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- Modulação combinada das vias de sinalização RAC1 e MAPK para potenciar a captação de iodo radioactivoPublication . Faria, Márcia; Domingues, Rita; Félix, Diana; Bugalho, Maria João; Matos, Paulo; Silva, Ana LuísaO simportador de Sódio e Iodo (NIS) é responsável pela captação de iodo pelas células foliculares da tiroide. A retenção da expressão funcional de NIS na maioria dos tumores bem diferenciados da tiroide permite o uso de iodo radioativo (RAI) como terapêutica sistémica para doença metastática. No entanto, uma percentagem de doentes com formas avançadas de carcinoma da tiroide perde a capacidade de resposta a esta terapia, sendo as alternativas disponíveis terapêuticas crónicas, dispendiosas e associadas a efeitos adversos importantes. A principal razão para esta reduzida captação de iodo é a deficiente expressão funcional de NIS, tendo esta sido associada à atividade de várias vias de sinalização pró-tumorigénicas. A sobreativação da via MAPK está implicada na tumorigénese da tiroide, assim como na regulação negativa de NIS. Assim, várias estratégias têm sido desenvolvidas no sentido de inibir a via MAPK com o objetivo de aumentar a captação de iodo em tumores refratários. A relevância deste tipo de estratégia foi anteriormente documentada num ensaio clínico que demonstrou um ganho significativo de incorporação de iodo num subgrupo de pacientes com neoplasia tiroideia refratária ao iodo radioativo, após o tratamento com selumetinib (AZD6244), um inibidor de MEK 1/2. No entanto, a recuperação da expressão de NIS, utilizando inibidores desta via, nem sempre foi suficiente para viabilizar a terapia com RAI, tornando-se clinicamente relevante a identificação de alvos adicionais envolvidos na regulação positiva do NIS. Assim, este estudo pretende avaliar se a recuperação da expressão de NIS induzida pela inibição da via MAPK pode ser otimizada aumentando a atividade da GTPase RAC1, um potenciador da expressão de NIS em sistemas celulares da tiroide.
- Evaluation of the SpeeDx ResistancePlus® GC and SpeeDx GC 23S 2611 (beta) molecular assays for prediction of antimicrobial resistance/susceptibility to ciprofloxacin and azithromycin in Neisseria gonorrhoeaePublication . Hadad, Ronza; Cole, Michelle Jayne; Ebeyan, Samantha; Jacobsson, Susanne; Tan, Lit Yeen; Golparian, Daniel; Erskine, Simon; Day, Michaela; Whiley, David; Unemo, Magnus; European collaborative groupBackground: Accurate molecular assays for prediction of antimicrobial resistance (AMR)/susceptibility in Neisseria gonorrhoeae (Ng) can offer individualized treatment of gonorrhoea and enhanced AMR surveillance. Objectives: We evaluated the new ResistancePlus® GC assay and the GC 23S 2611 (beta) assay (SpeeDx), for prediction of resistance/susceptibility to ciprofloxacin and azithromycin, respectively. Methods: Nine hundred and sixty-seven whole-genome-sequenced Ng isolates from 20 European countries, 143 Ng-positive (37 with paired Ng isolates) and 167 Ng-negative clinical Aptima Combo 2 (AC2) samples, and 143 non-gonococcal Neisseria isolates and closely related species were examined with both SpeeDx assays. Results: The sensitivity and specificity of the ResistancePlus® GC assay to detect Ng in AC2 samples were 98.6% and 100%, respectively. ResistancePlus® GC showed 100% sensitivity and specificity for GyrA S91 WT/S91F detection and 99.8% sensitivity and specificity in predicting phenotypic ciprofloxacin resistance. The sensitivity and specificity of the GC 23S 2611 (beta) assay for Ng detection in AC2 samples were 95.8% and 100%, respectively. GC 23S 2611 (beta) showed 100% sensitivity and 99.9% specificity for 23S rRNA C2611 WT/C2611T detection and 64.3% sensitivity and 99.9% specificity for predicting phenotypic azithromycin resistance. Cross-reactions with non-gonococcal Neisseria species were observed with both assays, but the analysis software solved most cross-reactions. Conclusions: The new SpeeDx ResistancePlus® GC assay performed well in the detection of Ng and AMR determinants, especially in urogenital samples. The GC 23S 2611 (beta) assay performed relatively well, but its sensitivity, especially for predicting phenotypic azithromycin resistance, was suboptimal and further optimizations are required, including detection of additional macrolide resistance determinant(s).
