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Occupational exposure to toxic elements can adversely affect health. The current study evaluated blood concentrations of potentially toxic elements (PTE) including As, Cd, Cr, Cu, Hg, Mn, Ni, Pb, Sb, Sn, and Zn in formal and informal workers. Additionally, the study investigated the associations between blood PTE concentrations and reported health outcomes in the study population. The exposed group included women engaged in informal jewelry welding within their homes in Limeira, São Paulo state, Brazil (n = 36) and men who worked at a steel company in Volta Redonda, Rio de Janeiro state, Brazil (n = 22). The control group comprised residents of the same neighborhoods as the workers but without occupational exposure to chemicals (n = 28 in Limeira; n = 27 in Volta Redonda). Triple Quadrupole Inductively Coupled Plasma Mass Spectrometry (TQ ICP-MS) was used to determine PTE concentrations in blood samples. Glycemia, insulin, and lipid profile tests were performed. All participants completed questionnaires on household risk and reported morbidity. The blood concentrations of Cd, As, and Pb, as well as glycemia, were higher in informal workers than in control subjects. No significant differences were observed between formal workers and control subjects. A robust Poisson regression model, adjusted for variables suggested by a Directed Acyclic Graph, disclosed associations of blood lead and arsenic concentrations with the prevalence of neurological manifestations in Limeira. Blood lead levels > 2.6 μg dL -1 were associated with 2.3 times the prevalence of self-reported neurological manifestations (95 % CI: 1.17-4.58; p = 0.02) than lower blood lead concentrations. Furthermore, a positive association between blood cadmium concentrations and glycemia was observed. Informal occupational exposure to these elements may indicate an increased risk of developing diseases. Monitoring exposure and implementing interventions to reduce PTE exposure in the work environment represent significant steps toward prevention., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The assessment of the mucoadhesive properties peak mucoadhesive force (F max ) and work of mucoadhesion (W muc ) with texture analyzers is a common in vitro method for analyzing formulation capabilities. Challenges arise in selecting and standardizing experimental conditions due to various variables influencing mucoadhesion. This complexity hampers direct product performance comparisons. In our study, we explored factors (contact force and time, probe speed and mucin in artificial saliva) impacting a model formulation's mucoadhesive capacity. Using Omcilon-A®Orabase on porcine buccal mucosa, we systematically varied experimental conditions, employing a statistical approach (Central Composite Design - CCD). Three variables (contact force, contact time, probe speed) and their interactions were assessed for their impact on F max and W muc . Results showed that contact time and force positively affected F max , while only contact time influenced W muc . In the mucin artificial saliva test, a force of 0.5 N, time of 600 s, and speed of 1 mm/s yielded optimal F max (0.587 N) and W muc (0.468 N.s). These conditions serve as a reference for comparing mucoadhesive properties of formulations for topical oral use., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Background: HIV Pre-Exposure Pophylaxis (PrEP) is provided free of charge by the Brazilian national health system. Though effective in preventing HIV infection, little is known about its impact on the health-related Quality of Life (QoL) of users., Objective: The present study aimed at assessing the impact of PrEP on the QoL of its users., Methods: Prospective cohort study with 114 HIV-negative participants aged 18 years or older. Participants' QoL was assessed before starting PrEP and after 7 months of use, using the self-responsive WHOQOL-bref questionnaire. Sociodemographic and behavioral aspects were described and the Wilcoxon signed-rank test with p ≤ 0.05 was considered statistically significant., Results: Improvement was seen in QoL scores for the environment domain (p = 0.02), which addresses feeling of physical safety, access to information and health services, and participation in leisure activities. Furthermore, participants reported improved satisfaction with their sex life, when questioned about the social relationships domain. There was no statistically significant change in the global QoL score, in the global health score, in the physical and psychological domains, nor in the total score for the social relationships domain. As for their socio-demographic profile, most participants were white and highly educated young cisgender men who have sex with men. 76.3% had unprotected sex in the 3 months before starting PrEP. 60.5% had reported substance use: marijuana (42.1%), club drugs (35.1%), and poppers (20.2%)., Conclusions: This study unveiled that PrEP benefited our cohort beyond its effectiveness in preventing HIV infection, having improved environmental aspects of QoL and self-satisfaction with sex life., Competing Interests: Declaration of competing interest Authors Takada-de-Souza MK, Picone CM, Avelino-Silva VI, Freitas AC and Segurado AC have no relevant financial or non-financial interests to disclose., (Copyright © 2024 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Background and Objective: Recent guidelines classify low prolactin levels as low as <7 ng/mL and high levels as >25 ng/mL, while the "Homeostatically Functionally Increased Transient Prolactinemia" (HomeoFIT-PRL) range (25-100 ng/mL) suggests that a temporary increase in prolactin could be metabolically beneficial if no related health issues are present. The aim of this study was to investigate the association between mean prolactin concentrations and disturbances in glycidic and lipidic metabolism and to identify the gray zone associated with prolactin inflection points that correlate with these metabolic changes., Methods: This cross-sectional study involved 65,795 adults who underwent HOMA-IR, glucose, insulin, total cholesterol, HDL-c, LDL-c, and triglyceride tests. Data was categorized into 106 partitions based on prolactin results. Employing an approach referred to in this study as "Hierarchical Multicriteria Analysis of Differences Between Groups - Statistical and Effect Size Approach" (HiMADiG-SESA) comparing the mean concentrations of metabolic tests across prolactin ranges. A machine learning model was utilized to determine inflection points and their corresponding confidence intervals (CIs). These CIs helped establish gray zones in mean prolactin results related to metabolic changes., Results: Statistically and clinically, metabolic test means differed for prolactin <7 ng/mL, except insulin. In the HomeoFIT-PRL range, means were lower except for HDL-c. The gray zones of the mean prolactin results associated with changes in glycidic and lipidic metabolism were 9.58-12.87 ng/mL and 13.81-18.73 ng/mL, respectively., Conclusion: A strong correlation was identified between mean prolactin concentrations and the results of metabolism tests below the gray zones associated with inflection points, indicating the potential role of prolactin in the appearance of metabolic disorders. Mean prolactin results can provide deeper insight into metabolic balance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: To characterize a cohort of T1D patients and to compare diabetes control between patients using different regimen of insulin therapy and glucose monitoring., Methods: Were included all T1D patients followed at the Pediatric Endocrinology Unit, between April 1st and June 30th, 2021. Several clinical and demographic variables were analyzed., Results: Our sample included 208 patients, 56.7 % males, mean age of 12.7 ± 4.6 years. The median HbA1c was 7.3 %. Most patients, 78.8% were treated with continuous subcutaneous insulin infusion (CSII) and 81.3 % used continuous glucose monitoring (CGM). CSII had a lower HbAc compared with multiple daily injections (MDI) users (7.1vs 8.1 %, p < 0.01). In the CSII group, those who used CGM had a lower HbAc (7.1 vs 7.5 %,p = 0.02). Analyzing the data of the ambulatory glucose report, the CSII users had a lower glucose management indicator, (7.2 % vs 7.6 %, p < 0.01), more time in range (58.0 % vs 52.4 %;p < 0.01) and less time above range > 250 mg/dL (12.4 % vs 20.5 %;p < 0.01) than MDI users., Conclusions: The median HbA1c was 7.3% very close to the recommended target. In Portugal, pediatric patients can access a CSII provided by the national health service and a CGM system due to an elevated reimbursement of their cost. This healthy policy allows us to achieve better goals without the risk of hypoglycemia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Purpose: Glioblastoma(GBM) is a lethal disease characterized by inevitable recurrence. Here we investigate the molecular pathways mediating resistance, with the goal of identifying novel therapeutic opportunities., Experimental Design: We developed a longitudinal in vivo recurrence model utilizing patient-derived explants to produce paired specimens(pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR). These specimens were evaluated for treatment response and to identify gene expression pathways driving treatment resistance. Findings were clinically validated using spatial transcriptomics of human GBMs., Results: These studies reveal in replicate cohorts, a gene expression profile characterized by upregulation of mesenchymal and stem-like genes at recurrence. Analyses of clinical databases revealed significant association of this transcriptional profile with worse overall survival and upregulation at recurrence. Notably, gene expression analyses identified upregulation of TGFβ signaling, and more than one-hundred-fold increase in THY1 levels at recurrence. Furthermore, THY1-positive cells represented <10% of cells in treatment-naïve tumors, compared to 75-96% in recurrent tumors. We then isolated THY1-positive cells from treatment-naïve patient samples and determined that they were inherently resistant to chemoradiation in orthotopic models. Additionally, using image-guided biopsies from treatment-naïve human GBM, we conducted spatial transcriptomic analyses. This revealed rare THY1+ regions characterized by mesenchymal/stem-like gene expression, analogous to our recurrent mouse model, which co-localized with macrophages within the perivascular niche. We then inhibited TGFBRI activity in vivo which decreased mesenchymal/stem-like protein levels, including THY1, and restored sensitivity