Head-to-head comparison of relevant cell sources of small extracellular vesicles for cardiac repair: Superiority of embryonic stem cells.

Small extracellular vesicles (sEV) derived from various cell sources have been demonstrated to enhance cardiac function in preclinical models of myocardial infarction (MI). The aim of this study was to compare different sources of sEV for cardiac repair and determine the most effective one, which nowadays remains limited. We comprehensively assessed the efficacy of sEV obtained from human primary bone marrow mesenchymal stromal cells (BM-MSC), human immortalized MSC (hTERT-MSC), human embryonic stem cells (ESC), ESC-derived cardiac progenitor cells (CPC), human ESC-derived cardiomyocytes (CM), and human primary ventricular cardiac fibroblasts (VCF), in in vitro models of cardiac repair. ESC-derived sEV (ESC-sEV) exhibited the best pro-angiogenic and anti-fibrotic effects in vitro. Then, we evaluated the functionality of the sEV with the most promising performances in vitro, in a murine model of MI-reperfusion injury (IRI) and analysed their RNA and protein compositions. In vivo, ESC-sEV provided the most favourable outcome after MI by reducing adverse cardiac remodelling through down-regulating fibrosis and increasing angiogenesis. Furthermore, transcriptomic, and proteomic characterizations of sEV derived from hTERT-MSC, ESC, and CPC revealed factors in ESC-sEV that potentially drove the observed functions. In conclusion, ESC-sEV holds great promise as a cell-free treatment for promoting cardiac repair following MI.

Targeting TRPV4 Channels for Cancer Pain Relief.

Despite the unique and complex nature of cancer pain, the activation of different ion channels can be related to the initiation and maintenance of pain. The transient receptor potential vanilloid 4 (TRPV4) is a cation channel broadly expressed in sensory afferent neurons. This channel is activated by multiple stimuli to mediate pain perception associated with inflammatory and neuropathic pain. Here, we focused on summarizing the role of TRPV4 in cancer etiology and cancer-induced pain mechanisms. Many studies revealed that the administration of a TRPV4 antagonist and TRPV4 knockdown diminishes nociception in chemotherapy-induced peripheral neuropathy (CIPN). Although the evidence on TRPV4 channels' involvement in cancer pain is scarce, the expression of these receptors was reportedly enhanced in cancer-induced bone pain (CIBP), perineural, and orofacial cancer models following the inoculation of tumor cells to the bone marrow cavity, sciatic nerve, and tongue, respectively. Effective pain management is a continuous problem for patients diagnosed with cancer, and current guidelines fail to address a mechanism-based treatment. Therefore, examining new molecules with potential antinociceptive properties targeting TRPV4 modulation would be interesting. Identifying such agents could lead to the development of treatment strategies with improved pain-relieving effects and fewer adverse effects than the currently available analgesics.

Byrsonima sericea Ethanol Extract Protected PC12 Cells from the Oxidative Stress and Apoptosis Induced by 6-Hydroxydopamine.

Parkinson's disease is characterized by the progressive loss of dopaminergic neurons in the nigrostriatal pathway and oxidative stress is one of the main mechanisms that lead to neuronal death in this disease. Previous studies have shown antioxidant activity from the leaves of Byrsonima sericea, a plant of the Malpighiaceae family. This study aimed to evaluate the cytoprotective activity of the B. sericea ethanolic extract (BSEE) against the cytotoxicity induced by 6-hydroxydopamine (6-OHDA) in PC12 cells, an in vitro model of parkinsonism. The identification of phenolic compounds in the extract by HPLC-DAD revealed the presence of geraniin, rutin, isoquercetin, kaempferol 3-O-ß-rutinoside, and quercetin. The BSEE (75-300 µg/mL) protected PC12 cells from toxicity induced by 6-OHDA (25 µg/mL), protected cell membrane integrity and showed antioxidant activity. BSEE was able to decrease nitrite levels, glutathione depletion, and protect cells from 6-OHDA-induced apoptosis. Thus, we suggest that the BSEE can be explored as a possible cytoprotective agent for Parkinson's disease due to its high antioxidant capacity and anti-apoptotic action.

