ASPECTS OF THE DEVELOPMENT OF NEW ANTI-LEISHMANIA DRUGS: FROM CONTROL OF NEGLECTED INFECTIONS TO PARASITE-HOST INTERACTIONS AND DRUG-RESISTANT PARASITES

Leishmaniasis is a neglected disease caused by parasites of the genus Leishmania. The disease leads to different clinical manifestations determined by parasite features like heterogeneity in the virulence of distinct species-zymodemes and host parameters such as genetic characteristics and immunological status./nVisceral leishmaniasis (VL) is the most severe disease form and is potentially fatal if untreated. Drugs in use against VL present several drawbacks including high toxicity, relevant contraindications and complicated administration regimens. In addition, 90% of world´s VL cases are concentrated in poorest locations like the Indian sub-continent where a number of factors contribute to an ineffective disease control including access to medicines and its relatively expensive price and the development of resistant Leishmania strains, not only to the classical antimonials drugs but also to miltefosine, the only oral drug available./nTherefore, the development of new drugs against VL is urgent and must have in consideration several aspects in order to achieve and be effective to most of the disease cases. Indeed, treatment outcomes vary substantially between different geographic regions and depend on the drug(s) used, drug exposure, severity of disease, host immunity, and the presence of coinfections.  /nSo, in order to improve the drug discovery process for anti-leishmanials the drug screening should involve recent clinical isolates of the L. donovani complex, with different susceptibility profiles to existing drugs and from different geographical origin./nBoth synthetic and natural product libraries might be screened, but evaluation of drugs already in use by developing new formulations or even drug repurposing might also contribute to a faster identification of new candidates. Additional short-term approaches might be combinatory therapies, some of which have proven to be useful mainly in coinfections with HIV./nOther important issue is the establishment of standard techniques for the selection of ’hit compounds‘  and the criteria established by the Global Health Innovative Technology  Fund represent an interesting approach: a given hit should present a 50% effective concentration (EC50 value) lower than 10?M against intracellular amastigotes of Leishmania sp. and for the in vivo model of VL (i.e. mouse or hamster infected with L. infantum or L. donovani), treatment schemes should result in 70% reduction of liver parasite load after up to 5 doses of 50mg/kg, orally, one or two times a day./nIn the last decades, technology advances have allowed the establishment of High-throughput screening (HTS), a potential efficient way of identifying active compounds able to eliminate the parasite without affecting the host. However, the lack of central database capable of concentrating positive and negative results from different research groups and compounds tested also contributes to delaying the identification of potential candidates against Leishmania protozoa. Also by applying bioinformatic tools such as a systematic in silico chemogenomics strategy in combination with the classical approach, its expected to identify new antiparasitic compounds that will be available for application in the pharmaceutical industry and further research lines./nA relevant portion of drug prospection for neglected diseases relies on academic and research institution but dealing with diseases of such relevance worldwide must require the incorporation of Government and private funding for basic and clinical research projects through direct investments and incentives to both academia and the private sector.Leishmaniasis is a neglected disease caused by parasites of the genus Leishmania. The disease leads to different clinical manifestations determined by parasite features like heterogeneity in the virulence of distinct species-zymodemes and host parameters such as genetic characteristics and immunological status./nVisceral leishmaniasis (VL) is the most severe disease form and is potentially fatal if untreated. Drugs in use against VL present several drawbacks including high toxicity, relevant contraindications and complicated administration regimens. In addition, 90% of world´s VL cases are concentrated in poorest locations like the Indian sub-continent where a number of factors contribute to an ineffective disease control including access to medicines and its relatively expensive price and the development of resistant Leishmania strains, not only to the classical antimonials drugs but also to miltefosine, the only oral drug available./nTherefore, the development of new drugs against VL is urgent and must have in consideration several aspects in order to achieve and be effective to most of the disease cases. Indeed, treatment outcomes vary substantially between different geographic regions and depend on the drug(s) used, drug exposure, severity of disease, host immunity, and the presence of coinfections.  /nSo, in order to improve the drug discovery process for anti-leishmanials the drug screening should involve recent clinical isolates of the L. donovani complex, with different susceptibility profiles to existing drugs and from different geographical origin./nBoth synthetic and natural product libraries might be screened, but evaluation of drugs already in use by developing new formulations or even drug repurposing might also contribute to a faster identification of new candidates. Additional short-term approaches might be combinatory therapies, some of which have proven to be useful mainly in coinfections with HIV./nOther important issue is the establishment of standard techniques for the selection of ’hit compounds‘  and the criteria established by the Global Health Innovative Technology  Fund represent an interesting approach: a given hit should present a 50% effective concentration (EC50 value) lower than 10?M against intracellular amastigotes of Leishmania sp. and for the in vivo model of VL (i.e. mouse or hamster infected with L. infantum or L. donovani), treatment schemes should result in 70% reduction of liver parasite load after up to 5 doses of 50mg/kg, orally, one or two times a day./nIn the last decades, technology advances have allowed the establishment of High-throughput screening (HTS), a potential efficient way of identifying active compounds able to eliminate the parasite without affecting the host. However, the lack of central database capable of concentrating positive and negative results from different research groups and compounds tested also contributes to delaying the identification of potential candidates against Leishmania protozoa. Also by applying bioinformatic tools such as a systematic in silico chemogenomics strategy in combination with the classical approach, its expected to identify new antiparasitic compounds that will be available for application in the pharmaceutical industry and further research lines./nA relevant portion of drug prospection for neglected diseases relies on academic and research institution but dealing with diseases of such relevance worldwide must require the incorporation of Government and private funding for basic and clinical research projects through direct investments and incentives to both academia and the private sector