to TMZ/IR in recurrent tumors., Conclusions: These findings reveal that GBM recurrence may result from tumor repopulation by pre-existing, therapy-resistant, THY1-positive, mesenchymal cells within the perivascular niche., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Tailings from iron mining are characterized by high concentrations of iron and manganese oxides, as well as high pH values. With these characteristics, most of the potentially toxic elements (PTE) contained in the tailings are somewhat unavailable. The aim of the present study was to evaluate how a reduction in the pH of iron mine tailings may affect PTE availabilities. The tailings were collected on the banks of the Gualaxo do Norte River (Mariana, MG, Brazil), one of the main areas impacted by the rupture of the Fundão Dam (Barragem de Fundão). A completely randomized experimental design was used, including five pH values (6.4, 5.4, 4.3, 3.7, and 3.4) and five replications. The concentrations of the PTE (Ba, Cr, Cd, Co, Cu, Fe, Mn, Pb, Ni, and Zn) were determined after extraction following different methodologies: USEPA 3051A, DTPA, Mehlich-1, Mehlich-3, and distilled water. A comparison of the available concentrations of the elements in the tailings with those in a soil not impacted by tailings shows that Cr, Cd, Cu, Fe, Mn, Ni, Ba, and Co were higher in the soil impacted by the tailings. The different methods used for evaluating the availability of PTE in the tailings at various pH exhibited the following decreasing order in relation to the quantity extracted: Mehlich-3 > Mehlich-1 > DTPA > distilled water. However, regarding sensitivity to change in pH, the order was DTPA > water > Mehlich-1 > Mehlich-3. The increases in the concentrations of PTE due to the reduction in the pH of the tailings did not lead to concentrations that exceed the limits of Brazilian regulations. The DTPA extractant exhibited higher coefficients of correlation between the PTE concentrations and the pH of the tailings, proving to be suitable for use in areas affected by the deposition of iron mine tailings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: estimate the risk for the occurrence of lethal violence against women and to identify the associated factors in the state of Paraná., Method: ecological study of deaths of women aged between 15 and 59 years, victims of aggression. The units of analysis were the cities of Paraná. Latent Bayesian Gaussian models with negative binomial probability distribution were used. The modeling considered intercept, spatial random effects and covariates, performed with the deterministic Integrated Nested Laplace Approximations approach., Results: There was a positive association between lethal violence against women and the percentage of mothers who were heads of households. Finally, male homicide rates, rates of non-lethal violence against women and the cities with women mayors and councilors were also associated., Conclusion: This type of violence was associated with low education, structural violence and the participation of women in politics., Competing Interests: Declaration of Competing Interest All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The neurodegeneration of Alzheimer's disease (AD) affects not only brain structures associate with cognition early in the progression of the disease, but other areas such as the hypothalamus, a region involved in the control of metabolism and appetite. In this context, we evaluated the effects of benfotiamine (BFT), a vitamin B1 analog that is being proposed as a therapeutical approach for AD-related cognitive alterations, which were induced by intracerebroventricular injection of streptozotocin (STZ). In addition to the already described effect of STZ on cognition, we show that this drug also causes metabolic changes which are linked to changes in hypothalamic insulin signaling and orexigenic and anorexigenic circuitries, as well as a decreased cellular integrated stress response. As expected, the supplementation with 150 mg/kg of BFT for 30 days increased blood concentrations of thiamine and its phosphate esters. This led to the prevention of body weight and fat loss in STZ-ICV-treated animals. In addition, we also found an improvement in food consumption, despite hypothalamic gene expression linked to anorexia after STZ exposure. Additionally, decreased apoptosis signaling was observed in the hypothalamus. In in vitro experiments, we noticed a high ability of BFT to increase insulin sensitivity in hypothalamic neurons. Furthermore, we also observed that BFT decreases the mitochondrial unfolded stress response damage by preventing the loss of HSP60 and reversed the mitochondria dysfunction caused by STZ. Taken together, these results suggest that benfotiamine treatment is a potential therapeutic approach in the treatment of hypothalamic dysfunction and metabolic disturbances associated with sporadic AD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: This study aimed to investigate the accuracy of TCS combined with the Sniffin' sticks olfactory test (SST-16) for differentiation between idiopathic PD patients and healthy controls compared to that of 99 m Tc-TRODAT-1 SPECT (TRODAT)., Methods: A cross-sectional study included PD patients diagnosed in accordance with United Kingdom PD Society Brain Bank criteria and a control group of age and sex- matched healthy subjects. All patients were examined by a movement disorder specialist and underwent brain SPECT using TRODAT, TCS examination and SST-16 test. Receiver Operating Characteristic (ROC) curves were used to calculate cut-off points for TCS, striatal TRODAT binding potentials and SST-16. The area under the ROC curve determined the diagnostic accuracy of the method., Results: Twenty patients with PD (13 males and 7 females) and nine healthy subjects were included. Median age of PD onset was 56.5 years with median disease duration of 5 years. A larger substantia nigra (SN) echogenic area was observed in the PD group (p = 0.013). SN echogenic area cut-off point of 0.22 cm 2 was obtained from a ROC curve for PD diagnosis. Considering this cut-off point, TCS diagnostic accuracy was estimated at 79.2% for PD diagnosis. The cut-off value of 0.90 for striatal TRODAT binding was associated with 99% diagnostic accuracy for the diagnosis of PD. SST-16 values equal or less than 9 points showed an 85.8% diagnostic accuracy for PD diagnosis. Combination of both SST-16 and TCS improved the diagnostic accuracy to 95% for PD diagnosis., Conclusion: Combined SST-16 and TCS assessment was indicated as accurate for distinguishing PD patients from healthy controls. The diagnostic accuracy of TCS combined with SST-16 for differentiation between idiopathic PD patients and healthy controls is similar to that of SPECT TRODAT., Competing Interests: Declarations of interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The present study is a systematic review of the evaluation of screening programs as a strategy for early detection of oral cancer. The aim of this study was to assess whether screening through visual inspection is able to identify injuries in early stages, to increase survival, and to decrease the incidence and mortality of oral cancer. Studies using visual inspection to screen for oral cancer and potentially malignant lesions in apparently healthy individuals over 18 years without previous diagnosis of the disease were included. The MEDLINE/PubMed, Cochrane databases Library, EMBASE, and LILACS, including manual search and gray literature, were searched through January 2021 with no language or date restrictions. The risk of bias and the methodological quality were evaluated according to the appropriate tool for each study design. The analysis of the results was narrative. Seventeen studies were reviewed that included cohort, accuracy, and randomized clinical trial studies. The tracking type performed was opportunistic and organized in a variety of environments. The age of participants ranged between 18 and 60 years old and, in some programs, only people with risk habits for oral cancer were included. The screeners were healthcare professionals, physicians, and dentists. Two studies reported data on the incidence rate of severe cases and mortality and showed a reduction when patients were at risk for the disease and participated in the program more than once. A limitation of this review was the great variability observed in the estimates of the screening effectiveness among the studies, which made comparisons difficult. If a screening program is continuous and able to ensure the inclusion of high-risk individuals, it can contribute to improvement in survival rates with a change of stage and can have a significant impact on incidence and mortality due to the disease. Registration in the Open Science Framebook (OSF) with the osf.io/zg8nr link., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: Increased mechanical sensitivity has been observed on the unaffected side in chronic pain conditions, suggesting generalized or widespread hypersensitivity. However, this cannot be considered as a universal response since this hypersensitivity is inconsistent across muscle pain pathologies. The aim of this study was to assess generalized hypersensitivity in chronic unilateral shoulder pain, using pressure pain threshold (PPT) mappings of the infraspinatus muscle. The proposed evaluation is based on the assessment of PPT on a limited subset of sites, reducing potential habituation or sensitization effects., Methods: Twenty-nine patients with unilateral shoulder pain (USP) and twenty-seven healthy volunteers were recruited. PPT was assessed using a manual pressure algometer. Six sites distributed over the infraspinatus muscle were assessed, and three repetitions were performed at each site. Mappings were derived using two-dimensional interpolation., Results: Lower PPT values were found in the symptomatic side in comparison with the asymptomatic side at all assessment sites (estimated difference: 1.42 ± 0.10 kgf/cm 2 , p < 0.001), but there were no differences among the asymptomatic side of USP patients and any of the sides in healthy volunteers (largest estimated difference: 0.17 ± 0.28 kgf/cm 2 , p = 0.927). Furthermore, the medial region of the infraspinatus muscle showed higher mechanical sensitivity in both healthy volunteers and USP patients., Conclusions: These results suggest that USP does not induce generalized hypersensitivity, in contrast with previously reported findings. Physiotherapists could take these results into account for the assessment and treatment of patients with USP., (Copyright © 2021. Published by Elsevier Ltd.)