Desafios da gestão e cuidado em centros de parto normal: estudo qualitativo com enfermeiros obstetras / Challenges of management and care in normal birth centers: qualitative study with obstetric nurses / Retos del manejo y atención en los centros de parto normal: estudio cualitativo con enfermeros obstétricos

RESUMO Objetivo: compreender os desafios para a gestão do trabalho e do cuidado em centros de parto normal por enfermeiras obstétricas. Método: estudo qualitativo realizado em centros de parto normal no Ceará, Brasil. Participaram 13 enfermeiros e coordenadores da assistência obstétrica, por entrevista, no período de abril a julho de 2020. As categorias temáticas foram organizadas no Software Nvivo 12 Pro® e discutidas com referencial teórico-filosófico da Sociologia das Profissões. Resultados: práticas de cuidado, como massagens de conforto, são realizadas associadas aos elementos da gestão do trabalho, como o dimensionamento da equipe de Enfermagem. Evidenciou-se que há habilidades importantes para atuar como autonomia e liderança da equipe de Enfermagem, mas elementos como a frágil confiança e a interação limitam o pleno desenvolvimento das atividades. Considerações finais: existem desafios para a gestão e o cuidado nos centros de parto normal, como a consolidação de autonomia e construção de confiança com a equipe de saúde.

ABSTRACT Objective: To understand obstetric nurses' challenges in managing work and care in normal birth centers. Method: A qualitative study was carried out in normal birth centers in Ceará, Brazil. Thirteen nurses and obstetric care coordinators were interviewed between April and July 2020. The thematic categories were organized in Nvivo 12 Pro® software and discussed using the theoretical-philosophical framework of the Sociology of Professions. Results: care practices, such as comfort massages, are carried out in conjunction with elements of work management, such as the sizing of the nursing team. It emerged that there are important skills for acting as autonomy and leadership of the nursing team, but elements such as fragile trust and interaction limit the full development of activities. Final considerations: there are challenges for management and care in normal birth centers, such as consolidating autonomy and building trust with the health team.

RESUMEN Objetivo: Comprender los desafíos para la gestión del trabajo y la atención en los centros de parto normal por parte de las enfermeras obstétricas. Método: estudio cualitativo realizado en centros de parto normal de Ceará, Brasil. Un total de 13 enfermeros y coordinadores de atención obstétrica participaron en entrevistas de abril a julio de 2020. Las categorías temáticas se organizaron en el Software Nvivo 12 Pro ® y se discutieron con el marco teórico-filosófico de la Sociología de las Profesiones. Resultados: las prácticas de cuidado, como los masajes de confort, se realizan asociadas a elementos de la gestión del trabajo, como el dimensionamiento del equipo de enfermería. Se evidenció que existen habilidades importantes para actuar como autonomía y liderazgo del equipo de enfermería, pero elementos como la confianza frágil y la interacción limitan el desarrollo pleno de las actividades. Consideraciones finales: existen desafíos para el manejo y la atención en los centros de parto normales, como la consolidación de la autonomía y la construcción de confianza con el equipo de salud.

Perception of professors and nurses about sexism in nursing / Percepção de enfermeiros e enfermeiras sobre o machismo na enfermagem

Know the perception of professors of a higher education institution who work in nursing care about sexism in their work environment. Therefore, the guiding question of this research was: What is the perception of professors and nurses about sexism in their work environment? Methodology: Descriptive and exploratory research, with a qualitative approach, carried out with nursing professionals and professors at a private college in the capital of Alagoas. Data were primarily collected through an electronic form developed by the researchers for qualitative analysis of the information, Bardin's content analysis was adopted. The research was approved by the Ethics Committee with opinion number: 4,719,368 Results: The study included 16 professors from the nursing course, who mostly reported having already suffered or witnessed sexist situations during care. Conclusion: From this research, it was observed that despite the predominance of women in nursing, there is still sexism present in care on the part of professionals and patients. Part of the professors participating in this study claimed to have suffered or witnessed situations of sexism and all agreed on the interference in the effectiveness of care. Awareness actions are needed for these professionals and the general public, including patients (AU).

