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Allogeneic hematopoietic stem cell transplantation (HSCT) is the only widely available curative treatment for sickle cell disease (SCD). Myeloablative conditioning regimens are associated with excellent outcomes in children with HLA-identical sibling donors but are limited by organ toxicity in adults. Here we report 48 children and adults who underwent HLA-identical sibling HSCT for SCD using a reduced toxicity conditioning (RTC) regimen (fludarabine, busulfan, and anti-thymocyte globulin), followed by cyclosporine plus methotrexate for graft-versus-host disease (GVHD) prophylaxis. Median (range) age at transplant and duration of follow-up were 16.5 (7–35) years and 77.5 (1-169) months, respectively. Indication for HSCT included neurological complications in 25 (52.1%) patients and 10 (20.8%) were alloimmunized against red blood cell antigens. All patients achieved engraftment, except one who died before engraftment period. Secondary graft failure, grade ≥ 2 acute GHVD and chronic GVHD were present in 7 (14.6%), 10 (20.8%) and 7 (14.6%) patients, respectively. Five-year overall survival (OS) and event-free survival (EFS) (95% CI) were 91% (77.8–96.5) and 80.3% (65.5–89.2), respectively. Survival curves were not different between children and adults (p = 0.37 and p = 0.33, respectively). RTC regimen is safe and effective, with acceptable toxicity and incidence of GVHD, in children and adults with SCD.

Survival of the African trypanosome within its mammalian hosts, and hence transmission between hosts, relies upon antigenic variation, where stochastic changes in the composition of their protective variant-surface glycoprotein (VSG) coat thwart effective removal of the pathogen by adaptive immunity. Antigenic variation has evolved remarkable mechanistic complexity in Trypanosoma brucei, with switching of the VSG coat executed by either transcriptional or recombination reactions. In the former, a single T. brucei cell selectively transcribes one telomeric VSG transcription site, termed the expression site (ES), from a pool of around 15. Silencing of the active ES and activation of one previously silent ES can lead to a co-ordinated VSG coat switch. Outside the ESs, the T. brucei genome contains an enormous archive of silent VSG genes and pseudogenes, which can be recombined into the ES to execute a coat switch. Most such recombination involves gene conversion, including copying of a complete VSG and more complex reactions where novel ‘mosaic’ VSGs are formed as patchworks of sequences from several silent (pseudo)genes. Understanding of the cellular machinery that directs transcriptional and recombination VSG switching is growing rapidly and the emerging picture is of the use of proteins, complexes and pathways that are not limited to trypanosomes, but are shared across the wider grouping of kinetoplastids and beyond, suggesting co-option of widely used, core cellular reactions. We will review what is known about the machinery of antigenic variation and discuss if there remains the possibility of trypanosome adaptations, or even trypanosome-specific machineries, that might offer opportunities to impair this crucial parasite-survival process.

El ultrasonido a la cabecera del paciente (UCP) es una herramienta esencial en la evaluación inicial del paciente crítico. Presentamos el caso de una mujer de 83 años que ingresó por un cuadro de alteración súbita del estado de consciencia. A su llegada estaba confusa, con hipoxemia, taquicardia y signos de mala perfusión periférica. El UCP mostró dilatación del ventrículo derecho compatible con la fuerte sospecha clínica de tromboembolismo pulmonar. Este caso demuestra la importancia de incluir el UCP en la evaluación de pacientes críticos, pues permite reducir el tiempo para el diagnóstico y tratamiento, mejorando su pronóstico.

