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Introduction: The infections by multidrug-resistant bacteria are a growing threat to human health, and the efficacy of the available antibiotics is gradually decreasing. As such, new antibiotic classes are urgently needed. Objectives: This study aims to evaluate the antimicrobial activity, safety and mechanism of action of phytochemical-based triphenylphosphonium (TPP+) conjugates. Methods: A library of phytochemical-based TPP+ conjugates was repositioned and extended, and its antimicrobial activity was evaluated against a panel of Gram-positive (methicillin-resistant Staphylococcus aureus – MRSA) and Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii) and fungi (Candida albicans, Cryptococcus neoformans var. grubii). The compounds’ cytotoxicity and haemolytic profile were also evaluated. To unravel the mechanism of action of the best compounds, the alterations in the surface charge, bacterial membrane integrity, and cytoplasmic leakage were assessed. Results: Structure-activity-toxicity data revealed the contributions of the different structural components (phenolic ring, carbon-based spacers, carboxamide group, alkyl linker) to the compounds’ bioactivity and safety. Dihydrocinnamic derivatives 5 m and 5n stood out as safe, potent and selective antibacterial agents against S. aureus (MIC 32 µg/mL; HC10 > 32 µg/mL). Mechanistic studies suggest that the antibacterial activity of compounds 5 m and 5n may result from interactions with the bacterial cell wall and membrane. Conclusions: Collectively, these studies demonstrate the potential of phytochemical-based TPP+ conjugates as a new class of antibiotics.

Introduction: Most lung cancers are diagnosed at an advanced stage. Common metastatic sites include the brain, bone, liver and adrenal glands. Ocular metastases, however, are extremely rare. We present a case of advanced lung adenocarcinoma presenting exclusively with photopsias attributable to retinal metastases. Case description: We describe a woman in her fifties, a lifetime non-smoker with an unremarkable medical and family history, who presented to the emergency department with photopsias for a week. Ophthalmology evaluation revealed decreased visual acuity bilaterally, and a fundus examination disclosed lesions suggestive of bilateral retinal metastases. A comprehensive evaluation diagnosed a stage IVb lung adenocarcinoma with exon 19 mutation on epidermal growth factor receptor gene. Subsequently, she developed complaints of headaches and dizziness. She received frontline osimertinib 80 mg daily, preceded by upfront whole-brain radiation therapy with partial orbital inclusion for symptomatic ocular and brain metastases. After ten radiation therapy sessions, her complaints were resolved and an ophthalmology revaluation revealed improvement in visual acuity and resolution of photopsia complaints. The patient is currently on osimertinib and preserves an ECOG score of 0. Conclusion: Retinal metastases usually indicate advanced disease, so presenting with isolated ocular symptoms is exceedingly rare. Especially in cases of uncommon metastases, a multidisciplinary approach is fundamental for a prompt diagnosis and timely treatment, impacting prognosis and quality of life.

Presentamos un trabajo enmarcado en la teoría antropológica de lo didáctico que aborda la relación entre los resultados de la investigación didáctica sobre el estudio escolar de cierto dominio de las matemáticas y el problema docente relativo al qué enseñar y cómo hacerlo en relación con dicho dominio. Nos centramos en el ámbito de la modelización funcional y del cálculo diferencial elemental y proponemos una estrategia de formación del profesorado que culmina en la construcción de una posible praxeología para la enseñanza, como punto de partida para un cambio de paradigma didáctico en la institución escolar, tan necesario como aplazado.

Abstract Machado-Joseph disease (MJD) or Spinocerebellar ataxia type 3 (SCA3) is the most common form of dominant SCA worldwide. Magnetic Resonance Imaging (MRI) and Proton Magnetic Resonance Spectroscopy (1H-MRS) provide promising non-invasive diagnostic and follow-up tools, also serving to evaluate therapies efficacy. However, pre-clinical studies showing relationship between MRI-MRS based biomarkers and functional performance are missing, which hampers an efficient clinical translation of therapeutics. This study assessed motor behaviour, neurochemical profiles, and morphometry of the cerebellum of MJD transgenic mice and patients aiming at establishing magnetic-resonance-based biomarkers. 1H-MRS and structural MRI measurements of MJD transgenic mice were performed with a 9.4 Tesla scanner, correlated with motor performance on rotarod and compared with data collected from human patients. We found decreased cerebellar white and grey matter and enlargement of the fourth ventricle in both MJD mice and human patients as compared to controls. N-acetylaspartate (NAA), NAA + N-acetylaspartylglutamate (NAA + NAAG), Glutamate, and Taurine, were significantly decreased in MJD mouse cerebellum regardless of age, whereas myo-Inositol (Ins) was increased at early time-points. Lower neurochemical ratios levels (NAA/Ins and NAA/total Choline), previously correlated with worse clinical status in SCAs, were also observed in MJD mice cerebella. NAA, NAA + NAAG, Glutamate, and Taurine were also positively correlated with MJD mice motor performance. Importantly, these 1H-MRS results were largely analogous to those found for MJD in human studies and in our pilot data in human patients. We have established a magnetic resonance-based biomarker approach to monitor novel therapies in preclinical studies and human clinical trials.

Long-term cognitive dysfunction, or “chemobrain”, has been observed in cancer patients treated with chemotherapy. Mitoxantrone (MTX) is a topoisomerase II inhibitor that binds and intercalates with DNA, being used in the treatment of several cancers and multiple sclerosis. Although MTX can induce chemobrain, its neurotoxic mechanisms are poorly studied. This work aimed to identify the adverse outcome pathways (AOPs) activated in the brain upon the use of a clinically relevant cumulative dose of MTX. Three-month-old male CD-1 mice were given a biweekly intraperitoneal administration of MTX over the course of three weeks until reaching a total cumulative dose of 6 mg/kg. Controls were given sterile saline in the same schedule. Two weeks after the last administration, the mice were euthanized and their brains removed. The left brain hemisphere was used for targeted profiling of the metabolism of glutathione and the right hemisphere for an untargeted metabolomics approach. The obtained results revealed that MTX treatment reduced the availability of cysteine (Cys), cysteinylglycine (CysGly), and reduced glutathione (GSH) suggesting that MTX disrupts glutathione metabolism. The untargeted approach revealed metabolic circuits of phosphatidylethanolamine, catecholamines, unsaturated fatty acids biosynthesis, and glycerolipids as relevant players in AOPs of MTX in our in vivo model. As far as we know, our study was the first to perform such a broad profiling study on pathways that could put patients given MTX at risk of cognitive deficits.

O objetivo do artigo proposto é apresentar os traços gerais da caracterização sociográfica dos ortoprotésicos licenciados pela Escola Superior de Tecnologia da Saúde de Lisboa (ESTeSL), considerando quatro dimensões: 1) perfil social e profissional; 2) condições de trabalho; 3) grau de autonomia; 4) principais problemas e projetos profissionais. A caracterização sociográfica exposta neste artigo resultou de um estudo quantitativo, em que a técnica de investigação utilizada foi o inquérito, aplicado por questionário, através de uma plataforma específica, à totalidade da população em estudo, ou seja, aos 221 ortoprotésicos licenciados pela ESTeSL até 2016. A percentagem de respostas obtidas foi de 61,4% (n=132), valor que confere uma dimensão apreciável aos dados apresentados. Esta primeira caracterização sociográfica de ortoprotésicos permite conhecer com rigor as características do grupo profissional e simultaneamente constituir uma base para o desenvolvimento de trabalhos de investigação futuros. Apresentam-se os principais traços do perfil social e profissional da população estudada (predominantemente feminina, particularmente jovem, a exercer principalmente na área das ortóteses, em ortopedias e na venda ao público, nos distritos de Lisboa e Setúbal, com uma proporção considerável a trabalhar noutros países), a forma como são avaliadas as condições de trabalho, o grau de autonomia, os principais problemas enfrentados pelo grupo profissional e os projetos profissionais principais.

Fucoidan has been reported to present diverse bioactivities, but each extract has specific features from which a particular biological activity, such as immunomodulation, must be confirmed. In this study a commercially available pharmaceutical-grade fucoidan extracted from Fucus vesiculosus, FE, was characterized and its anti-inflammatory potential was investigated. Fucose was the main monosaccharide (90 mol%) present in the studied FE, followed by uronic acids, galactose, and xylose that were present at similar values (3.8–2.4 mol%). FE showed a molecular weight of 70 kDa and a sulfate content of around 10%. The expression of cytokines by mouse bone-marrow-derived macrophages (BMDMs) revealed that the addition of FE upregulated the expression of CD206 and IL-10 by about 28 and 22 fold, respectively, in respect to control. This was corroborated in a stimulated pro-inflammatory situation, with the higher expression (60 fold) of iNOS being almost completely reversed by the addition of FE. FE was also capable of reverse LPS-caused inflammation in an in vivo mouse model, including by reducing macrophage activation by LPS from 41% of positive CD11C to 9% upon fucoidan injection. Taken together, the potential of FE as an anti-inflammatory agent was validated, both in vitro and in vivo.

