[Occupational Dermatoses in Healthcare Workers during the COVID-19 Pandemic: A Narrative Review]. / Dermatoses Ocupacionais em Profissionais de Saúde durante a Pandemia de COVID-19: Revisão Narrativa.

INTRODUCTION: On the 11th March 2020, the World Health Organization declared the novel coronavirus outbreak as a pandemic. Preventive measures such as the appropriate use of personal protective equipment and proper hand hygiene are essential in decreasing transmissibility. Healthcare workers have been required to wear personal protective equipment and to wash their hands even more frequently. These preventive measures are associated with an increased risk of skin conditions, namely, contact dermatitis and exacerbation of pre-existing skin lesions such as acne and seborrheic dermatitis. The aim of this article is to provide an overview of the main skin lesions, and highlighting the role in occupational dermatology and preventive measures. METHODS: A search was conducted on PubMed and some guidelines from organizations like World Health Organization and Portuguese General Directorate of Health were included. RESULTS: Most skin conditions seen in healthcare professionals throughout the pandemic were associated with hand hygiene and the use of personal protective equipment and comprised hand eczema, mask-induced contact dermatitis, personal protective equipment related irritant contact dermatitis, cheilitis and exacerbation of pre-existing conditions such as acne and seborrheic dermatitis. Prevention and early recognition of dermatitis associated with personal protective equipment and hand hygiene are essential to maximize work performance, healthcare workers' safety and the adherence to preventive measures. CONCLUSION: Protection of healthcare workers' health and safety is an essential measure in the fight against the pandemic. Occupational Health has a fundamental role, acting in terms of disease prevention and health promotion, for example, through educational sessions and orientation of skin conditions associated with work, thus maximizing workers' well-being.

Introdução: A 11 de março de 2020, a Organização Mundial da Saúde declarou a doença provocada pelo novo coronavírus uma pandemia. As medidas de prevenção, nomeadamente, o uso apropriado de equipamento de proteção individual e a higienização das mãos, são essenciais na diminuição da transmissibilidade. Os profissionais de saúde têm particular indicação para o seu uso e para o aumento da frequência e duração da lavagem e desinfeção das mãos. Estas medidas estão associadas a um maior risco de desenvolvimento de patologias cutâneas como a dermatite de contacto e a exacerbação de lesões cutâneas pré-existentes, tais como a acne e a dermatite seborreica. O objetivo deste artigo é apresentar uma descrição das principais lesões cutâneas, e salientar o papel da dermatologia ocupacional e medidas preventivas.Métodos: Foi realizada uma pesquisa na PubMed e incluídas orientações de organizações como a Direção-Geral da Saúde e a Organização Mundial da Saúde.Resultados: As principais patologias cutâneas observadas nos profissionais de saúde ao longo da pandemia associam-se à higienização das mãos e à utilização de equipamentos de proteção individual, consistindo, sucintamente, em eczema das mãos, dermatite de contacto induzida por máscaras, dermatite de contacto irritativa por traumatismo do equipamento de proteção individual, queilite e exacerbação de condições pré-existentes como acne e dermatite seborreica. A prevenção e o reconhecimento atempado das dermatites associadas ao uso de equipamento de proteção individual e ao reforço da higiene das mãos são fundamentais para otimizar o desempenho laboral e a segurança dos profissionais de saúde e maximizar a adesão às medidas preventivas.Conclusão: A proteção da saúde e da segurança dos profissionais de saúde constitui uma medida essencial no combate da pandemia, pelo que a Medicina do Trabalho assume um papel fundamental, atuando a nível da prevenção da doença e promoção da saúde, por exemplo, através da realização de sessões de educação e orientação das várias patologias cutâneas associadas ao trabalho, maximizando o bem-estar do trabalhador.

A Novel Murine Model of a High Dose Brachytherapy-Induced Actinic Proctitis.

