Targeting the reprogrammed metabolism in H3.3K27M pediatric high-grade gliomas.

Recent studies in Diffuse Midline Gliomas (DMG) demonstrated a strong connection between epigenome dysregulation and metabolic rewiring. Here, we evaluated the value of targeting a glycolytic protein named Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase 3 (PFKFB3) in H3.3K27M DMG. We observed that the viability of H3.3K27M cells is dramatically reduced by PFK15, a potent inhibitor of PFKFB3. Furthermore, PFKFB3 inhibition induced apoptosis and G2/M arrest. Interestingly, CRISPR-Knockout of the K27M mutant allele has a synergistic effect on the observed phenotype. Altogether, we identified PFKFB3 as a new target for H3.3K27M DMG, making PFK15 a potential candidate for future animal studies and clinical trials.

Hydroxytakakiamide and Other Constituents from a Marine Sponge-Associated Fungus Aspergillus fischeri MMERU23, and Antinociceptive Activity of Ergosterol Acetate, Acetylaszonalenin and Helvolic Acid.

An unreported prenylated indole derivative hydroxytakakiamide (4) was isolated, together with the previously described ergosterol (1), ergosterol acetate (2), and (3R)-3-(1H-indol-3-ylmethyl)-3, 4-dihydro-1H-1,4-benzodiazepine-2,5-dione (3), from the column fractions of the crude ethyl acetate extract of the culture of a marine sponge-associated fungus, Aspergillus fischeri MMERU 23. The structure of 4 was elucidated by the interpretation of 1D and 2D NMR spectral data and high-resolution mass spectrum. The absolute configuration of the stereogenic carbon in 3 was proposed to be the same as those of the co-occurring congeners on the basis of their biogenetic consideration and was supported by the comparison of its sign of optical rotation with those of its steroisomers. The crude ethyl acetate extract and 2 were evaluated, together with acetylaszonalenin (5) and helvolic acid (6), which were previously isolated from the same extract, for the in vivo antinociceptive activity in the mice model. The crude ethyl acetate extract exhibited antinociceptive activity in the acetic acid-induced writhing and formalin tests, while 2, 5, and 6 displayed the effects in the late phase of the formalin test. On the other hand, neither the crude ethyl acetate extract nor 2, 5, and 6 affected the motor performance of mice in both open-field and rotarod tests. Additionally, docking studies of 2, 5, and 6 were performed with 5-lipoxygenase (5-LOX) and phosphodiesterase (PDE) enzymes, PDE4 and PDE7, which are directly related to pain and inflammatory processes. Molecular docking showed that 6 has low affinity energy to PDE4 and PDE7 targets while retaining high affinity to 5-LOX. On the other hand, while 2 did not display any hydrogen bond interactions in any of its complexes, it achieved overall better energy values than 6 on the three antinociceptive targets. On the other hand, 5 has the best energy profile of all the docked compounds and was able to reproduce the crystallographic interactions of the 5-LOX complex.

Antinociceptive and anti-inflammatory properties of α-D-mannan from the yeast Kluyveromyces marxianus: evidence for a role in interleukin-6 inhibition.

The management of inflammatory states typically involves non-steroidal anti-inflammatory drugs (NSAIDs) and opiates. Understanding the mechanisms underlying the processing of nociceptive information from potential alternatives such as some polysaccharides may enable new and meaningful therapeutic approaches. In this study, α-D-mannan isolated from the Kluyveromyces marxianus cell wall produced antinociceptive effects in models of inflammatory pain (formalin and complete Freund's adjuvant tests). Furthermore, α-D-mannan reduced paw edema and interleukin-6 (IL-6) production after carrageenan-induced inflammation. The polysaccharide α-D-mannan was characterized by gas chromatography-mass spectrometry, methylation analysis, and spectroscopic techniques. Moreover, the Doehlert experimental design was applied to find the optimal conditions for biomass production, with the best conditions being 10.8 g/L and 117 h for the glucose concentration and the fermentation time, respectively. These results indicate that α-D-mannan from K. marxianus exerts anti-inflammatory and antinociceptive effects in mice, possibly via a mechanism dependent on the inhibition of IL-6 production.

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.

A conservative approach for unicystic ameloblastoma: Retrospective clinic-pathologic analysis of 12 cases.