Dual-energy X-ray absorptiometry is used to determine bone density in several pathologies, namely osteoporosis and fracture risk in post-menopausal women. The aim of this study was to identify, appraise and synthesize all available evidence about the correlation between Dual Energy X-ray Absorptiometry (DEXA) and Cone Beam Computed Tomography (CBCT) techniques through a systematic review. A systematic literature search was conducted in the following databases: PubMed via MEDLINE, Cochrane Library, EMBASE and Web of Science Core Collection, along with several sources of grey literature. The Cochrane Risk of Bias Tools were used to perform the qualitative assessment of the selected studies. A total of 913 articles were initially scrutinized and 11 were included for qualitative analysis, of which 3 were included in a meta-analysis. Most of the included studies revealed a low risk of bias (7 out of 11). A strong correlation (min r = 0.46 max r = 0.62) between DEXA and CBCT values were found. Thus, opportunistic CBCT scans may be used to assess the bone mineral density and fracture risk, improving the ability to track disease progression and providing better care.

Introdução: Diversos estudos referem Portugal como o segundo país com a prevalência de doenças psiquiátricas mais elevada da Europa (22,9%), sendo importante aumentar a literacia da população. Objetivo: O nosso objetivo foi avaliar a eficácia da formação sobre PHDA, realizada através da plataforma Bicho 7 Cabeças, no aumento do conhecimento de indivíduos adultos, sem formação na área da saúde. Material e Métodos: A amostra é constituída por 16 indivíduos, entre os 18 e os 29 anos, sendo cinco do sexo masculino. Destes, 50% têm o 12º ano, 31,25% são licenciados e 18,75% têm mestrado. Foram usados como medidas de conhecimento o valor obtido nos resultados após a formação e numa questão sobre do nivel de conhecimento do indivíduo sobre PHDA, juntamente com o questionário de usabilidade. Resultados: Os resultados demonstraram um aumento do conhecimento sobre PHDA, independentemente do sexo, idade e escolaridade. A média do conhecimento obtida na formação é de 8,36 em 10 e em todas as avaliações, a percentagem foi superior a 70%. A usabilidade da plataforma foi avaliada positivamente pelos indivíduos. Conclusão: Através do presente estudo foi possível verificar a eficácia da plataforma Bicho 7 Cabeças, no aumento da literacia da população.

Introduction: The SARS-CoV-2 infection has been associated with the acute onset of mental and behavioural symptoms and psychiatric disorders. The aim of this study was to assess the prevalence of the different neuropsychiatric diagnoses in hospitalized patients with SARS-CoV-2 infection assessed by Liaison Psychiatry. Material and Methods: We performed a cross-sectional study in a hospital near Lisbon, Portugal. We reviewed the electronic health records from all inpatients with a positive SARS-CoV-2 RT-PCR test that were assessed by the Liaison Psychiatry Unit (LPU) between February and December 2020. We reviewed relevant sociodemographic and clinical data, including 15 neuropsychiatric symptoms. The prevalence of psychiatric disorders was our main outcome. We also explored differences between two groups: patients with delirium (delirium group) and patients without delirium (no delirium group). Results: We included 46 cases [Age: median = 67 years; interquartile range (IQR) = 24)], with 60.9% male individuals. Delirium was the most frequent diagnosis in our sample (43.5%), followed by major depressive disorder (21.7%). Patients with delirium were more likely to suffer from COVID-19 symptoms (delirium: 19/20, 95%; no delirium: 14/26, 53.8%; p = 0.02), and to have a longer time interval between a positive SARS-CoV-2 RT-PCR test and an evaluation by the LPU (delirium: median = 16.5 days, IQR = 16; no delirium: median = 8 days, IQR = 16.3; p = 0.045). Agitation (52.2%) and cognitive symptoms (47.8%) were the most reported neuropsychiatric symptoms. Conclusion: We found a high prevalence of delirium in our sample. This finding is in line with recent literature concerning hospitalized COVID-19 patients The higher frequency of COVID-19 symptoms found in the delirium group suggests a possible association between symptomatic SARS-CoV-2 infection and delirium onset.

Abstract Introduction Cannabis is probably the most commonly used illicit drug. It is often regarded as a relatively nonharmful experience, even though evidence indicates otherwise. Legalization of non-medical cannabis, which has already taken place in several countries, is currently a controversial issue. Objective To provide an up-to-date overview of current models and policies and their outcomes that can inform future political decisions regarding non-medical cannabis use. Methods PubMed/MEDLINE and Google Scholar scientific databases were searched for articles written in English, Spanish, and Portuguese published between 1990 and December 2020. The reference lists of these articles were similarly used as bibliography sources. Gray literature was also included. Results While non-medical cannabis has been decriminalized in many countries, it has only been legalized in Uruguay, Canada, and some U.S. states. Several benefits of legalization were identified: decreases in cannabis-related crimes, law-enforcement and judicial costs; reduction in synthetic cannabis supply; decline in black economies and possible diminution of other illegal drug buying; and tax revenue increases. Reported legalization problems included: increases in cannabis use; cannabis-related disorders; and cannabis-related accidents and hospitalizations. Harm-reduction strategies are available in the scientific literature. Conclusion Growing, although incomplete, evidence exists to guide policy makers, minimize cannabis-related harm, and positively contribute to public health, if the legalization path is to be followed. Dialogue between legislators and science should be encouraged. There are more than a few legalization pathways, with diverse economic, social and health wellbeing effects. Public health-driven, instead of profit-driven models, seem to offer the most benefits regarding non-medical cannabis legalization. Most of the true public health effects of cannabis legalization are still unknown, for we are still in the early stages of these policies and their implications. Future studies should address the medium-to-long-term social, economic, and health consequences of legalization policies.

Resumen: Introducción: A pesar del tratamiento con hipotermia, el 40% de los neonatos con encefalopatía hipóxico-isquémica fallecen o sufren discapacidad moderada-grave. La espectroscopia cercana al infrarrojo (NIRS) se propone como una herramienta útil y no invasiva para establecer el pronóstico. Objetivos: Evaluar el valor pronóstico de la NIRS en el resultado del neurodesarrollo entre los 18-36 meses en neonatos con encefalopatía hipóxico-isquémica, y establecer el tiempo y los puntos de corte de la saturación cerebral de oxígeno que mejor se relacionan con el pronóstico. Pacientes y métodos: Se incluyeron todos los neonatos a término con encefalopatía hipóxico-isquémica, sometidos a hipotermia y NIRS, entre 2013-2016. Con respeto al resultado se constituyeron 3 grupos: neurodesarrollo normal, discapacidad moderada y grave. Resultados: Se incluyeron 28 neonatos (edad gestacional mediana: 39 semanas; peso al nacimiento mediano: 3.195 g). La saturación cerebral de oxígeno tendió a aumentar desde una mediana de 65% hasta 85% a las 48 horas de vida. El resultado del neurodesarrollo fue normal en 28,6%, el 35,7% adquirió discapacidad moderada y el 35,7% discapacidad grave (3 fallecieron). Se halló una diferencia estadística entre los grupos a las 48 horas (p = 0,005) y después de la hipotermia (p = 0,03), con valores más altos en los pacientes con discapacidad. Teniendo en cuenta el grupo con discapacidad grave frente a los otros, la curva de ROC a las 48 horas resultó en un área debajo de la curva (AUC) significativa de 0,872 (p = 0,001), con un punto de corte de saturación cerebral de oxígeno de 83,5%. Después de la hipotermia los valores de saturación cerebral de oxígeno por debajo del 66,0% (AUC 0,794; p = 0,017) predijeron el desarrollo normal, mientras que valores por encima del 82% (AUC 0,881; p = 0,001) predijeron discapacidad grave. Conclusiones: El NIRS parece constituir una herramienta útil en la predicción del resultado del neurodesarrollo de pacientes con encefalopatía hipóxico-isquémica, incluso después de la hipotermia, con valores más altos de saturación cerebral de oxígeno en pacientes con discapacidad. Abstract: Introduction: Despite treatment with hypothermia, 40% of newborns with hypoxic-ischaemic encephalopathy die or suffer moderate to severe disability. Near-infrared spectroscopy (NIRS) could be a useful, non-invasive tool to establish the prognosis. Objectives: To evaluate the prognostic value of NIRS in predicting neurodevelopmental outcomes at 18 to 36 months in newborns with hypoxic-ischaemic encephalopathy, and to establish the time points and cut-off values of regional cerebral oxygen saturation that exhibit the strongest correlation to these outcomes. Patients and methods: The study included all term newborns with hypoxic-ischaemic encephalopathy managed with hypothermia and NIRS between 2013 and 2016. We established 3 outcome categories: normal neurodevelopment, moderate disability and severe disability. Results: The sample comprised 28 newborns (median gestational age, 39 weeks; median birth weight, 3195 g). The median regional cerebral oxygen saturation increased from 65% to 85% at 48 hours post birth. Neurodevelopmental outcomes were normal in 28.6%, while 35.7% developed moderate disability and 35.7% severe disability; 3 patients died. We found a statistically significant difference between groups at 48 hours (P = .005) and after hypothermia (P = .03), with higher values in patients with disability. When we compared patients in the severe disability group with the other groups, we found a statistically significant area under the ROC curve at 48 hours of 0.872 (P = .001) applying a regional cerebral oxygen saturation cutoff of 83.5%. After hypothermia, regional cerebral oxygen saturation values below 66.0% (AUC, 0.794; P = .017) predicted normal development, while values above 82% (AUC, 0.881; P = .001) predicted severe disability. Conclusions: NIRS seems to be a valuable tool to predict neurodevelopmental outcomes in patients with hypoxic-ischaemic encephalopathy, even after hypothermia, with higher cerebral oxygen saturation values in patients with disability.

