Publications by authors named "Ana Bento"

33 Publications

HIV testing by public health centers and municipalities and new HIV cases during the COVID-19 pandemic in Japan.

J Acquir Immune Defic Syndr 2021 Feb 17. Epub 2021 Feb 17.

Department of Epidemiology and Biostatistics, Indiana University School of Public Health-Bloomington, IN, USA. Department of Global Health Policy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan. School of Human Evolution and Social Change, Arizona State University, Arizona, USA. Department of Health Policy and Management, School of Medicine, Keio University, Tokyo, Japan. Graduate School of Public Health, St. Luke's International University, Tokyo, Japan. Institute for Consumer Sciences and Human Life, Kinjo Gakuin University, Nagoya, Japan. Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, Japan. MIRAI, JST, Saitama, Japan. Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan. NEXT-Ganken Program, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan. Science Groove Inc., Fukuoka, Japan.

Background: During the COVID-19 outbreak, facility capacity for HIV testing has been limited. Further, people may have opted against HIV testing during this period to avoid COVID-19 exposure. We investigated the influence of the COVID-19 pandemic on HIV testing and the number of reported HIV cases in Japan.

Methods: We analyzed quarterly HIV/AIDS-related data from 2015 to the second quarter of 2020 using an anomaly detection approach. The data included the number of consultations, the number of HIV tests performed by public health centers or municipalities, and the number of newly reported HIV cases with and without an AIDS diagnosis. We further performed the same analysis for two subgroups: men who have sex with men (MSM) and non-Japanese persons.

Results: The number of HIV tests (9,584 vs. 35,908 in the year-before period) and consultations (11,689 vs. 32,565) performed by public health centers significantly declined in the second quarter of 2020, while the proportion of new HIV cases with an AIDS diagnosis (36.2% vs. 26.4%) significantly increased after removing the trend and seasonality effects. HIV cases without an AIDS diagnosis decreased (166 vs. 217), but the reduction was not significant. We confirmed similar trends for the MSM and non-Japanese subgroups.

Conclusion: During the COVID-19 pandemic, the current HIV testing system in Japan seems to have missed more cases of HIV before developing AIDS. Continuously monitoring the situation as well as securing sufficient test resources by use of self-testing is essential to understand the clear epidemiological picture of HIV incidence during the COVID-19 pandemic.
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http://dx.doi.org/10.1097/QAI.0000000000002660DOI Listing
February 2021

The COVID-19 outbreak in Sichuan, China: Epidemiology and impact of interventions.

PLoS Comput Biol 2020 12 28;16(12):e1008467. Epub 2020 Dec 28.

Department of Epidemiology and Biostatistics, School of Public Health, Indiana University Bloomington, Bloomington, Indiana, United States of America.

In January 2020, a COVID-19 outbreak was detected in Sichuan Province of China. Six weeks later, the outbreak was successfully contained. The aim of this work is to characterize the epidemiology of the Sichuan outbreak and estimate the impact of interventions in limiting SARS-CoV-2 transmission. We analyzed patient records for all laboratory-confirmed cases reported in the province for the period of January 21 to March 16, 2020. To estimate the basic and daily reproduction numbers, we used a Bayesian framework. In addition, we estimated the number of cases averted by the implemented control strategies. The outbreak resulted in 539 confirmed cases, lasted less than two months, and no further local transmission was detected after February 27. The median age of local cases was 8 years older than that of imported cases. We estimated R0 at 2.4 (95% CI: 1.6-3.7). The epidemic was self-sustained for about 3 weeks before going below the epidemic threshold 3 days after the declaration of a public health emergency by Sichuan authorities. Our findings indicate that, were the control measures be adopted four weeks later, the epidemic could have lasted 49 days longer (95% CI: 31-68 days), causing 9,216 more cases (95% CI: 1,317-25,545).
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http://dx.doi.org/10.1371/journal.pcbi.1008467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794025PMC
December 2020

APP Binds to the EGFR Ligands HB-EGF and EGF, Acting Synergistically with EGF to Promote ERK Signaling and Neuritogenesis.

Mol Neurobiol 2021 Feb 2;58(2):668-688. Epub 2020 Oct 2.

Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, Agra do Crasto, 3810-193, Aveiro, Portugal.

The amyloid precursor protein (APP) is a transmembrane glycoprotein central to Alzheimer's disease (AD) with functions in brain development and plasticity, including in neurogenesis and neurite outgrowth. Epidermal growth factor (EGF) and heparin-binding EGF-like growth factor (HB-EGF) are well-described neurotrophic and neuromodulator EGFR ligands, both implicated in neurological disorders, including AD. Pro-HB-EGF arose as a putative novel APP interactor in a human brain cDNA library yeast two-hybrid screen. Based on their structural and functional similarities, we first aimed to verify if APP could bind to (HB-)EGF proforms. Here, we show that APP interacts with these two EGFR ligands, and further characterized the effects of APP-EGF interaction in ERK activation and neuritogenesis. Yeast co-transformation and co-immunoprecipitation assays confirmed APP interaction with HB-EGF. Co-immunoprecipitation also revealed that APP binds to cellular pro-EGF. Overexpression of HB-EGF in HeLa cells, or exposure of SH-SY5Y cells to EGF, both resulted in increased APP protein levels. EGF and APP were observed to synergistically activate the ERK pathway, crucial for neuronal differentiation. Immunofluorescence analysis of cellular neuritogenesis in APP overexpression and EGF exposure conditions confirmed a synergistic effect in promoting the number and the mean length of neurite-like processes. Synergistic ERK activation and neuritogenic effects were completely blocked by the EGFR inhibitor PD 168393, implying APP/EGF-induced activation of EGFR as part of the mechanism. This work shows novel APP protein interactors and provides a major insight into the APP/EGF-driven mechanisms underlying neurite outgrowth and neuronal differentiation, with potential relevance for AD and for adult neuroregeneration.
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http://dx.doi.org/10.1007/s12035-020-02139-2DOI Listing
February 2021

Evidence from internet search data shows information-seeking responses to news of local COVID-19 cases.

