Compounds from Natural Products Candidates to Drug for Chikungunya Virus Infection: A Systematic Review.

INTRODUCTION: Chikungunya fever is a disease caused by infection with the Chikungunya virus, transmitted by Aedes aegypti and Aedes albopictus mosquitoes. Despite its self-limited character, more than 60% of patients have chronic recurrent arthralgia with debilitating pain that lasts for years. AIM: The objective of this review was to gather and analyze evidence from the literature on potential therapeutic strategies with molecules from natural products for the treatment of Chikungunya fever. METHODS: A search was performed for clinical trials, observational studies, in vitro or in vivo, without restriction of the year of publication or language in electronic databases (Medline/PubMed, EMBASE, Google Scholar, The Cochrane Library, LILACS (BVS), clinical trial registries (Clinical Trials.gov), digital libraries from CAPES theses and dissertations (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil) and conference abstracts. A quality assessment of the selected studies was performed using the SYRCLE, RoB2 and SciRAP tools. RESULTS: 42 studies were included, which showed molecules with potential antiviral pharmacological activity or with activity in reducing the joint complications caused by CHIKV infection. CONCLUSIONS: Among the molecules found in the survey of references, regarding the class of secondary metabolites, flavonoids stood out and for this reason, the molecules may be promising candidates for future clinical trials. Overall, evidence from in vitro studies was of acceptable quality; in vivo and intervention studies showed a high risk of bias, which is a limitation of these studies.

Evaluation of periodontal parameters on abutment teeth rehabilitated with single-unit crowns: A 12-month follow-up.

Purpose: This prospective study evaluated the effects of the metal-free crowns on the periodontal tissues of abutment teeth during a 12-month follow-up. Materials and Methods: A sample of 24 patients (N = 32 abutment teeth) who needed a single-tooth restoration were enrolled to receive either a metal-ceramic (n = 21) or lithium disilicate (n = 11). The single-unit crowns were evaluated at baseline, 3-and 12-month follow-up. The periodontal parameters were evaluated: plaque index (PI), gingival bleeding index (GBI), bleeding on probing (BOP), probing depth (PD), clinical attachment loss (CAL), radiographically and clinical crown fitting, bone resorption, and marginal finish lines. Statistical analyses were performed using the Exact Fisher and Mann-Whitney tests, and the Wilcoxon signed-rank test as a post hoc test for Friedman (95 % confidence interval). Results: The marginal finish line showed a statistical difference with a biomaterial type (p =.004). After a 12-months, a significant increase was observed in PI and mean PD for abutment teeth of metal-ceramic crowns. The metal-free crowns presented higher values for GBI and CAL (p2 < 0.05). Only distal cervical evaluation and dental biofilm formation in the abutment teeth showed a statistical difference between the groups at the 12-month follow-up. The supragingival margin metal-ceramic group revealed higher PI values (p2 = 0.005) between the period and the subgingival margin of both biomaterials showed greater GBI scores (p2 < 0.05). Conclusions: Metal-free crowns showed better periodontal outcomes compared to metal-ceramic crowns. Single-unit crown marginal location affects the periodontal tissue condition of the abutment teeth. The marginal fit was not changed regarding the biomaterial type.

Accuracy of acute hyperglycemia as a biomarker of severe brain damage in children with traumatic brain injury.