Introduction: Despite treatment with hypothermia, 40% of newborns with hypoxic-ischaemic encephalopathy die or suffer moderate to severe disability. Near-infrared spectroscopy (NIRS) could be a useful, non-invasive tool to establish the prognosis. Objectives: To evaluate the prognostic value of NIRS in predicting neurodevelopmental outcomes at 18–36 months in newborns with hypoxic-ischaemic encephalopathy, and to establish the time points and cut-off values of regional cerebral oxygen saturation that exhibit the strongest correlation to these outcomes. Patients and methods: The study included all term newborns with hypoxic-ischaemic encephalopathy managed with hypothermia and NIRS between 2013 and 2016. We established 3 outcome categories: normal neurodevelopment, moderate disability and severe disability. Results: The sample comprised 28 newborns (median gestational age, 39 weeks; median birth weight, 3195 g). The median regional cerebral oxygen saturation increased from 65% to 85% at 48 h post birth. Neurodevelopmental outcomes were normal in 28.6%, while 35.7% developed moderate disability and 35.7% severe disability; 3 patients died. We found a statistically significant difference between groups at 48 h (P = .005) and after hypothermia (P = .03), with higher values in patients with disability. When we compared patients with severe disability group with the other groups, we found a statistically significant area under the ROC curve at 48 h of 0.872 (P = .001) applying a regional cerebral oxygen saturation cutoff of 83.5%. After hypothermia, regional cerebral oxygen saturation values below 66.0% (AUC, 0.794; P = .017) predicted normal development, while values above 82% (AUC, 0.881; P = .001) predicted severe disability. Conclusions: NIRS seems to be a valuable tool to predict neurodevelopmental outcomes in patients with hypoxic-ischaemic encephalopathy, even after hypothermia, with higher cerebral oxygen saturation values in patients with disability. Resumen: Introducción: A pesar del tratamiento con hipotermia, el 40% de los neonatos con encefalopatía hipóxico-isquémica fallecen o sufren discapacidad moderada-grave. La espectroscopia cercana al infrarrojo (NIRS) se propone como una herramienta útil y no invasiva para establecer el pronóstico. Objetivos: evaluar el valor pronóstico de la NIRS en el resultado del neurodesarrollo entre los 18–36 meses en neonatos con encefalopatía hipóxico-isquémica y establecer el tiempo y los puntos de corte de la saturación cerebral de oxígeno que mejor se relacionan con el pronóstico. Pacientes y métodos: Se incluyeron todos los neonatos a término con encefalopatía hipóxico-isquémica, sometidos a hipotermia y NIRS, entre 2013−2016. Con respeto al resultado, se constituyeron tres grupos: neurodesarrollo normal, discapacidad moderada y grave. Resultados: Se incluyeron 28 neonatos (edad gestacional mediana: 39 semanas; peso al nacimiento mediano: 3195 gramos). La saturación cerebral de oxígeno tendió a aumentar desde una mediana de 65% hasta 85%, a las 48 horas de vida. El resultado del neurodesarrollo fue normal en 28,6%, el 35,7% adquirió discapacidad moderada y el 35,7% discapacidad grave (tres fallecieron). Se halló una diferencia estadística entre los grupos a las 48 horas (p = 0,005) y después de la hipotermia (p = 0,03), con valores más altos en los pacientes con discapacidad. Teniendo en cuenta el grupo con discapacidad grave frente a los otros, la curva de ROC a las 48 horas resultó en un área debajo de la curva (AUC) significativa de 0,872 (p = 0,001), con un punto de corte de saturación cerebral de oxígeno de 83,5%. Después de la hipotermia, los valores de saturación cerebral de oxígeno por debajo del 66,0% (AUC 0,794; p = 0,017) predijeron el desarrollo normal mientras que valores por encima del 82% (AUC 0,881; p = 0,001) predijeron discapacidad grave. Conclusiones: El NIRS parece constituir una herramienta útil en la predicción del resultado del neurodesarrollo de pacientes con encefalopatía hipóxico-isquémica, incluso después de la hipotermia, con valores más altos de saturación cerebral de oxígeno en pacientes con discapacidad.

Introdução: A profilaxia pré-exposição (PrEP) ganhou relevância como método de prevenção do VIH em determinados indivíduos e contextos. Após a entrada em vigor das normas para prescrição em Portugal, pretendemos aferir o conhecimento em relação à PrEP entre os estudantes de Medicina em Portugal. Material e Métodos: Foi enviado um questionário online aos estudantes de Medicina das escolas médicas portuguesas. Foi feita uma análise descritiva dos resultados e um estudo transversal analítico para identificar fatores associados a “conhecer a PrEP”, “ter tido uma aula de PrEP”, e “identificar grupos elegíveis corretamente”. Resultados: Dos 796 estudantes que responderam, 64,6% sabiam o que era a PrEP. Destes, 34,44% obteve conhecimento sobre a mesma durante a sua formação. Entre os respondentes, 4,77% identificaram correta e completamente os grupos elegíveis. Com o avançar do ano letivo, a probabilidade de conhecer a PrEP, ter tido uma aula de PrEP e identificar os grupos corretamente aumentava. No sexto ano, 43,48% tinham tido uma aula sobre PrEP e entre os que conheciam a PrEP, 28% identificaram os grupos elegíveis. Existem diferenças entre as escolas médicas após ajustamento para o ano letivo em relação aos resultados obtidos. A forma como se tomou conhecimento da PrEP não alterou de forma estatisticamente significativa a capacidade de identificar corretamente grupos elegíveis Conclusão: As diferenças entre as escolas médicas poderão ser harmonizadas. Esta temática poderá ser reforçada nos respetivos currículos.

Alzheimer’s disease (AD) is a chronic, progressive and fatal neurodegenerative disease, and is considered to be the main cause of dementia. It is currently one of the most prevalent diseases in the world, counting with millions of people suffering from dementia. Its exact etiology is not yet known; however, among the various hypotheses trying to explain the pathophysiology of AD, the one that has been more prominent in clinical research is the amyloid cascade hypothesis. Therefore, researchers have been using immunotherapy, particularly passive immunization, based on the use of effective monoclonal antibodies against the amyloid-β aggregates. Currently, several antibodies are already in phase 3 clinical trials. On June 7th, 2021, the monoclonal antibody Aducanumab gains Food and Drug Administration (FDA) approval to be used in patients in the early stages of the disease, becoming the first disease modifying drug for AD, contrary to other drugs that are already on the market, which only act on symptomatology.

Abstract Blood-brain barrier (BBB) disruption is a common feature in neurodegenerative diseases. However, BBB integrity has not been assessed in spinocerebellar ataxias (SCAs) such as Machado-Joseph disease/SCA type 3 (MJD/SCA3), a genetic disorder, triggered by polyglutamine-expanded ataxin-3. To investigate that, BBB integrity was evaluated in a transgenic mouse model of MJD and in human post-mortem brain tissues. Firstly, we investigated the BBB permeability in MJD mice by: i) assessing the extravasation of the Evans blue (EB) dye and blood-borne proteins (e.g fibrinogen) in the cerebellum by immunofluorescence, and ii) in vivo Dynamic Contrast Enhanced-Magnetic Resonance Imaging (DCE-MRI). The presence of ataxin-3 aggregates in brain blood vessels and the levels of tight junction (TJ)-associated proteins were also explored by immunofluorescence and western blotting. Human brain samples were used to confirm BBB permeability by evaluating fibrinogen extravasation, co-localization of ataxin-3 aggregates with brain blood vessels and neuroinflammation. In the cerebellum of the mouse model of MJD, there was a 5-fold increase in EB accumulation when compared to age-matched controls. Moreover, vascular permeability displayed a 13-fold increase demonstrated by DCE-MRI. These results were validated by the 2-fold increase in fibrinogen extravasation in transgenic animals comparing to controls. Interestingly, mutant ataxin-3 aggregates were detected in cerebellar blood vessels of transgenic mice, accompanied by alterations of TJ-associated proteins in cerebellar endothelial cells, namely a 29% decrease in claudin-5 oligomers and a 10-fold increase in an occludin cleavage fragment. These results were validated in post-mortem brain samples from MJD patients as we detected fibrinogen extravasation across BBB, the presence of ataxin-3 aggregates in blood vessels and associated microgliosis. Altogether, our results prove BBB impairment in MJD/SCA3. These findings contribute for a better understanding of the disease mechanisms and opens the opportunity to treat MJD with medicinal products that in normal conditions would not cross the BBB.