BACKGROUND: Unicystic ameloblastoma is an encapsulated odontogenic neoplasm with a single cyst cavity. The conservative or aggressive surgical approaches used to treat the tumor directly affect recurrence rates. However, there is a lack of a standard protocol that can guide its management. STUDY DESIGN: We retrospectively reviewed the clinicopathological findings and therapeutical procedures of 12 unicystic ameloblastoma cases treated by the same surgeon during the past 20 years. METHODS: All cases of unicystic ameloblastoma diagnosed by biopsy and treated by the same surgeon between 2002 and 2022 were reviewed. Eligibility criteria were patients with completely filled-out charts containing the follow-up period and confirmation of the diagnoses based on the microscopic findings of the whole excised specimens. Data collected were categorized into clinical, radiographic, histological, surgical, and recurrence aspects. RESULTS: There was a female predilection (2:1), and ages ranged between 18 and 61 years (mean: 27.25, ±12.45). Almost all (92%) affected the posterior mandible. Radiographically, the mean length of the lesions was 46.14 mm ± 14.28 mm which 92% were unilocular and 8.3% multilocular. Root resorption (n = 7, 58%), tooth displacement (n = 9, 75%), and cortical perforation (n = 5, 42%) were also observed. The mural histological subtype corresponded to 9 (75%) of the cases. The same conservative protocol was performed in all cases. The follow-up period ranged between 12 and 240 months (~62 ± 65) and recurrence occurred in only one patient (8%). CONCLUSION: Our findings suggest a conservative approach should be the first option for unicystic ameloblastoma treatment, even for those with mural proliferation.

Effects of fluoxetine withdrawal in the brainstem and hypothalamus of overnourished rats: Chronic modulation on oxidative stress levels.

Poor nutritional quality in the early stages of development is associated with neurological diseases in adulthood. Studies showed that obesity-induced oxidative stress contributes to the genesis of neurological diseases through dysregulation of the brainstem and hypothalamus. Fluoxetine (Fx) is an antidepressant member in the family of selective serotonin reuptake inhibitors (SSRI) that can induce positive effects by reducing oxidative damage in brain tissues. We aimed to evaluate the late effect of Fx in the brainstem and hypothalamus of overnourished rats during development. Male Wistar rats, after birth, were randomly divided into the normal-nourished group (N, n = 9) and the overnourished group (O, n = 3). On the 39th day of life, the groups were subdivided into normofed, and the overnourished group treated or not with fluoxetine (10 mg/kg daily) (NF, NV, OF, and OV). All groups were treated from the 39th to the 59th day of life, and within 90 days, the tissues were collected for oxidative stress analysis. Briefly, our results showed that Fx treatment induced a tissue-dependent long-lasting effect in overfed animals, increasing the enzymatic defense (i.e., CAT and GST activity) in the hypothalamus, but more intensive, increasing the non-enzymatic defense (i.e., Total Thiols and GSH levels) in the brainstem. Overall, our study suggests that serotonin modulation at the final stage of brain development causes a long-lasting impact on brain structures in overfed rats at a different mode.

Drugs and nanoformulations for the management of Leishmania infection: a patent and literature review (2015-2022).

INTRODUCTION: Leishmaniasis is an important disease caused by parasites of the Leishmania. Due to the urgent need for financial incentives and research and development of new anti-Leishmania, a point that stands out is the creation of patents that comprise drugs and nanoformulations in treating the disease. AREAS COVERED: Information on individual patents and patent families containing potential drugs and nanoformulations were obtained by searching the Orbit software (QUESTEL SAS, France) using the following terms: Leishmania; treatment; nanoparticle*; drug×. The data obtained ranged from 2015 to 2022. EXPERT OPINION: Meglumine antimoniate is a pentavalent antimonial widely used in the classic treatment of leishmaniasis. It is part of the classic treatment recommended by WHO, being the first-choice drug globally about 75 years ago. Thus, the need to introduce new anti-Leishmania therapies into clinical medicine is evident since cases of resistance to monotherapy and multitherapy have increased greatly. Associated with this, the search for patents that are good candidates in treating this disease assues interest in investments of financial resources and raises a ray of hope for safe, effective, and low-cost therapies to become licensed for the treatment of leishmaniasis.

Características clínicas e sociodemográficas dos usuários de um centro de atenção psicossocial infantojuvenil em Porto Alegre a partir do Sistema de Gerenciamento de Consultas (GERCON) / Clinical and sociodemographic characteristics of users of centro de atenção psicossocial infantojuvenil in Porto Alegre since the implementation of Sistema de Gerenciamento de Consultas (GERCON)