Relatório de Estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de Farmácia Este documento pertence à unidade "Estágio Curricular" do Mestrado Integrado em Ciências Farmacêuticas (MICF) e é constituído por duas partes. Na primeira parte é apresentado o relatório de estágio da farmácia comunitária realizado na Farmácia Monteiro (FM).Os farmacêuticos comunitários assumem um importante papel na sociedade, nomeadamente na promoção da saúde e no estado emocional dos utentes, sendo confidentes dos seus problemas, pois têm um contacto muito próximo com a população. Esta profissão vai muito para além da dispensa dos medicamentos, e cada vez se foca mais no doente ao invés do medicamento, preocupando-se sempre em proporcionar ao utente uma ótima qualidade de vida. O estágio em Farmácia Comunitária (FC) é por esta razão, muito importante para a aquisição de novos conhecimentos e também para colocar em prática todos aqueles que aprendi durante o Mestrado Integrado em Ciências Farmacêuticas. Assim, o presente relatório relata as experiências vividas ao longo do meu estágio na FC, nomeadamente as inúmeras tarefas que desempenhei, bem como uma análise SWOT dos pontos fortes, fracos, ameaças e oportunidades experienciadas durante o período de estágio. Para além disso, também contém alguns casos clínicos que tive a oportunidade de me deparar na Farmácia Monteiro.A segunda parte do documento é a apresentação da monografia intitulada "Os ácidos gordos livres e a disfunção endotelial no contexto da diabetes" sob orientação da Professora Doutora Sónia Santos. A Diabetes Mellitus (DM) é cada vez mais um problema de saúde pública, verificando-se em todo o mundo que a sua prevalência e incidência estão a aumentar rapidamente. Em indivíduos obesos e com DM Tipo 2 (DMT2) os ácidos gordos livres (AGL) encontram-se em elevados níveis no plasma contribuindo para os processos de aterosclerose (AT) e doenças cardiovasculares (DCV). A disfunção endotelial (DE) é responsável pelos fatores de risco das DCV e é o fator chave para a patogénese da AT. Os AGL assumem funções importantes como a regulação da homeostasia, ativando uma família de recetores acoplados à proteína G (G protein-coupled receptor, GPCRs) denominados recetores de ácidos gordos livres (free fatty acid receptor, FFARs). Os FFARs são potenciais alvos terapêuticos nos distúrbios metabólicos e doenças do sistema imunológico. A DE mediada pelos AGL envolve inúmeros mecanismos como ativação do sistema renina-angiotensina, interrupção da libertação de NO (Nitric Oxide) mediada pela sinalização de cálcio, stress oxidativo e processos inflamatórios, regulação negativa da via AMPK / PI3K / Akt / eNOS e apoptose das células endoteliais (CE). No entanto, os AGL, mais concretamente o ácido palmítico (AP), têm sido utilizados para contornar algumas limitações farmacocinéticas, nomeadamente de fármacos antidiabéticos como os agonistas do recetor do Glucagon-like Peptide I (GLP-1) associando o peptídeo ao ácido palmítico (AP) de forma a aumentar o tempo de semi-vida, sendo questionável a relação custo-benefício desta associação. Na DE induzida por AGL tem-se explorado alguns fármacos, originalmente com outras indicações terapêuticas, mas que se mostram promissores em estudos pré-clínicos, tais como o fenofibrato, capaz de restaurar a vasodilatação dependente do endotélio através da diminuição do stress oxidativo e pelo aumento da fosforilação de eNOS. Outros compostos como a quercetina, o butirato, o Tongxinluo e o Danshensu têm efeito protetor no stress oxidativo e na