Orthognathic surgery is a procedure used to correct intermaxillary discrepancies, thus promoting significant improvements in chewing and breathing. During the surgical planning stage, orthodontists often use two-dimensional imaging techniques. The assessment is based on CBCT images and dental cast models to overcome these limitations; however, the evaluation of soft tissues remains complex. The aim of the present study was to develop a co-registration method of CBCT and photo images that would result in realistic facial image reconstruction. CBCT images were three-dimensionally rendered, and the soft tissues were subsequently segmented resulting in the cranial external surface. A co-registration between the obtained surface and a frontal photo of the subject was then carried out. From this mapping, a photorealistic model capable of replicating the features of the face was generated. To assess the quality of this procedure, seven orthodontists were asked to fill in a survey on the models obtained. The survey results showed that orthodontists consider the three-dimensional model obtained to be realistic and of high quality. This process can automatically obtain a three-dimensional model from CBCT images, which in turn may enhance the predictability of surgical-orthognathic planning.

Despite its low prevalence, pancreatic cancer (PC) is one of the deadliest, typically characterised as silent in early stages and with a dramatically poor prognosis when in its advanced stages, commonly associated with a high degree of metastasis. Many efforts have been made in pursuing innovative therapeutical approaches, from the search for new cytotoxic drugs and other bioactive compounds, to the development of more targeted approaches, including improved drug delivery devices. Marine biotechnology has been contributing to this quest by providing new chemical leads and materials originating from different organisms. In this review, marine biodiscovery for PC is addressed, particularly regarding marine invertebrates (namely sponges, molluscs, and bryozoans), seaweeds, fungi, and bacteria. In addition, the development of biomaterials based on marine-originating compounds, particularly chitosan, fucoidan, and alginate, for the production of advanced cancer therapies, is also discussed. The key role that drug delivery can play in new cancer treatments is highlighted, as therapeutical outcomes need to be improved to give further hope to patients.

The successful integration of transplanted three-dimensional tissue engineering (TE) constructs depends greatly on their rapid vascularization. Therefore, it is essential to address this vascularization issue in the initial design of constructs for perfused tissues. Two of the most important variables in this regard are scaffold composition and cell sourcing. Collagens with marine origins overcome some issues associated with mammal-derived collagen while maintaining their advantages in terms of biocompatibility. Concurrently, the freshly isolated stromal vascular fraction (SVF) of adipose tissue has been proposed as an advantageous cell fraction for vascularization purposes due to its highly angiogenic properties, allowing extrinsic angiogenic growth factor-free vascularization strategies for TE applications. In this study, we aimed at understanding whether marine collagen 3D matrices could support cryopreserved human SVF in maintaining intrinsic angiogenic properties observed for fresh SVF. For this, cryopreserved human SVF was seeded on blue shark collagen sponges and cultured up to 7 days in a basal medium. The secretome profile of several angiogenesis-related factors was studied throughout culture times and correlated with the expression pattern of CD31 and CD146, which showed the formation of a prevascular network. Upon in ovo implantation, increased vessel recruitment was observed in prevascularized sponges when compared with sponges without SVF cells. Immunohistochemistry for CD31 demonstrated the improved integration of prevascularized sponges within chick chorioalantoic membrane (CAM) tissues, while in situ hybridization showed human cells lining blood vessels. These results demonstrate the potential of using cryopreserved SVF combined with marine collagen as a streamlined approach to improve the vascularization of TE constructs.

Introdução: As crises não-epilépticas funcionais (CNEF) ou convulsões dissociativas (CD) correspondem a episódios paroxísticos de alterações do comportamento motor, consciência ou percepção, que se assemelham a crises epilépticas, mas que no entanto não são atribuíveis a nenhuma perturbação orgânica neurológica. A psicoterapia é o tratamento de escolha e vários estudos sugerem que intervenções psicoterapêuticas podem reduzir a frequência das convulsões e optimizar o recurso aos serviços de saúde. A Psicoterapia Cognitivo-Comportamental (TCC) tem sido aplicada em perturbações somatoformes e mais recentemente no tratamento das perturbações de conversão e perturbações dissociativas como as CNEF. Objectivos: Explorar a aplicabilidade da terapia cognitivo-comportamental no tratamento de pacientes com convulsões dissociativas/ crises não-epilépticas funcionais. Métodos: Revisão não sistemática da literatura. Resultados e Conclusões: Pacientes com CNEF frequentemente revelam crenças significativamente distorcidas e desenvolvem padrões comportamentais contraproducentes e repetitivos, com afectos angodepressivos associados. Uma intervenção psicoterapêutica como a TCC pode ser útil no alívio da emocionalidade negativa e estigma associados às crises, assim como auxiliar os pacientes a lidar com o stress psicossocial associado à precipitação das convulsões. Um modelo explicativo plausível para as CNEF defende que estas podem representar uma resposta dissociativa a um estado de hiperexcitabilidade perante circunstâncias ameaçadoras ou intoleráveis, acompanhada de respostas comportamentais de evitamento, as quais actuam como um importante factor de manutenção das crises. A evidência científica apoia o uso de TCC no tratamento das CNEF e como estas podem responder favoravelmente a intervenções específicas. Intervenções cognitivo-comportamentais procuram interromper respostas comportamentais/fisiológicas/cognitivas experienciadas no início da crise, encorajando os pacientes a envolverem-se em actividades antes evitadas, abordando de forma adaptativa, cognições negativas e crenças erróneas relacionadas com o seu estado de saúde, que podem contribuir para a perpetuação das CNEF. Estudos sob metodologia controlada revelaram benefício da TCC ao nível da redução da frequência das CNEF e aumento do período livre sem convulsões. A TCC pode ser útil na gestão de conflitos emocionais, na melhoria de comorbilidades como a ansiedade e a depressão, assim como na recuperação da auto-estima, auto-confiança e sentido de autonomia nos pacientes.

Abstract Background and objectives: Sugamadex is a modified gamma-cyclodextrin, the first selective agent for reversal of neuromuscular blockade induced by steroidal non-depolarizing muscle relaxants, with greater affinity for rocuronium. In this article we present a case of severe bradycardia and asystole following sugammadex administration. Case report: A 54-year-old male patient, ASA II, with a history of hypertension, dyslipidemia and obesity, who underwent an emergency umbilical herniorrhaphy under balanced general anesthesia. Intraoperative muscle relaxation was maintained with rocuronium. At the end of the surgery, the patient maintained a neuromuscular block with two TOF responses, and sugammadex (200 mg) was administered. About thirty seconds after its administration, the patient developed marked bradycardia (HR 30 bpm) followed by asystole. Conclusions: Documented bradycardia and asystole were attributed to the administration of sugammadex. This case shows that, although rare, cardiac arrest is a possible adverse effect of this drug, and that the knowledge of this situation can be determinant for the patient’s evolution.

53BP1 is a key player in non-homologous end joining (NHEJ). Here the authors reveal an important role for the multifunctional homodimeric protein hub dynein light chain 1 (DYNLL1) in increasing the efficacy of 53BP1-mediated repair of DNA double-strand breaks (DSBs) by NHEJ.

Introduction: The co-association of benzodiazepines and opioids is associated with an increased risk of overdose, death, and poorer psychosocial prognosis. The aim of this study is to characterize the prevalence, pattern of use, and primary clinical outcomes in benzodiazepines users in a public opioid maintenance treatment unit. Material and Methods: We conducted a cross-sectional study involving 236 patients treated with opioid substitutes (methadone and buprenorphine). We conducted a descriptive, bivariable, and multivariable analysis to determine clinical differences between benzodiazepines users and non-users. Results: The prevalence of consumption of benzodiazepines was 25.4% (60). The benzodiazepines were obtained with a medical prescription (49.8%) or on the black market (42.6%). The most prescribed benzodiazepine was diazepam (29.1%), and the main reasons were to relieve insomnia (27.7%) or anxiety (26.9%) and to enhance the psychoactive effects of other drugs (19.7%). Regarding the clinical outcomes, we highlight: a very high prevalence of hepatitis C (51.7%); severe ongoing consumption of psychoactive drugs (73.7%); and a high rate of depression and anxiety (> 60%), significantly higher in the benzodiazepines-user group. In the multivariable analysis of benzodiazepine use, we found alcohol consumption (OR 0.482; IC 95% 0.247, 0.238) had a negative association and having hepatitis C (OR 2.544, IC 95% 1.273, 5.084) or anxiety symptoms (OR 5.591; IC 95% 2.345, 13.326) had positive associations. Discussion: Our results suggest the BZD users had a complex drug addiction problem and underline the importance of adequately addressing BZD use, contemplating psychological and psychiatric approach in this particular population. Conclusion: Past or current use of benzodiazepines is associated with poor clinical and psychiatric outcomes. A multidisciplinary approach with a focus on infectious diseases and mental health is critical in order to enhance the treatment effectiveness and overall prognosis.