Background: Radiation proctitis affects 1-20% of cancer patients undergoing radiation exposure due to pelvic malignancies, including prostate, gynecological and rectum cancers. The patients manifest rectal discomfort, pain, discharge, and bleeding. Notably, the efficacy of prophylactic measures remains controversial due to the lack of adequate animal models that mimic this condition. Objective: The present study then aimed to develop a murine model of high-dose-rate (HDR) brachytherapy-induced proctitis. Material/Methods: C57BL/6 male mice were subjected to HDR (radiation source: iridium-192 [Ir-192]) through a cylindrical propylene tube inserted 2 cm far from the anal verge into the rectum. The animals received radiation doses once a day for three consecutive days (fractions of 9.5 Grays [Gy]), 3.0 mm far from the applicator surface. The sham group received only the applicator with no radiation source. The survival rate was recorded, and a colonoscopy was performed to confirm the tissue lesion development. Following euthanasia, samples of the rectum were collected for histopathology, cytokines dosage (IL-6 and KC), and immunohistochemical analysis (TNF-α and COX-2). Results: HDR significantly reduced animals' survival ten days post first radiation exposure (14% survival vs. 100% in the non-irradiated group). Day seven was then used for further investigation. Mice exposed to radiation presented with rectum injury confirmed by colonoscopy and histopathology (P < 0.05 vs. the control group). The tissue damage was accompanied by an inflammatory response, marked by increased KC and IL-6 tissue levels, and immunostaining for TNF-α and COX-2 (P < 0.05 vs. control group). Conclusions: We established a novel animal model of actinic proctitis induced by HDR brachytherapy, marked by inflammatory damage and low animal mortality.

Immunoexpression of HSPA9 and CUL2 in prostatic tissue and adenocarcinoma.

CUL2 plays a crucial role in proteolysis by preserving the balance between normal growth and uncontrolled proliferation. HSPA9 safeguards the integrity of protein interactions and supports cellular homeostasis. In carcinomas, HSPA9 and CUL2 appear to protect neoplastic cells from internal and external damage. In prostate tumors they are apparently associated with increased risk of unfavorable outcomes, but information remains scarce. In this study we evaluated CUL2 and HSPA9 expression in neoplastic and non-neoplastic prostate tissue and Gleason pattern 3 and 4 adenocarcinoma to identify associations with ISUP prognostic groups and postoperative disease progression. The records of 636 radical prostatectomy patients were reviewed retrospectively and microarrays were mounted with paraffin-embedded adenocarcinoma and non-neoplastic tissue. We evaluated the ability of HSPA9 and CUL2 to predict postoperative PSA outcomes, response to adjuvant/salvage therapy and systemic disease. HSPA9 and CUL2 were diffusely expressed. HSPA9 expression was associated with increased risk of high-grade adenocarcinoma, while HSPA9 and CUL2 were associated with biochemical failure after salvage therapy. In conclusion, HSPA9 and CUL2 were highly expressed in prostate tissue, especially in neoplastic cells. HSPA9 and CUL2-positive Gleason pattern 3 adenocarcinoma was more likely to be associated with Gleason pattern 4 or 5, while HSPA9 and CUL2-positive Gleason pattern 4 adenocarcinoma was less likely to belong to ISUP groups 1 and 2. Staining for HSPA9 and CUL2 can help identify patients at increased risk of recurrence after salvage therapy.

Prognostic factors on surgically and non-surgically treated oral squamous cell carcinoma: Advances in survival in fifteen years of follow up.

BACKGROUND: Retrospectively to evaluate the influence of radiochemotherapy (RCT) in the treatment of surgically and non-surgically treated Oral Squamous Cell Carcinoma (OSCC). MATERIAL AND METHODS: We analysed 934 patients treated in Hospital Haroldo Juaçaba (2000-2014; 15 years of study) by extraction of data type of cancer, localization of tumour, sex, age, race, education level, risk factors (smoking and alcohol use), year of diagnosis, TNM stage, therapeutic approach, health system used (public or private) and overall survival (OS). Surgically and non-surgically treated OSCC were compared by chi-square and Fisher's exact tests, and their prognostic factors were analysed by log-rank Mantel-Cox plus Cox regression tests (SPSS 20.0, p<0.05). RESULTS: Non-surgically treated OSCC patients had a lower OS than surgically treated OSCC patients (p<0.001), but an increase in OS was shown in both groups. Although the 2010-2014 period (p=0.003), education level (p=0.032), tongue/mouth floor/palate localization (p=0.023) and TNM stage (p<0.05) were important in non-surgically treated OSCC OS, the major prognostic factors were node metastasis (p=0.003) and non-use of RCT (p=0.039) (multivariate analysis). In surgically treated OSCC patients, higher OS was shown in the 2010-2014 period (p<0.001), females (p=0.012), non-drinkers (p=0.011), non-smokers (p=0.009) and those with lower TNM stage (p<0.05), but the major prognostic factor was the 2010-2014 period (p=0.004) (multivariate analysis), which was directly associated with an increase in RCT indication (p<0.001). CONCLUSIONS: The increase in RCT improved the OS in this large cohort of surgically and non-surgically treated OSCC patients. Key words:Mouth neoplasms, neck, radiotherapy, drug therapy, combination.

High-fat diet effect on periapical lesions and hepatic enzymatic antioxidant in rats.