- Determinants of paediatric asthma: a three-level approachPublication . Paciência, Inês Ribeiro; Moreira, André; Fernandes, Eduardo de Oliveira; Madureira, Joana; Beirão, IdalinaDuring the 20th century, urbanization has increasing and represented a major demographic and environmental change in developed countries. Urban living may offer a greater possibility to better health care, education and social services, but is also associated with increased exposure to air pollution, outdoors and indoors, loss of natural environments and biodiversity and lifestyle changes. Furthermore, this ever-changing urban environment has an impact on diseases patterns and prevalence, namely on noncommunicable diseases, such as asthma and allergy, and poses many challenges to understand the relationship between the changing on the urban environment and the children health. The overall aim of this thesis was to study the role of the environmental determinants of paediatric asthma.
- Risk-benefit in food safety and nutrition - outcome of the 2019 Parma Summer SchoolPublication . Verhagen, H.; Alonso-Andicoberry, C.; Assunção, Ricardo; Cavaliere, F.; Eneroth, H.; Hoekstra, J.; Koulouris, S.; Kouroumalis, A.; Lorenzetti, S.; Mantovani, A.; Menozzi, D.; Naua, M.; Poulsen, M.; Rubert, J.; Siani, A.; Sirot, V.; Spaggiari, G.; Thomsen, S.T.; Trevisan, M.; Cozzini, P.Risk-benefit assessment is the comparison of the risk of a situation to its related benefits, i.e. a comparison of scenarios estimating the overall health impact. The risk–benefit analysis paradigm mirrors the classical risk analysis one: risk–benefit assessment goes hand-in-hand with risk–benefit management and risk–benefit communication. The various health effects associated with food consumption, together with the increasing demand for advice on healthy and safe diets, have led to the development of different research disciplines in food safety and nutrition. In this sense, there is a clear need for a holistic approach, including and comparing all of the relevant health risks and benefits. The risk–benefit assessment of foods is a valuable approach to estimate the overall impact of food on health. It aims to assess together the negative and positive health effects associated with food intake by integrating chemical and microbiological risk assessment with risk and benefit assessment in food safety and nutrition. The 2019 Parma Summer School on risk–benefit in food safety and nutrition had the objective was to provide an opportunity to learn from experts in the field of risk–benefit approach in food safety and nutrition, including theory, case studies, and communication of risk–benefit assessments plus identify challenges for the future. It was evident that whereas tools and approaches have been developed, more and more case studies have been performed which can form an inherent validation of the risk–benefit approach. Executed risk–benefit assessment case studies apply the steps and characteristics developed: a problem formulation (with at least 2 scenarios), a tiered approach until a decision can be made, one common currency to describe both beneficial and adverse effects (DALYs in most instances). It was concluded that risk–benefit assessment in food safety and nutrition is gaining more and more momentum, while also many challenges remain for the future. Risk-benefit is on the verge of really enrolling into the risk assessment and risk analysis paradigm. The interaction between risk–benefit assessors and risk–benefit managers is pivotal in this, as is the interaction with risk–benefit communicators.
