Rio de Janeiro State (n = 242) answered an electronic questionnaire on biosafety procedures, oral manifestations of AIDS, and knowledge of HIV infection. Collected information was stratified by gender, and data were analyzed using Chi-square and t tests. RESULTS: From the 14 oral manifestations investigated, oral candidiasis, necrotizing ulcerative gingivitis, and hairy leucoplakia were more associated with HIV, with no differences between the responses from men and women. Above 85% of the participants would be concerned about becoming infected with HIV after a needle/ sharp object injury and more than 80% of them were willing to be tested for HIV. However, significantly more women (98.8%), compared to men (91.3%), said they knew that HIV/ AIDS patients can contaminate dental care professionals, p = 0.007. There was a significant difference in the answers for the questions: "Are there special dental clinics for treatment of HIV/AIDS patients in Brazil?" (p = 0.044), and "Do the negative HIV tests surely indicate that the persons are free of viruses?" (p = 0.005). Significant differences between men and women were also observed regarding use of disposable mask (p = 0.01), and cap (p < 0.0001). CONCLUSION: Most dentists who participated in the study presented a good knowledge on the care of HIV/ AIDS individuals, including biosafety protocols and in terms of the oral manifestations commonly associated to AIDS.

In vitro and in silico validation of CA3 and FHL1 downregulation in oral cancer.

BACKGROUND: Aberrant methylation is a frequent event in oral cancer. METHODS: In order to better characterize these alterations, a search for genes downregulated by aberrant methylation in oral squamous cell carcinoma (OSCC) was conducted through the mining of ORESTES dataset. Findings were further validated in OSCC cell lines and patients' samples and confirmed using TCGA data. Differentially expressed genes were identified in ORESTES libraries and validated in vitro using RT-PCR in HNSCC cell-lines and OSCC tumor samples. Further confirmation of these results was performed using mRNA expression and methylation data from The Cancer Genome Atlas (TCGA) data. RESULTS: From the set of genes selected for validation, CA3 and FHL1 were downregulated in 60% (12/20) and 75% (15/20) of OSCC samples, respectively, and in HNSCC cell lines. The treatment of cell lines JHU-13 and FaDu with the demethylating agent 5'-aza-dC was efficient in restoring CA3 and FHL1 expression. TCGA expression and methylation data on OSCC confirms the downregulation of these genes in OSCC samples and also suggests that expression of CA3 and FHL1 is probably regulated by methylation. The downregulation of CA3 and FHL1 observed in silico was validated in HNSCC cell lines and OSCC samples, showing the feasibility of integrating different datasets to select differentially expressed genes in silico. CONCLUSIONS: These results showed that the downregulation of CA3 and FHL1 data observed in the ORESTES libraries was validated in HNSCC cell lines and OSCC samples and in a large cohort of samples from the TCGA database. Moreover, it suggests that expression of CA3 and FHL1 could probably be regulated by methylation having an important role the oral carcinogenesis.

What are the main oral manifestations in heart transplant patients? A scoping review.

OBJECTIVE: The purpose of this scoping review is to evaluate the oral manifestations (OM) of heart transplant (HT) patients undergoing immunosuppressive therapy (IT). MATERIAL AND METHODS: A literature search was performed using keywords and MeSH terms related to OM and HT in the Medline/PubMed, Web of Science, Cochrane Library, Scopus, LILACS/BBO databases and in gray literature without language or date restrictions until June 2023. Studies that evaluated HT individuals who used any IT and who reported the occurrence of OM were considered eligible. The results from the search were imported to EndNote Web, and duplicates were removed followed by title/abstract and full-text analysis. RESULTS: A total of 402 nonduplicated studies were found and 13 fulfilled the criteria and were included in the present review: 10 cross-sectional, 2 cohorts, and 1 clinical trial. The most reported OM were periodontal diseases, including drug-induced gingival enlargement (DIGE), gingival bleeding, gingivitis, and periodontitis. Reported in a minority of studies are oral cancer, opportunistic infections (oral hairy leukoplakia and erythematous candidiasis), enamel defects, and burning mouth. CONCLUSION: Considering the methodological heterogeneity of the studies analyzed, DIGE is the most commonly observed oral manifestation in HT individuals.