AIMS: To evaluate the effects of a high-fat diet (HFD) on the progression of apical periodontitis (AP), local inflammation, systemic antioxidant status, and blood lipid profile in rats. MAIN METHODS: Sixteen male Wistar rats were fed a standard diet (SD) or a HFD. At the sixth experimental week, the pulp chambers of the mandibular first molars were exposed to develop AP. A glucose tolerance test was performed the week before euthanasia. At the tenth experimental week, the animals were euthanized and the livers were collected to estimate catalase (CAT) and reduced glutathione (GSH) levels. Blood was acquired for biochemical analysis. The size of AP was estimated from radiographs and described as AP size-to-body weight ratio; inflammatory grade of AP was determined by histological analysis. KEY FINDINGS: At the end of the experimental period, the rats fed the HFD had 30% less weight (P < 0.0001) and higher blood glucose levels after 30 min of sucrose intake (P < 0.05) than those fed the SD. Animals from the HFD group had lower levels of CAT (P < 0.01), but the same was not observed in the GSH levels. Plasma insulin and total cholesterol were not affected by the diet. The rats fed the HFD presented greater AP than those fed the SD (P < 0.05). However, the local inflammatory infiltrate was similar in both groups. SIGNIFICANCE: The alterations promoted by the consumption of a HFD were not only observed systemically, but also locally, producing greater AP in rats than a SD.

Cirurgia ortopédica e Covid: quais os riscos e perspectivas? / Orthopedic surgery and Covid: risks and perspectives

A pandemia revolucionou a assistência médica global de uma maneira sem precedentes e com repercussões inimagináveis. A prática diária ortopédica foi significativamente afetada. O trauma e a ortopedia estão na linha de frente do coronavírus, uma vez que as operações ortopédicas de emergência ainda estão entre os procedimentos cirúrgicos de emergência mais comuns. No entanto, as indicações cirúrgicas foram reformuladas, com casos eletivos sendo adiados. De acordo com as diretrizes propostas pela Academia Americana de Cirurgiões Ortopédicos (AAOS) e Colégio Americano de Cirurgiões (ACS) as cirurgias eletivas devem ser criteriosamente adiadas, dependendo do local, prevalência de COVID-19 e disponibilidade de recursos. Estudos demonstraram que a chance do paciente que será operado ser portador assintomático do SARS-Cov-2 é de 0,07%, cerca de 1 em 1.400. A partir dessa informação, calcula-se que a chance de um paciente assintomático evoluir a óbito devido a COVID-19 após cirurgia ortopédica é de 1 em 7.000 casos. O risco de morte em cirurgia eletiva em um contexto de pandemia por COVID-19 serão cumulativos; no entanto, o risco do COVID-19 será menor do que o risco de morte por todas as causas em um determinado ano.

The COVID-19 pandemic has revolutionized global health care in an unprecedented way and with unimaginable repercussions. Daily orthopedic practice was significantly affected. Trauma and orthopedics surgeries are at the forefront of coronavirus, since emergency orthopedic operations are still among the most common emergency surgical procedures. However, surgical indications have been reformulated, with elective cases being postponed. According to the guidelines proposed by the American Academy of Orthopedic Surgeons (AAOS) and American College of Surgeons (ACS), elective surgeries should be carefully postponed, depending on the location, prevalence of COVID-19 and availability of resources. Studies have shown that the chance that the patient to be operated on will be asymptomatic with SARS-Cov-2 is 0.07%, about 1 in 1,400. From this information, it is estimated that the chance of an asymptomatic patient evolving to death due to COVID-19 after orthopedic surgery is 1 in 7,000 cases. The risk of death from elective surgery in a context of a COVID-19 pandemic will be cumulative; however, the risk of COVID-19 will be less than the risk of death from all causes in a given year.

Penile cancer: a Brazilian consensus statement for low- and middle-income countries.

PURPOSE: Penile cancer is highly prevalent in low- and middle-income countries, with significant morbidity and mortality rates. The first Brazilian consensus provides support to improve penile cancer patients' outcomes, based on expert's opinion and evidence from medical literature. METHODS: Fifty-one Brazilian experts (clinical oncologists, radiation oncologists, urologists, and pathologists) assembled and voted 104 multiple-choice questions, confronted the results with the literature, and ranked the levels of evidence. RESULTS: Healthcare professionals need to deliver more effective communication about the risk factors for penile cancer. Staging and follow-up of patients include physical examination, computed tomography, and magnetic resonance imaging. Close monitoring is crucial, because most recurrences occur in the first 2-5 years. Lymph-node involvement is the most important predictive factor for survival, and management depends on the location (inguinal or pelvic) and the number of lymph nodes involved. Conservative treatment may be helpful in selected patients without compromising oncological outcomes; however, surgery yields the lowest rate of local recurrence. CONCLUSION: This consensus provides an essential decision-making orientation regarding this challenging disease.