inflamação na DE induzida por AGL.A via Nrf2 / HO-1 é uma possível via alvo para inibir a DE induzida por AGL através da modulação de processos inflamatórios. This document belongs to the "curricular stage" of the Integrated Master´s degree in Pharmaceutical Sciences and consists of two parts. In the first part, the internship report of the community pharmacy at Farmácia Monteiro (FM). Community pharmacists play an important role in society, namely in promoting the health and emotional state of users, being confidants of their problems, as they have a very close contact with the population. This profession goes far beyond dispensing medication, and increasingly focuses on the patient rather than the medication, always concerned with providing the user with a great quality of life. The internship in Community Pharmacy (CF) is, for this reason, very important for the acquisition of new knowledge and also for putting into practice all those I learned during the Integrated Master in Pharmaceutical Sciences.Thus, this report reports the experiences lived during my internship at FC, namely the numerous tasks I performed, as well as a SWOT analysis of the strengths, weaknesses, threats and opportunities experienced during the internship period. In addition, it also contains some clinical cases that I had the opportunity to come across at Farmácia Monteiro .The second part of the document is the presentation of the monograph entitled "Free fatty acids and endothelial dysfunction in the context of diabetes" performed under supervision of Professor Doctor Sónia Santos. Diabetes Mellitus (DM) is increasingly a public health problem, with its prevalence and incidence increasing rapidly around the world. In obese individuals and with Type 2 DM (DMT2), free fatty acids (FFA) are found in high levels in the plasma, contributing to the processes of atherosclerosis (AT) and cardiovascular diseases (CVD). Endothelial dysfunction (ED) is responsible for CVD risk factors and is the key factor in the pathogenesis of AT.FFAs play important roles in regulating homeostasis, activating a family of G protein-coupled receptors (G protein-coupled receptors, GPCRs) called free fatty acid receptors (FFARs). FFARs are potential therapeutic targets in metabolic disorders and diseases of the immune system.FFA-mediated ED involves numerous mechanisms such as activation of the renin-angiotensin system, interruption of NO (Nitric Oxide) release mediated by calcium signaling, oxidative stress and inflammatory processes, negative regulation of the AMPK / PI3K / Akt / eNOS pathway and apoptosis of endothelial cells (EC). However, FFA, specifically palmitic acid (PA), have been used to circumvent some pharmacokinetic limitations, namely of antidiabetic drugs such as Glucagon-like Peptide I (GLP-1) receptor agonists, associating the peptide with palmitic acid (AP) in order to increase the half-life, and the cost-effectiveness of this association is questionable. In Endothelial dysfunction induced by AGL, some drugs have been explored, originally with other therapeutic indications, but which show promise in studies preclinical drugs, such as fenofibrate, capable of restoring endothelium-dependent vasodilation by decreasing oxidative stress and increasing eNOS phosphorylation. Other compounds such as quercetin, butyrate, Tongxinluo and Danshensu have a protective effect on oxidative stress and inflammation in FFA-induced ED.The Nrf2/HO-1 pathway is a possible target pathway to inhibit AGL-induced ED through modulation of inflammatory processes.