BackgroundSeveral studies have investigated the acoustic effects of diagnosed anxiety and depression. Anxiety and depression are not characteristics of the typical aging process, but minimal or mild symptoms can appear and evolve with age. However, the knowledge about the association between speech and anxiety or depression is scarce for minimal/mild symptoms, typical of healthy aging. As longevity and aging are still a new phenomenon worldwide, posing also several clinical challenges, it is important to improve our understanding of non-severe mood symptoms' impact on acoustic features across lifetime. The purpose of this study was to determine if variations in acoustic measures of voice are associated with non-severe anxiety or depression symptoms in adult population across lifetime.MethodsTwo different speech tasks (reading vowels in disyllabic words and describing a picture) were produced by 112 individuals aged 35-97. To assess anxiety and depression symptoms, the Hospital Anxiety Depression Scale (HADS) was used. The association between the segmental and suprasegmental acoustic parameters and HADS scores were analyzed using the linear multiple regression technique.ResultsThe number of participants with presence of anxiety or depression symptoms is low (>7: 26.8% and 10.7%, respectively) and non-severe (HADS-A: 5.4 ± 2.9 and HADS-D: 4.2 ± 2.7, respectively). Adults with higher anxiety symptoms did not present significant relationships associated with the acoustic parameters studied. Adults with increased depressive symptoms presented higher vowel duration, longer total pause duration and short total speech duration. Finally, age presented a positive and significant effect only for depressive symptoms, showing that older participants tend to have more depressive symptoms.ConclusionsNon-severe depression symptoms can be related to some acoustic parameters and age. Depression symptoms can be explained by acoustic parameters even among individuals without severe symptom levels.

Introduction: Chest pain is a very frequent reason for seeking medical care. When there is no obvious cause, patients are sometimes subjected to tests and treatments that may be unnecessary and potentially harmful. Mondor's disease is a rare but usually benign and self-limited entity characterized by thrombophlebitis in a specific region. Case report: We report the clinical case of a 51-year-old man admitted to the emergency department with a 24-hour history of left chest pain with no other symptoms. Physical examination revealed a palpable subcutaneous cord-like structure that ultrasound confirmed to be thrombophlebitis of a superficial vein in the mammary region. Secondary causes were ruled out, and the condition resolved with ibuprofen and the application of local ice. Discussion: Mondor’s disease can be associated with neoplasms, trauma or hyperviscosity states, but it is mostly idiopathic. Usually, it resolves completely in 4–8 weeks without specific treatment. Because this infrequent diagnosis mainly relies on clinical findings, it is important that clinicians can recognize the syndrome.

The aim of this study was to produce different “table olive flours” from fruits at different maturation stages. “Table olive flour” is here presented as an innovative product that can gain importance as a bioactive rich ingredient. Three types of natural table olives from cv. Cobrançosa, i.e., green, turning color, and black olives, were soaked, freeze-dried and ground to obtain three different flours. Their physical and nutritional characterization, lipid fraction (fatty acids and tocopherols profiles), phenolic profile, and antioxidant activity (total reducing capacity, radical scavenging activities of DPPH and ABTS●+) were analyzed. “Table olive flours” with different colors and different characteristics were obtained. The “green table olive flour” had the lowest fat content and energy. On the contrary, it showed the highest protein, carbohydrate contents, percentages of oleic acid (C18:1), and MUFA, as well as total tocopherols. It also showed the highest antioxidant activity. The “black table olive flour” was the one with the highest percentages of palmitic acid (C16:0), SFA, and total reducing capacity. In the three types of developed “flours”, nine phenolic compounds were detected, hydroxy-tyrosol being the major, followed by tyrosol, and luteolin. In conclusion, from natural table olives of cv. Cobrançosa, different “table olive flours” with distinct properties and high amounts of health-promoting compounds can be produced.

A primeira descrição clínica da síndrome da hiperémese dos canabinoides advém de um artigo de Allen et al publicado em 2004. Desde então, várias publicações têm-se focado na sua conceptualização e abordagem clínica, embora se mantenha pouco conhecida na comunidade médica. Esta síndrome é caracterizada pela tríade de consumo crónico de canabinoides, hiperémese cíclica, e banhos ou duches quentes compulsivos como forma de alívio sintomatológico. Podem ainda ocorrer dor abdominal e outros sintomas. A sua verdadeira prevalência é desconhecida, embora se acumule evidência de que é mais frequente do que outrora julgado. Foram aventadas várias hipóteses para a sua patogénese, nomeadamente relacionadas com recetores canabinoides e vaniloides, o eixo hipotálamo-hipófise-adrenal e o sistema nervoso simpático. Em termos terapêuticos, justificam-se medidas de suporte (p.e. hidratação) na fase aguda, existindo evidência para a utilização de benzodiazepinas (nomeadamente lorazepam), haloperidol ou capsaicina tópica para alívio sintomático. A única intervenção que interrompe o quadro é a abstinência dos consumos, devendo ser feita psicoeducação e orientação adequadas do doente. O conhecimento relativo a esta patologia encontra-se em crescimento. A falta de sensibilização para a doença pode conduzir a testes de diagnóstico invasivos e dispendiosos, inúmeras idas ao serviço de urgência e manutenção do quadro clínico sem resolução sintomatológica. O presente artigo visa sistematizar as linhas de intervenção clínica e fomentar uma maior consciencialização dos profissionais de saúde sobre esta entidade, permitindo uma melhor identificação e abordagem terapêutica deste quadro.

Summary: Using genome-wide radiogenetic profiling, we functionally dissect vulnerabilities of cancer cells to ionizing radiation (IR). We identify ERCC6L2 as a major determinant of IR response, together with classical DNA damage response genes and members of the recently identified shieldin and CTC1-STN1-TEN1 (CST) complexes. We show that ERCC6L2 contributes to non-homologous end joining (NHEJ), and it may exert this function through interactions with SFPQ. In addition to causing radiosensitivity, ERCC6L2 loss restores DNA end resection and partially rescues homologous recombination (HR) in BRCA1-deficient cells. As a consequence, ERCC6L2 deficiency confers resistance to poly (ADP-ribose) polymerase (PARP) inhibition in tumors deficient for both BRCA1 and p53. Moreover, we show that ERCC6L2 mutations are found in human tumors and correlate with a better overall survival in patients treated with radiotherapy (RT); this finding suggests that ERCC6L2 is a predictive biomarker of RT response.

For the purposes of professional development clinical education is crucial to speech-language pathologists (SLP). There is limited information about clinical education of SLP students in Portugal. The aim of this study was to describe and compare the mutual perceptions of Portuguese SLP’s clinical educators and students’ of SLP in a Portuguese private University Clinic. Five SLP clinical educators and nine students participated in a one on one semi-structured interview. Content analysis was used to explore interview data. The analysis led to the identification of four themes shared by both groups. Findings from this study provided an insight about clinical education characteristics and challenges reported by clinical educators and students in Portugal and to compare those results with others mentioned in other countries. The findings of this study suggest that clinical educators and students identify, in general, similar characteristics regarding effective/non-effective clinical educator profile and benefits regarding clinical education process. The sample provides preliminary data on Portuguese clinical educator’s and student’s experience of clinical education.

For aging speech, there is limited knowledge regarding the articulatory adjustments underlying the acoustic findings observed in previous studies. In order to investigate the age-related articulatory differences in European Portuguese (EP) vowels, the present study analyzes the tongue configuration of the nine EP oral vowels (isolated context and pseudoword context) produced by 10 female speakers of two different age groups (young and old). From the tongue contours automatically segmented from the US images and manually revised, the parameters (tongue height and tongue advancement) were extracted. The results suggest that the tongue tends to be higher and more advanced for the older females compared to the younger ones for almost all vowels. Thus, the vowel articulatory space tends to be higher, advanced, and bigger with age. For older females, unlike younger females that presented a sharp reduction in the articulatory vowel space in disyllabic sequences, the vowel space tends to be more advanced for isolated vowels compared with vowels produced in disyllabic sequences. This study extends our pilot research by reporting articulatory data from more speakers based on an improved automatic method of tongue contours tracing, and it performs an inter-speaker comparison through the application of a novel normalization procedure.