PURPOSE: Biomarkers are substances measured at the systemic level to evaluate organic responses in certain situations, establishing diagnoses, disease staging, and prognosis. Blood glucose is a biomarker recognized as a predictor of prognosis in children victims of traumatic brain injury (TBI). The scope of this study was to identify the accuracy of blood glucose as a biomarker of severe brain injury. METHODS: A retrospective analytical study was conducted through the consecutive review of medical records of children and teenage victims of TBI who underwent neurological surgery between 2016 and 2023 in a level 1 trauma center. Two groups were compared: children with Glasgow Coma Scale (GCS) score ≤ 8 and children with GCS > 8. We calculated the predictive values to define the accuracy of blood glucose as a biomarker of brain injury. RESULTS: Ninety-two medical records were included for analysis. Hyperglycemia predominated in cases with GCS ≤ 8 (48% vs 3%; p < 0.0001; OR, 30; 95% CI, 5.9902-150.2448). The glycemic measurement considering the cutoff point of 200 mg/dL or 11.1 mmol/L showed a specificity of 97%, a positive predictive value of 86%, an accuracy of 84%, and a likelihood ratio for a positive test of 16. CONCLUSION: Victims with GCS ≤ 8 are 16 times more likely to develop acute hyperglycemia after TBI when compared to those with GCS > 8. Blood glucose is a biomarker with an accuracy of 84% to predict severe brain injury, considering the cutoff point of 200 mg/dL or 11.1 mmol/L.

Impact of extended lung protection during mechanical ventilation on lung recovery in patients with COVID-19 ARDS: a phase II randomized controlled trial.

BACKGROUND: Protective ventilation seems crucial during early Acute Respiratory Distress Syndrome (ARDS), but the optimal duration of lung protection remains undefined. High driving pressures (ΔP) and excessive patient ventilatory drive may hinder lung recovery, resulting in self-inflicted lung injury. The hidden nature of the ΔP generated by patient effort complicates the situation further. Our study aimed to assess the feasibility of an extended lung protection strategy that includes a stepwise protocol to control the patient ventilatory drive, assessing its impact on lung recovery. METHODS: We conducted a single-center randomized study on patients with moderate/severe COVID-19-ARDS with low respiratory system compliance (CRS < 0.6 (mL/Kg)/cmH2O). The intervention group received a ventilation strategy guided by Electrical Impedance Tomography aimed at minimizing ΔP and patient ventilatory drive. The control group received the ARDSNet low-PEEP strategy. The primary outcome was the modified lung injury score (mLIS), a composite measure that integrated daily measurements of CRS, along with oxygen requirements, oxygenation, and X-rays up to day 28. The mLIS score was also hierarchically adjusted for survival and extubation rates. RESULTS: The study ended prematurely after three consecutive months without patient enrollment, attributed to the pandemic subsiding. The intention-to-treat analysis included 76 patients, with 37 randomized to the intervention group. The average mLIS score up to 28 days was not different between groups (P = 0.95, primary outcome). However, the intervention group showed a faster improvement in the mLIS (1.4 vs. 7.2 days to reach 63% of maximum improvement; P < 0.001), driven by oxygenation and sustained improvement of X-ray (P = 0.001). The intervention group demonstrated a sustained increase in CRS up to day 28 (P = 0.009) and also experienced a shorter time from randomization to room-air breathing (P = 0.02). Survival at 28 days and time until liberation from the ventilator were not different between groups. CONCLUSIONS: The implementation of an individualized PEEP strategy alongside extended lung protection appears viable. Promising secondary outcomes suggested a faster lung recovery, endorsing further examination of this strategy in a larger trial. Clinical trial registration This trial was registered with ClinicalTrials.gov (number NCT04497454) on August 04, 2020.

Feasibility of performing the 3-minute step test with remote supervision in children and adolescents with cystic fibrosis: A comparative study.

Importance: The 3-min step test is a simple option to monitor submaximal exercise capacity, although its use via remote video monitoring has not been investigated in children with cystic fibrosis (CF). Objective: This study aimed to assess the feasibility and reproducibility of performing the 3-min step test with remote supervision. Methods: A cross-sectional study including CF patients (6-18 years) from two CF services were performed. Demographic, anthropometric, clinical, and lung function data were collected and two 3-min step tests were performed: (i) in-person supervision, and (ii) remotely supervised by video monitoring. Before and after the tests, heart rate (HR), oxygen saturation (SpO2), and the Borg score for dyspnea and lower limb fatigue were monitored. Results: Twenty-three patients (10.7 ± 3.7 years) with a mean FEV1 of 89.5% ± 23.2% were included. There were no significant differences between tests, with mean differences (95% confidence intervals) in final HR of -3.3 (-8.9, 2.4), change in HR of -1.9 (-6.1, 2.1), final SpO2 of 0.3 (-0.4, 1.0), and final dyspnea of 0.1 (-0.8, 0.9). The intraclass correlation coefficient was 0.852 (final HR), 0.762 (final SpO2), and 0.775 (final lower limb fatigue). Significant and moderate correlations were found between tests for final HR (r = 0.75), change in HR (r = 0.61), and final SpO2 (r = 0.61). The Bland-Altman analysis showed a mean difference in final SpO2 between tests of 0.3% (limit of agreement -3.0%, 3.5%). Interpretation: Physiological responses between tests were similar, indicating it was feasible to perform the 3-min step test with remote supervision in CF children.