Situación epidemiológica del Dengue en la ciudad de Encarnación 2018

Resumen Introducción: El dengue se encuentra en 128 países a nivel mundial, produciendo 390 millones de infecciones cada año, solo 96 millones se manifiestan clínicamente. En el Paraguay, la primera epidemia se registró en el período 1988-1989 con la circulación de DEN-1. En el año 2018, se ha registrado 3.414 casos confirmados en todo el país, en Itapúa se registraron 684 probables y167 confirmados. Objetivo: Describir la situación epidemiológica del Dengue en Encarnación 2018. Materiales y Métodos: Estudio observacional de diseño retrospectivo en el cual se revisaron fichas epidemiológicas del 2018, se incluyeron solo aquellas notificaciones de pacientes provenientes de la ciudad de Encarnación. Este estudio contó con la aprobación del Comité de Ética de la Universidad Autónoma. Resultados: En el 2018 se registraron en Encarnación 1418 notificaciones de los cuales 8% fueron confirmados, y 48% sospechosos, el 33 % correspondieron a la zona rural y el 67 % a la zona urbana. Discusión: Al observar las cifras de casos confirmados para Dengue se tienen valores inferiores al 10%, sin embargo, el 2018 se caracterizó por tener una epidemia a nivel regional, así como también nacional, por lo tanto, resulta clave el análisis en el contexto epidemiológico. Conclusión: El reporte de casos confirmados revela un bajo porcentaje de la enfermedad, en contraposición al alto valor en número de casos sospechosos, por lo tanto, allí radica la importancia de la epidemiología pues en caso de no ser confirmada por métodos laboratoriales podrá ser igualmente tratada a tal manera de evitar posibles complicaciones.

Abstract Introduction : Dengue is found in 128 countries worldwide, producing 390 million infections every year, only 96 million manifests clinically. In Paraguay, the first epidemic was recorded in the period 1988-1989 with the circulation of DEN-1. In 2018, 3,414 confirmed cases were registered throughout the country, in Itapúa 167 confirmed and 684 probable were registered. Objective: Describe the epidemiological situation of Dengue in Encarnacion 2018 Materials and Methods : An observational retrospective study in which epidemiological records of 2018 were reviewed, only those notifications of patients from the city of Encarnacion were included. This study was approved by the Ethics Committee of the Autonomous University. Results: In 2018, 1418 notifications were registered in Encarnacion, 8% of which were confirmed, and 48% suspected, 33% corresponded to the rural area and 67% to the urban area, 39% corresponded to the San Pedro neighborhood, 25% the downtown area, 19% San Isidro and 18% San Roque Gonzales. The age range with the highest number of cases was 20 to 39 years, 34% corresponded to the male sex and 39% to the female sex. Conclusion: The report of confirmed cases reveals a low percentage of the disease, as opposed to the high value in the number of suspected cases, therefore, therein lies the importance of epidemiology because if it is not confirmed by laboratory methods it can also be treated Such a way to avoid possible deaths

P2X7 Purinergic Receptor Is Involved in the Pathophysiology of Mania: a Preclinical Study.

The pathophysiology of bipolar disorder remains incompletely elucidated. The purinergic receptor, P2X7 (P2X7R), plays a central role in neuroinflammation, the establishment, and maintenance of microglial activation and neuronal damage/death, all characteristics of bipolar disorder pathology. The present study aims to explore the participation of the P2X7R in a preclinical pharmacological model of mania. We analyzed the modulatory effects of the P2X7R antagonist, brilliant blue, on behavior, monoamines, gene expression, serum purine levels, and cell typing in a pharmacological model of mania induced by D-amphetamine (AMPH) in mice. Our results corroborate an association between the P2X7 receptor and the preclinical animal model of mania, as demonstrated by the decreased responsiveness to AMPH in animals with pharmacologically blocked P2X7R. This study further suggests a possible dopaminergic mechanism for the action of P2X7 receptor antagonism. Additionally, we observed increased peripheral levels of adenosine, a neuroprotective molecule, and increased central expression of Entpd3 and Entpd1 leading to the hydrolysis of ATP, a danger signal, possibly as an attempt to compensate for the damage induced by AMPH. Lastly, P2X7R antagonism in the AMPH model was found to potentially modulate astrogliosis. Our results support the hypothesis that P2X7R plays a vital role in the pathophysiology of mania, possibly by modulating the dopaminergic pathway and astrogliosis, as reflected in the behavioral changes observed. Taken together, this study suggests that a purinergic system imbalance is associated with the AMPH-induced preclinical animal model of mania. P2X7R may represent a promising molecular therapeutic target for bipolar disorder.