Polysaccharides and proteins are important macromolecules for developing hydrogels devoted to biomedical applications. Chemical hydrogels offer chemical, mechanical, and dimensional stability than physical hydrogels due to the chemical bonds among the chains mediated by crosslinkers. There are many crosslinkers to synthesize polysaccharides and proteins based on hydrogels. In this review, we revisited the crosslinking reaction mechanisms between synthetic or natural crosslinkers and polysaccharides or proteins. The selected synthetic crosslinkers were glutaraldehyde, carbodiimide, boric acid, sodium trimetaphosphate, N,N'-methylene bisacrylamide, and polycarboxylic acid, whereas the selected natural crosslinkers included transglutaminase, tyrosinase, horseradish peroxidase, laccase, sortase A, genipin, vanillin, tannic acid, and phytic acid. No less important are the reactions involving click chemistry and the macromolecular crosslinkers for polysaccharides and proteins. Literature examples of polysaccharides or proteins crosslinked by the different strategies were presented along with the corresponding highlights. The general mechanism involved in chemical crosslinking mediated by gamma and UV radiation was discussed, with particular attention to materials commonly used in digital light processing. The evaluation of crosslinking efficiency by gravimetric measurements, rheology, and spectroscopic techniques was presented. Finally, we presented the challenges and opportunities to create safe chemical hydrogels for biomedical applications., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Cohort studies have displayed mixed findings on changes in mental symptoms severity in 2020, when the COVID-19 pandemic outbreak started. Network approaches can provide additional insights by analyzing the connectivity of such symptoms. We assessed the network structure of mental symptoms in the Brazilian Longitudinal Study of Health (ELSA-Brasil) in 3 waves: 2008-2010, 2017-2019, and 2020, and hypothesized that the 2020 network would present connectivity changes. We used the Clinical Interview Scheduled-Revised (CIS-R) questionnaire to evaluates the severity of 14 common mental symptoms. Networks were graphed using unregularized Gaussian models and compared using centrality and connectivity measures. The predictive power of centrality measures and individual symptoms were also estimated. Among 2011 participants (mean age: 62.1 years, 58% females), the pandemic symptom 2020 network displayed higher overall connectivity, especially among symptoms that were related to general worries, with increased local connectivity between general worries and worries about health, as well as between anxiety and phobia symptoms. There was no difference between 2008 and 2010 and 2017-2019 networks. According to the network theory of mental disorders, external factors could explain why the network structure became more densely connected in 2020 compared to previous observations. We speculate that the COVID-19 pandemic and its innumerous social, economical, and political consequences were prominent external factors driving such changes; although further assessments are warranted., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Metal injection molding (MIM) has become an important manufacturing technology for biodegradable medical devices. As a biodegradable metal, pure iron is a promising biomaterial due to its mechanical properties and biocompatibility. In light of this, we performed the first study that manufactured and evaluated the in vitro and in vivo biocompatibility of samples of iron porous implants produced by MIM with a new eco-friendly feedstock from natural rubber (Hevea brasiliensis), a promisor binder that provides elastic property in the green parts. The iron samples were submitted to tests to determine density, microhardness, hardness, yield strength, and stretching. The biocompatibility of the samples was studied in vitro with adipose-derived mesenchymal stromal cells (ADSCs) and erythrocytes, and in vivo on a preclinical model with Wistar rats, testing the iron samples after subcutaneous implant. Results showed that the manufactured samples have adequate physical, and mechanical characteristics to biomedical devices and they are cytocompatible with ADSCs, hemocompatible and biocompatible with Wistars rats. Therefore, pure iron produced by MIM can be considered a promising material for biomedical applications., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Neglected tropical diseases (NTDs) are a group of twenty-one diseases classified by the World Health Organization that prevail in regions with tropical and subtropical climate and affect more than one billion people. There is an urgent need to develop new and safer drugs for these diseases. Protein kinases are a potential class of targets for developing new drugs against NTDs, since they play crucial role in many biological processes, such as signaling pathways, regulating cellular communication, division, metabolism and death. Bioinformatics is a field that aims to organize large amounts of biological data as well as develop and use tools for understanding and analyze them in order to produce meaningful information in a biological manner. In combination with chemogenomics, which analyzes chemical-biological interactions to screen ligands against selected targets families, these approaches can be used to stablish a rational strategy for prioritizing new drug targets for NTDs. Here, we describe how bioinformatics and chemogenomics tools can help to identify protein kinases and their potential inhibitors for the development of new drugs for NTDs. We present a review of bioinformatics tools and techniques that can be used to define an organisms kinome for drug prioritization, drug and target repurposing, multi-quinase inhibition approachs and selectivity profiling. We also present some successful examples of the application of such approaches in recent case studies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: Traditional risk scores improved the definition of the initial therapeutic strategy in acute coronary syndrome (ACS), but they were not designed for predicting long-term individual risks and costs. In parallel, attempts to directly predict costs from clinical variables in ACS had limited success. Thus, novel approaches to predict cardiovascular risk and health expenditure are urgently needed. Our objectives were to predict the risk of major/minor adverse cardiovascular events (MACE) and estimate assistance-related costs., Methods: We used a 2-step approach that: (1) predicted outcomes with a common pathophysiological substrate (MACE) by using machine learning (ML) or logistic regression (LR) and compared with existing risk scores; (2) derived costs associated with noncardiovascular deaths, dialysis, ambulatory-care-sensitive-hospitalizations (ACSH), strokes, and MACE. With consecutive ACS individuals (n = 1089) from 2 cohorts, we trained in 80% of the population and tested in 20% using a 4-fold cross-validation framework. The 29-variable model included socioeconomic, clinical/lab, and coronarography variables. Individual costs were estimated based on cause-specific hospitalization from the Brazilian Health Ministry perspective., Results: After up to 12 years follow-up (mean = 3.3 ± 3.1; MACE = 169), the gradient-boosting machine model was superior to LR and reached an area under the curve (AUROC) of 0.891 [95% CI 0.846-0.921] (test set), outperforming the Syntax Score II (AUROC = 0.635 [95% CI 0.569-0.699]). Individuals classified as high risk (>90th percentile) presented increased HbA1c and LDL-C both at <24 hours post-ACS and 1-year follow-up. High-risk individuals required 33.5% of total costs and showed 4.96-fold (95% CI 3.71-5.48, P < .00001) greater per capita costs compared with low-risk individuals, mostly owing to avoidable costs (ACSH). This 2-step approach was more successful for finding individuals incurring high costs than predicting costs directly from clinical variables., Conclusion: ML methods predicted long-term risks and avoidable costs after ACS., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Diabetes patients present a complex healing process due to several factors directly linked to their pathology. The use of medicinal plants that aid in tissue repair can bring great benefits to such individuals. This case report describes how the topical application of the aqueous extract produced from the leaves of Piper amalago L. was used to aid the healing of a lacerated wound in the left thumb of a patient with type 2 diabetes mellitus. The aqueous extract of the leaves of Piper amalago L. was prepared in boiling water. During the boiling process the dried leaves were submerged in the boiling water and left for five min. The injured thumb was submerged in the solution and the leaves were placed on the injury. The action of the aqueous extract obtained from the leaves of P. amalago was shown to be promising in the healing of a wound in a patient with type 2 diabetes mellitus. The topical application of the aqueous extract produced from the leaves of P. amalago assisted in the healing of a lacerated wound in the left thumb of a patient with type 2 diabetes mellitus over a period of 15 days., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The wild type strain Trichoderma harzianum was able to synthesize enzymes that can catalyse the hydrolysis of p-nitrophenyl-β-D-glucopyranoside (PNPGase) in glucose-limited chemostat cultures. Fructose/glucose and sucrose conditions provided low levels of PNPGase activity. To investigate whether under these conditions other enzymes were produced, a shotgun proteomics analysis of their supernatants was performed. The analysis has indicated that the different carbon sources used influenced the amounts of proteins secreted including 1,3-beta-glucanosyltransferase, alpha-1,2-mannosidase, alpha-galactosidase and glucan 1,3-beta-glucosidase. The analysis has also suggested the presence of beta-glucosidase, which could also be represented by PNPGase activity. Intracellular metabolites were quantified during PNPGase production for the condition using 20 g/L of glucose in the feed and differences were observed, indicating that intracellular glucose could be inhibiting PNPGase production. SIGNIFICANCE: This work shows that sugars such as glucose, fructose/glucose and sucrose can be used as substrates for the continuous synthesis of different enzymes under carbon-limited conditions by Trichoderma