Proc Natl Acad Sci U S A 2020 05 4;117(21):11220-11222. Epub 2020 May 4.

O'Neill School of Public and Environmental Affairs, Indiana University, Bloomington, IN 47405;

The COVID-19 outbreak is a global pandemic with community circulation in many countries, including the United States, with confirmed cases in all states. The course of this pandemic will be shaped by how governments enact timely policies and disseminate information and by how the public reacts to policies and information. Here, we examine information-seeking responses to the first COVID-19 case public announcement in a state. Using an event study framework for all US states, we show that such news increases collective attention to the crisis right away. However, the elevated level of attention is short-lived, even though the initial announcements are followed by increasingly strong policy measures. Specifically, searches for "coronavirus" increased by about 36% (95% CI: 27 to 44%) on the day immediately after the first case announcement but decreased back to the baseline level in less than a week or two. We find that people respond to the first report of COVID-19 in their state by immediately seeking information about COVID-19, as measured by searches for coronavirus, coronavirus symptoms, and hand sanitizer. On the other hand, searches for information regarding community-level policies (e.g., quarantine, school closures, testing) or personal health strategies (e.g., masks, grocery delivery, over-the-counter medications) do not appear to be immediately triggered by first reports. These results are representative of the study period being relatively early in the epidemic, and more-elaborate policy responses were not yet part of the public discourse. Further analysis should track evolving patterns of responses to subsequent flows of public information.
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http://dx.doi.org/10.1073/pnas.2005335117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260988PMC
May 2020

Evolutionary consequences of feedbacks between within-host competition and disease control.

Evol Med Public Health 2020 4;2020(1):30-34. Epub 2020 Feb 4.

Department of Ecology & Evolutionary Biology, University of Toronto, 25 Willcocks St., Toronto, ON M5S 3B2, Canada.

Lay Summary: Competition often occurs among diverse parasites within a single host, but control efforts could change its strength. We examined how the interplay between competition and control could shape the evolution of parasite traits like drug resistance and disease severity.
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http://dx.doi.org/10.1093/emph/eoaa004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027713PMC
February 2020

Paternal and maternal mutations in X-STRs: A GHEP-ISFG collaborative study.

Forensic Sci Int Genet 2020 05 5;46:102258. Epub 2020 Feb 5.

Laboratório de Diagnóstico por DNA (LDD), Universidade do Estado do Rio de Janeiro, Brazil.

The GHEP-ISFG organized a collaborative study to estimate mutation rates for the markers included in the Investigator Argus X-12 QS kit Qiagen. A total of 16 laboratories gathered data from 1,612 father/mother/daughter trios, which were used to estimate both maternal and paternal mutation rates, when pooled together with other already published data. Data on fathers and mothers' age at the time of birth of the daughter were also available for ∼93 % of the cases. Population analyses were computed considering the genetic information of a subset of 1,327 unrelated daughters, corresponding to 2,654 haplotypes from residents in several regions of five countries: Argentina, Brazil, Ecuador, Portugal and Spain. Genetic differentiation analyses between the population samples from the same country did not reveal signs of significant stratification, although results from Hardy-Weinberg and linkage disequilibrium tests indicated the need of larger studies for Ecuador and Brazilian populations. The high genetic diversity of the markers resulted in a large number of haplotype combinations, showing the need of huge databases for reliable estimates of their frequencies. It should also be noted the high number of new alleles found, many of them not included in the allelic ladders provided with the kit, as very diverse populations were analyzed. The overall estimates for locus specific average mutation rates varied between 7.5E-04 (for DXS7423) and 1.1E-02 (for DXS10135), the latter being a troublesome figure for kinship analyses. Most of the found mutations (∼92 %) are compatible with the gain or loss of a single repeat. Paternal mutation rates showed to be 5.2 times higher than maternal ones. We also found that older fathers were more prone to transmit mutated alleles, having this trend not been observed in the case of the mothers.
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http://dx.doi.org/10.1016/j.fsigen.2020.102258DOI Listing
May 2020

UBXD1 is a mitochondrial recruitment factor for p97/VCP and promotes mitophagy.

Sci Rep 2018 08 17;8(1):12415. Epub 2018 Aug 17.

Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.

Clearance of damaged mitochondria through mitophagy is critical for maintaining mitochondrial fidelity and the prevention of neurodegeneration. Here, we report on the UBX domain-containing, p97/VCP cofactor UBXD1/UBXN6/UBXDC2 and its role in mitophagy. Recognizing depolarized mitochondria via its C-terminal UBX domain, UBXD1 translocates to mitochondria in a Parkin-dependent manner. During Parkin-independent mitophagy, UBXD1 shows no mitochondrial translocation. Once translocated, UBXD1 recruits p97 to mitochondria via a bipartite binding motif consisting of its N-terminal VIM and PUB domains. Recruitment of p97 by UBXD1 only depends on the presence of UBXD1 on mitochondria without the need for further mitochondrial signals. Following translocation of UBXD1 to CCCP-depolarized mitochondria and p97 recruitment, formation of LC3-positive autolysosomes is strongly enhanced and autophagic degradation of mitochondria is significantly accelerated. Diminished levels of UBXD1 negatively impact mitophagic flux in Parkin-expressing cells after CCCP treatment. Thus, our data supports a model, whereby the p97 cofactor UBXD1 promotes Parkin-dependent mitophagy by specifically recognizing damaged mitochondria undergoing autophagic clearance.
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http://dx.doi.org/10.1038/s41598-018-30963-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098094PMC
August 2018

Core pertussis transmission groups in England and Wales: A tale of two eras.