Introdução: A surdez congénita ou precocemente adquirida afeta 1 a 3 por cada 1000 recém-nascidos sem fatores de risco e 20 a 40/1000 com fatores de risco. O rastreio auditivo neonatal universal permite a sua identificação precoce. As crianças com surdez congénita/precocemente adquirida têm uma maior prevalência de outras patologias, especialmente oftalmológicas e do neurodesenvolvimento, tendo pelo menos 30% a 40% uma comorbilidade associada. Material e Métodos: Realizámos um estudo transversal, multicêntrico onde participaram 83% (n = 30) dos hospitais/maternidades do Serviço Nacional de Saúde. Resultados: Todos os hospitais/maternidades inquiridos realizam, por rotina, o rastreio auditivo neonatal universal a todos os recém-nascidos antes da alta; 63% encaminham para Otorrinolaringologia crianças com fatores de risco de surdez. Todas as crianças com surdez congénita/precocemente adquirida são encaminhadas para Pediatria em 23% hospitais/maternidades. Em 23 hospitais/maternidades todas as crianças com surdez congénita/precocemente adquirida são encaminhadas para: Terapia da Fala em 44% hospitais/maternidades; Oftalmologia em 17% hospitais/maternidades; Sistema Nacional de Intervenção Precoce na Infância (SNIPI) em 30% hospitais/maternidades; referenciação para Genética de todas as crianças com surdez congénita/ precocemente adquirida, sem causa identificada, em 22% hospitais/maternidades. O número de diagnósticos de surdez nos anos de 2014 e 2015 foi de 2,5 e 1,5 por cada 1000 recém-nascidos, respetivamente, em 15 dos hospitais/maternidades. Discussão: O rastreio auditivo neonatal universal parece estar amplamente difundido no Serviço Nacional de Saúde. O número de crianças com SC/SPA tal como a percentagem dos diferentes tipos de surdez diagnosticados, foram idênticos aos encontrados noutros estudos e mostra a indiscutível importância do rastreio. A avaliação/acompanhamento destas crianças por outras especialidades, além da Otorrinolaringologia, mostrou-se heterogéneo nas diferentes entidades de saúde e revelou que nem todas as crianças com fatores de risco de surdez realizam o seguimento aconselhado pelas normas existentes. Conclusão: Os resultados mostram que Portugal realizou um percurso importante no âmbito do rastreio e seguimento das crianças com SC/SPA. Importa, com o fim último da melhoria continua da prestação de cuidados a estas crianças, refletir sobre o envolvimento de outras especialidades, além da Otorrinolaringologia, tal como do Sistema Nacional de Intervenção Precoce na Infância no seguimento destas crianças.

Resumen: Introducción: En casos de faringitis por estreptococo grupo A (EGA) se recomienda una pauta de 10 días de amoxicilina. No obstante, parece que pautas de menor duración resultan igualmente efectivas. El objeto de este estudio fue evaluar y comparar de manera retrospectiva la evolución de pacientes tratados con pautas de amoxicilina de 7 y 10 días de duración. Materiales y métodos: Análisis retrospectivo de todos los casos de faringitis por EGA atendidos en un servicio de urgencias en 2014. Se analizaron variables demográficas, uso y resultados de pruebas de detección rápida de antígeno (PDRA), tratamiento, complicaciones y reingreso en un plazo de 30 días. Se definieron 2 grupos para el análisis comparativo basados en la duración del tratamiento con amoxicilina: a) pauta corta (hasta 7 días), y b) pauta larga (10 días). Resultados: Se incluyó a 989 casos de faringitis por EGA. La edad mediana fue 5,2 años, el 50,1% fue de sexo masculino. La amoxicilina fue el antibiótico más prescrito (94,9%), con una duración media de 7 días. Se prescribieron pautas de 10 días al 31,9% de los pacientes. No se encontraron diferencias entre los grupos con pautas cortas y largas en cuanto a la edad (p = 0,600), el género (p = 0,429) o las complicaciones (p = 0,436). Concluimos que en lo referente a la variable de resultado «regreso al servicio de urgencias», la pauta de 7 días no es inferior a la de 10 días. Conclusión: El antibiótico prescrito con mayor frecuencia fue la amoxicilina, aunque solo se prescribió pauta de 10 días en unos pocos casos. Nuestro análisis no encontró beneficio aparente del tratamiento de larga duración con amoxicilina en casos de faringitis por EGA. Abstract: Introduction: In group A streptococcal (GAS) pharyngitis a ten-day course of amoxicillin is recommended. However, short-course treatments seem to be equally effective. The aim of this study was to retrospectively evaluate and compare the outcome of patients treated with 7-day course and 10-day course of amoxicillin. Materials and methods: Retrospective analysis of all GAS pharyngitis admitted to a paediatric emergency department in 2014. Demographic variables, the application and results of the rapid antigenic diagnostic test (RADT), treatment, complications and return in the next 30 days were analysed. Two groups were defined for comparative analysis according to the duration of treatment with amoxicillin: A) short-course (up to 7 days) and B) long-course (10 days). Results: Were included 989 GAS pharyngitis. The median age was 5.2 years, 50.1% male. Amoxicillin was the most prescribed antibiotic (94.9%) with a median duration of 7 days. 10-day course therapy was prescribed in 31.9% of the cases. There were no differences between short and long-course treatment groups regarding age (P=.600), gender (P=.429) and complications (P=.436). Considering the endpoint “return to the emergency department”, we concluded that up to 7 days of treatment was non-inferior to 10 days of treatment. Conclusion: The most commonly prescribed antibiotic was amoxicillin, but a 10-day course was prescribed in few cases. In our analysis there seems to be no benefit with long-course treatments with amoxicillin in GAS pharyngitis.

Introduction: In group A streptococcal (GAS) pharyngitis, a ten-day course of amoxicillin is recommended. However, short-course treatments seem to be equally effective. The aim of this study was to retrospectively evaluate and compare the outcome of patients treated with 7-day course and 10-day course of amoxicillin. Materials and methods: Retrospective analysis of all GAS pharyngitis admitted to a pediatric emergency department in 2014. Demographic variables, the application and results of the rapid antigenic diagnostic test (RADT), treatment, complications and return in the next 30 days were analyzed. Two groups were defined for comparative analysis according to the duration of treatment with amoxicillin: A) short-course (up to 7 days) and B) long-course (10 days). Results: Were included 989 GAS pharyngitis. The median age was 5.2 years, 50.1% male. Amoxicillin was the most prescribed antibiotic (94.9%) with a median duration of 7 days. 10-day course therapy was prescribed in 31.9% of the cases. There were no differences between short and long-course treatment groups regarding age (p = 0.600), gender (p = 0.429) and complications (p = 0.436). Considering the endpoint “return to the emergency department”, we concluded that up to 7 days of treatment was non-inferior to 10 days of treatment. Conclusion: The most commonly prescribed antibiotic was amoxicillin, but a 10-day course was prescribed in few cases. In our analysis there seems to be no benefit with long-course treatments with amoxicillin in GAS pharyngitis. Resumen: Introducción: En casos de faringitis por estreptococo grupo A (EGA) se recomienda una pauta de 10 días de amoxicilina. No obstante, parece que pautas de menor duración resultan igualmente efectivas. El objeto de este estudio fue evaluar y comparar de manera retrospectiva la evolución de pacientes tratados con pautas de amoxicilina de 7 y 10 días de duración. Materiales y métodos: Análisis retrospectivo de todos los casos de faringitis por EGA atendidos en un servicio de urgencias en 2014. Se analizaron variables demográficas, uso y resultados de pruebas de detección rápida de antígeno (PDRA), tratamiento, complicaciones y reingreso en un plazo de 30 días. Se definieron 2 grupos para el análisis comparativo basados en la duración del tratamiento con amoxicilina: A) pauta corta (hasta 7 días), y B) pauta larga (10 días). Resultados: Se incluyó a 989 casos de faringitis por EGA. La edad mediana fue 5,2 años, el 50,1% fue de sexo masculino. La amoxicilina fue el antibiótico más prescrito (94,9%), con una duración media de 7 días. Se prescribieron pautas de 10 días al 31,9% de los pacientes. No se encontraron diferencias entre los grupos con pautas cortas y largas en cuanto a la edad (p = 0,600), el género (p = 0,429) o las complicaciones (p = 0,436). Concluimos que en lo referente a la variable de resultado «regreso al servicio de urgencias», la pauta de 7 días no es inferior a la de 10 días. Conclusión: El antibiótico prescrito con mayor frecuencia fue la amoxicilina, aunque solo se prescribió pauta de 10 días en unos pocos casos. Nuestro análisis no encontró beneficio aparente del tratamiento de larga duración con amoxicilina en casos de faringitis por EGA.