Conhecer a percepção dos(as) docentes de uma instituição de ensino superior, que atuam na assistência de enfermagem sobre o machismo no seu ambiente de trabalho. Diante disso a questão norteadora desta pesquisa foi: Qual a percepção dos(as) docentes sobre o machismo no seu ambiente de trabalho? Métodos: Pesquisa descritiva e exploratória, de abordagem qualitativa, realizada com profissionais da enfermagem, docentes de uma faculdade particular da capital de Alagoas. Os dados foram primários, coletados através de um formulário eletrônico, elaborado pelas pesquisadoras, para análise qualitativa das informações foi adotada a análise de conteúdo de Bardin. Pesquisa aprovada pelo Comitê de Ética com nº de parecer: 4.719.368 Resultados: Foram participantes do estudo 16 docen-tes do curso de enfermagem, que referiram em sua maioria já ter sofrido ou presenciado situações machistas durante a assistência. Conclusão: A partir dessa pesquisa observou-se que ainda existe machismo na assistência, por parte de profissionais e pacientes. Parte dos docentes participantes deste estudo alegaram já ter sofrido ou presenciados situações de sexismo e todos acordaram em relação a interferência na eficácia da assistência. Sendo necessárias ações de conscientização destes profissionais e do público em geral, abrangendo também os pacientes (AU).

Characterization of Depression- and Anxiety-Like Behaviours in a Mouse Model of Relapsing-Remitting Multiple Sclerosis.

Relapsing-remitting multiple sclerosis (RRMS) is an autoimmune neurological disease and is the most common subtype of MS. In addition, it is associated with the development of depression and anxiety. To date, depressive- and anxiety-like behaviours were only studied using models of progressive MS, which causes severe motor alterations. Thus, we sought to standardise the depressive and anxiety-like behaviours in an RRMS model induced by experimental autoimmune encephalomyelitis (RR-EAE) in mice. The RR-EAE model was induced in C57BL/6 female mice using myelin oligodendrocyte glycoprotein (MOG35-55) antigen and Quillaja saponin (Quil A) as an adjuvant. The immunisation of RR-EAE did not induce locomotor alteration but caused relapsing-remitting induction of clinical scores in mice until 35 post-immunization (p.i.). Also, increased levels of tumour necrosis factor alpha (TNF-α), astrocyte marker (GFAP), and microglial markers (IBA-1) were detected in the prefrontal cortex at 35 p.i. of RR-EAE. In the open field test, RR-EAE mice showed decreased time spent at the centre and sniffing behaviour (at days 21 and 34 p.i.). Also, on day 35 p.i. the RR-EAE group spent less time in the open arms and had decreased open-arm entries compared to control mice in the elevated plus maze (EPM) test, confirming the anxiety-like behaviour. At day 36° p.i. in the tail suspension test, mice showed depression-like behaviour with decreased latency time and increased immobility time. Thus, the RR-EAE model mimics the neuroinflammatory and behavioural features of the RRMS, including depression- and anxiety-like symptoms.

Impact of disease duration on proteomic bioprofile and prognosis in rheumatoid arthritis patients.

OBJECTIVES: Cardiovascular disease worsens the prognosis of rheumatoid arthritis (RA) and vice-versa. Inflammation may be a common pathway for both conditions. It is expected that a longer RA duration leads to a greater inflammatory cumulative exposure burden; however, studies on the association between RA disease duration and outcomes are scarce. Our aim is to compare the characteristics, biomarker expression and outcomes according to the duration of RA. METHODS: Prospective cohort study including 399 RA patients, with detailed clinical, echocardiographic, and proteomic phenotyping that were compared across tertiles of RA disease duration. Cox proportional models were used to study the association of disease duration with cardiovascular outcomes. RESULTS: RA duration tertiles were: tertile 1 with median of 3.2; tertile 2 with median of 8.8; and tertile 3 with median of 21.8 years. Compared to tertile 1, patients in tertile 3 were older, had more erosive disease, more frequent echocardiographic alterations, lower haemoglobin and walked a shorter distance on the 6MWT. Natriuretic peptides, cathepsin L1, galectin 9, matrix metalloproteinase-12, adrenomedullin and tumour necrosis factor receptor 11A were higher in patients with longer disease duration. Compared to patients in tertile 1, those in tertile 3 had higher risk of a subsequent cardiovascular hospitalisation or cardiovascular death (HR 2.71, 95%CI 1.06-6.92, p=0.04). CONCLUSIONS: RA patients with longer disease duration had more organ damage and worse outcomes than those with shorter disease duration. Biomarker expression suggested that patients with longer RA duration had activation of pathways related to inflammation, extracellular matrix organisation, fibrosis and congestion.

Effects of Mauritia flexuosa L. f. buriti oil on symptoms induced by Bothrops moojeni snake envenomation.