Population Pharmacokinetic of the Diterpenes ent-Polyalthic Acid and Dihydro-ent-Agathic Acid from Copaifera Duckei Oil Resin in Rats.

Copaifera duckei oleoresin is a plant product extensively used by the Brazilian population for multiple purposes, such as medicinal and cosmetic. Despite its ethnopharmacological relevance, there is no pharmacokinetic data on this important medicinal plant. Due to this, we determined the pharmacokinetic profile of the major nonvolatile compounds of C. duckei oleoresin. The diterpenes ent-polyalthic acid and dihydro-ent-agathic acid correspond to approximately 40% of the total oleoresin. Quantification was performed using LC-MS/MS, and the validated analytical method showed to be precise, accurate, robust, reliable, and linear between 0.57 and 114.74 µg/mL plasma and 0.09 to 18.85 µg/mL plasma, respectively, for ent-polyalthic acid and dihydro-ent-agathic acid, making it suitable for application in preclinical pharmacokinetic studies. Wistar rats received a single 200 mg/kg oral dose (gavage) of C. duckei oleoresin, and blood was collected from their caudal vein through 48 h. Population pharmacokinetics analysis of ent-polyalthic and dihydro-ent-agathic acids in rats was evaluated using nonlinear mixed-effects modeling conducted in NONMEN software. The pharmacokinetic parameters of ent-polyalthic acid were absorption constant rate = 0.47 h-1, central and peripheral apparent volume of distribution = 0.04 L and 2.48 L, respectively, apparent clearance = 0.15 L/h, and elimination half-life = 11.60 h. For dihydro-ent-agathic acid, absorption constant rate = 0.28 h-1, central and peripheral apparent volume of distribution = 0.01 L and 0.18 L, respectively, apparent clearance = 0.04 L/h, and elimination half-life = 3.49 h. The apparent clearance, central apparent volume of distribution, and peripheral apparent volume of distribution of ent-polyalthic acid were approximately 3.75, 4.00-, and 13.78-folds higher than those of dihydro-ent-agathic.

Unveiling the intricacies of BPA and BPS: comprehensive insights into its toxic effects using a cutting-edge microphysiological system.

Concerns over Bisphenol A (BPA) and its substitute, Bisphenol S (BPS), have led to innovative exploration due to potential adverse health effects. BPS, replacing BPA in some regions to avoid toxic impacts, remains insufficiently studied. Besides this, the organ-on-a-chip technology emerges as a transformative solution in drug discovery and chemiclas toxicity testing, minimizing costs and aligning with ethical standards by reducing reliance on animal models, by integrating diverse tissues and dynamic cell environments enhances precision in predicting organ function. Here, we employ a 3-organ-on-a-chip microfluidic device with skin, intestine, and liver cultures to assess the effects of BPA and BPS via topical and oral administration. Our evaluation focused on gene markers associated with carcinogenicity, systemic toxicity, and endocrine disruption. BPA exhibited expected absorption profiles, causing liver injury and genetic modulation in related pathways. BPS, a safer alternative, induced adverse effects on gene expression, particularly in topical absorption, with distinct absorption patterns. Our findings underscore the urgency of addressing BPA and BPS toxicity concerns, highlighting the crucial role of organ-on-a-chip technology in understanding associated health risks. The study promotes the organ-on-a-chip methodology as a valuable tool for safe drug development and disease treatments, offering a novel liver toxicity screening alternative to traditional animal tests. This contributes to advancing comprehension of the biological effects of these compounds, fostering improved safety assessments in human health.