Action of Hyaluronic Acid as a Damage-Associated Molecular Pattern Molecule and Its Function on the Treatment of Temporomandibular Disorders.

The temporomandibular joint is responsible for fundamental functions. However, mechanical overload or microtraumas can cause temporomandibular disorders (TMD). In addition to external factors, it is known that these conditions are involved in complex biological mechanisms, such as activation of the immune system, activation of the inflammatory process, and degradation of extracellular matrix (ECM) components. The ECM is a non-cellular three-dimensional macromolecular network; its most studied components is hyaluronic acid (HA). HA is naturally found in many tissues, and most of it has a high molecular weight. HA has attributed an essential role in the viscoelastic properties of the synovial fluid and other tissues. Additionally, it has been shown that HA molecules can contribute to other mechanisms in the processes of injury and healing. It has been speculated that the degradation product of high molecular weight HA in healthy tissues during injury, a low molecular weight HA, may act as damage-associated molecular patterns (DAMPs). DAMPs are multifunctional and structurally diverse molecules that play critical intracellular roles in the absence of injury or infection. However, after cellular damage or stress, these molecules promote the activation of the immune response. Fragments from the degradation of HA can also act as immune response activators. Low molecular weight HA would have the ability to act as a pro-inflammatory marker, promoting the activation and maturation of dendritic cells, the release of pro-inflammatory cytokines such as interleukin 1 beta (IL-1ß), and tumor necrosis factor α (TNF-α). It also increases the expression of chemokines and cell proliferation. Many of the pro-inflammatory effects of low molecular weight HA are attributed to its interactions with the activation of toll-like receptors (TLRs 2 and 4). In contrast, the high molecular weight HA found in healthy tissues would act as an anti-inflammatory, inhibiting cell growth and differentiation, decreasing the production of inflammatory cytokines, and reducing phagocytosis by macrophages. These anti-inflammatory effects are mainly attributed to the interaction of high-weight HA with the CD44 receptor. In this study, we review the action of the HA as a DAMP and its functions on pain control, more specifically in orofacial origin (e.g., TMD).

Claudin-7 down-regulation is an important feature in oral squamous cell carcinoma.

AIMS: Claudins, a large family of essential tight junction (TJ) proteins, are abnormally regulated in human carcinomas, especially claudin-7. The aim of this study was to investigate claudin-7 expression and alterations in oral squamous cell carcinoma (OSCC). METHODS AND RESULTS: Expression of claudin-7 was analysed in 132 cases of OSCC organized in a tissue microarray. Claudin-7 mRNA transcript was evaluated using real-time polymerase chain reaction and the methylation status of the promoter was also assessed. Claudin-7 was negative in 58.3% of the cases. Loss of claudin-7 protein expression was associated with recurrence (P = 0.019), tumour size (P = 0.014), clinical stage of OSCC (P = 0.055) and disease-free survival (P = 0.015). Down-regulation of the claudin-7 mRNA transcripts was observed in 78% of the cases, in accordance with immunoexpression. Analysis of the methylation status of the promoter region of claudin-7 revealed that treatment of O28 cells (that did not express claudin-7 mRNA transcripts) with 5-Aza-2'-Deoxycytidine (5-Aza-dC) led to the re-expression of claudin-7 mRNA transcript. CONCLUSION: Loss of claudin-7 expression is associated with important subcellular processes in OSCC with impact on clinical parameters.

Neuromechanisms of SARS-CoV-2: A Review.

Recent studies have suggested the neuroinvasive potential of severe acute respiratory coronavirus 2 (SARS-CoV-2). Notably, neuroinvasiveness might be involved in the pathophysiology of coronavirus disease 2019 (COVID-19). Some studies have demonstrated that synapse-connected routes may enable coronaviruses to access the central nervous system (CNS). However, evidence related to the presence of SARS-CoV-2 in the CNS, its direct impact on the CNS, and the contribution to symptoms suffered, remain sparse. Here, we review the current literature that indicates that SARS-CoV-2 can invade the nervous system. We also describe the neural circuits that are potentially affected by the virus and their possible role in the progress of COVID-19. In addition, we propose several strategies to understand, diagnose, and treat the neurological symptoms of COVID-19.