Prevention of breast cancer through primary health care training / Prevenção do câncer de mama por meio da capacitação na atenção básica

Introduction: The main barrier to the management of breast cancer cases in Brazil is mainly due to the long periods of time between the diagnosis of the patient and the beginning of treatment. Objective: To improve access to information, treatment and screening of cancer cases through the training of primary health care professionals. Methods: Two "booklets" containing information on breast cancer were created: one for the Community Health Agents (CHAs) and the other for the Primary Health Care Nurses and Doctors (PHCND). Two theoretical and practical training modules were also created: one for the CHAs and another for the PHCNDs. The theoretical module consisted of lectures about breast cancer, and in the practical module, doctors and nurses were inserted in the mastology outpatient service of the Alcides Carneiro Hospital. Results: Clinical procedures in 2016 (before training) and 2017 (after training) showed a 31% increase in mastologist consultations, 41% in the number of patients undergoing surgeries and 42% in breast surgeries. From 2016 to 2017 there was a 16.5% reduction in the incidence of breast cancer and the number of deaths remained stable. Conclusions: Primary health care training increased and qualified the early detection of breast cancer in the city of Petrópolis-RJ, optimized the population's access to the specialized service and improved the quality of life of women with breast cancer. Prmary health care training was effective, low cost and could be replicated in other Brazilian municipalities.

Introdução: A principal barreira na condução do câncer mama no Brasil ocorre principalmente por conta do elevado tempo entre o diagnóstico e o tratamento efetivo da paciente. Objetivo: Melhorar o acesso à informação, ao tratamento e ao rastreamento dos casos de câncer por meio da capacitação dos profissionais da atenção básica. Métodos: Duas cartilhas contendo informações sobre o câncer de mama foram elaboradas: uma para os agentes comunitários de saúde (ACS) e a outra para enfermeiros e médicos da atenção básica (EMAB). Dois módulos de treinamentos teóricos e práticos também foram criados: um para os ACS e outro para EMAB. O módulo teórico consistiu de palestras sobre câncer de mama, e no módulo prático, médicos e enfermeiros foram inseridos nos ambulatórios de mastologia do Hospital Alcides Carneiro. Resultados: Os procedimentos clínicos em 2017 (após as capacitações) mostraram um aumento de 31% nas consultas com um mastologista, 41% no número de pacientes operados e 42% nas cirurgias de mamas, em comparação com 2016 (antes das capacitações). De 2016 para 2017 houve uma redução de 16,5% dos casos de câncer de mama e o número de óbitos ficou estável. Conclusões: A capacitação da atenção básica ampliou e qualificou a detecção precoce do câncer de mama no município de Petrópolis, Rio de Janeiro, agilizou o acesso da população ao serviço especializado e melhorou a qualidade de vida da mulher com câncer de mama. A capacitação na atenção básica foi efetiva, de baixo custo e poderá ser replicada em outros municípios brasileiros.

Early identification of first-year students at risk of dropping out of high-school entry medical school: the usefulness of teachers' ratings of class participation.

Dropping out from undergraduate medical education is costly for students, medical schools, and society in general. Therefore, the early identification of potential dropout students is important. The contribution of personal features to dropout rates has merited exploration. However, there is a paucity of research on aspects of student experience that may lead to dropping out. In this study, underpinned by theoretical models of student commitment, involvement, and engagement, we explored the hypothesis of using inferior participation as an indicator of a higher probability of dropping out in year 1. Class participation was calculated as an aggregate score based on teachers' daily observations in class. The study used a longitudinal dataset of six cohorts of high-school entry students (N = 709, 67% females) in one medical school with an annual intake of 120 students. The findings confirmed the initial hypothesis and showed that lower scores of class participation in year 1 added predictive ability to pre-entry characteristics (Pseudo-R2 raised from 0.22 to 0.28). Even though the inclusion of course failure in year 1 resulted in higher explanatory power than participation in class (Pseudo-R2 raised from 0.28 to 0.63), ratings of class participation may be advantageous to anticipate dropout identification, as those can be collected prior to course failure. The implications for practice are that teachers' ratings of class participation can play a role in indicating medical students who may eventually drop out. We conclude that the scores of class participation can contribute to flagging systems for the early detection of student dropouts.