Vaccine 2018 02 1;36(9):1160-1166. Epub 2018 Feb 1.

Odum School of Ecology, University of Georgia, Athens, GA, USA; Center for the Ecology of Infectious Diseases, University of Georgia, Athens, GA, USA; Department of Infectious Diseases, University of Georgia, Athens, GA, USA.

The recent resurgence of pertussis in England and Wales has been marked by infant deaths and rising cases in teens and adults. To understand which age cohorts are most responsible for these trends, we employed three separate statistical methods to analyze high-resolution pertussis reports from 1982 to 2012. The fine-grained nature of the time-series allowed us to describe the changes in age-specific incidence and contrast the transmission dynamics in the 1980s and during the resurgence era. Our results identified infants and school children younger than 10 years of age as a core group, prior to 2002: pertussis incidence in these populations was predictive of incidence in other age groups. After 2002, no core groups were identifiable. This conclusion is independent of methodology used. Because it is unlikely that the underlying contact patterns substantially changed over the study period, changes in predictability likely result from the introduction of more stringent diagnostics tests that may have inadvertently played a role in masking the relative contributions of core transmission groups.
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http://dx.doi.org/10.1016/j.vaccine.2018.01.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806206PMC
February 2018

Fibrin functionalization with synthetic adhesive ligands interacting with α6β1 integrin receptor enhance neurite outgrowth of embryonic stem cell-derived neural stem/progenitors.

Acta Biomater 2017 09 8;59:243-256. Epub 2017 Jul 8.

INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Portugal; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; Faculdade de Engenharia, Universidade do Porto, Portugal. Electronic address:

To enhance fibrin hydrogel affinity towards pluripotent stem cell-derived neural stem/progenitor cells (NSPCs) and its capacity to support NSPC migration and neurite extension, we explored the tethering of synthetic peptides engaging integrin α6β1, a cell receptor enriched in NSPCs. Six α6β1 integrin ligands were tested for their ability to support integrin α6β1-mediated adhesion of embryonic stem cell-derived NSPCs (ES-NSPs) and sustain ES-NSPC viability, migration, and neuronal differentiation. Due to their better performance, peptides T1, HYD1, and A5G81 were immobilized into fibrin and functionalized gels characterized in terms of peptide binding efficiency, structure and viscoelastic properties. Tethering of T1 or HYD1 successfully enhanced cell outgrowth from ES-NSPC neurospheres (up to 2.4-fold increase), which exhibited a biphasic response to peptide concentration. Inhibition assays evidenced the involvement of α6β1 and α3β1 integrins in mediating radial outgrowth on T1-/HYD1-functionalized gels. Fibrin functionalization also promoted neurite extension of single ES-NSPCs in fibrin, without affecting cell proliferation and neuronal differentiation. Finally, HYD1-functionalized gels were found to provide a permissive environment for axonal regeneration, leading up to a 2.0-fold increase in neurite extension from rat dorsal root ganglia explants as compared to unmodified fibrin, and to significant improved locomotor function after spinal cord injury (complete transection), along with a trend toward a higher area positive for growth associated protein 43 (marker for axonal growth cone formation). Our results suggest that conjugation of α6β1 integrin-binding motifs is of interest to increase the biofunctionality of hydrogels used in 3D platforms for ES-NSPC culture and potentially, in matrix-assisted ES-NSPC transplantation.

Statement Of Significance: Impact statement: The transplantation of NSPCs derived from pluripotent stem cells holds much promise for the treatment of central nervous system disorders. Moreover, the combinatorial use of biodegradable hydrogels with NSPCs was shown to contribute to the establishment of a more permissive environment for survival and integration of transplanted cells. In this study, fibrin hydrogels functionalized with a synthetic peptide engaging integrin α6β1 (HYD1) were shown to promote neurite extension of ES-NSPCs, which is fundamental for the formation of functional neuronal relay circuits after NSPC transplantation. Notably, HYD1-functionalized fibrin per se led to enhanced axonal growth ex vivo and to an improvement in locomotor function after implantation in a rat model of spinal cord injury. Conjugation of α6β1 integrin-binding motifs may therefore be of interest to confer bioactivity to NSPC hydrogel vehicles.
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http://dx.doi.org/10.1016/j.actbio.2017.07.013DOI Listing
September 2017

Maternal pertussis immunisation: clinical gains and epidemiological legacy.

Euro Surveill 2017 Apr;22(15)

Odum School of Ecology, University of Georgia, Athens, GA, United States.