Association between oral health-related quality of life and symptoms of temporomandibular disorder among older adults: A cross-sectional study.

OBJECTIVE: Evaluate the association between oral health-related quality of life (OHRQoL) and self-reported symptoms of TMD. METHODS: Representative samples of older adults (≥60 years) were included (n = 569). Both TMD symptoms and OHRQoL were assessed by Fonseca Anamnestic Index (FAI) and Oral Health Impact Profile-14 (OHIP-14), respectively. Prevalence (those answering "frequently" or "always" in at least one question), severity (total means scores), and extent (number of questions answered as "frequently" or "always") of OHRQoL were estimated. RESULTS: Overall, 33.4% and 9.5% had mild or moderate/severe TMD symptoms. Those with any symptom of TMD had a prevalence ratio (PR) 38% higher for the worst OHRQoL (95% confidence interval [95%CI]:1.04-1.82) compared to those without TMD symptoms. Worst OHRQoL were observed for those with mild (PR:1.35; 95%CI:1.01-1.81) and moderate/severe TMD (PR:1.53; 95%CI:1.04-2.26). Similar results were detected in the severity and extent of OHRQoL. CONCLUSION: Severity TMD was associated with worse ORHQoL.

Effect of a Neuromodulation Protocol Associated With Sports Training on the Precision Sports Performance of a Wheelchair Basketball Para-Athlete: A Case Study.

OBJECTIVE: To investigate whether transcranial direct-current stimulation (tDCS) optimizes the performance of a wheelchair basketball player on precision tasks. METHODS: A right-handed wheelchair basketball player (1.5 points functional class) with myelomeningocele (low lumbar level) participated in this case study. The tDCS neuromodulation protocol was applied throughout 10 interventions of 20 minutes with a current intensity of 2 mA, simultaneously with sport-specific training, 3 times a week for 4 weeks. Anodic stimulation was performed on the right cerebellar hemisphere (CB2) and cathodic stimulation in the left dorsolateral prefrontal cortex. A control participant was submitted to a sham-tDCS stimulation protocol for the same period. Functional performance was assessed before the intervention and after the 5th and 10th interventions using "pass accuracy," "free-throw shooting," and "spot shot" tests. Outcome measures were compared using percentage differences between preintervention, intermediate intervention, and postintervention values. RESULTS: There was a gradual increase in the athlete's total and average scores in all tests performed, with an overall improvement of 78% between the baseline and final assessments, while the control participant had an overall improvement of 6.5%. CONCLUSION: The tDCS protocol was effective in improving performance in precision activities in a wheelchair basketball player.

Loss of tumor suppressor TMEM127 drives RET-mediated transformation through disrupted membrane dynamics.

Internalization from the cell membrane and endosomal trafficking of receptor tyrosine kinases (RTKs) are important regulators of signaling in normal cells that can frequently be disrupted in cancer. The adrenal tumor pheochromocytoma (PCC) can be caused by activating mutations of the rearranged during transfection (RET) receptor tyrosine kinase, or inactivation of TMEM127, a transmembrane tumor suppressor implicated in trafficking of endosomal cargos. However, the role of aberrant receptor trafficking in PCC is not well understood. Here, we show that loss of TMEM127 causes wildtype RET protein accumulation on the cell surface, where increased receptor density facilitates constitutive ligand-independent activity and downstream signaling, driving cell proliferation. Loss of TMEM127 altered normal cell membrane organization and recruitment and stabilization of membrane protein complexes, impaired assembly, and maturation of clathrin-coated pits, and reduced internalization and degradation of cell surface RET. In addition to RTKs, TMEM127 depletion also promoted surface accumulation of several other transmembrane proteins, suggesting it may cause global defects in surface protein activity and function. Together, our data identify TMEM127 as an important determinant of membrane organization including membrane protein diffusability and protein complex assembly and provide a novel paradigm for oncogenesis in PCC where altered membrane dynamics promotes cell surface accumulation and constitutive activity of growth factor receptors to drive aberrant signaling and promote transformation.