Introdução: Desde maio de 2019, o acesso aos serviços especializados de saúde mental infantojuvenil do município de Porto Alegre ocorre através da regulação assistencial por intermédio do sistema Gerenciamento de Consultas (GERCON). O objetivo deste estudo foi caracterizar o perfil clínico e sociodemográfico dos usuários encaminhados para um Centro de Atenção Psicossocial Infantojuvenil (CAPSi) nos dois primeiros anos do GERCON. Métodos: Estudo transversal em que foram resgatados dados dos prontuários eletrônicos de crianças e adolescentes encaminhados para primeira consulta em um CAPSi de Porto Alegre, capital do estado do Rio Grande do Sul, no período de maio de 2019 a abril de 2021. Resultados: A maioria dos 134 usuários era do sexo masculino (59,8%), autodeclarados brancos (69,7%), naturais de Porto Alegre (87,9%) e com hipótese diagnóstica inicial de Retardo mental (28,9%), Transtornos emocionais e de comportamento com início usualmente ocorrendo na infância e adolescência (24,2%) e Transtornos do humor (20,3%). A média de idade foi 13,4 anos e a mediana 15 anos. A taxa de absenteísmo na primeira consulta foi de 24,7%. Conclusão: A maioria dos usuários encaminhados para o CAPSi HCPA era do sexo masculino, adolescente, natural de Porto Alegre e com a hipótese diagnóstica inicial de transtornos do neurodesenvolvimento. Há uma elevada taxa de absenteísmo. Ao planejar intervenções para crianças e adolescentes que necessitam de atendimento em CAPSi é importante considerar o perfil nosológico e as características sociodemográficas dos usuários, assim como pensar em estratégias para diminuir o absenteísmo.

Introduction: Since May 2019, access to child and adolescent mental health services in the city of Porto Alegre has been managed through a regulatory system called sistema de regulação assistencial (GERCON). The aim of this study is to describe the clinical and sociodemographic characteristics of users referred to a Child and Adolescent Psychosocial Care Center (Centro de Atenção Psicossocial Infantojuvenil [CAPSi]) in the first two years of GERCON. Methods: This is a cross-sectional study. Data were retrieved from electronic medical records of children and adolescents referred for their first consultation at a CAPSi in Porto Alegre, capital of the state of Rio Grande do Sul, from May 2019 to April 2021. Results: Most of the 134 users were male (59.8%), self declared white (69.7%), from Porto Alegre (87,9%) and with an initial diagnostic hypothesis of Mental retardation (28,9%), Behavioral and emotional disorders with onset usually occurring in childhood and adolescence (24,2%) e Mood disorders (20,3%). The mean age was 13.4 years and the median was 15 years. The rate of absenteeism in the first appointment was 24.7%. Conclusion: Most users referred to the CAPSi HCPA were male, teenagers, born in Porto Alegre and with the initial diagnostic hypothesis of neurodevelopmental disorders. There is a high rate of absenteeism. When planning interventions for children and adolescents who need CAPSi care, it is important to consider the nosological profile and sociodemographic characteristics, as well as thinking about strategies to reduce absenteeism.

Análise quanti e semiquantitativa do colágeno no reparo tecidual - um estudo comparativo / Quantitative and semiquantitative analysis of collagen in wound healing - a comparative study

Introdução: diversos estudos têm destacado a relevância do colágeno no contexto do reparo tecidual, em especial, sob influência de diferentes terapias biomoduladoras. A análise do colágeno tem sido realizada mediante diferentes abordagens metodológicas, entre as quais se destacam as análises semiquantitativa e histomorfométrica. Objetivos: O presente estudo Objetivou comparar os Resultados de dois tipos de análise acerca da presença de fibras colágenas na matriz extracelular durante a cicatrização cutânea, em ferimentos fotobiomodulados. Metodologia: vinte ratos machos Wistar, foram submetidos à indução de uma ferida cutânea padronizada dorsal e divididos em dois grupos, Controle (GC) e Fotobiomodulado com laser (GL). Os períodos de morte corresponderam ao 5º. e 10º. dias. As secções histológicas foram coradas com Sírius vermelho para análise semiquantitativa e histomorfométrica do colágeno. Resultados: dois parâmetros foram utilizados para comparar o desfecho primário, um critério de grandeza quantitativa em porcentagem (área de colágeno), e o segundo critério semiquantitativo, com grandezas conferidas de acordo com escores que variaram de leve a intenso. Não foram observados Resultados divergentes entre os dois tipos de análise. No 5º. dia, independente do tipo de análise, constatou-se diferença estatisticamente significativa entre o grupo controle e o submetido à Fotobiomodulação (p<0,05), embora tal efeito tenha sido considerado pequeno. Conclusão: estes dados sugerem que ambos os métodos de análise foram capazes de reproduzir Resultados semelhantes, cabendo ao pesquisador eleger aquele que melhor se adeque ao escopo de sua pesquisa.