ETHNOPHARMACOLOGICAL RELEVANCE: In Brazil, there are species of snakes that become involved in accidents and cause serious health problems to the inhabitants, highlighting the genus Bothrops for being responsible for approximately 90% of accidents reported annually. In the northern region of the country, this genus is responsible for the largest number of accidents, especially among rural dwellers. These populations invest in alternative treatments for with the purpose of improving the symptoms caused by snakebites. The species Mauritia flexuosa L. f., known as buriti, is traditionally used for the treatment of envenomation by snakes. AIM OF THE STUDY: This study aimed to evaluate the antiophidic potential of the oil of Mauritia flexuosa L. f. for Bothrops moojeni H. venom, confronting cultural and scientific knowledge. MATERIALS AND METHODS: The physicochemical properties were determined, and the components present in the oil, extracted from fruit pulp, were analyzed by Gas Chromatography Coupled with Mass Spectrometry. The in vitro inhibitory capacity of the oil for phospholipase, metalloprotease and serine protease activities was investigated. In the in vivo studies, male Swiss mice were used to evaluate the effect of oil on lethality and toxicity, and hemorrhagic, myotoxic and edematogenic activities were assessed. RESULTS: GC‒MS analysis identification of 90.95% of the constituents of the oil, with the main components being 9-eicosenoic acid, (Z)- (34.54%), n-hexadecanoic acid (25.55%) and (E)-9-octadecenoic acid ethyl ester (12.43%). For the substrates, the outcomes indicate that the oil inhibited the activity of the main classes of toxins present in Bothrops moojeni H. venom (VBm) at the highest dose tested (0.5 µL), with inhibition of 84% for the hydrolysis of the selective substrate for serine protease and inhibition of 60% for the hydrolysis of substrates for PLA2 and metalloproteases. The antiophidic activity in vivo was evaluated with two concentrations of the oil: 1.5 mg, the dosage the population, diluted in mineral oil to a volume of 1 tablespoon and 15 mg, administered by gavage 30 min before poisoning and at time zero (concomitant to poisoning), and both concentrations administered by gavage in combination with topical use at time zero. The bleeding time in the group treated with oil at a concentration of 15 mg administered at time zero was significantly lower than that in the control group (p < 0.05). However, a greater inhibition of bleeding time was observed when local application was combined with the gavage treatment at both concentrations tested at time zero (p < 0.05). In the myotoxicity test, oil was efficient in reducing the myotoxic effects induced by the venom at the two concentrations tested, with gavage administration at time zero and gavage plus topical administration at time zero (p < 0.05). CONCLUSIONS: The data obtained show that the oil is safe to use at the concentrations studied and contains fatty acids that may collaborate for cellular-level repair of the injuries caused by Bm poisoning. The in vitro and in vivo experiments showed that oil inhibits the main proteolytic enzymes present in the venom and that it has important activities to control the local effects caused by bothropic venom.

Impact of dietary supplementation with Cinnamomum cassia essential oil on silver catfish (Rhamdia quelen): Toxicological effects and muscle antioxidant and fatty acid profiles.

The aim of this study was to determine the biological effects of dietary supplementation with 0.05% and 0.1% cinnamon essential oil extracted from Cinnamomum cassia on silver catfish (Rhamdia quelen). The final body weight, weight gain, and specific growth rate were significantly higher in fish supplemented with 0.05% cinnamon essential oil than in the control(untreated) group. Muscle reactive oxygen species and lipid peroxidation levels were significantly lower in fish supplemented with 0.05% cinnamon essential oil but higher at the 0.1% concentration. Muscle antioxidant capacity against peroxyl radicals (ACAP) and superoxide dismutase activity were significantly higher in fish supplemented with 0.05% cinnamon essential oil, while ACAP levels were lower in fish supplemented with 0.1%. The total saturated fatty acid content was significantly higher in the muscle of supplemented fish than in controls, while the total monounsaturated fatty acid content was significantly higher only in fish fed 0.1% cinnamon essential oil. Finally, the total content of polyunsaturated fatty acids was significantly lower in fish fed 0.1% essential oil. Thus, data demonstrated that 0.05% C. cassia essential oil improves fish health by improving performance and muscle oxidant/antioxidant status. Higher doses of cinnamon essential oil produced oxidative stress in muscle, suggesting toxicity at the 0.1% level. Although this cinnamon essential oil diet exerted positive health effects, this diet impaired the muscle fatty acid profile, suggesting adverse impacts on human health.