MicroRNAs, Hypoxia and the Stem-Like State as Contributors to Cancer Aggressiveness.

MicroRNAs (miRNAs) are small non-coding RNA molecules that play key regulatory roles in cancer acting as both oncogenes and tumor suppressors. Due to their potential roles in improving cancer prognostic, predictive, diagnostic and therapeutic approaches, they have become an area of intense research focus in recent years. Several studies have demonstrated an altered expression of several miRNAs under hypoxic condition and even shown that the hypoxic microenvironment drives the selection of a more aggressive cancer cell population through cellular adaptations referred as the cancer stem-like cell. These minor fractions of cells are characterized by their self-renewal abilities and their ability to maintain the tumor mass, suggesting their crucial roles in cancer development. This review aims to highlight the interconnected role between miRNAs, hypoxia and the stem-like state in contributing to the cancer aggressiveness as opposed to their independent contributions, and it is based in four aggressive tumors, namely glioblastoma, cervical, prostate, and breast cancers.

Glioblastoma Therapy in the Age of Molecular Medicine.

Glioblastoma (GBM) is the most common and fatal primary malignant brain tumor. Despite advances in the understanding of the biology of gliomas, little has changed in the treatment of these tumors in the past decade. Phase III clinical trials showed no benefit for the use of bevacizumab in newly diagnosed patients, leading to a renewed search for new antiangiogenic drugs, as well as immunotherapeutic approaches, including checkpoint inhibitors, chimeric antigen receptor T cells, and intracerebral CpG-oligodeoxynucleotides. The emerging role of infiltrating microglia and macrophages, and of metabolic alterations, is also being taken into account in preclinical research and drug development. In this review, we discuss progress in the search for new therapeutic strategies, particularly approaches focusing on the tumor microenvironment.

miRNAs: Important Targets for Oral Cancer Pain Research.

Pain is a symptom shared by an incredible number of diseases. It is also one of the primary conditions that prompt individuals to seek medical treatment. Head and neck squamous cell carcinoma (HNSCC) corresponds to a heterogeneous disease that may arise from many distinct structures of a large, highly complex, and intricate region. HNSCC affects a great number of patients worldwide and is directly associated with chronic pain, which is especially prominent during the advanced stages of oral squamous cell carcinoma (OSCC), an anatomical and clinical subtype that corresponds to the great majority oral cancers. Although the cellular and molecular bases of oral cancer pain have not been fully established yet, the results of recent studies suggest that different epigenetic mechanisms may contribute to this process. For instance, there is strong scientific evidence that microRNAs (miRNAs), small RNA molecules that do not encode proteins, might act by regulating the mechanisms underlying cancer-related pain. Among the miRNAs that could possibly interfere in pain-signaling pathways, miR-125b, miR-181, and miR-339 emerge as some of the most promising candidates. In fact, such molecules apparently contribute to inflammatory pain. Moreover, these molecules possibly influence the activity of endogenous pain control systems (e.g., opioidergic and serotonergic systems), which could ultimately result in peripheral and central sensitization, central nervous system (CNS) phenomena innately associated with chronic pain. This review paper focuses on the current scientific knowledge regarding the involvement of miRNAs in cancer pain, with special attention dedicated to OSCC-related pain.

Enhanced amyloidogenic processing of amyloid precursor protein and cell death under prolonged endoplasmic reticulum stress in brain endothelial cells.