harzianum. As far as we know, this is the first work about the continuous synthesis of enzymes under carbon-limited conditions suggesting that different easily assimilated carbon sources can be used to generate different enzymatic cocktails. Each enzyme or uncharacterized protein suggested by shotgun proteomics has the potential to become a promising product for biotechnological applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: To evaluate physical fitness and cardiovascular effects in rats with renovascular hypertension, two kidneys, one clip (2K1C) submitted to voluntary exercise (ExV)., Main Methods: 24 h after surgery (SHAM and 2K1C) rats were submitted to ExV for one week (adaptation). ExV adherent rats were separated into exercise (2K1C-EX and SHAM-EX) or sedentary (2K1C-SED and SHAM-SED) groups. After 4 weeks, exhaustion test, plasma lactate, cardiovascular parameters were evaluated and gastrocnemius muscle was removed for evaluation of gene expression of muscle metabolism markers (PGC1α; AMPK, SIRT-1, UCP-3; MCP-1; LDH) and of the redox process., Key Findings: ExV decreased blood lactate concentration and increased SOD and CAT activity and a SIRT-1 and UCP-3 gene expression in the gastrocnemius muscle of 2K1C-ExV rats compared to 2K1C-SED rats. Gene expressions of PGC1α, UCP-3, MCT-1, AMPK were higher in 2K1C-ExV rats compared to SHAM-SED rats. Blood pressure in 2K1C-ExV was lower compared to 2K1C-SED and higher in SHAM-SED rats. Reflex bradycardia in 2K1C-EX rats increased compared to 2K1C-SED and was similar to SHAM-SED. The variation in mean blood pressure induced by ganglion blocker hexamethonium and Ang II AT1 receptor antagonist, losartan in the 2K1C-ExV rats was smaller compared to the 2K1C-SED rats and it was similar to the SHAM-SED rats., Significance: O ExV induced adaptive responses in 2K1C-ExV rats by decreasing sympathetic and Ang II activities and stimulating intracellular signaling that favors redox balance and reduced blood lactate concentration. These adaptive responses, then, contribute to reduced arterial pressure, improved baroreflex sensitivity and physical fitness of 2K1C rats., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020. Published by Elsevier Inc.)

Background: Induction chemotherapy in locally-advanced head and neck squamous cell carcinoma (LAHNSCC) patients is potentially associated to serious adverse events. Biomarkers associated with toxicity could tailor its indication. This study evaluated the association between single-nucleotide polymorphisms (SNPs) in metabolic genes and toxicity to induction chemotherapy., Methods: 59 LAHNSCC phase II clinical trial patients (NCT00959387) were assessed regarding 47 metabolic genes (366 SNPs). Toxicities were graded (CTCAE 3.0) and statistical analysis was performed., Results: The SNPs rs8187710 (ABCC2) and rs1801131 (MTHFR) were associated to increased risk of gastrointestinal toxicity, whereas the SNPs rs3788007 (ABCG1) and rs4148943 (CHST3) were associated to decreased risk. Two other SNPs, rs2301159 (SLC10A2) and rs2470890 (CYP1A2), were associated with increased risk of hematological toxicity. Nevertheless, these SNPs did not remain significant after adjusting for multiple comparisons., Conclusions: This study could not demonstrate relationship between SNPs and toxicity to induction chemotherapy in LAHNSCC patients. The small number of patients may have affected the results., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aim: Investigate cardiac electrical and mechanical dysfunctions elicited by chronic anabolic steroid (AS) overdose., Methods: Male Wistar rats were treated with nandrolone decanoate (DECA) or vehicle (CTL) for 8 weeks. Electrocardiography and heart rate variability were assessed at weeks 2, 4, and 8. Cardiac reactivity to isoproterenol was investigated in isolated rat hearts. Action potential duration (APD) was measured from left ventricular (LV) muscle strips. L-type Ca 2+ current (I CaL ), and transient outward potassium current (I to ) were recorded by whole-cell patch-clamp in LV cardiomyocytes. Sarcoplasmic reticulum (SR) Ca 2+ mobilization and Ca 2+ -induced contractile response sensitivity were evaluated in skinned cardiac fibers. Muscarinic type 2 receptor (M 2 R), β 1 -adrenergic receptor (β 1 AR), sarcoplasmic Ca 2+ ATPase (SERCA-2a), type 2 ryanodine receptor (RyR2), L-type Ca 2+ channel (CACNA1), Kv4.2 (KCND2), and Kv4.3 (KCND3) mRNA expression levels were measured by quantitative RT-PCR., Results: Compared with CTL group, DECA group exhibited decreased high frequency band power density (HF) and increased low frequency power density (LF), Cardiac M 2 R mRNA level was decreased. QTc interval at 2nd, 4th, and 8th week as well as APD 30 and APD 90 were increased by DECA. I to density was decreased, while I CaL density was increased by DECA. SR Ca 2+ loading and release were decreased by DECA, while contractile sensitivity to Ca 2+ was increased versus CTL group., Conclusion: DECA overdose induced cardiac rhythmic and mechanical abnormalities that can be associated with autonomic imbalance, up-regulated I CaL and down-regulated I to , abnormal SR Ca 2+ mobilization, and increased contractile sensitivity to Ca 2+ ., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: There is evidence that acute periapical lesions present a greater potential for cyst formation. Recently, it was found that these lesions have cells with characteristics of pluripotent stem cells, which may influence cyst development. However, a more complete phenotype investigation of stem cells in a specific sample of periapical abscesses is required. The aim of this study was to analyze the immunohistochemical expression of mesenchymal stem cell (MSC) markers in periapical abscesses and to evaluate differences in their expression in relation to acute and chronic periapical lesions., Methods: Immunohistochemistry was used to access MSC marker expression (CD44, CD73, and CD105) in samples of periapical abscesses (n = 10), granulomas (n = 10), cysts (n = 10), and apical papillae (n = 10). Immunohistochemical expression was evaluated by a quantitative scoring system. The chi-square test was used to assess the association between MSC marker expression and the histopathological diagnosis at a 5% significance level., Results: CD44 and CD73 immunostaining was observed in mesenchymal cells located in the outer portion of the abscess and periapical cyst specimens. CD105 immunoexpression was found predominantly in mesenchymal and vascular endothelial cells of the lesions studied. MSC marker expression was higher in the periapical abscesses, with a significant association between MSCs and the histopathological diagnosis of an abscess (P < .05)., Conclusions: The periapical region is a rich source of MSCs. The greater presence of MSCs in periapical abscesses found in this study could hold an important clue into understanding the pathological pathway of periapical cyst formation., (Copyright © 2019 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

The presence of lymphovascular invasion is considered a prognostic determinant for different human neoplasms and is frequently taken into account by surgeons and oncologists to determine patients' treatment. However, the exact frequency of this microscopic event and its prognostic impact for patients affected by adenoid cystic carcinoma (AdCC) remains unclear. Therefore, the aim of this study was to carry out a systematic review and meta-analysis to address the prevalence and the prognostic potential of lymphovascular invasion in head and neck AdCC. A literature search on PubMed, Scopus, ClinicalTrials.gov, Web of Science and ProQuest databases was undertaken in January 2019. The primary outcomes of interest were overall survival (OS) and disease-free survival (DFS). The relative frequency of lymphovascular invasion and its possible association with other clinicopathological parameters were addressed. A total of 22 studies and 2117 patients were included in this study. The frequency of lymphovascular invasion ranged from 5.2% to 72.5%. Lymphovascular invasion was associated with an increased likelihood of lymph node metastasis (OR = 2.58; 95% CI 1.61-4.12; p = 0.0001) and death (OR = 3.09; 95% CI 1.82-5.26; p = 0.0001), solid/higher-grade AdCC were more likely to present lymphovascular invasion (OR = 5.51; 95% CI 1.87-16-21; p = 0.002) and patients with this microscopic finding had a significantly lower OS (HR = 8.30; 95% CI 1.68-40.91; p = 0.009) and DFS (HR = 3.76; 95% CI 1.13-12.53; p = 0.03). In conclusion, lymphovascular invasion seems to be a significant predictor of poor prognosis for head and neck AdCC patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The aim of the present study was to verify the effect of selenomethionine (SM) supplementation in the diet of chickens on performance, carcass yield, apparent retention, meat quality, and selenium (Se) deposition in tissues. In the first experiment, 2,100 day-old male chicks from the Hubbard Flex strain were randomly distributed in 84 plots with 12 treatments and 7 replicates. The treatments consisted of SM (1,600 ppm) supplementation at levels of 0.3 and 0.5 ppm in substitution of sodium selenite (45.7%) in different preslaughter phases. In the second experiment, 224 day-old male chicks from Hubbard Flex strain were randomly distributed in 28 metabolic cages. Poultry were distributed in 4 treatments with 7 replicates (8 poultry) in the experimental period from 1 to 21 D and experimental plot with 4 poultry aged from 22 to 42 D. Treatments consisted of 4 SM addition levels (0.3, 0.4, 0.5, and 0.6 ppm). In both experiments, the performance (1 to 21 and 1 to 42 D), carcass yield and cuts, apparent retention of Se (33 to 35 D), physical and chemical characteristics of the breast meat were evaluated: objective color, drip loss (DL), cooking loss (CL), pH, peroxide value, and Se deposition in tissues. In experiment I, it was found that SM at 0.3 ppm improved the weight gain and feed conversion of 1 to 42 D. The use of SM at 0.5 ppm resulted in lower DL and CL. The highest Se deposition in muscles was obtained using the SM at 0.5 ppm of 1 to 42 D. Using the SM at 0.5 ppm, only in the last week there was a deposition similar to the use of SM at 0.3 ppm of 1 to 42 D. In experiment II, it can be observed that increased SM levels provided lower DL and lower pH values. Se deposition in tissues of broiler chickens increased linearly at the SM level from 0.3 to 0.6 ppm., (© 2018 Poultry Science Association Inc.)