The increase in whooping cough (pertussis) incidence in many countries with high routine vaccination coverage is alarming, with incidence in the US reaching almost 50,000 reported cases per year, reflecting incidence levels not seen since the 1950s. While the potential explanations for this resurgence remain debated, we face an urgent need to protect newborns, especially during the time window between birth and the first routine vaccination dose. Maternal immunisation has been proposed as an effective strategy for protecting neonates, who are at higher risk of severe pertussis disease and mortality. However, if maternally derived antibodies adversely affect the immunogenicity of the routine schedule, through blunting effects, we may observe a gradual degradation of herd immunity. 'Wasted' vaccines would result in an accumulation of susceptible children in the population, specifically leading to an overall increase in incidence in older age groups. In this Perspective, we discuss potential long-term epidemiological effects of maternal immunisation, as determined by possible immune interference outcomes.
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http://dx.doi.org/10.2807/1560-7917.ES.2017.22.15.30510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476979PMC
April 2017

Three-dimensional culture of single embryonic stem-derived neural/stem progenitor cells in fibrin hydrogels: neuronal network formation and matrix remodelling.

J Tissue Eng Regen Med 2017 12 29;11(12):3494-3507. Epub 2016 Dec 29.

INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Portugal.

In an attempt to improve the efficacy of neural stem/progenitor cell (NSPC) based therapies, fibrin hydrogels are being explored to provide a favourable microenvironment for cell survival and differentiation following transplantation. In the present work, the ability of fibrin to support the survival, proliferation, and neuronal differentiation of NSPCs derived from embryonic stem (ES) cells under monolayer culture was explored. Single mouse ES-NSPCs were cultured within fibrin (fibrinogen concentration: 6 mg/ml) under neuronal differentiation conditions up to 14 days. The ES-NSPCs retained high cell viability and proliferated within small-sized spheroids. Neuronal differentiation was confirmed by an increase in the levels of βIII-tubulin and NF200 over time. At day 14, cell-matrix constructs mainly comprised NSPCs and neurons (46.5% βIII-tubulin cells). Gamma-aminobutyric acid (GABA)ergic and dopaminergic/noradrenergic neurons were also observed, along with a network of synaptic proteins. The ES-NSPCs expressed matriptase and secreted MMP-2/9, with MMP-2 activity increasing along time. Fibronectin, laminin and collagen type IV deposition was also detected. Fibrin gels prepared with higher fibrinogen concentrations (8/10 mg/ml) were less permissive to neurite extension and neuronal differentiation, possibly owing to their smaller pore area and higher rigidity. Overall, it is shown that ES-NSPCs within fibrin are able to establish neuronal networks and to remodel fibrin through MMP secretion and extracellular matrix (ECM) deposition. This three-dimensional (3D) culture system was also shown to support cell viability, neuronal differentiation and ECM deposition of human ES-NSPCs. The settled 3D platform is expected to constitute a valuable tool to develop fibrin-based hydrogels for ES-NSPC delivery into the injured central nervous system. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/term.2262DOI Listing
December 2017

Forecasting Epidemiological Consequences of Maternal Immunization.

Clin Infect Dis 2016 Dec;63(suppl 4):S205-S212

Odum School of Ecology.

Background:  The increase in the incidence of whooping cough (pertussis) in many countries with high vaccination coverage is alarming. Maternal pertussis immunization has been proposed as an effective means of protecting newborns during the interval between birth and the first routine dose. However, there are concerns regarding potential interference between maternal antibodies and the immune response elicited by the routine schedule, with possible long-term population-level effects.

Methods:  We formulated a transmission model comprising both primary routine and maternal immunization. This model was examined to evaluate the long-term epidemiological effects of routine and maternal immunization, together with consequences of potential immune interference scenarios.

Results:  Overall, our model demonstrates that maternal immunization is an effective strategy in reducing the incidence of pertussis in neonates prior to the onset of the primary schedule. However, if maternal antibodies lead to blunting, incidence increases among older age groups. For instance, our model predicts that with 60% routine and maternal immunization coverage and 30% blunting, the incidence among neonates (0-2 months) is reduced by 43%. Under the same scenario, we observe a 20% increase in incidence among children aged 5-10 years. However, the downstream increase in the older age groups occurs with a delay of approximately a decade or more.

Conclusions:  Maternal immunization has clear positive effects on infant burden of disease, lowering mean infant incidence. However, if maternally derived antibodies adversely affect the immunogenicity of the routine schedule, we predict eventual population-level repercussions that may lead to an overall increase in incidence in older age groups.
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http://dx.doi.org/10.1093/cid/ciw557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5106624PMC
December 2016

EpiJSON: A unified data-format for epidemiology.

Epidemics 2016 06 29;15:20-6. Epub 2015 Dec 29.

MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, London, United Kingdom.

Epidemiology relies on data but the divergent ways data are recorded and transferred, both within and between outbreaks, and the expanding range of data-types are creating an increasingly complex problem for the discipline. There is a need for a consistent, interpretable and precise way to transfer data while maintaining its fidelity. We introduce 'EpiJSON', a new, flexible, and standards-compliant format for the interchange of epidemiological data using JavaScript Object Notation. This format is designed to enable the widest range of epidemiological data to be unambiguously held and transferred between people, software and institutions. In this paper, we provide a full description of the format and a discussion of the design decisions made. We introduce a schema enabling automatic checks of the validity of data stored as EpiJSON, which can serve as a basis for the development of additional tools. In addition, we also present the R package 'repijson' which provides conversion tools between this format, line-list data and pre-existing analysis tools. An example is given to illustrate how EpiJSON can be used to store line list data. EpiJSON, designed around modern standards for interchange of information on the internet, is simple to implement, read and check. As such, it provides an ideal new standard for epidemiological, and other, data transfer to the fast-growing open-source platform for the analysis of disease outbreaks.
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http://dx.doi.org/10.1016/j.epidem.2015.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104924PMC
June 2016

Nutritional and phytochemical composition of Annona cherimola Mill. fruits and by-products: Potential health benefits.

Food Chem 2016 Feb 16;193:187-95. Epub 2014 Jun 16.