Introduction: several studies highlighted the relevance of collagen in the context of wound healing, especially under the influence of different biomodulatory therapies. Collagen analysis has been performed using different methodological approaches, among which semi-quantitative and histomorphometric analyzes stand out. The present study aimed to compare the Results of two methods of analysis regarding the presence of collagen fibers in the extracellular matrix during wound healing, in photobiomodulated wounds. Methods: twenty male Wistar rats were submitted to the induction of a standardized dorsal skin wound and divided into two groups, Control (GC) and Laser Photobiomodulated (GL). The periods of death corresponded to the 5th. and 10th. days. Histological sections were stained with Sirius red for semiquantitative and histomorphometric analysis of collagen. Results: two parameters were used to compare the primary outcome, a quantitative magnitude criterion in percentage (collagen area), and the second semiquantitative criterion, with magnitudes conferred according to scores that varied from mild to severe. No divergent Results were observed between the two types of analysis. On the 5th. day, regardless of the type of analysis, there was a statistically significant difference between the control group and the group submitted to Photobiomodulation (p<0.05), although this effect was considered small. Conclusion:these data suggest that both analysis methods were able to reproduce similar Results, leaving the researcher to choose the one that best fits the scope of his research.

Percepção do autocuidado nos usuários portadores de feridas crônicas / Percepción del autocuidado en usuarios con heridas crónicas / Perception of self-care in users with chronic wounds

Objetivo: compreender a percepção dos portadores de feridas crônicas acerca do autocuidado. Método:estudo descritivo-exploratório, de abordagem qualitativa, realizado junto a 10 pacientes no período de agosto de 2021, no Centro de referência em Prevenção e Tratamento de Úlceras Crônicasda cidade de Parnamirim/Rio Grande do Norte. Utilizou-se um roteiro de entrevista semiestruturada e análise de conteúdo de acordo com a proposta de Bardin, com uso da técnica de análise de conteúdo e decodificação dos dados em categorias. Sendo aprovado pelo comitê de ética do Centro Universitário Maurício de Nassau. Resultados:Identificou-se as dificuldades no que se refere ao autocuidado no portador de ferida crônica, suas implicações na qualidade de vidacomo: dor, desconforto, dificuldade de locomoção e desgaste psicológico, além de informações superficiais por parte dos profissionais.Conclusão:Evidenciou-se a relevância da atuação do enfermeirocomo mediador do autocuidado, para garantir a autonomia e melhora da qualidade de vida em pacientes portadores de feridas crônicas e a necessidade do fortalecimento de práticas educativas na vida diária.(AU)

Objective: to understand the perception of patients with chronic wounds about self-care. Method: descriptive- exploratory study, with a qualitative approach, conducted with 10 patients in august 2021, at the Reference Center for Prevention and Treatment of Chronic Ulcers in the city of Parnamirim/Rio Grande do Norte. A semi-structured interview script and content analysis were used according to Bardin's proposal, using the technique of content analysis and decoding of data into categories. Being approved by the ethics committee of the Maurício de Nassau University Center. Results: Difficulties with self-care in chronic wound patients were identified, their implications on quality of life such as: pain, discomfort, difficulty in locomotion and psychological exhaustion, as well as superficial information on the part ofprofessionals. Conclusion: The relevance of nurses' actions as a mediator of self-care was evidenced to ensure autonomy and improvement of quality of life in patients with chronic wounds and the need to strengthen educational practices in daily life.(AU)

Objetivo: comprender la percepción de los pacientes con heridas crónicas sobre el autocuidado. Método: estudio descriptivo-exploratorio, con abordaje cualitativo, realizado con 10 pacientes en agosto de 2021, en el Centro de Referencia para la Prevención y Tratamiento de Úlceras Crónicas de la ciudad de Parnamirim/Rio Grande do Norte. Se utilizó un guión de entrevista semiestructurado y un análisis de contenido de acuerdo con la propuesta de Bardin, utilizando la técnica de análisis de contenido y decodificación de datos en categorías. Ser aprobado por el comité de ética del Centro Universitario Maurício de Nassau. Resultados: Se identificaron dificultades con el autocuidado en pacientes con heridas crónicas, sus implicaciones en la calidad de vida como:dolor, malestar, dificultad en la locomoción y agotamiento psicológico, así como información superficial por parte de los profesionales. Conclusión: Se evidenció la relevancia de las acciones de las enfermeras como mediadores del autocuidado para asegurar la autonomía y mejora de la calidad de vida en pacientes con heridas crónicas y la necesidad de fortalecer las prácticas educativas en la vida cotidiana.(AU)

Unveiling Targets for Treating Postoperative Pain: The Role of the TNF-α/p38 MAPK/NF-κB/Nav1.8 and Nav1.9 Pathways in the Mouse Model of Incisional Pain.