Twenty-one isovanillin derivatives were prepared in order to evaluate their cytotoxic properties against the cancer cell lines B16F10-Nex2, HL-60, MCF-7, A2058 and HeLa. Among them, seven derivatives exhibited cytotoxic activity. We observed that for obtaining smaller IC 50 values and for increasing the index of selectivity, two structural features are very important when compared with isovanillin (1); a hydroxymethyl group at C-1 and the replacement of the hydroxyl group at C-3 by different alkyl groups. As the lipophilicity of the compounds was changed, we decided to investigate the interaction of the cytotoxic isovallinin derivatives on cell membrane models through Langmuir monolayers by employing the lipids DPPC (1,2-diplamitoyl-sn-glycero-3-phosphocoline) and DPPS (1,2-diplamitoyl-sn-glycero-3-phosphoserine). The structural changes on the scaffold of the compounds modulated the interaction with the phospholipids at the air-water interface. These results were very important to understand the biophysical aspects related to the interaction of the cytotoxic compounds with the cancer cell membranes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: The objective of the present study was to investigate the expression of immune checkpoints (PD-L1, PD-L2, PD-1 and CTLA-4), immune inhibitory molecule HLA-G, markers of tumor-infiltrating lymphocytes (TIL) and dendritic cells (DC), as well as its association with clinicopathological features of adenoid cystic carcinomas (ACC) of the salivary glands., Materials and Methods: Thirty-six samples from patients with ACC were analyzed immunohistochemically for the expression of PD-L1, PD-L2, PD-1, CTLA-4, HLA-G, CD8, GrB, CD1a and CD83. Positivity of HLA-G, PD-L1 and PD-L2 expression was defined by cut-offs values. CD8 + TIL was measured semiquantitatively and also using cut-off values obtained by the ROC curve considering recurrence of the lesion., Results: ACC showed low CD8 + , GrB +  TIL, CD1a and CD83 populations, as well as scarce positivity for CTLA-4 and PD-1. In contrast, PD-L2 and HLA-G expression was increased, while no PD-L1 expression was detected. Interestingly, cases with lower CD8 + TIL density presented greater recurrence rates., Conclusion: Our findings suggest that the ACC microenvironment exhibits low immunogenicity, represented by low TIL and DC density. Moreover, there seems to be activation of the immune inhibitory proteins/PD-L2 and HLA-G, a scenario that may favor tumor escape from the immune system and partially explain the poor prognosis of ACC., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Diseases involving cilia dysfunction, such as Usher Syndrome (USH), often involve visual and auditory loss. Psychophysical evidence has suggested that this may also hold true for the peripheral olfactory domain. Here we aimed to go a step further by attempting to establish relations between the integrity of cortical structures and olfactory function in this condition. We investigated olfactory function for USH types 1 (USH1) and 2 (USH2). Bilateral olfactory bulb (OB) volume and olfactory sulcus (OS) depth were also analysed. Thirty-three controls with no previous olfactory deficits were age, sex and handedness-matched to 32 USH patients (11 USH1, 21 USH2). A butanol detection threshold test was performed to measure olfactory function. For OB volume and OS depth, morphometric measurements were performed using magnetic resonance imaging (MRI) based on detailed segmentation by three independent operators. Averaged values across these were used for the statistical analyses. Total intracranial volume was estimated using Freesurfer to account for head size variability. Olfactory threshold was significantly lower in controls when compared to USH, USH1, and USH2. OS depth was found to be shallower in both hemispheres in USH patients when compared with the control group. OB volume was not significantly different between control and USH groups, or respective subgroups. Nevertheless, butanol threshold was negatively correlated with the left OB volume for the USH type 1 subgroup. The main effect of OS depth reduction was found to be mainly due to the comparison between USH2 and controls. Our results provide evidence for morphometric changes and olfactory dysfunction in patients with USH. This correlated with a reduction in left OB volume in the USH1 subgroup, the most severe USH phenotype. The main effect of reduced OS depth was found to stem mainly from USH2 raising questions regarding a possible complex interaction between sensory olfactory loss and central cortical changes in this disease., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

To1, previously named Tc49b, is a peptide neurotoxin isolated from venom of the scorpion Tityus obscurus that is responsible for lethal human poisoning cases in the Brazilian Amazonian region. Previously, To1 was shown to be lethal to mice and to change Na + permeation in cerebellum granular neurons from rat brain. In addition, To1 did not affect Shaker B K + channels. Based on sequence similarities, To1 was described as a β-toxin. In the present work, To1 was purified from T. obscurus venom and submitted to an electrophysiological characterization in human and invertebrate Na V channels. The analysis of the electrophysiological experiments reveal that To1 enhances the open probability at more negative potentials of human Na V 1.3 and 1.6, of the insect channel BgNa V 1 and of arachnid VdNa V 1 channel. In addition, To1 reduces the peak of Na + currents in some of the Na V s tested. These results support the classification of the To1 as a β-toxin. A structure and functional comparison to other β-toxins that share sequence similarity to To1 is also presented., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: This study's aim was to evaluate the local effect of clarithromycin associated with antimicrobial photodynamic therapy (aPDT) in the treatment of generalized aggressive periodontitis., Materials and Methods: The study sample comprised 72 periodontal pockets on single-rooted teeth in multiple quadrants, with both probing depth and clinical attachment level ≥5 mm, and with bleeding on probing. The pockets were randomly distributed into four groups (n = 18 each) that received ultrasonic periodontal debridement in addition to placebo (the UPD group), systemic clarithromycin (the UPD + CLM group), aPDT (the UPD + aPDT group), or both systemic clarithromycin and aPDT (the UPD + CLM + aPDT group). The measurements were performed prior to treatment (baseline) and at 3 and 6 months postoperatively. The following parameters were evaluated: plaque index, bleeding on probing, probing depth, gingival recession, and clinical attachment level. A 5% significance level was used in the statistical analysis., Results: At 3 months, UPD + aPDT, UPD + CLM, and UPD + CLM + aPDT groups all exhibited reduced probing depths relative to the UPD group (p <  0.05). However, at 6 months, the reduction in mean probing depth was greater in the antibiotic groups (UPD+CLM and UPD+CLM+aPDT) than in the UPD and UPD+aPDT groups (p <  0.05). Regarding clinical attachment level, only the UPD+CLM+aPDT group presented a significant gain relative to the UPD and UPD + PDT groups (p <  0.05)., Conclusions: Ultrasonic periodontal debridement has greater clinical advantages when associated with clarithromycin than with associated with aPDT. However, the joint application of aPDT and clarithromycin did not present additional benefits., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Preclinical repeated-dose toxicity and efficiency studies developed by our group suggest the potential of FITOPROT in treating mucositis. This serious limiting side effect is observed at a rate of 40-100% in patients under antineoplastic therapy and despite different palliative measures and therapeutic agents have been investigated, still no therapy was completely successful. Therefore, this study aimed to establish the safety and recommended phase II dose of FITOPROT for the prevention and treatment of chemoradiotherapy-induced oral mucositis (OM) in patients with head and neck cancer. Twenty healthy adult participants were randomized into two groups that received pre-established concentrations of the collutory: group 1 (FITOPROT A - mucoadhesive formulation containing 10 mg/mL of curcuminoids extract plus 20% v/v of Bidens pilosa L. extract) and group 2 (FITOPROT B - mucoadhesive formulation containing 20 mg/mL of curcuminoids extract, plus 40% v/v of Bidens pilosa L. extract). Participants rinsed their mouths with FITOPROT, three times daily, for ten consecutive days. No participant experienced toxicity or unacceptable discomfort and/or adverse reactions (CTCAE v5.0), with laboratory and clinical parameters under normal conditions. Side effects observed were low intensity and temporary mucosa/dental surface pigmentation (n = 7) and tooth sensitivity (n = 4), which disappeared after formulation use ceased. No significant cellular genotoxic effects were observed (p > 0.05), and micronuclei frequencies were not changed (p > 0.05). Biochemical assays reveled no altered levels of myeloperoxidase (p = 0.2268), malondialdehyde (p = 0.1188) nor nitric oxide (p = 0.5709) concentration, and no significant difference were found in the levels of pro-inflammatory cytokines (p > 0.05). Thus, FITOPROT demonstrated to be safe and tolerable in both tested doses and is suitable for evaluation in a phase II trial as treatment against OM., (Copyright © 2018. Published by Elsevier B.V.)