Cerebral amyloid angiopathy resulting from the deposition of misfolded amyloid beta (Aß) peptide in the walls of brain's blood vessels is exhibited by the majority of Alzheimer's disease (AD) patients, suggesting that alterations in protein quality control contribute to AD-associated vascular dysfunction. The present work addressed the role of ER stress in the amyloidogenic amyloid precursor protein (APP) processing and subsequent Aß generation in brain endothelial cells (ECs). For that purpose, the RBE4 cell line was exposed to the classical ER stressors thapsigargin or brefeldin A to mimic the altered ER homeostasis observed in AD. In treated cells, an increase in the levels of markers of ER stress (XBP1 and GRP78) and of the ER stress-induced apoptotic pathway (caspase-12, JNK, and CHOP) was observed concomitantly with the accumulation of reactive oxygen species. Under these conditions, a significant ER-to-mitochondria Ca(2+) transfer was also found, which culminated in mitochondrial Ca(2+) overload and activation of mitochondria-dependent apoptosis. Moreover, it was showed that prolonged ER stress induces intracellular APP accumulation, which colocalizes with the ER chaperone GRP78, and activation of ß-secretase, leading to increased intracellular Aß levels, together with a decrease in secreted Aß. Finally, it was demonstrated that ER stress-induced changes in Aß levels and apoptotic cell death can be ameliorated by a blocker of the mitochondrial Bax channel. These observations suggest that chronic ER stress triggers APP accumulation in early comportments along the secretory pathway in brain ECs and increases its amyloidogenic processing and Aß generation leading to apoptotic cell death.

[The nurse's participation in implementing the Family Health Program (PSF0 in Belo Horizonte]. / A participaçao do enfermeiro na implantação do Programa de Saúde da família em Belo Horizonte.

This study analyzes the nurse's participation in implementing the Family Health Program (PSF) in Belo Horizonte and aims at understanding their inclusion and expectations as an agent in the organization of health services and in overcoming problems found in the implementation of the program in a large city. A qualitative approach is used based on dialectic historic materialism. Eleven nurses participating in the PSF were the subjects of the research. Data was collected by means of a semi-structured interview and submitted to a discourse analysis treatment. The results demonstrate that the nurse has been involved with family health and playing a significant role ever since the implementation of the Community Health Agents Program (PACS) and that their inclusion in the PSF is favored both by their generalist background and their experience in planning, executing and evaluating health actions. Factors related to the nurse's work conditions, such as inadequacy of the environment, differentiated salary and treatment in relation to the doctor in team activities and the overload of tasks and responsibilities stand out as difficulty factors in implementing the PSF in Belo Horizonte.

Peri-implant status in partially edentulous individuals subjected to dental implant rehabilitation

Objective:Oral rehabilitation with dental implants has become a daily routine in dental clinics. However, peri-implant diseases can affect the tissues around dental implants over time. The aim of this study was to evaluate peri-implant health status in partially edentulous individuals rehabilitated with dental implants in comparison with either periodontally healthy individuals or those with periodontitis. Methods: Study participants were subjected to anamnestic questionnaires and full periodontal/ peri-implant examination. Twenty-five dental implant carriers (45% women; mean age, 57.2 years), 35 periodontally healthy individuals (28.6% women; mean age, 24.1 years), and 25 subjects with periodontitis (20% women; mean age, 47.5 years) were included. Those in the healthy and periodontitis groups had no dental implants. Significant differences were analyzed by Wilcoxon, Chi-square, and Kruskal-Wallis tests. Results: The dental implant carriers had an average of 3.9 implants with an average time of 5.1 years since insertion. Peri-implant disease was detected in 75% of individuals in the Dental Implant Carriers group (70% had peri-implant mucositis). Dental implants presented probing depths and clinical attachment levels significantly higher when compared with those of unaffected teeth from the same individuals (pd"0.004), or with teeth from periodontally healthy individuals (p<0.0001). Although implants presented less dental biofilm, they presented higher percentages of bleeding on probing compared with unaffected teeth in the same individuals (p=0.002) and with teeth in periodontally healthy individuals (p<0.0001). The population studied had a relatively high prevalence of peri-implant disease. Conclusion: It is possible to verify that the clinical characteristics of the peri-implant tissues resembled those of individuals with periodontitis.