Although the mouse model of incisional pain is broadly used, the mechanisms underlying plantar incision-induced nociception are not fully understood. This work investigates the role of Nav1.8 and Nav1.9 sodium channels in nociceptive sensitization following plantar incision in mice and the signaling pathway modulating these channels. A surgical incision was made in the plantar hind paw of male Swiss mice. Nociceptive thresholds were assessed by von Frey filaments. Gene expression of Nav1.8, Nav1.9, TNF-α, and COX-2 was evaluated by Real-Time PCR in dorsal root ganglia (DRG). Knockdown mice for Nav1.8 and Nav1.9 were produced by antisense oligodeoxynucleotides intrathecal treatments. Local levels of TNF-α and PGE2 were immunoenzymatically determined. Incised mice exhibited hypernociception and upregulated expression of Nav1.8 and Nav1.9 in DRG. Antisense oligodeoxynucleotides reduced hypernociception and downregulated Nav1.8 and Nav1.9. TNF-α and COX-2/PGE2 were upregulated in DRG and plantar skin. Inhibition of TNF-α and COX-2 reduced hypernociception, but only TNF-α inhibition downregulated Nav1.8 and Nav1.9. Antagonizing NF-κB and p38 mitogen-activated protein kinase (MAPK), but not ERK or JNK, reduced both hypernociception and hyperexpression of Nav1.8 and Nav1.9. This study proposes the contribution of the TNF-α/p38/NF-κB/Nav1.8 and Nav1.9 pathways to the pathophysiology of the mouse model of incisional pain.

The multiple functions of PrPC in physiological, cancer, and neurodegenerative contexts.

Cellular prion protein (PrPC) is a highly conserved glycoprotein, present both anchored in the cell membrane and soluble in the extracellular medium. It has a diversity of ligands and is variably expressed in numerous tissues and cell subtypes, most notably in the central nervous system (CNS). Its importance has been brought to light over the years both under physiological conditions, such as embryogenesis and immune system homeostasis, and in pathologies, such as cancer and neurodegenerative diseases. During development, PrPC plays an important role in CNS, participating in axonal growth and guidance and differentiation of glial cells, but also in other organs such as the heart, lung, and digestive system. In diseases, PrPC has been related to several types of tumors, modulating cancer stem cells, enhancing malignant properties, and inducing drug resistance. Also, in non-neoplastic diseases, such as Alzheimer's and Parkinson's diseases, PrPC seems to alter the dynamics of neurotoxic aggregate formation and, consequently, the progression of the disease. In this review, we explore in detail the multiple functions of this protein, which proved to be relevant for understanding the dynamics of organism homeostasis, as well as a promising target in the treatment of both neoplastic and degenerative diseases.

Avaliação do conhecimento de enfermeiros sobre a prevenção de quedas em idosos no ambiente hospitalar / Evaluación de los conocimientos de las enfermeras sobre la prevención de caídas en personas mayores en el ámbito hospitalario / Evaluation of the knowledge of nurses on the prevention of falls in the elderly in the hospital environment

Objetivo: avaliar o conhecimento de enfermeiros sobre a prevenção de quedas em idosos no ambiente hospitalar. Método: estudo descritivo-exploratório, de abordagem qualitativa, realizado junto a 10 enfermeiros no período de agosto de 2021, no hospital regional da cidade de Parnamirim/Rio Grande do Norte. Utilizou-se um roteiro de entrevista semiestruturada e análise de conteúdo de acordo com a proposta de Bardin. Sendo aprovado pelo comitê de ética da LIGA Norte Riograndese Contra o Câncer, sob o CAAE: 48345621.3.0000.5293. Resultados: identificou-se que as maiores causas de quedas em idosos estão relacionadas a estrutura física e reações medicamentosas, a não implementação de um protocolo de prevenção de quedas, falta de investimento e recentemente as consequências da pandemia do sars-cov-2. Conclusão: evidenciou-se que o enfermeiro conhece seu papel na prevenção de quedas em idosos, entretanto, algumas barreiras limitam sua atuação nesse cenário, como sobrecarga de trabalho, estrutura física e falta de insumos. (AU)