In vitro maturation of oocytes as a laboratory approach to polycystic ovarian syndrome (PCOS): From oocyte to embryo.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age, which in some case leads to infertility. This disorder is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Infertile PCOS women that need in vitro fertilization (IVF) have greater risk of ovarian hyperstimulation syndrome (OHSS) if conventional ovarian stimulation is used. In vitro oocyte maturation (IVM) is an alternative technique that prevents OHSS in infertile PCOS women. In the last decade, IVM protocols have improved, particularly with the development of biphasic IVM culture accounting for better pregnancy and live birth rates. This technique has been extended to other treatments like, fertility preservation, when patients have no time, or a contra-indication for ovarian stimulation, and poor responders. In this review, we will discuss IVM as a viable option for PCOS infertile patients. This article is categorized under: Reproductive System Diseases > Molecular and Cellular Physiology Reproductive System Diseases > Environmental Factors Reproductive System Diseases > Genetics/Genomics/Epigenetics.

Influence of Apical Diameter on Filling Material Extrusion during Retreatment - A Micro-CT and CBCT evaluation

Abstract Aim: To investigate whether foraminal widening performed at primary treatment has an effect on the amount of apically extruded obturator material during retreatment and to evaluate the sensitivity of cone beam computed tomography (CBCT) in detecting extruded obturator material. Methods: Forty palatal roots of maxillary molars were selected based on micro-CT and divided into two groups (n=20): with foraminal widening (WE) and without foraminal widening (NE). To standardize the apical foramen, all specimens were instrumented to the foramen using the Protaper Next system, up to instrument X3. The WE group was instrumented to the foramen up to instrument X5, and the NE group was instrumented 1 mm lower. The canals were obturated 1 mm below the apical foramen with gutta-percha and AH Plus and stored for 7 days at 37 °C and 95% humidity. Roots were fixed in microtubes filled with 1.5% agar gel. The obturation material was removed with Reciproc R50. Scans of the teeth and agar were performed using micro-CT and CBCT. Comparison between groups and between methods was performed using Mann-Withney test (p ≤0.05). Results: No statistical difference was found when comparing the extruded material between groups using micro-CT (p = 0.589) or CBCT (p = 0.953). CBCT measured a greater volume of extruded material than micro- CT (p = 0.0004). Conclusion: Foraminal widening had no effect on the extrusion of filling material during retreatment. The CBCT favored the evaluation of apically extruded filling material.

Resumo Objetivo: Investigar se o alargamento do foramen realizado durante o tratamento primário tem um efeito na quantidade de material obturador apicalmente extruído durante oretratamento e verificar a sensibilidade da tomografia computorizada de feixe cônico (TCFC) na detecção de material obturador extruído. Métodos: Quarenta raízes palatinas de molares superiores foram selecionadas de acordo com a microtomografia computorizada, e foram divididas em dois grupos (n=20): com alargamento do foraminal (CA) e sem alargamento do foraminal (SA). Para padronizar o forame apical, todas as amostras foram instrumentadas com o sistema ProTaper Next até ao instrumento X3 até o forame. O grupo CA foi instrumentado até ao instrumento X5 até o forame, e o grupo SA foi instrumentado 1 mm aquém. Os canais foram obturados 1 mm abaixo do forame apical com gutta-percha e AH Plus e armazenados durante 7 dias a 37 °C e 95% de umidade. As raízes foram fixadas em microtubos preenchidos com gel de ágar a 1,5%. O material obturador foi removido com Reciproc R50. Os escaneamentos dos dentes e do ágar foram realizados com micro-CT e CBCT. A comparação entre grupos e entre métodos foi realizada utilizando o teste Mann-Withney (p ≤0.05). Resultados: Não foi encontrada diferença estatística ao comparar o material extruído entre grupos utilizando o Micro-CT (p = 0,589) ou TCFC (p = 0,953). Foi medido um volume maior de material extruído com a TCFC do que com a Micro- CT (p = 0,0004). Conclusão: O alargamento foraminal não teve qualquer efeito na extrusão do material obturador durante o retratamento. A TCFC favoreceu a avaliação do material de obturador apicalmente extruído.