Background Takotsubo cardiomyopathy is characterized by transient left systolic dysfunction that can mimic acute myocardial infarction. Atrioventricular (AV) block associated with Takotsubo is rare, but a few cases have been reported in recent years. Methods We present the case of a 77-year-old woman presenting with second-degree AV and Takotsubo syndrome. Results The diagnosis of Takotsubo syndrome was based on echocardiogram changes and the absence of coronary artery obstruction on coronary angiography. Conclusions We describe a patient with a diagnosis of Takotsubo syndrome and AV conduction defect. These conditions rarely occur simultaneous, but when they do, a dilemma arises regarding pacemaker implantation. LEARNING POINTS Takotsubo syndrome is a rare disorder that can mimic acute myocardial infarction.Takotsubo syndrome normally resolves by itself, but the associated arrhythmias may need treatment and pacemaker implantation.The timing of pacemaker implantation has to be evaluated on a case-by-case basis.

Highly selective gene expression is a key requirement for antigenic variation in several pathogens, allowing evasion of host immune responses and maintenance of persistent infections1. African trypanosomes-parasites that cause lethal diseases in humans and livestock-employ an antigenic variation mechanism that involves monogenic antigen expression from a pool of >2,600 antigen-coding genes2. In other eukaryotes, the expression of individual genes can be enhanced by mechanisms involving the juxtaposition of otherwise distal chromosomal loci in the three-dimensional nuclear space3-5. However, trypanosomes lack classical enhancer sequences or regulated transcription initiation6,7. In this context, it has remained unclear how genome architecture contributes to monogenic transcription elongation and transcript processing. Here, we show that the single expressed antigen-coding gene displays a specific inter-chromosomal interaction with a major messenger RNA splicing locus. Chromosome conformation capture (Hi-C) revealed a dynamic reconfiguration of this inter-chromosomal interaction upon activation of another antigen. Super-resolution microscopy showed the interaction to be heritable and splicing dependent. We found a specific association of the two genomic loci with the antigen exclusion complex, whereby VSG exclusion 1 (VEX1) occupied the splicing locus and VEX2 occupied the antigen-coding locus. Following VEX2 depletion, loss of monogenic antigen expression was accompanied by increased interactions between previously silent antigen genes and the splicing locus. Our results reveal a mechanism to ensure monogenic expression, where antigen transcription and messenger RNA splicing occur in a specific nuclear compartment. These findings suggest a new means of post-transcriptional gene regulation.

The organization of actin filaments into a wide range of subcellular structures is a defining feature of cell shape and dynamics, important for tissue development and homeostasis. Nervous system function requires morphological and functional plasticity of neurons and glial cells, which is largely determined by the dynamic reorganization of the actin cytoskeleton in response to intrinsic and extracellular signals. Oligodendrocytes are specialized glia that extend multiple actin-based protrusions to form the multilayered myelin membrane that spirally wraps around axons, increasing conduction speed and promoting long-term axonal integrity. Myelination is a remarkable biological paradigm in development, and maintenance of myelin is essential for a healthy adult nervous system. In this review, we discuss how structure and dynamics of the actin cytoskeleton is a defining feature of myelinating oligodendrocytes' biology and function. We also review "old and new" concepts to reflect on the potential role of the cytoskeleton in balancing life and death of myelin membranes and oligodendrocytes in the aging central nervous system.

We applied an empirical modelling approach for gross primary productivity (GPP) estimation from hyperspectral reflectance of Mediterranean grasslands undergoing different fertilization treatments. The objective of the study was to identify combinations of vegetation indices and bands that best represent GPP changes between the annual peak of growth and senescence dry out in Mediterranean grasslands. In situ hyperspectral reflectance of vegetation and CO2 gas exchange measurements were measured concurrently in unfertilized (C) and fertilized plots with added nitrogen (N), phosphorus (P) or the combination of N, P and potassium (NPK). Reflectance values were aggregated according to their similarity (r≥90 %) in 26 continuous wavelength intervals (Hyp). In addition, the same reflectance values were resampled by reproducing the spectral bands of both the Sentinel-2A Multispectral Instrument (S2) and Landsat 8 Operational Land Imager (L8) and simulating the signal that would be captured in ideal conditions by either Sentinel-2A or Landsat 8. An optimal procedure for selection of the best subset of predictor variables (LEAPS) was applied to identify the most effective set of vegetation indices or spectral bands for GPP estimation using Hyp, S2 or L8. LEAPS selected vegetation indices according to their explanatory power, showing their importance as indicators of the dynamic changes occurring in community vegetation properties such as canopy water content (NDWI) or chlorophyll and carotenoids ∕ chlorophyll ratio (MTCI, PSRI, GNDVI) and revealing their usefulness for grasslands GPP estimates. For Hyp and S2, bands performed as well as vegetation indices to estimate GPP. To identify spectral bands with a potential for improving GPP estimates based on vegetation indices, we applied a two-step procedure which clearly indicated the short-wave infrared region of the spectra as the most relevant for this purpose. A comparison between S2- and L8-based models showed similar explanatory powers for the two simulated satellite sensors when both vegetation indices and bands were included in the model. Altogether, our results describe the potential of sensors on board Sentinel-2 and Landsat 8 satellites for monitoring grassland phenology and improving GPP estimates in support of a sustainable agriculture management.