Objective: to evaluate the knowledge of nurses about the prevention of falls in the elderly in the hospital environment. Method: descriptive-exploratory study, with a qualitative approach, conducted with 10 nurses in august 2021, in the regional hospital of the city of Parnamirim/Rio Grande do Norte. A semi-structured interview script and content analysis were used according to Bardin's proposal. Being approved by the ethics committee of LIGA Norte Riograndese Against Cancer, under the CAAE: 48345621.3.0000.5293. Results: it was identified that the major causes of falls in the elderly are related to physical structure and drug reactions, the non-implementation of a protocol to prevent falls, lack of investment and recently the consequences of the pandemic of sars-cov-2. Conclusion: it was evidenced that nurses know their role in the prevention of falls in the elderly, however, some barriers limit their performance in this scenario, such as work overload, physical structure and lack of insum.(AU)

Objetivo: evaluar el conocimiento de las enfermeras sobre la prevención de caídas en ancianos en el ámbito hospitalario. Método: estudio descriptivo-exploratorio, con enfoque cualitativo, realizado con 10 enfermeras en agosto de 2021, en el hospital regional de la ciudad de Parnamirim/Rio Grande do Norte. Se utilizó un guión de entrevista semiestructurado y un análisis de contenido de acuerdo con la propuesta de Bardin. Aprobado por el comité de ética de LIGA Norte Riograndese Contra el Cáncer, bajo el CAAE: 48345621.3.0000.5293. Resultados: se identificó que las principales causas de caídas en los ancianos están relacionadas con la estructura física y las reacciones a los medicamentos, la no implementación de un protocolo para prevenir caídas, la falta de inversión y recientemente las consecuencias de la pandemia de sars-cov-2. Conclusión: se evidenció que las enfermeras conocen su rol en la prevención de caídas en los ancianos, sin embargo, algunas. (AU)

TLR4 mutation protects neurovascular function and cognitive decline in high-fat diet-fed mice.

BACKGROUND: Metabolic syndrome (MS) is defined as a low-grade proinflammatory state in which abnormal metabolic and cardiovascular factors increase the risk of developing cardiovascular disease and neuroinflammation. Events, such as the accumulation of visceral adipose tissue, increased plasma concentrations of free fatty acids, tissue hypoxia, and sympathetic hyperactivity in MS may contribute to the direct or indirect activation of Toll-like receptors (TLRs), specifically TLR4, which is thought to be a major component of this syndrome. Activation of the innate immune response via TLR4 may contribute to this state of chronic inflammation and may be related to the neuroinflammation and neurodegeneration observed in MS. In this study, we investigated the role of TLR4 in the brain microcirculation and in the cognitive performance of high-fat diet (HFD)-induced MS mice. METHODS: Wild-type (C3H/He) and TLR4 mutant (C3H/HeJ) mice were maintained under a normal diet (ND) or a HFD for 24 weeks. Intravital video-microscopy was used to investigate the functional capillary density, endothelial function, and endothelial-leukocyte interactions in the brain microcirculation. Plasma concentrations of monocyte chemoattractant protein-1 (MCP-1), adipokines and metabolic hormones were measured with a multiplex immunoassay. Brain postsynaptic density protein-95 and synaptophysin were evaluated by western blotting; astrocytic coverage of the vessels, microglial activation and structural capillary density were evaluated by immunohistochemistry. RESULTS: The HFD-induced MS model leads to metabolic, hemodynamic, and microcirculatory alterations, as evidenced by capillary rarefaction, increased rolling and leukocyte adhesion in postcapillary venules, endothelial dysfunction, and less coverage of astrocytes in the vessels, which are directly related to cognitive decline and neuroinflammation. The same model of MS reproduced in mice deficient for TLR4 because of a genetic mutation does not generate such changes. Furthermore, the comparison of wild-type mice fed a HFD and a normolipid diet revealed differences in inflammation in the cerebral microcirculation, possibly related to lower TLR4 activation. CONCLUSIONS: Our results demonstrate that TLR4 is involved in the microvascular dysfunction and neuroinflammation associated with HFD-induced MS and possibly has a causal role in the development of cognitive decline.

Stepwise Protocols for Preparation and Use of Porcine Ear Skin for in Vitro Skin Permeation Studies Using Franz Diffusion Cells.

The skin, the largest organ of the body, is an attractive route of topical and systemic drug administration. During the development of topical formulations, in vitro skin permeation studies using biological membranes mounted in Franz diffusion cells are a useful tool to assess the permeation of substances through the skin, and are recommended by the Organization for Economic Cooperation and Development (OECD). Among the types of biological membranes used in such studies, porcine ear skin has been identified as the most promising, due to its similarities to human skin and its greater accessibility as compared to human skin. To standardize techniques for the preparation and use of porcine ear skin as biological membrane, here we present systematic procedures for the selection of porcine ears, their cleaning, the removal of skin from cartilage, its transformation into membranes, and its use for the in vitro assessment of the permeation of drugs from topical formulations. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Obtaining porcine ear membranes Basic Protocol 2: Preparation of membranes from porcine ear skin and use of membranes for in vitro skin permeation studies.