Objectives: The goal of this study was to demonstrate that cardiac magnetic resonance could reveal anthracycline-induced early tissue remodeling and its relation to cardiac dysfunction and left ventricular (LV) atrophy., Background: Serum biomarkers of cardiac dysfunction, although elevated after chemotherapy, lack specificity for the mechanism of myocardial tissue alterations., Methods: A total of 27 women with breast cancer (mean age 51.8 ± 8.9 years, mean body mass index 26.9 ± 3.6 kg/m 2 ), underwent cardiac magnetic resonance before and up to 3 times after anthracycline therapy. Cardiac magnetic resonance variables were LV ejection fraction, normalized T2-weighted signal intensity for myocardial edema, extracellular volume (ECV), LV cardiomyocyte mass, intracellular water lifetime (τ ic ; a marker of cardiomyocyte size), and late gadolinium enhancement., Results: At baseline, patients had a relatively low (10-year) Framingham cardiovascular event risk (median 5%), normal LV ejection fractions (mean 69.4 ± 3.6%), and normal LV mass index (51.4 ± 8.0 g/m 2 ), a mean ECV of 0.32 ± 0.038, mean τ ic of 169 ± 69 ms, and no late gadolinium enhancement. At 351 to 700 days after anthracycline therapy (240 mg/m 2 ), mean LV ejection fraction had declined by 12% to 58 ± 6% (p < 0.001) and mean LV mass index by 19 g/m 2 to 36 ± 6 g/m 2 (p < 0.001), and mean ECV had increased by 0.037 to 0.36 ± 0.04 (p = 0.004), while mean τ ic had decreased by 62 ms to 119 ± 54 ms (p = 0.004). Myocardial edema peaked at about 146 to 231 days (p < 0.001). LV mass index was associated with τ ic (β = 4.1 ± 1.5 g/m 2 per 100-ms increase in τ ic , p = 0.007) but not with ECV. Cardiac troponin T (mean 4.6 ± 1.4 pg/ml at baseline) increased significantly after anthracycline treatment (p < 0.001). Total LV cardiomyocyte mass, estimated as: (1 - ECV) × LV mass, declined more rapidly after anthracycline therapy, with peak cardiac troponin T >10 pg/ml. There was no evidence for any significant interaction between 10-year cardiovascular event risk and the effect of anthracycline therapy., Conclusions: A decrease in LV mass after anthracycline therapy may result from cardiomyocyte atrophy, demonstrating that mechanisms other than interstitial fibrosis and edema can raise ECV. The loss of LV cardiomyocyte mass increased with the degree of cardiomyocyte injury, assessed by peak cardiac troponin T after anthracycline treatment. (Doxorubicin-Associated Cardiac Remodeling Followed by CMR in Breast Cancer Patients; NCT03000036)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Four human iPSC cell lines (one Jervell and Lange-Nielsen Syndrome, one Long QT Syndrome-type 1 and two healthy controls) were generated from peripheral blood obtained from donors belonging to the same family. CytoTune™-iPS 2.0 Sendai Reprogramming Kit (containing OCT3/4, KLF4, SOX2 and cMYC as reprogramming factors) was used to generate all cell lines. The four iPSCs have normal karyotype, express pluripotency markers as determined by RT-PCR and flow cytometry and differentiated spontaneously in vitro into cells of the three germ layers, confirming their pluripotent capacity., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Amblyomma rotundatum is an ixodid tick strictly associated with cold-blooded animals, among them the toad Rhinella jimi. This work aimed to evaluate the seasonal dynamics of larvae, nymphs, and adults of A. rotundatum parasitizing R. jimi in an area within the semi-arid Caatinga Biome of northeastern Brazil. Monthly sampling from February 2014 to January 2016 resulted in a total of 592 R. jimi toads captured and inspected for infestation by ticks, which were counted and identified. After the procedure, the toads were released with their ticks at the same capture site. During the study period, a total of 658 A. rotundatum were counted, comprising 497 larvae, 110 nymphs, and 51 females. The two-year mean abundances of larvae, nymphs, and adults were 0.84, 0.19, and 0.09, respectively. The two-year mean infestation intensities of larvae, nymphs, and adults were 3.65, 1.45, and 1.34, respectively. Comparing the monthly values of prevalence, mean abundance, and mean infestation intensity of A. rotundatum life stages, differences were observed between the first and second year of study; however, with no clear seasonal pattern., (Copyright © 2018. Published by Elsevier GmbH.)

