a pilot study in mice

Pneumocystis pneumonia (PcP) is a major cause of mortality and morbidity in immunocompromised patients. There are limited alternative therapeutic choices to trimethoprim-sulfamethoxazole (TMP-SMX) which is the standard first line therapy/prophylaxis for PcP. The efficacy of low doses of caspofungin and caspofungin in association with TMP-SMX standard-prophylactic dose was evaluated in an experimental model of Pneumocystis. Susceptibility of Pneumocystis spp. to low doses of caspofungin and caspofungin/TMP-SMX was evaluated in Balb/c immunosuppressed mice, infected intranasally with P. murina. Caspofungin was administered once daily at 0.1 mg/kg, 0.05 mg/kg, and 0.001 mg/kg and TMP-SMX was administered by oral gavage (12.25 mg/62.5 mg/day), for 21 days. Efficacy was calculated based on the reduction in organism burden determined through quantitative fluorescent-based real-time PCR (qPCR). Serum β-1,3-D-glucan was measured as an additional marker of infection. The present data showed that caspofungin demonstrated anti-Pneumomocystis effect. However, the doses administrated were too low to achieve Pneumocystis eradication, which suggests that echinocandin treatment should not be administrated as mono-therapy. After 21 days of treatment, P. murina was not detected in the lungs of mice with either TMP-SMX or caspofungin/TMP-SMX. The results showed that, even at the lowest concentrations tested, the efficacy of caspofungin in association with TMP-SMX was higher than the efficacy of either drug used alone. The administration of caspofungin/TMP-SMX was at least 1.4 times more effective against P. murina infection than TMP-SMX used alone. The most promising result was achieved with the combination of caspofungin 0.05 mg/kg/day with TMP-SMX 12.5 mg–62.5 mg/day, which reduced the parasite burden to undetectable levels immediately at the 14th day of treatment, showing a highly marked anti-Pneumomocystis effect. These data suggest that the administration of low doses of caspofungin in combination with low doses of TMP-SMX may provide an improved treatment protocol for Pneumocystis infection clearance.publishersversionpublishe

Lusophone community in the digital age: the ambiguous place of scepticism and performance

(Excerto) "This article addresses the setting up of the political Community of the Portuguese Language Countries (Comunidade dos Países de Língua Portuguesa (CPLP)) and its present-day social and cultural dynamics. As the other articles in this Special Section from Martins, Salgado and Santos also demonstrate, media and communication systems are playing a role in the development of this loose aggregation and in the internal dynamics of the Portuguese language countries."(undefined)info:eu-repo/semantics/publishedVersio

Laboratory services contribution to supporting public health and health services in Portuguese-speaking countries

Objetivo: promover o debate sobre a importância do laboratório no apoio à saúde pública e aos serviços de saúde nos países de língua portuguesa, numa perspetiva global e de uma só saúde. Métodos: revisão de literatura, análise dos documentos preparatórios das comunicações do 5º Congresso Nacional de Medicina Tropical, apresentações realizadas pelos oradores de Cabo Verde, Angola e Portugal e o debate que se seguiu. Resultados: identificaram-se os desafios que deverão ser ultrapassados de forma a criar uma rede de laboratórios de diagnóstico que possa estimular o acesso universal das populações aos cuidados de saúde, tendo-se proposto medidas e estratégias com base na experiência dos sistemas de saúde dos diferentes países de língua portuguesa. Reviu-se o contributo dos Laboratórios do IHMT/NOVA para esta estratégia. Conclusão: não há acesso universal a cuidados de saúde de qualidade sem serviços de diagnóstico laboratorial de qualidade. Assim, deve-se promover uma correta, eficaz e sustentável inter-relação entre laboratórios de referência nacionais, hospitalares e privados e ainda laboratórios de investigação, todos cooperando em sintonia com os serviços de saúde de modo a garantir os melhores cuidados de saúde. Objective: To promote the debate on the importance of the laboratory services in supporting public health and health services in Portuguese-speaking countries, from a global and One Health perspective. Methods: literature review, analysis of the preparatory papers for the 5th Tropical Medicine National Congress, presentations by speakers from Cape Verde, Angola and Portugal and the ensuing debate. Results: we identified the challenges that must be overcome in order to create a network of diagnostic laboratories that can stimulate universal access to health care for the populations. Measures and strategies based on the experience of health systems in different Portuguese-speaking countries are proposed. The contribution of the IHMT/NOVA Laboratories to this strategy was reviewed. Conclusion: There is no universal access to quality health care with-out quality laboratory diagnostic services and without promoting a correct, effective and sustainable interrelationship between national reference laboratories, hospital and private, and research laboratories, all cooperating in line with health services to ensure the best quality health care.publishersversionpublishe