Introduction Minimally invasive gynecological surgery such as hysteroscopy has a small risk of complications. These include uterine perforation (with or without adjacent pelvic organ lesion), bleeding and infection, and are more common in the presence of risk factors such as smoking, history of pelvic inflammatory disease (PID) and endometriosis. Case Presentation A patient submitted to a diagnostic hysteroscopy with no immediate complications was admitted five days later to the emergency department in septic shock. The diagnosis of ruptured tubal abscess was made, requiring emergency laparotomy with sub-total hysterectomy and bilateral adnexectomy. Despite multiple organ failure requiring admission to the intensive care unit, the patient made a full recovery. Conclusion Ascending infection can be a life-threatening complication of hysteroscopy, even in the absence of previously known risk factors., Highlights • Septic shock can be a serious complication of office hysteroscopy. • Ascending infection can occur even with no prior history of sexual intercourse. • Patient awareness of alarm signs is key in preventing complications. • Prompt recognition and treatment of sepsis are needed to avoid morbidity.

Dissertação de mestrado em Ciências da Comunicação (área de especialização em Publicidade e Relações Públicas), Numa altura em que os canais de comunicação provenientes do digital evoluem de dia para dia e as audiências atingem dimensões expressivas, a função da comunicação passa a ser considerada de uma forma ainda mais estratégica do que no passado. Isto significa que, para além da necessidade de um diagnóstico rigoroso e de um planeamento eficaz, as organizações passam também a integrar, de forma interativa, os seus públicos nas ações realizadas, reforçando assim os laços entre organização e cliente. O consumidor é agora “um parceiro, um colaborador que dá ideias para que o (...) produto/serviço responda melhor às suas necessidades, e, consequentemente, se destaque da concorrência” (Barreto, 2011). É com esta nova estratégia em mente – mais relacional e interativa - que os profissionais de comunicação decidem incluir as ferramentas digitais nas suas ações de comunicação, como elemento necessário à coprodução. Todas estas mudanças digitais, reforçadas pelo aparecimento do e-commerce, vieram revolucionar as indústrias mais competitivas do mercado, como é o caso do setor da moda. Apesar de uma adaptação complexa a vários níveis, a área da moda apresenta-se hoje na vanguarda das novas tecnologias e da comunicação digital. Este tema será debatido ao longo do presente relatório, por meio de uma pesquisa teórica que será posteriormente cruzada com as ações implementadas durante a experiência de estágio curricular realizado na marca de calçado e acessórios, Josefinas Portugal. Ao longo do documento será relatada a constante tentativa de unir os canais online e offline, bem como todos os desafios e oportunidades inerentes, que culminaram num conjunto de ações de comunicação, entre as quais a campanha de responsabilidade social In Her Shoes., At a time when communication channels from the digital evolve from day to day and audiences reach expressive dimensions, the communication function is now considered in a much more strategic way than in the past. This means that, in addition to the need for rigorous planning, organizations also begin to integrate their audiences into the actions undertaken, thus reinforcing the bonds between organization and client. The consumer is now a partner, a collaborator who contributes so that the product/service accomplishes their needs, and consequently stands out from the competition (Barreto, 2011). With this new strategy in mind - more relational and interactive - communication professionals decide to include digital tools in their communication actions, as a necessary element for co-production. All these digital changes, reinforced by the appearance of e-commerce, have revolutionized the most competitive industries in the market, as is the case of the fashion sector. Despite a complex adaptation regarding several aspects, the fashion area stands today at the forefront of new technologies and digital communication. This theme will be discussed throughout this paper, through theoretical research that will be later crossed with the actions implemented during the curricular internship experience carried out in the footwear and accessories brand, Josefinas Portugal. Throughout the document will be reported the constant attempt to link the online and offline channels, as well as all the inherent challenges and opportunities, which culminated in a set of communication actions, among which the social responsibility campaign In Her Shoes.