Background: Tooth sensitivity commonly occurs during and immediately after dental bleaching. The authors conducted a trial to compare tooth sensitivity after in-office bleaching after the use of either a topical dipyrone or placebo gel., Methods: A split-mouth, triple-blind, randomized, multicenter clinical trial was conducted among 120 healthy adults having teeth that were shade A2 or darker. The facial tooth surfaces of the right or left sides of the maxillary arch of each patient were randomly assigned to receive either topical dipyrone or placebo gel before 2 in-office bleaching sessions (35% hydrogen peroxide) separated by 2 weeks. Visual analog and numerical rating scales were used to record tooth sensitivity during and up to 48 hours after bleaching. Tooth color change from baseline to 1 month after bleaching was measured with shade guide and spectrophotometer measures. The primary outcome variable was absolute risk of tooth sensitivity. An intention-to-treat analysis was used to analyze data from all patients who were randomly assigned to receive the dipyrone and placebo gels., Results: No statically significant difference was found in the absolute risk of tooth sensitivity between the dipyrone and placebo gels (83% and 90%, respectively, P = .09; relative risk, 0.92; 95% confidence interval, 0.8 to 1.0). A whitening effect was observed in both groups with no statistically significant difference (P > .05) between them. No adverse effects were observed., Conclusion: Topical use of dipyrone gel before tooth bleaching, at the levels used in this study, did not reduce the risk or intensity of bleaching-induced tooth sensitivity., Practical Implications: Topical application of dipyrone gel does not reduce bleaching-induced tooth sensitivity., (Copyright © 2018 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Introduction: The aim of this article was to evaluate the influence of applying filters in cone-beam computed tomography (CBCT) images at different resolutions. These CBCT images were obtained for diagnosing mesiodistal vertical root fractures (VRFs) in teeth with metal posts., Methods: Forty teeth were treated endodontically, and 20 received metal posts. Ten teeth without posts and 10 teeth with posts were subjected to VRF in the mesiodistal direction. The sample was submitted to periapical radiographs and CBCT exams with a voxel of 0.25 and 0.30 mm. To reduce the influence of the metal artifact in the CT images, the teeth were evaluated with and without the application of filters ("Sharpen" and "Hard"). The images were evaluated by 2 radiologists who identified the presence of VRF. Accuracy values (receiver operating characteristic curves) for the different variables were compared by using analysis of variance and t test., Results: No difference was observed between images with and without filter application (P > .05). Images obtained with a 0.25-mm voxel were more accurate (P < .05). The presence of the metal post reduced the accuracy of the diagnosis of VRF (P < .05), and the CBCT images showed superior results compared with periapical radiographs (P < .05)., Conclusions: The presence of a metal post and the voxel size significantly interfere with the diagnosis of VRF. Despite the formation of metal artifacts associated with metallic cores, applying filters did not improve the diagnosis. For mesiodistal VRF, the CBCT images are superior to the periapical radiographs., (Copyright © 2017 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Aims: This study evaluated the mechanisms involved in the chemopreventive effects of a mucoadhesive formulation (FITOPROT), containing curcuminoids from Curcuma longa L. (Zingiberaceae) and Bidens pilosa L. (Asteraceae) extract, against 5-FU-induced cellular toxicity using an in vitro oral mucositis model., Main Methods: Effects of FITOPROT on 5-FU-induced cytotoxicity in HaCaT and SSC-4 cells were evaluated by MTT assay. For mechanistic analyses, HaCaT cells were first pretreated with FITOPROT (0.005%) for 24h followed by treatment with FITOPROT and simultaneously exposed to 5-FU (10μg/mL) for additional 24h., Key Findings: FITOPROT was able to protect HaCaT cells from 5-FU-triggered cell damage. Moreover, the FITOPROT+5-FU association showed higher cytotoxic effects on SSC-4 cancer cells. Flow cytometry and/or fluorescence microscopy analysis showed FITOPROT was able to significantly reduce ROS generation and prevent mitochondrial changes in HaCaT cells. In addition, it avoided the release of cytochrome c from mitochondria to the cytoplasm in cells exposed to 5-FU, and restored their proliferative activity via Ki-67 expression. Furthermore, FITOPROT regulated 5-FU-induced oxidative stress via Nrf2 involvement. HaCaT cells pretreated/treated with FITOPROT also showed normal expression of TNF-R1 and NF-κB inflammatory proteins and decreased levels of pro-inflammatory cytokines (TNF, IL-1β, IL-6 and IL-8). Moreover, a high-resolution liquid chromatography-mass spectrometry analysis showed the presence of flavonoids rutin, glucoronylated quercetin and dimethylquercetin rutenoside in FITOPROT., Significance: It was showed that FITOPROT, an antioxidant phytochemicals-rich mucoadhesive formulation, exerts chemopreventive effects against 5-FU-triggered toxicity through antioxidant and anti-inflammatory mechanisms and restoration of proliferative capacity in HaCaT cells., (Copyright © 2017. Published by Elsevier Inc.)

Objectives: To investigate the frequency of malignant oral and maxillofacial lesions among children and adolescents from representative geographic regions of Brazil., Materials and Methods: A retrospective study was conducted on biopsies obtained from 1990 to 2016 at six Brazilian oral and maxillofacial pathology referral centers. A total of 85,105 biopsy specimens from children and adolescents were analyzed. Gender, age, anatomical location, symptomatology and histopathological diagnosis were evaluated. Data were analyzed using descriptive statistical methods., Results: Fifty-eight (0.06%) malignant oral and maxillofacial lesions were diagnosed in children (19%) and adolescents (81%). The lesions were more frequent among females (60.3%) and adolescents. The most prevalent lesions were mucoepidermoid carcinomas (22.4%), osteosarcomas (13.8%), squamous cell carcinomas (12.1%), and Burkitt's lymphomas (12.1%). The most commonly affected sites were the palate (19%), mandible (13.8%), and maxilla (13.8%). Almost half the patients were asymptomatic., Conclusion: Pediatric oral and maxillofacial malignant lesions were infrequent and showed wide diversity, with a prevalence of mucoepidermoid carcinomas. Analysis of malignant lesions in children and adolescents helps pediatric dentists and oncologists to obtain a better understanding of such lesions and to reduce the time for diagnosis, with a consequent improvement of prognosis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In this review of cell therapies in Chagas disease, we cover aspects related to the disease, its treatment and world demographics, before proceeding to describe the preclinical and clinical trials performed using cell therapies in the search for an alternative therapy for the most severe and lethal form of this disease, chronic chagasic cardiomyopathy., (Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Scientific evidences have highlighted 5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)-2H-tetrazole (LQFM021) as a promising anti-inflammatory, analgesic and antinociceptive agent due to its effects on peripheral opioid receptors associated with activation of the nitric oxide/cGMP/K ATP pathway. Despite these important pharmacological findings, toxicity data of LQFM021 are scarce. Thus, this study investigated the in vitro genotoxicity of LQFM021 through cytokinesis-block micronucleus assay (OECD Nº 487/2014). Moreover, zebrafish model was used to assess the embryotoxicity potential of LQFM021 using fish embryo toxicity test (OECD Nº 236/2013) with extended exposure to evaluate subchronic larval development. In vivo subchronic toxicity of LQFM021 in rats (OECD Nº 407/2008) was also conducted. This compound at the lower concentrations tested (3.1 and 31 μg/mL) did not promote changes in micronuclei frequency in HepG2 cells. However, in the higher concentrations of LQFM021 (310 and 620 μg/mL) triggered a significant increase of micronucleated HepG2 cells, showing an alert signal of potential genotoxicity. Regarding the oral treatment of rats with LQFM021 (62.5, 125 or 250 mg/kg) for 28 days, the main findings showed that LQFM021 promoted renal and liver changes in a dose-dependent manner, being irreversible damage for kidneys while liver tissue showed a recovery after 14 days post treatment. Regarding embryotoxicity, although the lower concentrations used did not show toxicity, the concentration of LQFM021 (39.8 and 100 mg/L) promoted malformations in zebrafish embryo-larvae stage, in especial cardiac tissue changes. In conclusion, anti-inflammatory compound LQFM021 seems to have some limiting factors as a new therapeutic option to be used orally and in high repeated doses, related to those found in the non-steroidal anti-inflammatory drugs (NSAIDs)., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We report a case of a patient with lymphocutaneous sporotrichosis in the right upper limb. The fungus was identified as Sporothrix schenckii senso stricto by calmodulin gene sequencing. The initial treatment was itraconazole (200 mg/day), but in vitro antifungal susceptibility demonstrated high resistant to this and another six antifungals, with exception to terbinafine. The lesions did not regress with itraconazole treatment. Thus, 500 mg/day of terbinafine was prescribed and clinical cure was obtained after four months.