Objetivo: A reabilitação oral com o emprego de implantes dentários é uma rotina na clínica odontológica. Entretanto, as doenças peri-implantares podem se estabelecer ao redor dos implantes dentários com o passar do tempo. O objetivo deste estudo foi avaliar a saúde peri-implantar de indivíduos submetidos a tratamento com implantes dentários comparados a indivíduos com saúde periodontal e periodontite. Métodos : Os participantes do estudo foram submetidos a questionários anamnésicos e exame periodontal/ peri-implantar completo. Foram incluídos 20 indivíduos Portadores de Implantes Dentários (45% mulheres; idade média de 57,2 anos), 35 indivíduos com Saúde Periodontal (28,6% mulheres; idade média de 24,1 anos) e 25 indivíduos com Periodontite (20% mulheres; idade média de 47,5 anos). Estes últimos não possuíam implantes dentários. Diferenças significativas foram analisadas através dos testes Wilcoxon, Qui-quadrado e Kruskal- allis. Resultados : O grupo Portadores de Implantes Dentários possuía uma média de 3,9 implantes com tempo médio de instalação de 5,1 anos. Doença peri-implantar foi detectada em 75% dos indivíduos com implantes dentários, sendo 70% mucosite peri-implantar. Implantes dentários apresentaram profundidade de sondagem e nível clínico de inserção significativamente maior quando comparado a dentes dos mesmos indivíduos (p d" 0,004), ou de indivíduos com saúde periodontal (p < 0,0001). Apesar de implantes apresentarem menor acúmulo de biofilme dental, apresentaram maiores porcentuais de sangramento à sondagem comparado a dentes (nos mesmos indivíduos; p = 0,002) e a indivíduos com saúde periodontal (p < 0,0001). Conclusão : A população estudada apresenta uma relativamente alta prevalência de doença peri-implantar. Além disto, foi possível constatar que as características clínicas do tecido peri-implantar se assemelharam àquelas de indivíduos com periodontite.

Innovations in Curriculum Designs Do Not Guarantee Students' Patient-Centered Attitudes Running Title: Curricula and Patient-Centered Attitudes / Inovações no Desenho Curricular não Garantem Atitudes Centradas no Paciente entre os Estudantes

ABSTRACT Background Medical schools all around the world are engaged in curricular reforms aimed at fostering patient- and learner-centeredness, implementing curricular transformations in order to counterbalance the erosion of humanistic and professional values and the loss of idealism of recent graduate physicians. In Brazil, medical schools are facing the challenge of redesigning medical curricula towards more learner-centered and patient-centered approaches, stimulated by recent national medical education guidelines. However, desirable outcomes towards medical education have not been fully achieved. Aim To access medical students' attitudes and determine predictors of medical students' patient-centered attitudes among students from different curricular designs (traditional, innovative and advanced). Methods Medical students from 1st to 6th year from 21 Brazilian medical schools participating in the project for evaluating change and trends proposed by the Brazilian Association of Medical Education, with different stages of curricular designs (traditional, innovative and advanced), answered the Brazilian version of the Patient-Practitioner Orientation Scale (B-PPOS) and a questionnaire with curricular and sociodemographic variables. Results Brazilian medical students care more than they share information, power and responsibility (p < 0.001; d = 0.599). They are more concerned with the psychosocial context than with patient's perspective (p < 0.001; d = 0.797) and share more power and responsibility than understanding (p < 0.001, d = 0.455). Female gender (B = 0.180), students from public schools (B = 0.132), year of medical training (B = 0.021), preference for future medical practice in public services (B = 0.053) and extracurricular activities (B = 0.068) were predictors of patient-centered attitudes among medical students (p < 0.05). Meanwhile, the father's educational level and choice to study surgical specialties (p < 0.05) were predictors of less patient-centered attitudes among students. Different curricular designs were not associated with students' patient-centered attitudes (p > 0.05). Conclusion tant predictors of patient-centered attitudes among medical students. Further research should investigate the direct influence of faculty professionalism development programs on students' patient centered-attitudes.