- 4-hydroxy-2-alkenals in foods: a review on risk assessment, analytical methods, formation, occurrence, mitigation and future challengesPublication . Albuquerque, T.G.; Costa, H.S.; Oliveira, M.B.P.P.Undoubtedly, significant advances were performed concerning 4-hydroxy-2-alkenals research on foods, and their formation by double oxidation of polyunsaturated fatty acids. But further studies are still needed, especially on their occurrence in foods enriched with n-3 and n-6 fatty acids, as well as in foods for infants and processed foods. Major factors concerning the formation of 4-hydroxy-2-alkenals were discussed, namely the influence of fatty acids composition, time/temperature,processing conditions, salt, among others. Regarding mitigation, the most effective strategies are adding phenolic extracts to foods matrices, as well as other antioxidants, such as vitamin E. Exposure assessment studies revealed 4-hydroxy-2-alkenals values that could not be considered a risk for human health. However, these toxic compounds remain unaltered after digestion and can easily reach the systemic circulation. Therefore, it is crucial to develop in vivo research, with the inclusion of the colon phase, as well as, cell membranes of the intestinal epithelium. In conclusion, according to our review it is possible to eliminate or effectively decrease 4-hydroxy-2-alkenals in foods using simple and economic practices.
- A comprehensive review on carotenoids in foods and feeds: status quo, applications, patents, and research needsPublication . Meléndez-Martínez, A.J.; Mandić, A.I.; Bantis, F.; Böhm, V.; Borge, G.I.A.; Brnčić, M.; Bysted, A.; Cano, M.P.; Dias, M.G.; Elgersma, A.; Fikselová, M.; García-Alonso, J.; Giuffrida, D.; Gonçalves, V.S.S.; Hornero-Méndez, D.; Kljak, K.; Lavelli, V.; Manganaris, G.A.; Mapelli-Brahm, P.; Marounek, M.; Olmedilla-Alonso, B.; Periago-Castón, M.J.; Pintea, A.; Sheehan, J.J.; Tumbas Šaponjac, V.; Valšíková-Frey, M.; Meulebroek, L.V.; O'Brien, N.Carotenoids are isoprenoids widely distributed in foods that have been always part of the diet of humans. Unlike the other so-called food bioactives, some carotenoids can be converted into retinoids exhibiting vitamin A activity, which is essential for humans. Furthermore, they are much more versatile as they are relevant in foods not only as sources of vitamin A, but also as natural pigments, antioxidants, and health-promoting compounds. Lately, they are also attracting interest in the context of nutricosmetics, as they have been shown to provide cosmetic benefits when ingested in appropriate amounts. In this work, resulting from the collaborative work of participants of the COST Action European network to advance carotenoid research and applications in agro-food and health (EUROCAROTEN, www.eurocaroten.eu, https://www.cost.eu/actions/CA15136/#tabs|Name:overview) research on carotenoids in foods and feeds is thoroughly reviewed covering aspects such as analysis, carotenoid food sources, carotenoid databases, effect of processing and storage conditions, new trends in carotenoid extraction, daily intakes, use as human, and feed additives are addressed. Furthermore, classical and recent patents regarding the obtaining and formulation of carotenoids for several purposes are pinpointed and briefly discussed. Lastly, emerging research lines as well as research needs are highlighted.