Unpredictable Sound Stress Model Causes Migraine-Like Behaviors in Mice With Sexual Dimorphism.

Migraine represents one of the major causes of disability worldwide and is more prevalent in women; it is also related to anxiety symptoms. Stress, such as sound stress, is a frequently reported trigger in migraine patients, but the underlying mechanisms are not fully understood. However, it is known that patients with migraine have higher levels of plasma inflammatory cytokines and calcitonin gene-related peptide (CGRP). Stress mediated by unpredictable sound is already used as a model of painful sensitization, but migraine-like behaviors and sexual dimorphism have not yet been evaluated. This study characterized nociception and anxiety-related symptoms after the induction of sound stress in mice. C57BL/6 mice (20-30 g) were exposed to unpredictable sound stress for 3 days, nonconsecutive days. We observed enhanced plasma corticosterone levels on day 1 after stress induction. First, 7 days after the last stress session, mice developed hind paw and periorbital mechanical allodynia, grimacing pain behavior, anxiety-like symptoms, and reduced exploratory behavior. The nociceptive and behavioral alterations detected in this model were mostly shown in female stressed mice at day 7 post-stress. In addition, on day 7 post-stress nociception, these behaviors were consistently abolished by the CGRP receptor antagonist olcegepant (BIBN4096BS, 100 mg/kg by intraperitoneal route) in female and male stressed mice. We also demonstrated an increase in interleukine-6 (IL-6), tumor necrosis factor (TNF-α), and CGRP levels in stressed mice plasma, with female mice showing higher levels compared to male mice. This stress paradigm allows further preclinical investigation of mechanisms contributing to migraine-inducing pain.

Clinical profile and mortality predictors for tuberculosis disease among patients with solid tumours.

BACKGROUND: The characteristics of Mycobacterium tuberculosis (MTb) disease are still obscure in patients with solid tumours, as well as the benefits of screening and treating latent tuberculosis infection (LTBI) in these patients. Our objective was to trace the clinical profile of these individuals and assess the mortality predictors related to tuberculosis (TB). METHODS: We reviewed the medical records of 126 patients with solid tumours malignancy and who developed TB disease between January 2009 and April 2018 at a cancer referral centre. RESULTS: The most common locations of malignancy were head and neck, with squamous cell carcinoma being the most frequent histological type, the majority (97/126) presenting locally invasive tumours (T3 or T4). A total of 120 had TB pulmonary and the microbiological diagnosis was performed in 103/126. The following variables were associated with the risk of death from TB: DPOC lung cancer, BMI, malnutrition, metastasis and ECOG 3 or 4. Previous chemotherapy treatment was a protective factor. CONCLUSIONS: Male, usage of alcohol and smoking were the most predominant patients characteristics in our sample. In the multivariate analysis, lung cancer, presence of metastasis and ECOG ≥ 3 were associated with death from TB.

Development and validation of predictive model for long-term hospitalization, readmission, and in-hospital death of patients over 60 years old.

OBJECTIVE: To develop and validate a high-risk predictive model that identifies, at least, one common adverse event in older population: early readmission (up to 30 days after discharge), long hospital stays (10 days or more) or in-hospital deaths. METHODS: This was a retrospective cohort study including patients aged 60 years or older (n=340) admitted at a 630-beds tertiary hospital, located in the city of São Paulo, Brazil. A predictive model of high-risk indication was developed by analyzing logistical regression models. This model prognostic capacity was assessed by measuring accuracy, sensitivity, specificity, and positive and negative predictive values. Areas under the receiver operating characteristic curve with 95% confidence intervals were also obtained to assess the discriminatory power of the model. Internal validation of the prognostic model was performed in a separate sample (n=168). RESULTS: Statistically significant predictors were identified, such as current Barthel Index, number of medications in use, presence of diabetes mellitus, difficulty chewing or swallowing, extensive surgery, and dementia. The study observed discrimination model acceptance in the construction sample 0.77 (95% confidence interval: 0.71-0.83) and good calibration. The characteristics of the validation samples were similar, and the receiver operating characteristic curve area was 0.687 (95% confidence interval: 0.598-0.776). We could assess an older patient's adverse health events during hospitalization after admission. CONCLUSION: A predictive model with acceptable discrimination was obtained, with satisfactory results for early readmission (30 days), long hospital stays (10 days), or in-hospital death.