Increased susceptibility to Mycobacterium avium in hemochromatosis protein HFE-deficient mice

Mycobacterium avium is an opportunistic infectious agent in immunocompromised patients, living inside macrophage phagosomes. As for other mycobacterial species, iron availability is a critical factor for M. avium survival and multiplication. Indeed, an association between host secondary iron overload and increased susceptibility to these mycobacteria is generally acknowledged. However, studies on the impact of primary iron overload on M. avium infection have not been performed. In this work, we used animal models of primary iron overload that mimic the human disease hereditary hemochromatosis. This pathology is characterized by increased serum transferrin saturation with iron deposition in parenchymal cells, mainly in the liver, and is most often associated with mutations in the gene encoding the molecule HFE. In this paper, we demonstrate that mice of two genetically determined primary iron overload phenotypes, Hfe(-/-) and beta 2m(-/-), show an increased susceptibility to experimental infection with M. avium and that during infection these animals accumulate iron inside granuloma macrophages. beta 2m(-/-) mice were found to be more susceptible than Hfe(-/-) mice, but depleting Hfe(-/-) mice of CD8(+) cells had no effect on resistance to infection. Overall, our results suggest that serum iron, rather than total liver iron, levels have a considerable impact on susceptibility to M. avium infection

“Se eu pudesse trabalharia só oito horas”: As condições de trabalho dos mototaxistas e vendedores ambulantes de Palmas/TO