Research and Development Unit, Department of Food and Nutrition, National Institute of Health Dr. Ricardo Jorge, I.P., Av. Padre Cruz, 1649-016 Lisbon, Portugal; REQUIMTE/Faculdade de Farmácia da Universidade do Porto, R. Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal. Electronic address:

Annona cherimola Mill., commonly known as cherimoya, is a tropical fruit well known due to its tasty flavour. In the present study the antioxidant activity of pulp, peel and seeds of four cultivars from A. cherimola Mill. from Madeira Island (Madeira, Funchal, Perry Vidal and Mateus II) was analysed. Moreover, nutritional composition (proximates and vitamins) and bioactive compounds content were determined. The peel of Madeira cultivar showed the highest antioxidant capacity, with an EC50 of 0.97mg/mL, and total flavonoids (44.7 epicatechin equivalents/100g). The most abundant carotenoid was lutein, with values ranging from 129 to 232μg/100g. The highest l-ascorbic acid content (4.41mg/100g) was found in the peel of Perry Vidal cultivar. These results highlight A. cherimola Mill. antioxidant properties, especially in its by-products and encourage their application in cosmetic, pharmaceutical and food processing industries, as added value natural extracts.
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http://dx.doi.org/10.1016/j.foodchem.2014.06.044DOI Listing
February 2016

A review of epidemiological parameters from Ebola outbreaks to inform early public health decision-making.

Sci Data 2015 26;2:150019. Epub 2015 May 26.

MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College London , London W2 1PG, UK.

The unprecedented scale of the Ebola outbreak in West Africa has, as of 29 April 2015, resulted in more than 10,884 deaths among 26,277 cases. Prior to the ongoing outbreak, Ebola virus disease (EVD) caused relatively small outbreaks (maximum outbreak size 425 in Gulu, Uganda) in isolated populations in central Africa. Here, we have compiled a comprehensive database of estimates of epidemiological parameters based on data from past outbreaks, including the incubation period distribution, case fatality rate, basic reproduction number (R 0 ), effective reproduction number (R t ) and delay distributions. We have compared these to parameter estimates from the ongoing outbreak in West Africa. The ongoing outbreak, because of its size, provides a unique opportunity to better understand transmission patterns of EVD. We have not performed a meta-analysis of the data, but rather summarize the estimates by virus from comprehensive investigations of EVD and Marburg outbreaks over the past 40 years. These estimates can be used to parameterize transmission models to improve understanding of initial spread of EVD outbreaks and to inform surveillance and control guidelines.
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http://dx.doi.org/10.1038/sdata.2015.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4443880PMC
December 2015

First report of chronic hepatitis E in renal transplant recipients in Portugal.

J Infect Dev Ctries 2014 Dec 15;8(12):1639-42. Epub 2014 Dec 15.

Liver Disease Unit, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

Hepatitis E virus (HEV) infection can be responsible for chronic hepatitis in immunocompromised patients, and can rapidly evolve into fibrosis and/or hepatic cirrhosis. We present two cases of chronic hepatitis E, emphasizing the need to be aware of this entity as a growing etiology of hepatitis in transplant and immunocompromised patients.
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http://dx.doi.org/10.3855/jidc.4637DOI Listing
December 2014

Endometriosis-induced intussusception of the caecal appendix.

BMJ Case Rep 2014 Dec 4;2014. Epub 2014 Dec 4.

Department of Cirurgia B, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

Appendicular intussusception is an uncommon entity, with a reported incidence of 0.01%. The diagnosis is difficult and often only performed at the time of surgery. Intussusception has multiple causes including tumours, foreign bodies and polyps. The definitive treatment is surgical, and the extent of resection is determined by the underlying pathology and degree of invagination. Endometriosis is a rare cause of appendicular intussusception, with 194 cases described in the English literature. We report a case of a 42-year-old woman who presented with chronic abdominal pain in the lower right quadrant. A mass at the caecum was identified during investigations for renal stones by CT. Colonoscopy showed a polypoid lesion, with presumed origin in the appendix. Ileocaecal resection was performed because an appendicular tumour was suspected. Pathological examination identified endometriosis of the appendix and associated peritoneum with invagination of the caecum. The patient was discharged 7 days after surgery and is currently asymptomatic.
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http://dx.doi.org/10.1136/bcr-2013-200098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4256665PMC
December 2014

Collaborative EDNAP exercise on the IrisPlex system for DNA-based prediction of human eye colour.

Forensic Sci Int Genet 2014 Jul 21;11:241-51. Epub 2014 Apr 21.

Department of Forensic Molecular Biology, Erasmus MC University Medical Centre Rotterdam, Rotterdam, The Netherlands. Electronic address:

The IrisPlex system is a DNA-based test system for the prediction of human eye colour from biological samples and consists of a single forensically validated multiplex genotyping assay together with a statistical prediction model that is based on genotypes and phenotypes from thousands of individuals. IrisPlex predicts blue and brown human eye colour with, on average, >94% precision accuracy using six of the currently most eye colour informative single nucleotide polymorphisms (HERC2 rs12913832, OCA2 rs1800407, SLC24A4 rs12896399, SLC45A2 (MATP) rs16891982, TYR rs1393350, and IRF4 rs12203592) according to a previous study, while the accuracy in predicting non-blue and non-brown eye colours is considerably lower. In an effort to vigorously assess the IrisPlex system at the international level, testing was performed by 21 laboratories in the context of a collaborative exercise divided into three tasks and organised by the European DNA Profiling (EDNAP) Group of the International Society of Forensic Genetics (ISFG). Task 1 involved the assessment of 10 blood and saliva samples provided on FTA cards by the organising laboratory together with eye colour phenotypes; 99.4% of the genotypes were correctly reported and 99% of the eye colour phenotypes were correctly predicted. Task 2 involved the assessment of 5 DNA samples extracted by the host laboratory from simulated casework samples, artificially degraded, and provided to the participants in varying DNA concentrations. For this task, 98.7% of the genotypes were correctly determined and 96.2% of eye colour phenotypes were correctly inferred. For Tasks 1 and 2 together, 99.2% (1875) of the 1890 genotypes were correctly generated and of the 15 (0.8%) incorrect genotype calls, only 2 (0.1%) resulted in incorrect eye colour phenotypes. The voluntary Task 3 involved participants choosing their own test subjects for IrisPlex genotyping and eye colour phenotype inference, while eye photographs were provided to the organising laboratory and judged; 96% of the eye colour phenotypes were inferred correctly across 100 samples and 19 laboratories. The high success rates in genotyping and eye colour phenotyping clearly demonstrate the reproducibility and the robustness of the IrisPlex assay as well as the accuracy of the IrisPlex model to predict blue and brown eye colour from DNA. Additionally, this study demonstrates the ease with which the IrisPlex system is implementable and applicable across forensic laboratories around the world with varying pre-existing experiences.
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http://dx.doi.org/10.1016/j.fsigen.2014.04.006DOI Listing
July 2014

Antitumor activity of new enantiopure pybox-ruthenium complexes.

Dalton Trans 2013 Oct 8;42(38):13955-67. Epub 2013 Aug 8.

Departamento de Química Orgánica e Inorgánica, Instituto de Química Organometálica "Enrique Moles" (Unidad Asociada al C.S.I.C.). Universidad de Oviedo, 33006 Oviedo, Principado de Asturias, Spain.

New ruthenium complexes containing enantiopure 2,6-bis[4'(R)-phenyloxazolin-2'-il-pyridine] ((R,R)-Ph-pybox), 2,6-bis[4'(S)-isopropyloxazolin-2'-il-pyridine] ((S,S)-(i)Pr-pybox) or 2,6-bis[4'(R)-isopropyloxazolin-2'-il-pyridine] ((R,R)-(i)Pr-pybox) and water soluble 1,3,5-triaza-7-phosphaadamantane (PTA) or N-substituted PTA phosphanes have been synthesized in high yields and fully characterized. The interactions of these compounds with plasmidic DNA and their cytotoxic activity against the human cervical cancer HeLa cell line are reported, pointing out for the first time the different behaviour of ruthenium enantiomers affecting the cell cycle in HeLa tumor cells.
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http://dx.doi.org/10.1039/c3dt51160jDOI Listing
October 2013

Rapid human melanoma cell death induced by sanguinarine through oxidative stress.

Eur J Pharmacol 2013 Apr 13;705(1-3):109-18. Epub 2013 Mar 13.

Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.

Sanguinarine is a natural isoquinoline alkaloid derived from the root of Sanguinaria canadensis and from other poppy fumaria species, and is known to have a broad spectrum of pharmacological properties. Here we have found that sanguinarine, at low micromolar concentrations, showed a remarkably rapid killing activity against human melanoma cells. Time-lapse videomicroscopy showed rapid morphological changes compatible with an apoptotic cell death, which was further supported by biochemical markers, including caspase activation, poly(ADP-ribose) polymerase (PARP) cleavage and DNA breakdown. Pan-caspase inhibition blocked sanguinarine-induced cell death. Sanguinarine treatment also induced an increase in intracellular calcium concentration, which was inhibited by dantrolene, and promoted cleavage of BAP-31, thus suggesting a putative role for Ca(2+) release from endoplasmic reticulum and a cross-talk between endoplasmic reticulum and mitochondria in the anti-melanoma action of sanguinarine. Sanguinarine disrupted the mitochondrial transmembrane potential (ΔΨm), released cytochrome c and Smac/DIABLO from mitochondria to cytosol, and induced oxidative stress. Overexpression of Bcl-XL by gene transfer did not prevent sanguinarine-mediated cell death, oxidative stress or release of mitochondrial apoptogenic proteins. However, preincubation with N-acetyl-l-cysteine (NAC) prevented sanguinarine-induced oxidative stress, PARP cleavage, release of apoptogenic mitochondrial proteins, and cell death. Pretreatment with glutathione (GSH) also inhibited the anti-melanoma activity of sanguinarine. Thus, pretreatment with the thiol antioxidants NAC and GSH abrogated the killing activity of sanguinarine. Taking together, our data indicate that sanguinarine is a very rapid inducer of human melanoma caspase-dependent cell death that is mediated by oxidative stress.
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http://dx.doi.org/10.1016/j.ejphar.2013.02.035DOI Listing
April 2013

Endowing indole-based tubulin inhibitors with an anchor for derivatization: highly potent 3-substituted indolephenstatins and indoleisocombretastatins.

J Med Chem 2013 Apr 20;56(7):2813-27. Epub 2013 Mar 20.

Laboratorio de Química Orgánica y Farmacéutica, CIETUS and IBSAL, Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.