Dendritic Morphology Predicts Pattern Recognition Performance in Multi-compartmental Model Neurons with and without Active Conductances

This is an Open Access article published under the Creative Commons Attribution license CC BY 4.0 which allows users to read, copy, distribute and make derivative works, as long as the author of the original work is citedIn this paper we examine how a neuron’s dendritic morphology can affect its pattern recognition performance. We use two different algorithms to systematically explore the space of dendritic morphologies: an algorithm that generates all possible dendritic trees with 22 terminal points, and one that creates representative samples of trees with 128 terminal points. Based on these trees, we construct multi-compartmental models. To assess the performance of the resulting neuronal models, we quantify their ability to discriminate learnt and novel input patterns. We find that the dendritic morphology does have a considerable effect on pattern recognition performance and that the neuronal performance is inversely correlated with the mean depth of the dendritic tree. The results also reveal that the asymmetry index of the dendritic tree does not correlate with the performance for the full range of tree morphologies. The performance of neurons with dendritic tapering is best predicted by the mean and variance of the electrotonic distance of their synapses to the soma. All relationships found for passive neuron models also hold, even in more accentuated form, for neurons with active membranesPeer reviewedFinal Published versio

Direct comparison of methionine restriction with leucine restriction on the metabolic health of C57BL/6J mice

EKL was the recipient of a BBSRC postgraduate studentship. This work was funded by Tenovus Scotland project grant to MD and NM (G13/07) and BBSRC DTG. MD is also supported by the British Heart Foundation (PG/09/048/27675, PG/11/8/28703 and PG/14/43/30889) and Diabetes UK (14/0004853). NM is funded by British Heart Foundation (PG/16/90/32518).Peer reviewedPublisher PD

Do critical thinkers drink too much alcohol, forget to do class assignments, or cheat on exams? Using a critical thinking measure to predict college students’ real-world outcomes

Critical thinking is a higher-order way of reasoning composed of the skill and will to use cognitive abilities and knowledge on a daily basis. It is identified as essential by higher education institutions, corporations, and society in general. To analyze whether college students are critical thinkers in their daily lives, the Halpern Critical Thinking Assessment (HCTA; Halpern in Halpern Critical Thinking Assessment (Measurement instrument), Schuhfried, Mödling, 2012) and the real-world outcomes inventory (RWO; Butler in Appl Cogn Psychol 26(5):721–729, 2012) were administered to 238 students. We performed a cluster analysis (K-means-constrained clustering method), and ANOVAs for each cluster solution tested to identify the most suitable clustering solution, taking the RWO inventory dimensions as dependent variables and cluster membership as an independent variable. Four separate clusters emerged, each representing a different profile related to students’ everyday negative outcomes resulting from a lack of critical thinking. We performed multinomial logistic regression to examine which dimensions of the HCTA test, as well as gender, age, and disciplinary area, predicted the four singular groups of students that emerged: “Mature,” “Risk-taking,” “Lost in translation,” and “Reflective.” Results indicate that: (1) age is a relevant predictor of slackness, rashness, and health neglect, all characteristics of “Mature” students; (2) students who are particularly skilled in hypothesis testing tend to be “Risk-taking,” while it is less likely that students who are specifically competent in argument analysis will be in this group; (3) gender is relevant to predict “Lost in translation” students, while argument analysis is negatively related to the chances of being in this group. Our study supports the relevance of critical thinking in daily decisions and everyday outcomes.FCT -Fundação para a Ciência e a Tecnologia(Advanced Training)info:eu-repo/semantics/publishedVersio

Direct-acting antivirals are effective and safe in HCV/HIV-coinfected liver transplant recipients who experience recurrence of hepatitis C: A prospective nationwide cohort study.