Relatório de Mestrado em Ensino de Educação Física nos Ensinos Básico e Secundário

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We applied an empirical modelling approach for Gross Primary Productivity (GPP) estimation from hyperspectral surface reflectance of Mediterranean grasslands undergoing different fertilization treatments. The objective of the study was to identify combinations of vegetation indices and bands that better represent GPP changes between the annual-peak of growth and senescence dry out in Mediterranean grasslands. In situ, hyperspectral measurements of vegetation reflectance, were collected at the same time as CO2 gas exchange measurements were performed in control (C) and fertilized plots with added nitrogen (N), phosphorus (P) or the combination of N, P and potassium (NPK). Reflectance values were aggregated, according to their similarity (r > 90 %), in 26 continuous wavelength intervals (Hyp). Also, the same reflectance values were resampled reproducing the wavebands of both Sentinel-2A Multispectral Instrument (S2) and Landsat 8 Operation Land Imager (L8). This lead to a set of reflectance values simulating the signal that would be captured in ideal conditions by either Sentinel-2A or Landsat 8. The LEAPS procedure was applied to select the best set of the vegetation indices or spectral bands for GPP estimation using Hyp, S2 or L8. The LEAPS selected some vegetation indices putting in evidence their exploratory power as indicators of the dynamic changes of community vegetation properties such as canopy water content (NDWI) or chlorophyll and carotenoids/chlorophyll ratio (MTCI, PSRI, GNDVI), underlining their importance for grasslands GPP estimates. For Hyp and S2, spectral bands showed similar exploratory power than vegetation indices to estimate GPP. A two-step LEAPS procedure allowed us also to identify spectral bands with potential for improving GPP estimates. This procedure clearly indicates the shortwave infrared region of the spectra as promising for this purpose. The comparison of S2 and L8 based models showed similar explanatory power of the two simulated satellite sensors when spectral bands were adopted. Altogether our results show the potential of sensors on board of Sentinel 2 and Landsat 8 satellites for monitoring grasslands phenology and improving GPP estimates in support of a sustainable agriculture management.

The adequate training of health workforce in the field of excessive alcohol consumption is essential to provide health professionals with the necessary tools for an adequate provision of care, thus leading to a decrease in alcohol consumption. Proper planning of such training is thus essential, but literature in this area is still scarce. This paper proposes an optimization model based on mathematical programming for supporting the planning of health workforce training in the field of excessive alcohol consumption in National Health Service-based countries – the WFTMalcohol. The model aims at informing on (i) how many health professionals (physicians and nurses) should be trained per year and health unit, and (ii) which training packages should be available per year. The model allows exploring the impact of considering different objectives relevant in this sector, including the minimization of costs and the maximization of multiple performance indicators. Acknowledging that several sources of uncertainty may affect planning decisions, a sensitivity analysis on key parameters of the model is performed. To illustrate the applicability of the model, a case study based on the Oeste Sul ACES in Lisbon is analyzed. Results confirm that there is a shortage of trained professionals in this field in Portugal. info:eu-repo/semantics/acceptedVersion

The trypanosomatids, Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp, are causative agents of important human diseases such African sleeping sickness, Chagas' disease and Leishmaniasis, respectively. The high impact of these diseases on human health and economy worldwide, the unsatisfactory available chemotherapeutic options and the absence of human effective vaccines, strongly justifies the search for new drugs. The pentose phosphate pathway has been proposed to be a viable strategy to defeat several infectious diseases, including those from trypanosomatids, as it includes an oxidative branch, important in the maintenance of cell redox homeostasis, and a non-oxidative branch in which ribose 5-phosphate and erythrose 4-phosphate, precursors of nucleic acids and aromatic amino acids, are produced. This review provides an overview of the available chemotherapeutic options against these diseases and discusses the potential of genetically validated enzymes from the pentose phosphate pathway of trypanosomatids to be explored as potential drug targets. This article is a result of the projects NORTE-01-0145-FEDER-000012, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) and from the European Community's Seventh Framework Programme under grant agreements No. 602773 (Project KINDRED). JT is an Investigator FCT funded by National funds through FCT and co-funded through European Social Fund within the Human Potential Operating Programme.