Pharmacological interventions targeting mitochondria present several barriers for a complete efficacy. Therefore, a new mitochondriotropic antioxidant (AntiOxBEN3) based on the dietary antioxidant gallic acid was developed. AntiOxBEN3 accumulated several thousand-fold inside isolated rat liver mitochondria, without causing disruption of the oxidative phosphorylation apparatus, as seen by the unchanged respiratory control ratio, phosphorylation efficiency, and transmembrane electric potential. AntiOxBEN3 showed also limited toxicity on human hepatocarcinoma cells. Moreover, AntiOxBEN3 presented robust iron-chelation and antioxidant properties in both isolated liver mitochondria and cultured rat and human cell lines. Along with its low toxicity profile and high antioxidant activity, AntiOxBEN3 strongly inhibited the calcium-dependent mitochondrial permeability transition pore (mPTP) opening. From our data, AntiOxBEN3 can be considered as a lead compound for the development of a new class of mPTP inhibitors and be used as mPTP de-sensitiser for basic research or clinical applications or emerge as a therapeutic application in mitochondria dysfunction-related disorders.

Tumor thrombosis of the internal jugular vein (IJV) represents an uncommon event, usually in the setting of underlying thyroid neoplasms. Extraosseous plasmacytoma (EMP) with tumor thrombosis of the IJV has not yet been reported in the literature. We present a unique case of a plasmacytoma in the left parapharyngeal space with direct extension to the left IJV, documented with contrast enhanced computed tomography and US Doppler. Presence of avid thrombus enhancement allowed differentiation between tumoral extension and thrombothic changes. Keywords: Plasmacytoma, Jugular vein, Tumoral thrombus

Abstract Oxidative stress and mitochondrial dysfunction have been associated with metabolic and age-related diseases. Thus, the prevention of mitochondrial oxidative damage is nowadays a recognized pharmacological strategy to delay disease progression. Epidemiological studies suggested an association between the consumption of polyphenol-rich diet and the prevention of different pathologies, including diseases with a mitochondrial etiology. The development of mitochondrial-targeted antioxidants based on dietary antioxidants may decrease mitochondrial oxidative damage. Herein, we report the design and synthesis of two new mitochondriotropic antioxidants based on hydroxybenzoic acids (AntiOxBENs). The results obtained showed that the novel antioxidants are accumulated inside rat liver mitochondria driven by the organelle transmembrane electric potential and prevented lipid peroxidation, exhibiting low toxicity. Some of the observed effects on mitochondrial bioenergetics resulted from an increase of proton leakage through the mitochondrial inner membrane. The new derivatives present a higher lipophilicity than the parent compounds (protocatechuic and gallic acids) and similar antioxidant and iron chelating properties. AntiOxBENs are valid mitochondriotropic antioxidant prototypes, which can be optimized and used in a next future as drug candidates to prevent or slow mitochondrial oxidative stress associated to several pathologies.

We report a case of a laboratory-confirmed Dengue and Chikungunya viruses co-infection imported from India to Portugal in early November 2016. The patient developed fever, retro-orbital pain and generalized myalgia after returning from Delhi, Jaipur, Agra, Rishikesh, Goa and Mumbai. This case highlights the importance of these arboviruses to public health in India where high rates of co-infection have been reported in the last few years, and demonstrates how challenging the laboratory diagnosis of imported co-infection cases can be in non-endemic areas.

The global impact of cancer emphasizes the importance of developing innovative, effective and minimally invasive therapies. In the context of superficial cancers, the development of a multifunctional nanoparticle-based system and its in vitro and in vivo safety and efficacy characterization are, herein, proposed as a proof-of-concept. This multifunctional system consists of gold nanoparticles coated with hyaluronic and oleic acids, and functionalized with epidermal growth factor for greater specificity towards cutaneous melanoma cells. This nanoparticle system is activated by a near-infrared laser. The characterization of this nanoparticle system included several phases, with in vitro assays being firstly performed to assess the safety of gold nanoparticles without laser irradiation. Then, hairless immunocompromised mice were selected for a xenograft model upon inoculation of A375 human melanoma cells. Treatment with near-infrared laser irradiation for five minutes combined with in situ administration of the nanoparticles showed a tumor volume reduction of approximately 80% and, in some cases, led to the formation of several necrotic foci, observed histologically. No significant skin erythema at the irradiation zone was verified, nor other harmful effects on the excised organs. In conclusion, these assays suggest that this system is safe and shows promising results for the treatment of superficial melanoma.

The crystal structures of three benzamide derivatives, viz. N-(6-hydroxyhexyl)-3,4,5-trimethoxybenzamide, C16H25NO5, (1), N-(6-anilinohexyl)-3,4,5-trimethoxybenzamide, C22H30N2O4, (2), and N-(6,6-diethoxyhexyl)-3,4,5-trimethoxybenzamide, C20H33NO6, (3), are described. These compounds differ only in the substituent at the end of the hexyl chain and the nature of these substituents determines the differences in hydrogen bonding between the molecules. In each molecule, the m-methoxy substituents are virtually coplanar with the benzyl ring, while the p-methoxy substituent is almost perpendicular. The carbonyl O atom of the amide rotamer is trans related with the amidic H atom. In each structure, the benzamide N—H donor group and O acceptor atoms link the molecules into C(4) chains. In 1, a terminal –OH group links the molecules into a C(3) chain and the combined effect of the C(4) and C(3) chains is a ribbon made up of screw related R22(17) rings in which the ...O—H... chain lies in the centre of the ribbon and the trimethoxybenzyl groups forms the edges. In 2, the combination of the benzamide C(4) chain and the hydrogen bond formed by the terminal N—H group to an O atom of the 4-methoxy group link the molecules into a chain of R22(17) rings. In 3, the molecules are linked only by C(4) chains.

A Escola assume um papel cada vez mais significativo na vida dos jovens, propondo-se garantir uma educação integral a todos os que acolhe, independentemente da sua proveniência ou características. A necessidade imperiosa de responder aos desafios provocados pelas mudanças sociais “exige-lhe” uma desmedida ambição pedagógica; trata-se de chegar a todos, esbater desigualdades, contribuir para um processo de igualdade de oportunidades. Torna-se, pois, imprescindível dotar a escola de meios que possam servir tão grandes exigências, cada vez mais próximas do domínio da acção socioeducativa. A proposta de acompanhamento tutorial, que apresentamos, assenta neste propósito, enquadrando e reflectindo o papel fundamental da figura do Professor Tutor, cujas competências e perfil foram legislados desde o princípio da década de noventa. Uma das formas possíveis de perspectivar o papel do Professor Tutor passa por enquadrá-lo no que designamos de Equipa Multidisciplinar de Actuação Imediata (EMAI) constituída pelos seguintes técnicos: Psicólogo, Assistente Social e Educador Social, para além dos profissionais da estrutura da organização do sistema educativo (caso do director de turma). Depois de identificadas algumas das funções de cada elemento, apresentar-se-á uma proposta de acompanhamento tutorial, em contexto escolar, cuja missão deverá terminar com a maioridade do menor sinalizado ou no momento do seu ingresso no mundo de trabalho. Esta equipa deverá, ainda, para cumprimento dos seus intentos, interagir com a família do menor e com as redes sociais de apoio local, de forma coordenada, no sentido da promoção de acções de carácter preventivo e interventivo no âmbito do plano de acção tutorial definido.

Disinfection is crucial to control and prevent microbial pathogens on surfaces. Nonetheless, disinfectants misuse in routine disinfection has increased the concern on their impact on bacterial resistance and cross-resistance. This work aims to develop a formulation for surface disinfection based on the combination of a natural product, cinnamaldehyde, and a widely used biocide, cetyltrimethylammonium bromide. The wiping method was based on the Wiperator test (ASTM E2967−15) and the efficacy evaluation of surface disinfection wipes test (EN 16615:2015). After formulation optimization, the wiping of a contaminated surface with 6.24 log10 colony-forming units (CFU) of Escherichia coli or 7.10 log10 CFU of Staphylococcus aureus led to a reduction of 4.35 log10 CFU and 4.27 log10 CFU when the wipe was impregnated with the formulation in comparison with 2.45 log10 CFU and 1.50 log10 CFU as a result of mechanical action only for E. coli and S. aureus, respectively. Furthermore, the formulation prevented the transfer of bacteria to clean surfaces. The work presented highlights the potential of a combinatorial approach of a classic biocide with a phytochemical for the development of disinfectant formulations, with the advantage of reducing the concentration of synthetic biocides, which reduces the potentially negative environmental and public health impacts from their routine use.

6-Bromochromone-2-carboxylic acid (3) was synthesized by a microwave-assisted process. The optimization of the reaction was performed varying parameters, such as type of base/number of reagent equivalents, solvent, temperature and reaction time. The yield of the reaction was improved to 87%. The new synthetic route is versatile as several chromone-2-carboxylic acids (compounds 4B−10B) were obtained with good yields (54−93%). Only in the case of the nitro substituent (compound 11B), an ester was obtained instead of the desired carboxylic acid. Following this synthetic route chromone carboxylic acids can be attained with a high degree of purity, without the need of the tedious and expensive purification processes through column chromatography. The reaction is safe, cost-effective, fast and robust, and can be used in the development of concise and diversity-oriented libraries based on chromone scaffold. The overall study can be looked as a step forward to speed-up the discovery of chromone-based multitarget-directed ligands.