Colchicine site ligands with indole B rings are potent tubulin polymerization inhibitors. Structural modifications at the indole 3-position of 1-methyl-5-indolyl-based isocombretastatins (1,1-diarylethenes) and phenstatins endowed them with anchors for further derivatization and resulted in highly potent compounds. The substituted derivatives displayed potent cytotoxicity against several human cancer cell lines due to tubulin inhibition, as shown by cell cycle analysis, confocal microscopy, and tubulin polymerization inhibitory activity studies and promoted cell killing mediated by caspase-3 activation. Binding at the colchicine site was confirmed by means of fluorescence measurements of MTC displacement. Molecular modeling suggests that the tropolone-binding region of the colchicine site of tubulin can adapt to hosting small polar substituents. Isocombretastatins accepted substitutions better than phenstatins, and the highest potencies were achieved for the cyano and hydroxyiminomethyl substituents, with TPI values in the submicromolar range and cytotoxicities in the subnanomolar range. A 3,4,5-trimethoxyphenyl ring usually afforded more potent derivatives than a 2,3,4-trimethoxyphenyl ring.
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http://dx.doi.org/10.1021/jm3015603DOI Listing
April 2013

Congenital pancreas malformations: a clinical case report.

Rev Assoc Med Bras (1992) 2013 Jan-Feb;59(1):35-9

Universidade de Coimbra, Coimbra, Portugal.

Objective: This study aimed to review the congenital malformation known as agenesis of the dorsal pancreas (ADP) and other pancreatic birth defects, based on a rare and exemplary clinical case of pancreatic malformations. The intent was to review the latest information published in the national and international literature on pancreatic birth defects, and to investigate the diversity of clinical presentations of ADP and other congenital pancreas abnormalities. The purpose was to identify which situations have therapeutic indication, the most appropriate time to institute treatment, and the currently available medical or surgical treatment of pancreatic congenital malformations.

Results: ADP is a very rare malformation that occurs during organogenesis. In the last decades, a large volume of embryological and genetic information has been obtained, helping to understand the causes of pancreatic malformations, which must be studied and understood as a whole.

Conclusion: Pancreatic malformations are infrequently studied causes of acute and chronic pancreatic in adults. The possibility of pancreatic malformations should always be considered in patients with acute or chronic pancreatitis with no evident cause.
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October 2013

Lignopurines: a new family of hybrids between cyclolignans and purines. Synthesis and biological evaluation.

Eur J Med Chem 2012 Dec 26;58:377-89. Epub 2012 Oct 26.

Departamento de Química Farmacéutica, Facultad de Farmacia, CIETUS-IBSAL, Campus Miguel de Unamuno, Universidad de Salamanca, E-37007 Salamanca, Spain.

A new family of hybrids between cyclolignans related to podophyllic aldehyde, a non-lactonic cyclolignan, and purines were prepared and evaluated against several human tumour cell lines. Both fragments, cyclolignan and purine, were linked through aliphatic and aromatic chains. The influence on the cytotoxicity of the purine substitution and the nature of the linker is analyzed. The new family was slightly less cytotoxic than the parent podophyllic aldehyde, although the selectivity is maintained or even improved and among the linkers used, the presence of an aromatic ring gave the most potent and selective derivatives within the new series tested. Cell cycle and confocal studies demonstrate that these derivatives interfere with the tubulin polymerization and arrest cells at the G(2)/M phase, in the same way than the parent compounds podophyllotoxin and podophyllic aldehyde do.
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http://dx.doi.org/10.1016/j.ejmech.2012.10.026DOI Listing
December 2012

Neuropeptide Y promotes neurogenesis and protection against methamphetamine-induced toxicity in mouse dentate gyrus-derived neurosphere cultures.

Neuropharmacology 2012 Jun 22;62(7):2413-23. Epub 2012 Feb 22.

Laboratory of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Methamphetamine (METH) is a psychostimulant drug of abuse that causes severe brain damage. However, the mechanisms responsible for these effects are poorly understood, particularly regarding the impact of METH on hippocampal neurogenesis. Moreover, neuropeptide Y (NPY) is known to be neuroprotective under several pathological conditions. Here, we investigated the effect of METH on dentate gyrus (DG) neurogenesis, regarding cell death, proliferation and differentiation, as well as the role of NPY by itself and against METH-induced toxicity. DG-derived neurosphere cultures were used to evaluate the effect of METH or NPY on cell death, proliferation or neuronal differentiation. Moreover, the role of NPY and its receptors (Y(1), Y(2) and Y(5)) was investigated under conditions of METH-induced DG cell death. METH-induced cell death by both apoptosis and necrosis at concentrations above 10 nM, without affecting cell proliferation. Furthermore, at a non-toxic concentration (1 nM), METH decreased neuronal differentiation. NPY's protective effect was mainly due to the reduction of glutamate release, and it also increased DG cell proliferation and neuronal differentiation via Y(1) receptors. In addition, while the activation of Y(1) or Y(2) receptors was able to prevent METH-induced cell death, the Y(1) subtype alone was responsible for blocking the decrease in neuronal differentiation induced by the drug. Taken together, METH negatively affects DG cell viability and neurogenesis, and NPY is revealed to be a promising protective tool against the deleterious effects of METH on hippocampal neurogenesis.
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http://dx.doi.org/10.1016/j.neuropharm.2012.02.015DOI Listing
June 2012

Methamphetamine exerts toxic effects on subventricular zone stem/progenitor cells and inhibits neuronal differentiation.

Rejuvenation Res 2011 Apr 31;14(2):205-14. Epub 2011 Mar 31.