Stability and efficacy of combined nystatin and chlorhexidine against suspensions and biofilms of Candida albicans.

OBJECTIVE: Nystatin and chlorhexidine are extensively used in oral medicine; however, there is some controversy about the possibility of these drugs showing antagonism. To clarify this issue, this study investigated the efficacy and stability of nystatin and chlorhexidine in combination. DESIGN: An in vitro study was conducted to analyze the effect of nystatin and chlorhexidine combined on Candida albicans ATCC 18804, using the drugs mixed as a single formulation and as independent formulations used sequentially with different time intervals between them. The minimum inhibitory concentration (MIC) and effects on C. albicans suspensions and biofilms were evaluated. Also, the stability of nystatin and chlorhexidine in a mixture was tested by high performance liquid chromatography (HPLC). RESULTS: When nystatin and chlorhexidine were mixed in a single formulation, there was no significant difference in MIC compared to that of the drugs used alone (as the only treatment). However, when these drugs were used as independent formulations, sequentially with time intervals in between, their MICs were higher than the respective MIC of the drug used alone, except for the MIC of chlorhexidine with a 10-min interval. Nystatin/chlorhexidine combinations showed lower activity against C. albicans biofilms, except for that with a 30-min interval. The drugs when combined showed high percentages of degradation at all the times evaluated. CONCLUSIONS: The combination of nystatin and chlorhexidine seems to interfere with the efficacy of the drugs and to increase their rate of degradation.

Pre-clinical effects of metformin and aspirin on the cell lines of different breast cancer subtypes.

Background Breast cancer is highly prevalent among women worldwide. It is classified into three main subtypes: estrogen receptor positive (ER+), human epidermal growth factor receptor 2 positive (HER2+), and triple negative breast cancer (TNBC). This study has evaluated the effects of aspirin and metformin, isolated or in a combination, in breast cancer cells of the different subtypes. Methods The breast cancer cell lines MCF-7, MDA-MB-231, and SK-BR-3 were treated with aspirin and/or metformin (0.01 mM - 10 mM); functional in vitro assays were performed. The interactions with the estrogen receptors (ER) were evaluated in silico. Results Metformin (2.5, 5 and 10 mM) altered the morphology and reduced the viability and migration of the ER+ cell line MCF-7, whereas aspirin triggered this effect only at 10 mM. A synergistic effect for the combination of metformin and aspirin (2.5, 5 or 10 mM each) was observed in the TNBC cell subtype MDA-MB-231, according to the evaluation of its viability and colony formation. Partial inhibitory effects were observed for either of the drugs in the HER2+ cell subtype SK-BR-3. The effects of metformin and aspirin partly relied on cyclooxygenase-2 (COX-2) upregulation, without the production of lipoxins. In silico, metformin and aspirin bound to the ERα receptor with the same energy. Conclusion We have provided novel evidence on the mechanisms of action of aspirin and metformin in breast cancer cells, showing favorable outcomes for these drugs in the ER+ and TNBC subtypes.

Manganese(II) Chloride Alters Nucleotide and Nucleoside Catabolism in Zebrafish (Danio rerio) Adult Brain.

ATP and adenosine, the main signaling molecules of purinergic system, are involved in toxicological effects induced by metals. The manganese (Mn) exposure induces several cellular changes, which could interfere with signaling pathways, such as the purinergic system. In this study, we evaluated the effects of exposure to manganese(II) chloride (MnCl2) during 96 h on nucleoside triphosphate diphosphohydrolase (NTPDase), ecto-5'-nucleotidase, and adenosine deaminase (ADA) activities, followed by analyzing the gene expression patterns of NTPDases (entpd1, entpd2a.1, entpd2a.2, entpd2-like, entpd3) and ADA (ADA 1 , ADA 2.1 , ADA 2.2 , ADAasi, ADAL) families in zebrafish brain. In addition, the brain metabolism of nucleotides and nucleosides was evaluated after MnCl2 exposure. The results showed that MnCl2 exposure during 96 h inhibited the NTPDase (1.0 and 1.5 mM) and ecto-ADA (0.5, 1.0, and 1.5 mM) activities, further decreasing ADA2.1 expression at all MnCl2 concentrations analyzed. Purine metabolism was also altered by the action of MnCl2. An increased amount of ADP appeared at all MnCl2 concentrations analyzed; however, AMP and adenosine levels are decreased at the concentrations of 1.0 and 1.5 mM MnCl2, whereas decreased inosine (INO) levels were observed at all concentrations tested. The findings of this study demonstrated that MnCl2 may inhibit NTPDase and ecto-ADA activities, consequently modulating nucleotide and nucleoside levels, which may contribute for the toxicological effects induced by this metal.