- Trends on Aspergillus Epidemiology-Perspectives from a National Reference Laboratory Surveillance ProgramPublication . Sabino, Raquel; Gonçalves, Paulo; Martins Melo, Aryse; Simões, Daniela; Oliveira, Mariana; Francisco, Mariana; Viegas, Carla; Carvalho, Dinah; Martins, Carlos; Ferreira, Teresa; Toscano, Cristina; Simões, Helena; Veríssimo, CristinaIdentification of Aspergillus to species level is important since sibling species may display variable susceptibilities to multiple antifungal drugs and also because correct identification contributes to improve the knowledge of epidemiological studies. Two retrospective laboratory studies were conducted on Aspergillus surveillance at the Portuguese National Mycology Reference Laboratory. The first, covering the period 2017-2018, aimed to study the molecular epidemiology of 256 Aspergillus isolates obtained from patients with respiratory, subcutaneous, or systemic infections and from environmental samples. The second, using our entire collection of clinical and environmental A. fumigatus isolates (N = 337), collected between 2012 and 2019, aimed to determine the frequency of azole-resistant A. fumigatus isolates. Aspergillus fumigatus sensu stricto was the most frequent species in both clinical and environmental samples. Overall, and considering all Aspergillus sections identified, a high frequency of cryptic species was detected, based on beta-tubulin or calmodulin sequencing (37% in clinical and 51% in environmental isolates). Regarding all Fumigati isolates recovered from 2012-2019, the frequency of cryptic species was 5.3% (18/337), with the identification of A. felis (complex), A. lentulus, A. udagawae, A. hiratsukae, and A. oerlinghauensis. To determine the frequency of azole resistance of A. fumigatus, isolates were screened for azole resistance using azole-agars, and 53 possible resistant isolates were tested by the CLSI microdilution reference method. Nine A. fumigatus sensu stricto and six Fumigati cryptic isolates showed high minimal inhibitory concentrations to itraconazole, voriconazole, and/or posaconazole. Real-time PCR to detect cyp51A mutations and sequencing of cyp51A gene and its promoter were performed. The overall frequency of resistance to azoles in A. fumigatus sensu stricto was 3.0%. With this retrospective analysis, we were able to detect one azole-resistant G54R mutant A. fumigatus environmental isolate, collected in 2015. The TR34/L98H mutation, linked to environmental transmission route of azole resistance, was the most frequently detected mutation (N = 4; 1.4%). Our findings underline the demand for correct identification and susceptibility testing of Aspergillus isolates.
- Congenital anomalies in children with postneonatally acquired cerebral palsy: an international data linkage studyPublication . Goldsmith, Shona; McIntyre, Sarah; Scott, Heather; Himmelmann, Kate; Smithers‐Sheedy, Hayley; Andersen, Guro L.; Blair, Eve; Badawi, Nadia; Garne, Ester; Comprehensive CA-CP Study GroupAim: To describe the major congenital anomalies present in children with postneonatally acquired cerebral palsy (CP), and to compare clinical outcomes and cause of postneonatally acquired CP between children with and without anomalies. Method: Data were linked between total population CP and congenital anomaly registers in five European and three Australian regions for children born 1991 to 2009 (n=468 children with postneonatally acquired CP; 255 males, 213 females). Data were pooled and children classified into mutually exclusive categories based on type of congenital anomaly. The proportion of children with congenital anomalies was calculated. Clinical outcomes and cause of postneonatally acquired CP were compared between children with and without anomalies. Results: Major congenital anomalies were reported in 25.6% (95% confidence interval [CI] 21.7-29.9) of children with postneonatally acquired CP. Cardiac anomalies, often severe, were common and present in 14.5% of children with postneonatally acquired CP. Clinical outcomes were not more severe in children with congenital anomalies than those without anomalies. Cause of postneonatally acquired CP differed with the presence of congenital anomalies, with cerebrovascular accidents predominating in the anomaly group. Congenital anomalies were likely associated with cause of postneonatally acquired CP in 77% of children with anomalies. Interpretation: In this large, international study of children with postneonatally acquired CP, congenital anomalies (particularly cardiac anomalies) were common. Future research should determine specific causal pathways to postneonatally acquired CP that include congenital anomalies to identify opportunities for prevention. What this paper adds: One-quarter of children with postneonatally acquired cerebral palsy (CP) have a major congenital anomaly. Cardiac anomalies, often severe, are the most common anomalies. Causes of postneonatally acquired CP differ between children with and without congenital anomalies.