Dual-functional porous and cisplatin-loaded polymethylmethacrylate cement for reconstruction of load-bearing bone defect kills bone tumor cells.

Malignant bone tumors are usually treated by resection of tumor tissue followed by filling of the bone defect with bone graft substitutes. Polymethylmethacrylate (PMMA) cement is the most commonly used bone substitute in clinical orthopedics in view of its reliability. However, the dense nature of PMMA renders this biomaterial unsuitable for local delivery of chemotherapeutic drugs to limit the recurrence of bone tumors. Here, we introduce porosity into PMMA cement by adding carboxymethylcellulose (CMC) to facilitate such local delivery of chemotherapeutic drugs, while retaining sufficient mechanical properties for bone reconstruction in load-bearing sites. Our results show that the mechanical strength of PMMA-based cements gradually decreases with increasing CMC content. Upon incorporation of ≥3% CMC, the PMMA-based cements released up to 18% of the loaded cisplatin, in contrast to cements containing lower amounts of CMC which only released less than 2% of the cisplatin over 28 days. This release of cisplatin efficiently killed osteosarcoma cells in vitro and the fraction of dead cells increased to 91.3% at day 7, which confirms the retained chemotherapeutic activity of released cisplatin from these PMMA-based cements. Additionally, tibias filled with PMMA-based cements containing up to 3% of CMC exhibit comparable compressive strengths as compared to intact tibias. In conclusion, we demonstrate that PMMA cements can be rendered therapeutically active by introducing porosity using CMC to allow for release of cisplatin without compromising mechanical properties beyond critical levels. As such, these data suggest that our dual-functional PMMA-based cements represent a viable treatment option for filling bone defects after bone tumor resection in load-bearing sites.

Sex differences in circulating proteins of patients with rheumatoid arthritis: A cohort study.

OBJECTIVES: Differences in proteomic profiles between men and women may provide insights into the biological pathways that contribute to known sex differences in rheumatoid arthritis (RA). Studies focusing on sex differences in circulating proteins in RA patients are scarce. Our objective was to investigate the sex differences in circulating proteins of RA patients. METHODS: Cohort study enrolling 399 RA patients. Ninety-four circulating protein-biomarkers (92CVDIIOlink®  + troponin-T + C-reactive protein) were measured. Clinical, demographic, and echocardiographic characteristics were compared between men and women. Sex differences in biomarker expression were assessed using regression modeling. RESULTS: In all, 306 (76.7%) patients were women. Compared with men, women had less visceral fat, smoked less, had diabetes and chronic obstructive pulmonary disease less frequently, and expressed more fatigue, anxiety, and depression. The association with cardiovascular outcomes did not differ between sexes. After adjusting for potential confounders, women expressed higher levels of circulating proteins related to adipokine signaling and vascular function (eg, leptin and vascular endothelial growth factor), whereas men expressed higher levels of circulating proteins related to extracellular matrix organization and inflammation (eg, matrix metalloproteinase-2 and C-reactive protein). These results were not found in patients without RA. CONCLUSION: Sex differences in circulating proteins reflect distinct pathways implicated in the pathogenesis of RA, including inflammation, adiposity, angiogenesis, and extracellular matrix organization. These findings may help further investigations into factors underlying sex-based differences and allow future studies focused on sex-specific personalized treatment approaches in RA. CLINICALTRIALS: gov ID: NCT03960515.

Oxylipin metabolism is controlled by mitochondrial ß-oxidation during bacterial inflammation.

Oxylipins are potent biological mediators requiring strict control, but how they are removed en masse during infection and inflammation is unknown. Here we show that lipopolysaccharide (LPS) dynamically enhances oxylipin removal via mitochondrial ß-oxidation. Specifically, genetic or pharmacological targeting of carnitine palmitoyl transferase 1 (CPT1), a mitochondrial importer of fatty acids, reveal that many oxylipins are removed by this protein during inflammation in vitro and in vivo. Using stable isotope-tracing lipidomics, we find secretion-reuptake recycling for 12-HETE and its intermediate metabolites. Meanwhile, oxylipin ß-oxidation is uncoupled from oxidative phosphorylation, thus not contributing to energy generation. Testing for genetic control checkpoints, transcriptional interrogation of human neonatal sepsis finds upregulation of many genes involved in mitochondrial removal of long-chain fatty acyls, such as ACSL1,3,4, ACADVL, CPT1B, CPT2 and HADHB. Also, ACSL1/Acsl1 upregulation is consistently observed following the treatment of human/murine macrophages with LPS and IFN-γ. Last, dampening oxylipin levels by ß-oxidation is suggested to impact on their regulation of leukocyte functions. In summary, we propose mitochondrial ß-oxidation as a regulatory metabolic checkpoint for oxylipins during inflammation.