Neuroprotection and Neurogenesis in Brain Repair Group, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

Methamphetamine (METH) is a potent and widely consumed psychostimulant drug that causes brain functional and structural abnormalities. However, there is little information regarding METH impact on adult neurogenic niches and, indeed, nothing is known about its consequences on the subventricular zone (SVZ). Thus, this work aims to clarify the effect of METH on SVZ stem/progenitor cells dynamics and neurogenesis. For that purpose, SVZ neurospheres were obtained from early postnatal mice and treated with increasing concentrations of METH (1  μM to 500  μM). Exposure to 100, 250, or 500  μM METH for 24  h triggered cell death both by necrosis and apoptosis, as assessed by propidium iodide uptake, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and quantification of the proapoptotic caspase-3 activity. Furthermore, we showed that METH inhibited SVZ progenitor cells proliferation as it decreased BrdU incorporation. Interestingly, at non-toxic concentrations (1 and 10  μM), METH decreased neuronal differentiation and maturation, which were evaluated by quantification of the number of neuronal nuclei-positive neurons and measurements of phospho-c-Jun-NH(2)-terminal kinase signal in growing axons, respectively. Altogether, our data demonstrate that METH has a negative impact on SVZ stem/progenitor cells, inducing cell death and inhibiting neurogenesis, effects that in vivo may challenge the cell replacement capacities displayed by endogenous populations of brain stem/progenitor cells.
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http://dx.doi.org/10.1089/rej.2010.1109DOI Listing
April 2011

Story organization and narrative by school-age children with typical language development.

Pro Fono 2010 Oct-Dec;22(4):503-8

Faculdade de Medicina, Universidade de São Paulo.

Background: The narrative abilities provide valuable information about the linguistic, cognitive and social development of school-age children with typical language development (TLD).

Aim: To examine the temporal ordering of figures and the narrative abilities of school-age children with TLD in relation to the type of discourse presented.

Method: Participants of this study included 60 children with TLD aged between seven and ten years of age. Fifteen stories were used in the study. Each story was illustrated by four figures. The sequences of figures were created and classified as mechanical, behavioral and intentional according to the relationships presented among the characters. Data were transcribed and analyzed regarding the type of discourse (descriptive, causal and intentional) and the type of organization of the figures.

Results: No differences between age groups were observed for temporal ordering. For all age groups, the most frequently presented discourse type was the causal one. Statistically significant differences were observed among age groups for the causal and intentional discourse type. Inasmuch as the age increased, school-age children with TLD reduced the use of the descriptive discourse and increased the use of the intentional one.

Conclusion: The ability of temporal ordering is already developed in children with TLD at seven-years of age. The type of discourse was influenced by age and by the type of story presented.
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http://dx.doi.org/10.1590/s0104-56872010000400024DOI Listing
October 2011

Phonological representation of children with Specific Language Impairment (SLI).

Pro Fono 2010 Jul-Sep;22(3):305-10

Fonoaudióloga, Faculdade de Medicina, Universidade de São Paulo, Brazil.

Background: children with Specific Language Impairment (SLI) have difficulties with speech processing. These difficulties affect the development of phonologic representations.

Aim: to evaluate the abilities of children with normal language development (NLD) and those with SLI in distinguishing words from non-words in a lexical decision task.

Method: two groups were involved in this study: the Control Group (GC), with no language disorders, composed by 36 subjects, and the Research Group (RG), with 18 subjects, all diagnosed with SLI, aging form 4 to 8:9 years. Children from both groups were arranged in three subgroups, according to the receptive vocabulary. Forty eight three syllable words were selected, being 24 real words and 24 that were manipulated in order to obtain non-words. Three variables were considered: (a) modification extension, (b) modification positioning and (c) modification type. Children had to decide whether a phonological sequence consisted of a word or a non-word.

Results: even though children were matched by lexical age, there were differences between GC and RG. The RG presented more difficulty in lexical decision, not only for words but also for non-words. Both groups, with lexical age of 4 years, struggled more in this task when compared with groups with lexical age of 5 and 6 years.

Conclusion: children with SLI presented deficit in phonological representation when compared with children with NLD. This difference in performance can be explained by differences in the formation and retention of working memory representations, auditory discrimination and motor planning and execution.
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http://dx.doi.org/10.1590/s0104-56872010000300025DOI Listing
August 2011

Semantic representation and naming in children with specific language impairment.

Pro Fono 2010 Apr-Jun;22(2):113-8

Departamento de Fisioterapia, Fonoaudiologia e Terapia Ocupacional, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.

Background: children with Specific Language Impairment (SLI) show lexical deficits as the first noticeable sign of such disorder, characterized as difficulties in lexical access during naming and speech tests. Studies that compare picture naming and drawings seem perfect to clarify lexical deficits.

Aim: to compare the performance of children with normal language development (NLD) to that of children with SLI in naming, drawing and definition tasks, aiming to explore the the quality of semantic representation of the lexicon.

Method: Two groups were involved in this study: the Control Group (CG), with no language disorders, composed by 40 subjects, and the Research Group (RG), with 20 subjects, all diagnosed with SLI, aging from five to seven years. Tasks of naming, picture drawing and definition were performed, using 20 different pictures. In the naming task, the types of errors were analyzed and sorted as follows: semantic, phonological, none specified and others. The analysis of the drawing and definition tasks was based only on the correct answers, semantic and none specified errors.

Results: children of the RG presented a greater number of semantic errors in the picture naming task when compared to the CG. Besides that, definitions presented by the RG seemed more simple and incomplete even when the child was capable of naming the picture correctly. Drawings of correctly named objects were better than those that were named incorrectly.

Conclusions: it was possible to discriminate within SLI children those that present greater lexical deficits. It was also possible to explore the possible reasons for failures in naming tasks.
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http://dx.doi.org/10.1590/s0104-56872010000200008DOI Listing
February 2011