Direct-acting antivirals have proved to be highly efficacious and safe in monoinfected liver transplant (LT) recipients who experience recurrence of hepatitis C virus (HCV) infection. However, there is a lack of data on effectiveness and tolerability of these regimens in HCV/HIV-coinfected patients who experience recurrence of HCV infection after LT. In this prospective, multicenter cohort study, the outcomes of 47 HCV/HIV-coinfected LT patients who received DAA therapy (with or without ribavirin [RBV]) were compared with those of a matched cohort of 148 HCV-monoinfected LT recipients who received similar treatment. Baseline characteristics were similar in both groups. HCV/HIV-coinfected patients had a median (IQR) CD4 T-cell count of 366 (256-467) cells/µL. HIV-RNA was <50 copies/mL in 96% of patients. The DAA regimens administered were SOF + LDV ± RBV (34%), SOF + SMV ± RBV (31%), SOF + DCV ± RBV (27%), SMV + DCV ± RBV (5%), and 3D (3%), with no differences between the groups. Treatment was well tolerated in both groups. Rates of SVR (negative serum HCV-RNA at 12 weeks after the end of treatment) were high and similar for coinfected and monoinfected patients (95% and 94%, respectively; P = .239). Albeit not significant, a trend toward lower SVR rates among patients with advanced fibrosis (P = .093) and genotype 4 (P = .088) was observed. In conclusion, interferon-free regimens with DAAs for post-LT recurrence of HCV infection in HIV-infected individuals were highly effective and well tolerated, with results comparable to those of HCV-monoinfected patients

Tau mislocation in glucocorticoid-triggered hippocampal pathology

The exposure to high glucocorticoids (GC) triggers neuronal atrophy and cognitive deficits, but the exact cellular mechanisms underlying the GC-associated dendritic remodeling and spine loss are still poorly understood. Previous studies have implicated sustained GC elevations in neurodegenerative mechanisms through GC-evoked hyperphosphorylation of the cytoskeletal protein Tau while Tau mislocation has recently been proposed as relevant in Alzheimer's disease (AD) pathology. In light of the dual cytoplasmic and synaptic role of Tau, this study monitored the impact of prolonged GC treatment on Tau intracellular localization and its phosphorylation status in different cellular compartments. We demonstrate, both by biochemical and ultrastructural analysis, that GC administration led to cytosolic and dendritic Tau accumulation in rat hippocampus, and triggered Tau hyperphosphorylation in epitopes related to its malfunction (Ser396/404) and cytoskeletal pathology (e.g., Thr231 and Ser262). In addition, we show, for the first time, that chronic GC administration also increased Tau levels in synaptic compartment; however, at the synapse, there was an increase in phosphorylation of Ser396/404, but a decrease of Thr231. These GC-triggered Tau changes were paralleled by reduced levels of synaptic scaffolding proteins such as PSD-95 and Shank proteins as well as reduced dendritic branching and spine loss. These in vivo findings add to our limited knowledge about the underlying mechanisms of GC-evoked synaptic atrophy and neuronal disconnection implicating Tau missorting in mechanism(s) of synaptic damage, beyond AD pathology.We would like to thank Rui Fernandes for TEM technical support. IS was supported by the Portuguese Foundation for Science and Technology (FCT).This work was funded by the Portuguese Foundation for Science and Technology (FCT) (grant NMC-113934 to IS and grant SFRH/BPD/80118/2011 to JC), Canon Foundation and project DoIT - Desenvolvimento e Operacionalização da Investigação de Translação (N° do projeto 13853), funded by Fundo Europeu de Desenvolvimento Regional (FEDER) through the Programa Operacional Fatores de Competitividade (POFC).info:eu-repo/semantics/publishedVersio

Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci.

Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow-up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 × 10(-6)) and rs8057927 in CDH13 (P=1.39 × 10(-5)). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 × 10(-7)). A region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10(-7)). This signal was replicated in the follow-up analysis (P=2.3 × 10(-2)). Significant interaction with maternal CMV infection was found for rs7902091 (P(SNP × CMV)=7.3 × 10(-7)) in CTNNA3, a gene not previously implicated in schizophrenia, stressing the importance of including environmental factors in genetic studies