Práticas de enfermagem: contexto ambiental e a relação com o materialismo histórico dialético / Nursing practices: environmental context and the relationship with dialectical historical materialism / Prácticas de enfermería: contexto ambiental y la relación con el materialismo histórico dialéctico

Objetivo: Descrever as práticas dos enfermeiros em nossa sociedade e sob as circunstâncias que podem contribuir para a inclusão das práticas avançadas. Métodos: Estudo descritivo, de abordagem qualitativa e delineamento transversal, sob a perspectiva da teoria do materialismo histórico-dialético de Karl Marx, estruturada pela utilização do instrumento COREQ. Resultados: O campo de atuação do enfermeiro na atenção primária à saúde é diversificado, extrapola os muros do consultório. Muitas vezes o dinamismo das atividades traduz o empenho de obter os melhores resultados por meio de sua assistência. E o materialismo histórico-dialético reflete justamente a busca por uma assistência de qualidade e as mudanças no ambiente laboral, onde a interação de diversos fatores contribuem de forma direta no ambiente laboral e social. Conclusão: Os enfermeiros da atenção primária à saúde brasileira atuam nos mais diversos territórios, desse modo, precisam dinamizar os seus atendimentos para contemplar as necessidades sociais. Perante esses aspectos, as diversidades sociodemográficas brasileiras demonstraram que a escassez de recursos em regiões remotas é um dos fatores que fortalece a inclusão das práticas avançadas de enfermagem na atenção primária à saúde no Brasil. (AU)

Objective: To describe the practices of nurses in our society and under circumstances that may contribute to the inclusion of advanced practices. Methods: Descriptive study, with a qualitative approach and cross-sectional design, from the perspective of Karl Marx's dialectical historical materialism theory, structured by using the COREQ instrument. Results: The nurse's field of action in primary health care is diverse, it goes beyond the walls of the office. Often the dynamism of activities translates the effort to obtain the best results through their assistance. And dialectical historical materialism precisely reflects the search for quality care and changes in the work environment, where the interaction of several factors directly contribute to the work and social environment. Conclusion: Brazilian primary health care nurses work in the most diverse territories, therefore, they need to streamline their care to address social needs. In view of these aspects, Brazilian sociodemographic diversity has shown that the scarcity of resources in remote regions is one of the factors that strengthens the inclusion of advanced nursing practices in primary health care in Brazil. (AU)

Objetivo: Describir las prácticas de los enfermeros en nuestra sociedad y en circunstancias que puedan contribuir a la inclusión de prácticas avanzadas. Métodos: Estudio descriptivo, con enfoque cualitativo y diseño transversal, desde la perspectiva de la teoría del materialismo histórico dialéctico de Karl Marx, estructurado mediante el uso del instrumento COREQ. Resultados: El campo de actuación del enfermero en la atención primaria de salud es diverso, va más allá de las paredes del consultorio. Muchas veces el dinamismo de las actividades se traduce en el esfuerzo por obtener los mejores resultados a través de su asistencia. Y el materialismo histórico dialéctico refleja precisamente la búsqueda de cuidados de calidad y cambios en el ambiente laboral, donde la interacción de varios factores contribuyen directamente al ambiente laboral y social. Conclusión: Las enfermeras brasileñas de atención primaria de salud actúan en los más diversos territorios, por lo tanto, necesitan optimizar su atención para atender las necesidades sociales. Frente a estos aspectos, la diversidad sociodemográfica brasileña ha demostrado que la escasez de recursos en regiones remotas es uno de los factores que fortalece la inclusión de prácticas avanzadas de enfermería en la atención primaria de salud en Brasil. (AU)

Impact of feeding native Caatinga pasture on the rumen histomorphometry of sheep raised in semi-extensive management.