We are currently living in a scenario in which the increase of unemployment rates, the worsening of working conditions and setbacks in the scope of social rights have been amplifying the poverty as well as increasing the number of workers looking for alternative means to guarantee income and survival. The activities carried out by the poor population are escalating in Brazilian cities in number and variety and it is intensifying the divisions of labor, assumed in this research, as a starting point to understand the theory of the circuits of the urban economy. We intend to analyze the working conditions present in the lower circuit of Palmas, from two niches of activities: the motorcycle taxi service and the street commerce. For this study we chose documentary and bibliographic research and, in the field work, we conducted interviews with 65 workers enrolled in the investigated activities. The results indicated that the lower circuit in Palmas follows a national trend, that means it is in the midst of an expansion process, having the current crisis of employment and the expansion of the entrepreneurship and self-employment discourse as drivers, these factors have been used by capital and supported by a neoliberal state as strategies to expand the forms of domination of the working class. On top of that, it also reinforces that unemployment and precariousness are inherent to the capitalist mode of production. In addition to that, the research indicates the deterioration of the living conditions most of the workers interviewed suffer, given the precarious and unprotected ways in which they work. The activities of the lower circuit in the capital city of Tocantins have become an exile for a contingent of unemployed people, rather than the solution to the serious problem the productive world is currently experiencing. Thus, the motorcycle taxi people and street vendors experience the process of precariousness not only at work, but also of their lives.Em um cenário marcado pelo aumento do desemprego e das expressões da precarização do trabalho, retrocessos no âmbito dos direitos sociais e na multiplicação da pobreza, um número cada vez maior de trabalhadores busca meios alternativos de obtenção de renda e garantia de sobrevivência. Ampliam-se nas cidades brasileiras, em número e variedade, as atividades realizadas pela população pobre, intensificando as divisões do trabalho, entendidas nessa pesquisa como ponto de partida para a compreensão da teoria dos circuitos da economia urbana. Nesse sentido, buscamos realizar uma análise sobre as condições de trabalho presentes no circuito inferior de Palmas, a partir de duas atividades, o serviço de mototáxi e o comércio ambulante. Recorremos às pesquisas documental, bibliográfica e, no trabalho de campo, entrevistamos 65 trabalhadores inscritos nas atividades investigadas. Os resultados apontaram que o circuito inferior em Palmas, seguindo uma tendência nacional, está em pleno processo de expansão, tendo como propulsores a atual crise do emprego e ampliação do discurso do empreendedorismo e do trabalho por conta própria, fatores utilizados pelo capital, com apoio do Estado neoliberal, como estratégias para ampliar as formas de dominação da classe que vive do trabalho, reforçando que o desemprego e a precarização são inerentes ao modo de produção capitalista. A pesquisa apontou para a deterioração das condições de vida da maior parte dos trabalhadores entrevistados, dadas às formas precárias e desprotegidas em que atuam. As atividades do circuito inferior na capital tocantinense tornaram-se exílio para um contingente de desempregados, mas não a solução para o grave problema que o mundo produtivo vive no período presente. Os mototaxistas e os ambulantes vivenciam o processo de precarização não somente do trabalho, mas também de vida

Climate change impact on flood hazard in a central Portugal alluvial plain

Paper Abstract This paper presents the flood hazard projections under climate change scenarios, for a period between 2021 and 2050, in the Lis river alluvial plain located at the Centre of Portugal. Furthermore, the paper also aim at understanding the hydrological processes in the study area by coupling a hydrological (HEC – HMS) and hydrodynamic model (HEC – RAS). The Lis river basin is becoming more favourable to the production of high water flows, due to the increase of impervious areas and deforestation which have reduced the time concentration on the river basin, empowering flood events with high flood peaks and water flood levels with serious consequences for the facilities (pumping stations, centre pivots) and infrastructures (irrigation networks and roads) in the alluvial plain. The methodology was developed using the daily outputs of the ALADIN and HIRHAM from the EURO-CORDEX project with a 12.5 km horizontal resolution for the RCP4.5 scenario and coupled calibrated hydrological– hydrodynamic models. The results indicated that the annual rainfall would vary for the ALADIN model between a decrease of -24% and an increase of 22% and for the HIRHAM model between a decrease of -85% and an increase of 24%. The results also projected increases in higher runoffs and water level under future climate change scenarios. The HIRHAM model was considered unsuitable for flood impact assessment

Use of superabsorbent polymers to mitigate autogenous shrinkage in ultra-high performance concrete