Fatores de risco associados a hiperglicemia: estudantes de 11 a 16 anos em Paranavaí-Brasil e Cáceres-Espanha / Risk factors associated with hyperglycemia: students of 11 to 16 years in Paranavaí-Brasil and Cáceres-Spain

Resumo Introdução Metabolismo anormal da glicose precede o desenvolvimento da diabetes mellitus tipo 2. Objetivo Análise da hiperglicemia e fatores de risco associados em estudantes de Paranavaí-Brasil e Cáceres-Espanha. Método Estudo analítico em amostra de 804 estudantes de seis escolas em cada cidade. Analisados: sexo, idade, dependência administrativa da escola, estatura, massa, perímetro da cintura, IMC, relação cintura estatura, pressão arterial, comportamento sedentário, atividade física, colesterol, HDL e LDL, triglicerídeos e glicose. Resultados A prevalência foi alta para níveis de glicose em jejum (9,1% vs. 13,1%; p-valor = 0,216, espanhóis e brasileiros, respectivamente) e da maioria dos indicadores associados (p-valor < 0,05). Observou-se resultados favoráveis para as meninas espanholas (obesidade abdominal: 2,4% vs. 31,1%; comportamento sedentário: 5,3% vs. 43,4%; colesterol: 2,4% vs. 55,3%; triglicerídeos: 15,5% vs. 29,5%). Os meninos da Espanha levaram vantagem sobre os brasileiros (obesidade abdominal: 13,6% vs. 35,2%; pouco ativos: 23,5% vs. 39,0%; comportamento sedentário: 21,5% vs. 51,0%; colesterol: 3,7% vs. 41,0%), p < 0,05. Não houve associação da glicose com nenhum fator de risco. Conclusão Atenção deve ser dada aos jovens para evitar uma exposição precoce e prolongada a fatores de risco modificáveis que alteram os níveis de glicose.

Abstract Background Abnormal glucose metabolism precedes the development of type 2 diabetes mellitus. Objective Analysis of hyperglycemia and associated risk factors was performed in students from Paranavaí-Brazil and Cáceres-Spain. Method Analytical study on a sample of 804 students selected in six schools in each city. Analyzed: sex, age, school administrative dependence, height, mass, waist circumference, BMI, waist height ratio, blood pressure, sedentary behavior, level of physical activity, cholesterol, HDL and LDL, triglycerides and glucose. Results Prevalence was high for elevated fasting glucose levels (9.1% vs. 13.1%; p-value = 0.216, in the Spanish and Brazilian groups) and most of the associated indicators (p-value ≤ 0.05). Favorable results were observed for Spanish girls (abdominal obesity: 2.4% vs. 31.1%; sedentary behavior: 5.3% vs. 43.4%; cholesterol: 2.4% vs. 55.3% triglycerides: 15.5% vs. 29.5%). Boys from Spain had an advantage over Brazilians (abdominal obesity: 13.6% vs. 35.2%; activity level: 23.5% vs. 39.0%; sedentary behavior: 21.5% vs. 51.0%; cholesterol: 3.7% vs. 41.0%), p ≤ 0.05. There was no association of glucose with any risk factor. Conclusion Special attention should be given to youths to prevent early and prolonged exposure to modifiable risk factors that may alter glucose levels.

Data-driven cognitive phenotypes in subjects with bipolar disorder and their clinical markers of severity.

BACKGROUND: Subjects with bipolar disorder (BD) show heterogeneous cognitive profile and that not necessarily the disease will lead to unfavorable clinical outcomes. We aimed to identify clinical markers of severity among cognitive clusters in individuals with BD through data-driven methods. METHODS: We recruited 167 outpatients with BD and 100 unaffected volunteers from Brazil and Spain that underwent a neuropsychological assessment. Cognitive functions assessed were inhibitory control, processing speed, cognitive flexibility, verbal fluency, working memory, short- and long-term verbal memory. We performed hierarchical cluster analysis and discriminant function analysis to determine and confirm cognitive clusters, respectively. Then, we used classification and regression tree (CART) algorithm to determine clinical and sociodemographic variables of the previously defined cognitive clusters. RESULTS: We identified three neuropsychological subgroups in individuals with BD: intact (35.3%), selectively impaired (34.7%), and severely impaired individuals (29.9%). The most important predictors of cognitive subgroups were years of education, the number of hospitalizations, and age, respectively. The model with CART algorithm showed sensitivity 45.8%, specificity 78.4%, balanced accuracy 62.1%, and the area under the ROC curve was 0.61. Of 10 attributes included in the model, only three variables were able to separate cognitive clusters in BD individuals: years of education, number of hospitalizations, and age. CONCLUSION: These results corroborate with recent findings of neuropsychological heterogeneity in BD, and suggest an overlapping between premorbid and morbid aspects that influence distinct cognitive courses of the disease.