Alzheimer's disease (AD) is a multifactorial age-related disease associated with oxidative stress (OS) and impaired cholinergic transmission. Accordingly, targeting mitochondrial OS and restoring cholinergic transmission can be an effective therapeutic strategy toward AD. Herein, we report for the first time dual-target hydroxybenzoic acid (HBAc) derivatives acting as mitochondriotropic antioxidants and cholinesterase (ChE) inhibitors. The studies were performed with two mitochondriotropic antioxidants AntiOxBEN1 (catechol derivative), and AntiOxBEN2 (pyrogallol derivative) and compounds 15–18, which have longer spacers. Compounds AntiOxBEN1 and 15, with a shorter carbon chain spacer (six- and eight-carbon) were shown to be potent antioxidants and BChE inhibitors (IC50 = 85 ± 5 and 106 ± 5 nM, respectively), while compounds 17 and 18 with a 10-carbon chain were more effective AChE inhibitors (IC50 = 7.7 ± 0.4 and 7.2 ± 0.5 μM, respectively). Interestingly, molecular modeling data pointed toward bifunctional ChEs inhibitors. The most promising ChE inhibitors acted by a non-competitive mechanism. In general, with exception of compounds 15 and 17, no cytotoxic effects were observed in differentiated human neuroblastoma (SH-SY5Y) and human hepatocarcinoma (HepG2) cells, while Aβ-induced cytotoxicity was significantly prevented by the new dual-target HBAc derivatives. Overall, due to its BChE selectivity, favorable toxicological profile, neuroprotective activity and drug-like properties, which suggested blood-brain barrier (BBB) permeability, the mitochondriotropic antioxidant AntiOxBEN1 is considered a valid lead candidate for the development of dual acting drugs for AD and other mitochondrial OS-related diseases.

A literatura recente tem apontado a existência de fragilidades, ao nível escolar e da aprendizagem, nas crianças e jovens que se encontram em situação de acolhimento institucional. O objetivo desta investigação foi analisar e compreender os processos de estudo e aprendizagem em instituições de acolhimento, de crianças e jovens do 2.º e 3.º ciclos e ensino secundário, examinando o papel de variáveis individuais e contextuais nos processos de autorregulação da aprendizagem. A amostra incluiu 248 jovens acolhidos em 20 lares de infância e juventude da zona norte de Portugal. Os instrumentos consistiram numa Ficha de Dados Pessoais e Académicos, no Inventário de Processos de Autorregulação da Aprendizagem (Rosário et al., 2010) e numa Ficha de Caracterização da Instituição. Os resultados evidenciaram diferenças significativas na autorregulação da aprendizagem em função do género e do histórico de retenções, realçando também a importância da autoeficácia, valorização da aprendizagem e aspirações educacionais. O local e o tempo de estudo, assim como as dificuldades em estudar relatadas pelos participantes, mostraram-se relevantes nos processos de autorregulação da aprendizagem A dimensão da instituição não assumiu relevância. São discutidas as implicações destes resultados na promoção de uma melhor educação e aprendizagem nos contextos de acolhimento institucional.

The anodic oxidation of oxytetracycline was performed with success using as anode a boron-doped diamond electrode. The experiments were conducted in batch mode, using two different electrochemical cells: an up-flow cell, with recirculation, that was used to evaluate the influence of recirculation flow rate; and a stirred cell, used to determine the influence of the applied current density. Besides oxytetracyclin electrodegradation rate and mineralization extent, oxidation by-products were also assessed. Both the flow rate and the applied current density have shown positive influence on the oxytetracycline oxidation rate. On the other hand, the mineralization degree presented the highest values at the lowest flow rate and the lowest current density tested. The main oxidation by-products detected were oxalic, oxamic and maleic acids.

Tuberous sclerosis (also referred to as Tuberous Sclerosis Complex) is an autosomal dominant neurocutaneous syndrome that can involve multiple organs such as the brain, heart, kidney, lung, liver, skin and eye. The diagnosis is clinical and most patients are identified during childhood, in the context of a severe epileptic or neuropsychiatric disorder. Here we report a case of TSC diagnosed in an adult woman with dermatological and vascular involvement that were only recognized as manifestations of TSC after the diagnosis of her infant daughter. This case highlights how important it is that physicians recognize the full spectrum of manifestations of TSC, including the most unusual, so not to miss the diagnosis

Cryopreservation of Senegalese sole sperm can represent an alternative to overcome some reproductive problems of this species. However, it is important to guarantee the safe use of cryopreserved sperm by selecting an appropriate protocol according to a high demand quality need to be ensured. It has been demonstrated that traditional assays such as motility and viability do not provide enough information to identify specific damage caused by cryopreservation process (freezing and thawing). Specific tests, including lipid peroxidation and DNA damage, should be performed. In the present study, motility and lipid peroxidation were performed as specific tests allowing us to discard cryopreservation conditions such as methanol as internal cryoprotectant and bovine serum albumin as external cryoprotectant. In addition, a caspase 3/7 detection by flow cytometry was performed to analyze apoptosis activity in the best selected conditions. Moreover, new highly sensitive tests based on transcript number detection have recently been described in fish sperm cryopreservation. For this reason, a transcript level detection assay was performed on certain oxidative and chaperone genes related to fertilization ability and embryo development (hsp70, hsp90BB, hsp90AA, gpx) to select the best cryopreservation conditions. DMSO+ egg yolk proved to be the best cryoprotectant combination in terms of transcript level. This study describes an optimized cryopreservation protocol for Solea senegalensis sperm demonstrating for the first time that transcript degradation is the most sensitive predictor of cell status in this species after cryopreservation.

In Krabbe's disease (KD), a leukodystrophy caused by β-galactosylceramidase deficiency, demyelination and a myelin-independent axonopathy contributes to the severe neuropathology. Beyond axonopathy, we show that in Twitcher mice, a model of KD, a decreased number of axons both in the PNS and in the CNS, and of neurons in dorsal root ganglia (DRG), occurred before the onset of demyelination. Despite the early axonal loss, and although in vitro Twitcher neurites degenerated over time, Twitcher DRG neurons displayed an initial neurite overgrowth and, following sciatic nerve injury, Twitcher axons were regeneration-competent, at a time point where axonopathy was already ongoing. Psychosine, the toxic substrate that accumulates in KD, induced lipid raft clustering. At the mechanistic level, TrkA recruitment to lipid rafts was dysregulated in Twitcher neurons, and defective activation of the ERK1/2 and AKT pathways was identified. Besides defective recruitment of signaling molecules to lipid rafts, the early steps of endocytosis and the transport of endocytic and synaptic vesicles were impaired in Twitcher DRG neurons. Defects in axonal transport, specifically in the retrograde component, correlated with decreased levels of dynein, abnormal levels of post-translational tubulin modifications and decreased microtubule stability. The identification of the axonal defects that precede demyelination in KD, together with the finding that Twitcher axons are regeneration-competent when axonopathy is already installed, opens new windows of action to effectively correct the neuropathology that characterizes this disorder.

Theranostics has emerged in recent years to provide an efficient and safer alternative in cancer management. This review presents an updated description of nanotheranostic formulations under development for skin cancer (including melanoma), head and neck, thyroid, breast, gynecologic, prostate, and colon cancers, brain-related cancer, and hepatocellular carcinoma. With this focus, we appraised the clinical advantages and drawbacks of metallic, polymeric, and lipid-based nanosystems, such as low invasiveness, low toxicity to the surrounding healthy tissues, high precision, deeper tissue penetration, and dosage adjustment in a real-time setting. Particularly recognizing the increased complexity and multimodality in this area, multifunctional hybrid nanoparticles, comprising different nanomaterials and functionalized with targeting moieties and/or anticancer drugs, present the best characteristics for theranostics. Several examples, focusing on their design, composition, imaging and treatment modalities, and in vitro and in vivo characterization, are detailed herein. Briefly, all studies followed a common trend in the design of these theranostics modalities, such as the use of materials and/or drugs that share both inherent imaging (e.g., contrast agents) and therapeutic properties (e.g., heating or production reactive oxygen species). This rationale allows one to apparently overcome the heterogeneity, complexity, and harsh conditions of tumor microenvironments, leading to the development of successful targeted therapies.

Uma das competências e atribuições da Direção Geral do Património Cultural (DGPC) é assegurar o inventário do património classificado e em vias de classificação, assim como o inventário do património arqueológico em Portugal continental. Sistematizar normas de inventário e executar a inventariação sistemática e atualizada dos bens que integram o património cultural são mais do que tarefas primordiais; como veremos, são instrumentos essenciais na gestão e salvaguarda desse património. O inventário do património urbano (arqueológico e arquitetónico) reveste-se de particular complexidade, com linhas de atuação interligadas com a gestão do território.