In the northeastern region of Brazil, sheep and goat farming, encompassing around 20 million animals, is predominantly a subsistence activity. Forage quality plays a crucial role in animal productivity, posing a complex interplay between plant and animal aspects. The Caatinga biome, vital for livestock in the region, serves as a significant source for animal diet through pastures. This study aimed to conduct a histomorphometric evaluation of sheep rumens in a semi-extensive system, comparing those feeding on native Caatinga pastures to those on cultivated pastures. Histological processing followed standard protocols, with morphometry focusing on six viable rumen papillae and the submucosa and muscular layer thickness. Statistical correlation analysis revealed morphological differences in papillae across various rumen regions. Morphometric data indicated no significant difference in papillae area between the groups, with average values in Group A surpassing those in Group B, except for width. This study establishes a morphological and morphometric pattern for rumen regions linked to diet types-native or cultivated. The findings not only enhance understanding of the dietary foundation in the Caatinga's extensive system, but also contribute valuable insights for formulating nutritional strategies to enhance sheep production in the region. This research sheds light on the intricacies of forage-based animal nutrition, particularly in semi-extensive systems, offering a foundation for future studies and practices to optimise livestock management in the northeastern Brazilian context.

Clinical, laboratory, and molecular characteristics of a cohort of children with hemoglobinopathy S/beta-thalassemia.

INTRODUCTION: Hemoglobinopathy Sß-thalassemia (HbSß-thal) has a wide range of clinical and laboratory severity. There is limited information on the natural history of HbSß-thal and its modulating factors. We described the molecular, hematological, and clinical characteristics of a cohort of children with HbSß-thal and estimated its incidence in Minas Gerais, Brazil. METHODS: Laboratory and clinical data were retrieved from medical records. Molecular analysis was performed by HBB gene sequencing, PCR-RFLP, gap-PCR, and MLPA. RESULTS: Eighty-nine children were included in the study. Fourteen alleles of ß-thal mutations were identified. The incidence of HbSß-thal in the state was 1 per 22,250 newborns. The most common ßS-haplotypes were CAR and Benin. The most frequent ßthal-haplotypes were V, II, and I. Coexistence of 3.7 kb HBA1/HBA2 deletion was present in 21.3 % of children. ß-thalassemia mutations were associated with several clinical and laboratory features. In general, the incidence of clinical events per 100 patient-years was similar for children with HbSß0-thal, IVS-I-5 G>A, and IVS-I-110 G>A. Children with HbSß+-intermediate phenotypes had a more severe laboratory and clinical profile when compared with those with HbSß+-mild ones. ßS-haplotypes and α-thalassemia did not meaningfully influence the phenotype of children with HbSß-thal. CONCLUSION: The early identification of ß-thalassemia alleles may help the clinical management of these children.

In Situ Preparation of Dehydrodieugenol-Loaded Silver Nanoparticles and their Antischistosomal Activity.

Schistosomiasis is a major neglected disease that imposes a substantial worldwide health burden, affecting approximately 250 million people globally. As praziquantel is the only available drug to treat schistosomiasis, there is a critical need to identify new anthelmintic compounds, particularly from natural sources. To enhance the activity of different natural products, one potential avenue involves its combination with silver nanoparticles (AgNP). Based on this approach, a one-step green method for the in situ preparation of dehydrodieugenol (DHDG) by oxidation coupling reaction using silver and natural eugenol is presented. AgNP formation was confirmed by UV-Vis spectroscopy due to the appearance of the surface plasmon resonance (SPR) band at 430 nm which is characteristic of silver nanoparticles. The nanoparticles were spherical with sizes in the range of 40 to 50 nm. Bioassays demonstrated that the silver nanoparticles loaded with DHDG exhibited significant anthelmintic activity against Schistosoma mansoni adult worms without toxicity to mammalian cells and an in vivo animal model (Caenorhabditis elegans), contributing to the development of new prototypes based on natural products for the treatment of schistosomiasis.

Factors associated with infant feeding intention among usual-risk pregnant women.