Ultra-high performance concrete (UHPC) with low w/c-ratio is very prone to the formation of cracks due to autogenous shrinkage. These cracks can lead to a decreased durability of the concrete, resulting in higher maintenance and/or repair costs in the future. Superabsorbent polymers (SAPs) can be added to cementitious materials to provide internal curing and as a result reduce or even mitigate this autogenous shrinkage. In this paper, two different types of SAPs were added to cement paste to see their influence on mitigating autogenous shrinkage. One SAP is a commercially available SAP whereas the other SAP is especially developed within the framework of the LORCENIS project by the company ChemStream, with the aim to mitigate autogenous shrinkage and induce self-healing of cracks. The SAPs from ChemStream were based on a copolymerization of sodium vinyl sulfonate (SVS) with 2-acryloylamino-2-methyl-propane-1-sulfonate (NaAMPS) and contained 1.0 mol% N,N’-methylenebisacrylamide (MBA) with respect to the monomer as cross-linker. The commercial SAP from BASF was based on poly(acrylamide-co-acrylic acid). In case SAPs were used, an additional fixed amount of water was added to mitigate autogenous shrinkage. The amount of SAPs used was determined based on their swelling capacity in cement filtrate and in order to obtain the same workability as the reference mixture. The amount of SAPs needed was in the range of 0.2-0.26 m% of the cement weight. To see whether the size of the SAPs plays a role in the efficiency of mitigating autogenous shrinkage, two average particle sizes, namely 40 and 100 µm, were tested. With the used amount of SAPs, a reduction or even complete counteraction of autogenous shrinkage was observed for the cement pastes

Mitigating autogenous shrinkage by means of superabsorbent polymers : effect on concrete properties

(Ultra-)high performance concrete ((U)HPC) is very prone to autogenous shrinkage cracking. These cracks can create preferential pathways for the ingress of harmful substances which can facilitate the corrosion process of the steel reinforcement, resulting in a decreased durability and structural integrity of the concrete structure. Superabsorbent polymers (SAPs) can reduce or even mitigate autogenous shrinkage as they absorb water in the fresh concrete mix and provide it to the cement particles at the right moment in the hydration process, acting as internal curing agent for the concrete. To study the mitigation of autogenous shrinkage by SAPs, five different superabsorbent polymers based on the copolymerization of acrylic acid (AA) with dimethylaminoethyl methacrylate (DMAEMA) were synthesized at Ghent University. This paper focusses on the compatibility tests aiming at evaluating the effect of these SAPs on initial flow and slump life (rheology), hydration kinetics (reactivity) and mechanical properties (3, 7 and 28 days strength). The most promising SAPs will be further studied on their effect to mitigate autogenous shrinkage

Physicochemical characteristics of sheep and goat pâtés. differences between fat sources and proportions

The physicochemical composition of sheep and goat pâtés with different sources and percentage of fat (10% and 30%; pork belly or olive oil) were evaluated. A low-fat content (9.7-18.2%) was observed in the pâtés comparing with similar meat products. Cholesterol was lower in pâtés with olive oil than with pork fat. The source of fat (pork belly or olive oil) and the proportion of fat influenced significantly the fatty acid profile. Pâtés with olive oil have lower saturated fat content and highest monounsaturated fat while and goat meat pâtés have higher polyunsaturated fat content The polyunsaturated versus saturated fatty acids ratio varying from 0.21 to 0.39 and the total unsaturated fatty acids showed that sheep and goat pâtés are balanced products and could be an interesting way to the added value of animals with low commercial and consumer acceptability.Work included in the Portuguese PRODER research Project number 020260013013 “New goat and sheep processed meat products” BISOVICAP – Processing meat from pigs, sheep and goats, to produce new products. Ham and pâté, Project PROTEC, SI I&DT - Projects in Co- Promotion, nº 21511. The authors are grateful to Laboratory of Carcass and Meat Quality of Agriculture School of Polytechnic Institute of Bragança ‘Cantinho do Alfredo’. The authors are members of the MARCARNE network, funded by CYTED (ref. 116RT0503).info:eu-repo/semantics/publishedVersio

Costo económico del tratamiento de las úlceras por presión : una aproximación teórica