Nickel exposure alters behavioral parameters in larval and adult zebrafish.

Nickel is a heavy metal that, at high concentrations, leads to environmental contamination and causes health problems. We evaluated the effects of NiCl2 exposure on cognition and behavior in larval and adult zebrafish. Larval and adult zebrafish were exposed to NiCl2 concentrations (0.025, 2.0, 5.0, and 15.0mg/L) or water (control) in two treatment regimens: acute and subchronic. Larvae were exposed to NiCl2 for 2h (acute treatment: 5-day-old larvae treated for 2h, tested after treatment) or 11days (subchronic treatment: 11-day-old larvae treated since fertilization, tested at 5, 8 and 11days post-fertilization, dpf). Adults were exposed for 12h (acute treatment) or 96h (subchronic treatment) and were tested after the treatment period. In both regimens, exposed zebrafish showed concentration-dependent increases in body nickel levels compared with controls. For larvae, delayed hatching, decreased heart rate and morphological alterations were observed in subchronically treated zebrafish. Larvae from subchronic treatment tested at 5dpf decrease distance and mean speed at a low concentration (0.025mg/L) and increased at higher concentrations (5.0 and 15.0mg/L). Subchronic treated larvae decrease locomotion at 15.0mg/L at 8 and 11dpf, whereas decreased escape responses to an aversive stimulus was observed at 2.0, 5.0 and 15.0mg/L in all developmental stages. For adults, the exploratory behavior test showed that subchronic nickel exposure induced anxiogenic-like behavior and decrease aggression, whereas impaired memory was observed in both treatments. These results indicate that exposure to nickel in early life stages of zebrafish leads to morphological alterations, avoidance response impairment and locomotor deficits whereas acute and subchronic exposure in adults resulst in anxiogenic effects, impaired memory and decreased aggressive behavior. These effects may be associated to neurotoxic actions of nickel and suggest this metal may influence animals' physiology in doses that do not necessarily impact their survival.

Influence of sex on activated partial thromboplastin time (aPTT) and prothrombin time (PT) in sheep.

Haemostasis is a physiological process that prevents excessive blood loss. In laboratory, the prothrombin time (PT) and the activated partial thromboplastin time (aPTT) are used to examine clotting systems. However, the influence of sex on PT and aPTT values is unknown. The present work aimed to determine the values for PT and aPTT in adult sheep and to evaluate their dependence on the sex of the animal. Blood samples were collected from 40 adults (1-6 years old) of mixed breed sheep (20 males and 20 females) via jugular venepuncture conducted using vacuum tubes containing 3.8% sodium citrate as an anticoagulant. PT and aPTT were determined by visual detection of clot formation. The mean PT and aPTT values for all sheep were 7.71 ± 0.87 s and 35.7 ± 3.57 s, respectively. The aPTT values showed a significant difference (P = 0.0013) between male and female samples, while the difference in PT values was not significant (P = 0.0565). Thus, the animal sex influences the function of the plasma blood-clotting system in sheep. In contrast with table 1 data, in particular, aPTT values are significantly higher in female sheep than in males.

Effects of caffeine on behavioral and inflammatory changes elicited by copper in zebrafish larvae: Role of adenosine receptors.

This study investigated the effects of caffeine in the behavioral and inflammatory alterations caused by copper in zebrafish larvae, attempting to correlate these changes with the modulation of adenosine receptors. To perform a survival curve, 7dpf larvae were exposed to 10µM CuSO4, combined to different concentrations of caffeine (100µM, 500µM and 1mM) for up to 24h. The treatment with copper showed lower survival rates only when combined with 500µM and 1mM of caffeine. We selected 4 and 24h as treatment time-points. The behavior evaluation was done by analyzing the traveled distance, the number of entries in the center, and the length of permanence in the center and the periphery of the well. The exposure to 10µM CuSO4 plus 500µM caffeine at 4 and 24h changed the behavioral parameters. To study the inflammatory effects of caffeine, we assessed the PGE2 levels by using UHPLC-MS/MS, and TNF, COX-2, IL-6 and IL-10 gene expression by RT-qPCR. The expression of adenosine receptors was also evaluated with RT-qPCR. When combined to copper, caffeine altered inflammatory markers depending on the time of exposure. Adenosine receptors expression was significantly increased, especially after 4h exposure to copper and caffeine together or separately. Our results demonstrated that caffeine enhances the inflammation induced by copper by decreasing animal survival, altering inflammatory markers and promoting behavioral changes in zebrafish larvae. We also conclude that alterations in adenosine receptors are related to those effects.