OBJECTIVE: To identify the factors associated with infant feeding intention among usual-risk pregnant women. METHODS: A quantitative cross-sectional study was conducted in two primary healthcare institutions in Fortaleza, Ceará, Brazil, with usual-risk pregnant women. A non-probabilistic convenience sampling method was used, and 119 pregnant women participated. Data collection took place from May 2022 to February 2023. The data collection process involved using forms and the Infant Feeding Intention Scale. Ethical considerations were strictly adhered to. RESULTS: The study revealed statistically significant differences in the infant's means. The majority of pregnant women (96.6%) declared that they would breastfeed after giving birth. The intention to breastfeed exclusively was statistically higher in mothers with younger children and previous experience of breastfeeding or complications in the current pregnancy. CONCLUSION: This study clarified that the intention to breastfeed up to 6 months is influenced by variables encompassing the age of the youngest child, previous breastfeeding experience, and pregnancy complications, emphasizing the intricate nature of the determinants of intention to breastfeed.

Loss of Tumour Suppressor TMEM127 Drives RET-mediated Transformation Through Disrupted Membrane Dynamics.

Internalization from the cell membrane and endosomal trafficking of receptor tyrosine kinases (RTK) are important regulators of signaling in normal cells that can frequently be disrupted in cancer. The adrenal tumour pheochromocytoma (PCC) can be caused by activating mutations of the RET receptor tyrosine kinase, or inactivation of TMEM127, a transmembrane tumour suppressor implicated in trafficking of endosomal cargos. However, the role of aberrant receptor trafficking in PCC is not well understood. Here, we show that loss of TMEM127 causes wildtype RET protein accumulation on the cell surface, where increased receptor density facilitates constitutive ligand-independent activity and downstream signaling, driving cell proliferation. Loss of TMEM127 altered normal cell membrane organization and recruitment and stabilization of membrane protein complexes, impaired assembly, and maturation of clathrin coated pits, and reduced internalization and degradation of cell surface RET. In addition to RTKs, TMEM127 depletion also promoted surface accumulation of several other transmembrane proteins, suggesting it may cause global defects in surface protein activity and function. Together, our data identify TMEM127 as an important determinant of membrane organization including membrane protein diffusability, and protein complex assembly and provide a novel paradigm for oncogenesis in PCC where altered membrane dynamics promotes cell surface accumulation and constitutive activity of growth factor receptors to drive aberrant signaling and promote transformation.

Transcutaneous Electric Nerve Stimulation in Animal Model Studies: From Neural Mechanisms to Biological Effects for Analgesia.

OBJECTIVE: This systematic and meta-analysis review evaluated the transcutaneous electrical nerve stimulation (TENS)-induced action mechanisms for animal analgesia. MATERIALS AND METHODS: Two independent investigators identified relevant articles published until February 2021 through a literature review, and a random-effects meta-analysis was performed to synthesize the results. RESULTS: Of the 6984 studies found in the data base search, 53 full-text articles were selected and used in the systematic review. Most studies used Sprague Dawley rats (66.03%). High-frequency TENS was applied to at least one group in 47 studies, and most applications were performed for 20 minutes (64.15%). Mechanical hyperalgesia was analyzed as the primary outcome in 52.83% of the studies and thermal hyperalgesia in 23.07% of studies using a heated surface. More than 50% of the studies showed a low risk of bias on allocation concealment, random housing, selective outcome reporting, and acclimatization before the behavioral tests. Blinding was not performed in only one study and random outcome assessment in another study; acclimatization before the behavioral tests was not performed in just one study. Many studies had an uncertain risk of bias. Meta-analyses indicated no difference between low-frequency and high-frequency TENS with variations among the pain models. CONCLUSIONS: This systematic review and meta-analysis suggests that TENS has presented a substantial scientific foundation for its hypoalgesic effect in preclinical studies for analgesia.

Effects of docetaxel on metastatic prostate (DU-145) carcinoma cells cultured as 2D monolayers and 3D multicellular tumor spheroids.