Introdução Escolas médicas de todo o mundo estão engajadas em reformas curriculares com o objetivo de melhorar a centralidade do ensino no paciente e no aluno, implementando transformações curriculares a fim de contrabalançar a erosão dos valores humanísticos e profissionais, bem como a perda do idealismo de médicos recém-formados. Escolas médicas brasileiras encaram o desafio de redesenhar os currículos médicos em direção a abordagens mais centradas no paciente e no aluno, estimuladas pelas recentes diretrizes curriculares nacionais dos cursos de Medicina. Entretanto, os resultados desejados não têm sido totalmente alcançados. Objetivo Acessar as atitudes dos estudantes de Medicina e determinar preditores das atitudes mais centradas no paciente entre os estudantes de Medicina de diferentes desenhos de currículo (tradicional, inovador e avançado). Método Estudantes de Medicina do primeiro ao sexto ano de 21 escolas médicas brasileiras que participaram do projeto de avaliação de tendências de mudanças no curso de graduação nas escolas médicas brasileiras proposta pela Associação Brasileira de Educação Médica, com diferentes estágios de currículo (tradicional, inovador e avançado), responderam à versão brasileira da Escala de Orientação Médico-Paciente (EOMP) e a um questionário com variáveis sociodemográficas e curriculares. Resultados Estudantes de Medicina brasileiros cuidam mais do que compartilham informação, poder e responsabilidade (p < 0.001; d = 0.599). Cuidam mais do contexto psicossocial do que da perspectiva do paciente (p < 0.001; d = 0.797) e compartilham mais poder e responsabilidade do que entendimento (p < 0.001, d = 0.455). Gênero feminino (B = 0.180), estudantes de escolas médicas públicas (B = 0.132), ano de treinamento médico (B = 0.021), preferência por futura prática em serviços públicos (B = 0.053) e atividades extracurriculares (B = 0.068) foram preditores de atitudes mais centradas no paciente entre os estudantes de Medicina (p < 0.05). Diferentes desenhos curriculares não foram associados com atitudes mais centradas no paciente (p > 0.05). Conclusões Desenhos curriculares não predizem atitudes dos estudantes de Medicina. Ser mulher e frequentar uma escola médica pública foram importantes preditores de atitudes mais centradas no paciente entre os estudantes de Medicina.

Gliomas and the vascular fragility of the blood brain barrier.

Astrocytes, members of the glial family, interact through the exchange of soluble factors or by directly contacting neurons and other brain cells, such as microglia and endothelial cells. Astrocytic projections interact with vessels and act as additional elements of the Blood Brain Barrier (BBB). By mechanisms not fully understood, astrocytes can undergo oncogenic transformation and give rise to gliomas. The tumors take advantage of the BBB to ensure survival and continuous growth. A glioma can develop into a very aggressive tumor, the glioblastoma (GBM), characterized by a highly heterogeneous cell population (including tumor stem cells), extensive proliferation and migration. Nevertheless, gliomas can also give rise to slow growing tumors and in both cases, the afflux of blood, via BBB is crucial. Glioma cells migrate to different regions of the brain guided by the extension of blood vessels, colonizing the healthy adjacent tissue. In the clinical context, GBM can lead to tumor-derived seizures, which represent a challenge to patients and clinicians, since drugs used for its treatment must be able to cross the BBB. Uncontrolled and fast growth also leads to the disruption of the chimeric and fragile vessels in the tumor mass resulting in peritumoral edema. Although hormonal therapy is currently used to control the edema, it is not always efficient. In this review we comment the points cited above, considering the importance of the BBB and the concerns that arise when this barrier is affected.

Methylation pattern of IFNG in periapical granulomas and radicular cysts.

INTRODUCTION: Interferon-γ plays an important role in the pathogenesis of periapical lesions, and the methylation of IFNG has been associated with transcriptional inactivation. The purpose of the present study was to investigate IFNG promoter methylation in association with gene transcription and protein levels in periapical granulomas and radicular cysts. METHODS: Methylation-specific polymerase chain reaction was used to assess the DNA methylation pattern of the IFNG gene in 16 periapical granulomas and 13 radicular cyst samples. The transcription levels of IFNG mRNA were verified by quantitative real-time polymerase chain reaction, and protein expression was evaluated by immunohistochemistry. RESULTS: All the periapical lesion samples exhibited partial or total methylation of the IFNG gene. In addition, an increased methylation profile was found in radicular cysts compared with periapical granulomas. Increased IFNG mRNA expression was observed in the partially methylated periapical lesion samples relative to the samples that were completely methylated. CONCLUSIONS: The present study provides the first evidence of the possible impact of IFNG methylation on IFNG transcription in periapical lesions.