Fibrous mats built from biopolymer have been extensively explored for tissue engineering due mainly to their mimic structure to the extracellular matrix. The incorporation of drug in such scaffolds represents a growing interest for control drug delivery system in order to promote the tissue repair. In the present work, we present an experimental investigation of morphological, thermal, mechanical, drug release, antibacterial and cytotoxicity properties of electrospun PVA/Chitosan and PVA/Chitosan/Tetracycline hydrochloride (TCH) mats for wound dressing. Fibrous mats with cross-linked three-dimensional nanofibers were formed from the polymer blends. A uniform incorporation of drug was achieved along the nanofibers with not significant change on the morphological and thermal properties of the mats. Furthermore, the TCH release profile with a burst delivery during the first 2h allows an effective antibacterial activity on the Gram-negative Escherichia coli as well as on the Gram-positive Staphylococci epidermidis and Staphylococcus aureus. In vitro indirect MTT assay also showed that the developed drug-loaded nanofibrous scaffolds have good cytocompatibility, which was confirmed by scratch assay, indicating that the investigated scaffold may be used as antibacterial wound dressing for healing promotion., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Cardiac arrhythmias are one of the main causes of death in ChCP and other dilated cardiomyopathies. Previous studies demonstrated that ventricular arrhythmias are associated with the presence of autoantibodies with beta-adrenergic activity, Ab-β., Objectives: The aim of this study was to investigate whether Ab-β, present in chronic chagasic patients (ChCP), induce cardiac arrhythmias in the pharmacological type-2 long QT syndrome model (LQTS-2)., Methods/results: The LQTS2 was established by perfusion of Tyrode saline solution with a potassium channel blocker E-4031 (5μM) in isolated rabbit hearts or in rabbit cardiac strips, in order to record ECG or action potential, respectively. Autoantibodies from ChCP activating (Ab-β) or not (Ab-NR) cardiac beta 1-adrenergic receptors were used. Ab-β, but not Ab-NR, were able to significantly shorten QT, QTc and increase Tpeak-Tend interval in the LQTS-2. A positive correlation between higher QTc and Tpeak-Tend was found after Ab-β perfusion in the same model. In addition, in the LQTS-2 model, in almost 75% (11/15) of the hearts perfused with Ab-β, ventricular and atrio-ventricular electrical disturbances were observed. Atenolol abolished all Ab-β-induced arrhythmias. Ab-β, when perfused in a cellular LQTS-2, drastically reduced the action potential duration and evoked early afterdepolarization (EAD's), while Ab-NR did not modulate the AP properties in the LQTS-2., Conclusion: The results indicate that Ab-β were able to induce cardiac arrhythmias and EAD's. This phenomenon can explain, at least in part, the cellular mechanism of Ab-β-induced arrhythmias. Furthermore, atenolol is effective for the treatment of Ab-β-induced arrhythmias., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the influence of lip retraction on cone beam computed tomography (CBCT) assessment of bone and gingival tissues on the labial surface of the anterior maxilla., Study Design: A retrospective study was conducted using measurements of bone and gingival tissues collected from 120 maxillary incisors. The thicknesses of the bone and gingival tissues of different regions were measured on CBCT images, with and without a lip retractor. The thicknesses of the gingival tissues obtained from CBCT were correlated with measurements performed by clinical probing., Results: The thickness of bone in the more cervical region presented a higher mean value for exams performed with a lip retractor (P = .021). The thickness of bone found a significant correlation with the thickness of the gingiva (P ≤ .020) with a lip retractor in CBCT exams. The thickness of the gingival tissue obtained from CBCT scans with lip retraction found significant correlations with those obtained clinically (P ≤ .001)., Conclusions: The use of lip retractors is a simple and reliable practice that allows the measurement of gingival tissues on CBCT images. This practice can exempt a patient from an invasive clinical procedure for measuring the thickness of the gingival tissue for implant cases of the anterior segment., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to investigate the expression of human leukocyte antigens (HLAs) G and E and programmed death-ligand 1 (PD-L1) in oral osteosarcoma (OO) (n = 13). The relationship between the expression of these molecules and histologic grading and metastasis was also evaluated., Study Design: HLA-G, HLA-E, and PD-L1 were identified by immunohistochemistry. Samples of normal bone tissue (n = 6) were used as controls. The sections were evaluated using a semiquantitative scoring system with an immunoreactive score, where a score of 0 was considered absent, ≤2 was low, and >2 was high expression., Results: We identified high expression of HLA-G, HLA-E, and PD-L1 by malignant osteoblastic cells in 69.2% of OO cases, which was statistically higher than that in controls (P < .05). Overexpression of these proteins was identified in 8 of 11 samples of high-grade and 1 of 2 samples of low-grade OO. Additionally, 66.6% of patients with metastases (n = 4) and 71.4% of patients without metastases (n = 5) had high expression of HLA-G, HLA-E, and PD-L1 in tumor samples (P > .05)., Conclusion: OO had high expression of HLA-G, HLA-E, and PD-L1 irrespective of clinicopathologic parameters, including histologic grading and metastasis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Eisenmenger syndrome (ES) precipitates the extreme manifestation of pulmonary hypertension, which leads to severe functional limitation and poor quality of life. The propose of the current study was: 1) examined the acute effects of 40% oxygen supplementation during the 6-minute walk test (6MWT); and 2) evaluate the relation between exercise capacity and clinical cardiac parameters in patients with ES., Methods: Thirty subjects were prospectively included; all were submitted to a 6MWT with compressed air and with 40% of oxygen. Heart rate recovery at the first minute (HRR 1 ) and perceived effort Borg scale for dyspnea and lower limb fatigue were recorded in both tests scenarios., Results: The 6MWT distance was modestly, negatively associated with pulmonary vascular resistance (PVR) [r=0.46, p=0.02]. Patients improved 6MWT distance (p<0.001) and exhibited a faster HRR 1 (p<0.001) with 40% supplemental oxygen compared to compressed air. With 40% supplemental oxygen, subjects revealed lower dyspnea and lower limb fatigue compared to 6MWT without oxygen supplementation (p<0.001). The amount of change in the 6MWT distance from air to oxygen was moderate, positively associated with tricuspid annular plane systolic excursion (TAPSE) and right ventricular fractional area change (RV FAC ) [r=0.50, p=0.03; r=0.64, p<0.001, respectively]., Conclusion: Acute 40% oxygen supplementation in patients with Eisenmenger syndrome led to an improvement in 6MWT distance, faster HRR 1 and lower dyspnea and lower limb fatigue perception. Moreover, functional capacity was positively associated with right ventricular parameters., (Copyright © 2017. Published by Elsevier B.V.)

Background: A pharmacodynamic comparison between ticagrelor and prasugrel after fibrinolytic therapy has not yet been performed., Methods: In the single-center SAMPA trial, 50 consecutive STEMI patients previously treated with clopidogrel and undergoing a pharmacoinvasive strategy were randomized to either a ticagrelor (n=25) 180mg loading dose followed by 90mg bid, or a prasugrel (n=25) 60mg loading dose followed by 10mg/day, initiated after fibrinolytic therapy but before angiography. Platelet reactivity was assessed with the VerifyNow P2Y 12 assay at 0, 2, 6, and 24h after randomization., Results: Mean times from fibrinolysis to prasugrel or ticagrelor administration were 11.1±6.9 and 13.3±6.3h, respectively (p=0.24). The values of PRU decreased significantly from baseline to 2h (all p<0.001) and from 2h to 6h (all p<0.001) in both groups. There was no difference in PRU values between 6h and 24h. The mean PRU values at 0, 2, 6, and 24h were 234.9, 127.8, 45.4, and 48.0 in the prasugrel group and 233.1, 135.1, 67.7, and 56.9 in the ticagrelor group, respectively. PRU values did not significantly differ between groups at any time period of the study., Conclusions: In patients with STEMI treated with fibrinolytic therapy, platelet inhibition after clopidogrel is suboptimal and can be further increased with more potent agents. Ticagrelor and prasugrel demonstrated a similar extent of P2Y 12 receptor inhibition within 24h, although maximal platelet inhibition after these potent agents was not achieved for 6h., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

A new molecule, LQFM048, originally designed through molecular hybridization using green chemistry approach, is in development as a photoprotective agent. Eye irritation, skin toxicity and genotoxicity evaluations are mandatory for predicting health risks. In this context, the purpose of this study was to investigate the eye irritation potential of LQFM048 by combining Short Time Exposure (STE), Bovine Corneal Opacity and Permeability (BCOP) associated with corneal histomorphometry and Hen's Egg Test-Chorioallantoic Membrane (HET-CAM). Additionally, skin toxicity was evaluated by interleukin-18 production in the HaCaT keratinocyte, Local Lymph Node Assay (LLNA:BrdU-ELISA) method, 3T3 Neutral red uptake (NRU) assay and in vivo phototoxicity test. Genotoxic potential of LQFM048 was also analyzed by cytokinesis-block micronucleus assay (MNvit test-cytoB) in HepG2 cells. Our results showed that LQFM048 did not induce eye irritation and it was classified as UN GHS No Category for both STE and BCOP assays and non-irritating for HET-CAM test. LQFM048 showed non-potential skin sensitization with stimulation index (SI=0.7) in the LLNA:BrdU-ELISA method. Corroborating in vivo tests, it did not promote significant cytotoxicity in HaCaT cells and it showed similar levels of IL-18 when compared to control. Furthermore, LQFM048 induced non-phototoxic potential with photo-irritation factor (PIF) and mean photo effect (MPE) of 1 and -0.138, respectively, for 3T3 cells. Similarly, it was not phototoxic for in vivo testing with or without exposure to UVA, showing SI values of 1 and 1.2, respectively. The micronucleus test showed that LQFM048 was not genotoxic, under the conditions tested.In conclusion, LQFM048, a heterocyclic compound obtained through an environmentally acceptable simple synthetic route, seems to be safe for human use, especially for the development of a new sunscreen product, since it is neither an eye irritant, nor a contact allergen, nor mutagenic and nor phototoxic., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)