Docetaxel (DTX) is one of the chemotherapeutic drugs indicated as a first-line treatment against metastatic prostate cancer (mPCa). This study aimed to compare the impact of DTX on mPCa (DU-145) tumor cells cultured as 2D monolayers and 3D multicellular tumor spheroids (MCTS) in vitro. The cells were treated with DTX (1-96 µM) at 24, 48, or 72 hr in cell viability assays (resazurin, phosphatase acid, and lactate dehydrogenase). Cell death was assessed with fluorescent markers and proliferation by clonogenic assay (2D) and morphology, volume, and integrity assay (3D). The cell invasion was determined using transwell (2D) and extracellular matrix (ECM) (3D). Results showed that DTX decreased cell viability in both culture models. In 2D, the IC50 (72 hr) values were 11.06 µM and 14.23 µM for resazurin and phosphatase assays, respectively. In MCTS, the IC50 values for the same assays were 114.9 µM and 163.7 µM, approximately 10-fold higher than in the 2D model. The % of viable cells decreased, while the apoptotic cell number was elevated compared to the control in 2D. In 3D spheroids, only DTX 24 µM induced apoptosis. DTX (≥24 µM at 216 hr) lowered the volume, and DTX 96 µM completely disintegrated the MCTS. DTX reduced the invasion of mPCa cells to matrigel (2D) and migration from MCTS to the ECM. Data demonstrated significant differences in drug response between 2D and 3D cell culture models using mPCa DU-145 tumor cells. MCTS resembles the early stages of solid tumors in vivo and needs to be considered in conjunction with 2D cultures when searching for new therapeutic targets.

Synthesis, molecular docking, ADMET, and evaluation of the anxiolytic effect in adult zebrafish of synthetic chalcone (E)-3-(4-(dimethylamino)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one: An in vivo and in silico approach.

BACKGROUND: Anxiety disorders represent the complex interaction between biological, psychological, temperamental, and environmental factors; drugs available to treat anxiety such as benzodiazepines (BZDs) are associated with several unwanted side effects. Although there are useful treatments, there is still a need for more effective anxiolytics with better safety profiles than BZDs. Chalcones or 1,3-diphenyl-2-proper-1-ones can be an alternative since this class of compounds has shown therapeutic potential mainly due to interactions with GABAA receptors and serotonergic system. OBJECTIVES: This study evaluated the anxiolytic potential of chalcone (E)-3-(4-(dimethylamino)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (C2OHPDA) in adult zebrafish (Danio rerio) (ZFa). METHODS: Each animal (n = 6/group) was treated intraperitoneally (i.p.; 20 µL) with the chalcone (4, 20, and 40 mg/kg) and with the vehicle (DMSO 3%; 20 µL), being submitted to the tests of locomotor activity and 96-h acute toxicity. The light/dark test was also performed, and the serotonergic mechanism (5-HT) was evaluated through the antagonists of the 5-HTR1 , 5-HTR2A/2C , and 5-HTR3A/3B receptors. It was investigated the prediction of the chalcone's position and preferential orientation concerning its receptor, as well as the pharmacokinetic parameters (ADMET) involved in the process after administration. RESULTS: As a result, C2OHPDA was not toxic and reduced the locomotor activity of ZFa. Furthermore, chalcone demonstrated an anxiolytic effect on the central nervous system (CNS), mediated by the serotonergic system, with action on 5-HT2A and 5-HTR3A/3B receptors. The interaction of C2OHPDA with 5-HT2A R and 5-HT3A receptors was confirmed by molecular docking study, the affinity energy observed was -8.7 and -9.1 kcal/mol, respectively. CONCLUSION: Thus, this study adds new evidence and highlights that chalcone can potentially be used to develop compounds with anxiolytic properties.

Reversible Tricuspid Regurgitation Due to Beriberi.

We report a case of cardiac beriberi in a 76-year-old man who was hospitalized with a congestive condition of subacute onset, diagnosed as high-output heart failure associated with severe tricuspid regurgitation and indication for caval valve implantation, which, after thiamine replacement, resulted in improvement of all conditions. (Level of Difficulty: Beginner.).