Analysis of Extracellular Nucleotide Metabolism in Adult Zebrafish After Embryological Exposure to Valproic Acid.

Autism is a neurodevelopmental disorder characterized by symptoms related to stereotyped movements, deficits in social interaction, impaired communication, anxiety, hyperactivity, and the presence of restricted interests. Evidence indicates an important role of extracellular ATP and adenosine as signaling molecules in autism. ATP hydrolysis by ectonucleotidases is an important source of adenosine, and adenosine deaminase (ADA) contributes to the control of the nucleoside concentrations. Considering zebrafish is an animal model that may contribute towards to understanding the mechanisms that underlie social behavior, we investigated the purinergic signaling in a model of embryological exposure to valproic acid (VPA) that induces social interaction deficit in adult zebrafish. We demonstrated embryological exposure to VPA did not change ATP and ADP hydrolysis in zebrafish at 120 dpf, and the cytosolic (soluble) ADA activity was not altered. However, we observed an increase of AMP hydrolysis (12.5 %) whereas the ecto-ADA activity was decreased (19.2 %) in adult zebrafish submitted to embryological exposure to VPA. Quantitative reverse transcription PCR (RT-PCR) analysis showed changes on ntpd8, ADA 2.1, and A2a1 mRNA transcript levels. Brain ATP metabolism showed a rapid catabolism of ATP and ADP, whereas the extracellular metabolism of AMP and adenosine (ADO) occurred slowly. We demonstrated that embryological exposure to VPA altered biochemical and molecular parameters related to purinergic system in adult zebrafish. These findings indicate that the enzyme activities involved in the control of ATP and adenosine levels may be involved in the pathophysiological mechanisms of diseases related to the impairment of social interaction, such as autism.

Manganese(II) chloride alters behavioral and neurochemical parameters in larvae and adult zebrafish.

Manganese (Mn) is an essential metal for organisms, but high levels can cause serious neurological damage. The aim of this study was to evaluate the effects of MnCl2 exposure on cognition and exploratory behavior in adult and larval zebrafish and correlate these findings with brain accumulation of Mn, overall brain tyrosine hydroxylase (TH) levels, dopamine (DA) levels, 3,4-dihydroxyphenylacetic acid (DOPAC) levels and cell death markers in the nervous system. Adults exposed to MnCl2 for 4days (0.5, 1.0 and 1.5mM) and larvae exposed for 5days (0.1, 0.25 and 0.5mM) displayed decreased exploratory behaviors, such as distance traveled and absolute body turn angle, in addition to reduced movement time and an increased number of immobile episodes in larvae. Adults exposed to MnCl2 for 4days showed impaired aversive long-term memory in the inhibitory avoidance task. The overall brain TH levels were elevated in adults and larvae evaluated at 5 and 7 days post-fertilization (dpf). Interestingly, the protein level of this enzyme was decreased in larval animals at 10dpf. Furthermore, DOPAC levels were increased in adult animals exposed to MnCl2. Protein analysis showed increased apoptotic markers in both the larvae and adult nervous system. The results demonstrated that prolonged exposure to MnCl2 leads to locomotor deficits that may be associated with damage caused by this metal in the CNS, particularly in the dopaminergic system.

Inclusion of Yucca schidigera extract in diets with different protein levels for dogs.

This study evaluated the effects of inclusion of Yucca schidigera extract (YSE) in two diets with different levels of crude protein (CP) for dogs on facal odour, nutrient digestibility, ammonia concentration in feces and hematological and serum biochemical profiles. Twenty adults Beagles were used, distributed in a randomized block design in a 2 × 4 factorial design (two diets, 25% and 34% CP, and four YSE levels: 0, 250, 500 and 750 mg/kg) with five replicates, obtained during two experimental periods. The fecal odour reduced (P < 0.05) when 500 mg/kg of YSE was used in diets with higher CP. The inclusion of YSE reduced (P < 0.05) fecal ammonia, and the inclusion of 250 and 500 mg/kg YSE reduced intestinal gas. The inclusion of 750 mg/kg YSE increased the mean corpuscular hemoglobin (MCH), alanine aminotransferase (ALT) activity and tended to increase the serum cholesterol concentration, regardless of the protein level of the diets. There was no effect on the digestibility of nutrients, fecal consistency, nitrogen balance and thickness of the intestinal wall. The inclusion of 500 mg/kg YSE is effective in reducing fecal odour in dogs receiving diets with 34% of CP. Regardless of the protein content, YSE reduces fecal ammonia, but may cause adverse effects if included at higher doses.