- From inequitable to sustainable e-waste processing for reduction of impact on human health and the environmentPublication . Ádám, Balázs; Göen, Thomas; Scheepers, Paul T.J.; Adliene, Diana; Batinic, Bojan; Budnik, Lygia T.; Duca, Radu-Corneliu; Ghosh, Manosij; Giurgiu, Doina I.; Godderis, Lode; Goksel, Ozlem; Hansen, Karoline K.; Kassomenos, Pavlos; Milic, Natasa; Orru, Hans; Paschalidou, Anastasia; Petrovic, Maja; Puiso, Judita; Radonic, Jelena; Sekulic, Maja T.; Teixeira, Joao Paulo; Zaid, Hilal; Au, William W.Recycling of electric and electronic waste products (e-waste) which amounted to more than 50 million metric tonnes per year worldwide is a massive and global operation. Unfortunately, an estimated 70-80% of this waste has not been properly managed because the waste went from developed to low-income countries to be dumped into landfills or informally recycled. Such recycling has been carried out either directly on landfill sites or in small, often family-run recycling shops without much regulations or oversights. The process traditionally involved manual dismantling, cleaning with hazardous solvents, burning and melting on open fires, etc., which would generate a variety of toxic substances and exposure/hazards to applicators, family members, proximate residents and the environment. The situation clearly calls for global responsibility to reduce the impact on human health and the environment, especially in developing countries where poor residents have been shouldering the hazardous burden. On the other hand, formal e-waste recycling has been mainly conducted in small scales in industrialised countries. Whether the latter process would impose less risk to populations and environment has not been determined yet. Therefore, the main objectives of this review are: 1. to address current trends and emerging threats of not only informal but also formal e-waste management practices, and 2. to propose adequate measures and interventions. A major recommendation is to conduct independent surveillance of compliance with e-waste trading and processing according to the Basel Ban Amendment. The recycling industry needs to be carefully evaluated by joint effort from international agencies, producing industries and other stakeholders to develop better processes. Subsequent transition to more sustainable and equitable e-waste management solutions should result in more effective use of natural resources, and in prevention of adverse effects on health and the environment.
- Comparison of the mutation spectrum and association with pre and post treatment lipid measures of children with heterozygous familial hypercholesterolaemia (FH) from eight European countriesPublication . Futema, Marta; Ramaswami, Uma; Tichy, Lukas; Bogsrud, Martin P.; Holven, Kirsten B.; Roeters van Lennep, Jeanine; Wiegman, Albert; Descamps, Olivier S.; De Leener, Anne; Fastre, Elodie; Vrablik, Michal; Freiberger, Tomas; Esterbauer, Harald; Dieplinger, Hans; Greber-Platzer, Susanne; Medeiros, Ana M.; Bourbon, Mafalda; Mollaki, Vasiliki; Drogari, Euridiki; Humphries, Steve E.Background and aims: Familial hypercholesterolaemia (FH) is commonly caused by mutations in the LDLR, APOB or PCSK9 genes, with untreated mean low density lipoprotein-cholesterol (LDL-C) concentrations being elevated in APOB mutation carriers, even higher in LDLR mutation and highest in those with a PCSK9 mutation. Here we examine this in children with FH from Norway, UK, The Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece. Methods: Differences in characteristics and pre- and post-treatment lipid concentrations in those with different molecular causes were compared by standard statistical tests. Results: Data were obtained from 2866 children, of whom 2531 (88%) carried a reported LDLR/APOB/PCSK9 variant. In all countries, the most common cause of FH was an LDLR mutation (79% of children, 297 different), but the prevalence of the APOB p.(Arg3527Gln) mutation varied significantly (ranging from 0% in Greece to 39% in Czech Republic, p < 2.2 × 10-16). The prevalence of a family history of premature CHD was significantly higher in children with an LDLR vs APOB mutation (16% vs 7% p=0.0005). Compared to the LDLR mutation group, mean (±SD) concentrations of pre-treatment LDL-C were significantly lower in those with an APOB mutation (n = 2260 vs n = 264, 4.96 (1.08)mmol/l vs 5.88 (1.41)mmol/l, p < 2.2 × 10-16) and lowest in those with a PCSK9 mutation (n = 7, 4.71 (1.22)mmol/l). Conclusions: The most common cause of FH in children from eight European countries was an LDLR mutation, with the prevalence of the APOB p.(Arg3527Gln) mutation varying significantly across countries. In children, LDLR-FH is associated with higher concentrations of LDL-C and family history of CHD compared to those with APOB-FH.