O presente artigo consiste numa abordagem teórica sobre a problemática dos custos económicos das úlceras por pressão. Parte-se do conhecimento do problema, numa perspetiva conceptual, para, de seguida, apresentar resultados de estudos de prevalência, a partir dos quais foram delineados estudos de impacto económico. O objectivo deste artigo é o de reflectir sobre os custos económicos associados às úlceras por pressão, quer numa perspetiva global, considerando a repercussão financeira, quer numa vertente personalista, atendendo aos custos intangíveis. Relativamente ao impacto económico das úlceras por pressão, foi efectuada uma estimativa ao nível da Região Autónoma dos Açores do custo total do tratamento por ambiente de cuidados. Nos cuidados domiciliários o custo com o tratamento de todas as categorias é calculado em 7.086.415 euros; nos cuidados hospitalares, em 1.723.509 euros, e nos cuidados prestados em lares de idosos, em 1.002.562 euros. Nos Açores, a estimativa do custo total do tratamento das úlceras por pressão, considerando todas as suas categorias, ronda os 9.812.486 euros. Quanto ao impacto emocional associado, este tem elevados custos para pessoa e para os familiares, nomeadamente pelo sofrimento gerado. De facto, as úlceras por pressão acarretam elevados custos económicos associados ao tratamento, bem como custos intangíveis pelo sofrimento vivenciado por pessoas e cuidadores.RESUMEN: El presente artículo consiste en una reflexión teórica sobre el problema de los costos económicos de las úlceras por presión. Se empieza por el conocimiento del problema, desde una perspectiva conceptual, y, a continuación, se presentan los resultados de estudios de prevalencia, a partir de los cuales se diseñaron estudios de impacto económico. El objetivo del artículo es reflexionar sobre los costos económicos asociados a las úlceras por presión tanto en una perspectiva global, considerando la repercusión financiera, como en una vertiente personalista, de acuerdo a los costos intangibles. En cuanto al impacto económico de las úlceras por presión, se realizó una estimación de la Región Autónoma de Açores del costo total del tratamiento por ámbito de atención. En la atención domiciliaria el costo con el tratamiento de todas las categorías se estima en € 7.086.415, en la atención hospitalaria, se estima € 1.723.509 y en la atención en los asilos se estima en €1.002.562. En Açores, el costo total estimado del tratamiento de las úlceras por presión en todas las categorías, es de alrededor de € 9.812.486. En cuanto al impacto emocional asociado, éste tiene elevados costos para la persona y para los familiares, principalmente, por el sufrimiento causado. De hecho, las úlceras por presión implican altos costos económicos asociados con el tratamiento, así como, costos intangibles generados por el sufrimiento experimentado por los individuos y los cuidadores.ABSTRACT: The present study consisted of a theoretical approach to the problem posed by the economic costs associated with pressure ulcers (PUs). The initial aim was to assess the target problem from a conceptual perspective and then to report the results of prevalence studies that formed the basis for investigations of the disease’s economic impact. The purpose of the present article is to discuss the economic costs associated with PUs from both the global point of view (appraising their financial repercussion) and the individual point of view (addressing the intangible costs). Regarding the economic impact of the costs associated with PUs, the total cost of treatment per healthcare setting was estimated relative to the Autonomous Community of Azores. The total cost of all the PU categories was EUR 7,086,415 in the homecare setting, EUR 1,723,509 in the hospital setting, and EUR 1,002,562 in older people’s homes. Therefore, the estimated total treatment cost of all the PU categories was approximately EUR 9,812,486 in Azores. However, the emotional impact of this disease imposes high costs on patients and their relatives as a function of the resultant suffering. Indeed, PUs impose high costs not only related to the treatment but also related to the intangible costs of the suffering caused to patients and their caregivers.Project ICE 2 – Investigação Científica em Enfermagem – Estudo do “Custo Económico das Úlceras por Pressão na Macaronésia” (MAC/1/A029) de Iniciativa Comunitária – Programa de Cooperação Transnacional Madeira-Açores-Canárias 2007-2013info:eu-repo/semantics/publishedVersio