Maternal polyphenol intake impairs cerebellar redox homeostasis in newborn rats.

INTRODUCTION: Polyphenols are compounds found in plants that have been extensively studied due to the health benefits of its consumption in adulthood. Meanwhile, recent evidence suggests that polyphenol consumption during pregnancy may not be safe for the fetus. OBJECTIVE: The goal of this study was to evaluate the effect of naringenin supplementation during pregnancy on brain redox homeostasis and mitochondrial activity of the newborn rat. METHODS: Adult female Wistar rats were divided into two groups: (1) vehicle (1 mL/Kg p.o.) or (2) naringenin (50 mg/Kg p.o.). Naringenin was administered once a day during pregnancy. The offspring were euthanized on postnatal day 7, as well the dams, and brain regions were dissected. RESULTS: The offspring cerebellum was the most affected region, presenting increased activity of the mitochondrial electron transport system, allied to increased reactive species levels, lipid peroxidation, and glutathione concentration. The nitric oxide levels suffered structure-dependent alteration, with decreased levels in the pups' cerebellum and increased in the hippocampus. The offspring parietal cortex was not affected, as well as the parameters evaluated in the dams' brains. CONCLUSION: Maternal consumption of naringenin alters offspring cerebellar redox homeostasis, which could be related to adverse effects on the motor and cognitive development in the descendants.

TRPV4 Role in Neuropathic Pain Mechanisms in Rodents.

Neuropathic pain is a chronic pain caused by a disease or damage to the somatosensory nervous system. The knowledge about the complete mechanisms is incomplete, but the role of oxidative compounds has been evaluated. In this context, we highlight the transient potential receptor vanilloid 4 (TRPV4), a non-selective cation channel, that can be activated by oxidated compounds. In clinical trials, the TRPV4 antagonist (GSK2798745) has been well-tolerated in healthy volunteers. The TRPV4 activation by oxidative compounds, such as hydrogen peroxide (H2O2) and nitric oxide (NO), has been researched in neuropathic pain models. Thus, the modulation of TRPV4 activation by decreasing oxidated compounds could represent a new pharmacological approach for neuropathic pain treatment. Most models evaluated the TRPV4 using knockout mice, antagonist or antisense treatments and detected mechanical allodynia, hyposmotic solution-induced nociception and heat hyperalgesia, but this channel is not involved in cold allodynia. Only H2O2 and NO were evaluated as TRPV4 agonists, so one possible target to reduce neuropathic pain should focus on reducing these compounds. Therefore, this review outlines how the TRPV4 channel represents an innovative target to tackle neuropathic pain signaling in models induced by trauma, surgery, chemotherapy, cancer, diabetes and alcohol intake.

Free acquisition of psychotropic drugs by the Brazilian adult population and presence on the National List of Essential Medicines

Abstract The aims of the present study were to estimate the free-of-charge acquisition of psychotropic drugs among Brazilian adults; analyze the distribution of psychotropics according to their presence on the Relação Nacional de Medicamentos Essenciais (RENAME [National List of Essential Medicines]) and acquisition according to the source of funding (free of charge or direct payment); and estimate the proportion of free-of-charge psychotropic drugs according to therapeutic class and presence on the RENAME. This study involved the analysis of data from the 2014 National Survey on the Accessibility, Use and Promotion of the Rational Use of Medicines considering psychotropic drugs used by the adult population (≥20 years; n = 32,348). The prevalence of the acquisition of free-of-charge psychotropic drugs was 53.3% and 64.6% of these drugs were on the RENAME. Among the psychotropic drugs acquired by direct payment, 70.8% were not on the national list. Regarding free-of-charge acquisition according to the therapeutic class and presence on the RENAME, differences were found for antidepressants, anxiolytics and antipsychotics (p <0.05). In conclusion, the most used psychotropic medicines were listed in the RENAME, but free-of-charge acquisition was not provided for all of them