Unveiling metabolic changes in marsupialized odontogenic keratocyst: A pilot study.

OBJECTIVE: We aimed to assess which metabolic pathways would be implicated in the phenotypic changes of the epithelial lining of odontogenic keratocyst after marsupialization, comparing pre- and post-marsupialized lesions with adjacent oral mucosa. MATERIALS AND METHODS: Eighteen formalin-fixed and paraffin-embedded tissues from six subjects were divided into three paired groups: odontogenic keratocyst pre- (n = 6) and post-marsupialization (n = 6), and adjacent oral mucosa (n = 6). The metabolic pathways found in these groups were obtained by high-performance liquid chromatography-mass spectrometry-based untargeted metabolomics performed. RESULTS: Through putative metabolite annotation followed by pathway enrichment and predictive analysis with automated algorithms (Mummichog and Gene Set Enrichment Analysis), we found differences in many cellular processes that may be involved in inflammation, oxidative stress response, keratinocyte-basal membrane attachment, differentiation, and proliferation functions, all relevant to odontogenic keratocyst pathobiology and the phenotype acquired after marsupialization. CONCLUSION: Our study was able to identify several metabolic pathways potentially involved in the metaplastic changes induced by marsupialization of odontogenic keratocysts. An improved comprehension of this process could pave the way for the development of targeted therapies.

Validity and Reliability of the Digital Functioning Assessment Short Test (D-FAST) in the Brazilian Sample.

Background: The COVID-19 pandemic has caused major disruptions in all aspects of daily functioning, from school and work to interactions with friends and family. The Functioning Assessment Short Test (FAST) is an interviewer-administered scale validated in the psychiatric sample with no previous study assessing its validity and reliability in a digital format. Thus, we aimed to analyse the psychometric properties of the digital version of the FAST and understand the implications of COVID-19 and restrictive measures on functioning. Methods: Data were collected using an online survey. The psychometric properties of the digital FAST were assessed by confirmatory factor analysis, Cronbach's alpha, and discriminant functional by cluster analysis in a community sample. Results: Out of the total sample, 2,543 (84.1%) were female, and the mean (SD) age was 34.28 (12.46) years. The digital FAST retained the six factors structure observed in the original version, with Cronbach's alpha above 0.9. In addition, we showed evidence of discriminant validity by differentiating three clusters of psychosocial functioning. Clinical and demographic differences between groups explained, in part, the heterogeneity of functioning, thus providing support for the construct validity of the instrument. Conclusion: The digital FAST is a simple and easy-to-understand instrument that provides a multidimensional assessment of functioning without the need for an interviewer. Furthermore, our findings may help to better understand the psychosocial implications of the pandemic and the importance of planning specific interventions to rehabilitee the affected group.

Physical education in early childhood education in Maringá-pr: construction and implementation of an educational public policy / Educação física na educação infantil em Maringá-pr: construção e implementação de uma política pública educacional

ABSTRACT This research aimed to describe and analyze the process of structuring and implementing Law No. 8392/2009, of the Municipality of Maringá-PR, which includes Physical Education as a mandatory component in the Early Childhood Education curriculum. It is characterized as both a descriptive case and a documentary study, conducted through semi-structured interviews with the researcher in charge and with the parliamentary author of the Law; questionnaires, applied to 27 Physical Education teachers working at Municipal Child Education Centers; and consultation to the legislation and internal documents of the Municipal Department of Education. From the information obtained, it was concluded that the analyzed process took place in a satisfactory way, consolidating the educational public policy in focus.

RESUMO Esta pesquisa objetivou descrever e analisar o processo de estruturação e implementação da Lei nº 8392/2009, do Município de Maringá-PR, que inclui a Educação Física como componente obrigatório no currículo da Educação Infantil. Caracteriza-se como um estudo de caso descritivo e documental, por meio de realização de entrevistas semiestruturadas com o parlamentar responsável pelo projeto de lei e com a pesquisadora, cujo estudo subsidiou o referido projeto; aplicação de questionários a 27 professores de Educação Física atuantes nos Centros Municipais de Educação Infantil; e consulta à legislação e documentos internos da Secretaria Municipal de Educação. A partir das informações obtidas, concluiu-se que o processo analisado ocorreu de forma satisfatória, consolidando a política pública educacional em questão.