Avaliação econômica e contábil das cadeias produtivas do arroz beneficiado no Rio Grande do Sul (Brasil) e Uruguai com aplicação da Matriz de Análise de Políticas

Rice is the basis of diet for almost half of the world population, and its culture is one of the strategic agroindustrial production chains in the agribusiness environment, in both economic and social levels. Thus, the comparative analysis between the production chains of rice milled in Rio Grande do Sul (RS), Brazil, and Uruguay was mainly motivated by the interest in knowing the differences in the business environment and public policies that impact the competitiveness of this chain in both study regions. Therefore, the objective of this study was to assess the economic efficiency, competitiveness, and effects of public policies of the rice production chain of milled rice in RS (Brazil) relative to Uruguay. The data collected in this study are from the 2011-2012 harvests and indicators were calculated by applying the concepts of the policy analysis matrix (PAM). Results showed that the chains in both study regions were competitive under the existing market and policy conditions, revealed comparative advantage, transferred a high load of resources to other sectors of the economy, and satisfactorily remuneration of the domestic production factors. However, the competitiveness and comparative advantage shown in this study were not due to the encouraging intervention policies, as both production systems pay high taxes.O arroz é a base da alimentação para quase metade da população mundial, e sua cultura se situa como uma das cadeias produtivas agroindustriais estratégicas no ambiente do agronegócio, tanto no nível econômico como no social. Assim, a análise comparativa entre as cadeias produtivas do arroz beneficiado no Rio Grande do Sul (RS), Brasil e no Uruguai foi motivada, principalmente, pelo interesse em conhecer as diferenças no ambiente de negócios e nas políticas públicas que afetam a competitividade desta cadeia nas respectivas regiões. Portanto, o objetivo deste estudo foi avaliar a eficiência econômica, competitividade, e efeitos de políticas públicas da cadeia produtiva de arroz beneficiado no RS (Brasil) em relação ao Uruguai. Os dados coletados neste estudo são das safras de 2011-2012 e, os indicadores foram calculados aplicando os conceitos da matriz de análise de políticas (MAP). Os resultados mostraram que as cadeias em ambas as regiões de estudo foram competitivas sob as condições de mercado e políticas existentes, evidenciaram vantagem comparativa, transferiram alto volume de recursos para outros setores da economia, remunerando satisfatoriamente os fatores domésticos de produção. Entretanto, tal competitividade e vantagem comparativa demonstrada não se deveram às intervenções políticas de incentivo, pois ambos sistemas de produção pagam elevados tributos

Iron Related Gene Expression and Biochemical Phenotype Support Iron Homeostasis Dysregulation in Alzheimer’s Disease

This research was supported by the Fundação para a Ciência e a Tecnologia (FCT) [SFRH/BPD/29354/2006 to MM, SFRH/BD/60718/2009 to BS, and SFRH/BD/48671/2008 to LM]; Fundação Astrazeneca (Research Grant awarded through the “Programme of Support to Research”); Instituto Nacional de Saúde Dr. Ricardo Jorge; Portuguese Ministry of Health (Research Grant 53/2007 of the “Comissão de Fomento da Investigação em Cuidados de Saúde”); Lundbeck Portugal, Lda (Research Grant)

Decrease in APP and CP mRNA expression in Alzheimer’s disease patients suggests impairment of cellular iron export in this dementia

Recentemente tem-se assistido a um acumular de evidência sugerindo a implicação de uma desregulação do metabolismo do ferro (Fe) na fisiopatologia da doença de Alzheimer (DA). Neste trabalho, pretendemos esclarecer melhor os mecanismos moleculares subjacentes à homeostasia deste metal na DA, particularmente ao nível do efluxo celular. Assim, mediu-se em células mononucleares do sangue periférico de 73 doentes com DA e 74 controlos a expressão de genes diretamente envolvidos na regulação e exportação celular de Fe, utilizando a técnica de PCR quantitativo. Os resultados mostraram uma diminuição significativa na expressão dos genes aconitase (ACO1; P=0,007); ceruloplasmina (CP; P<0,001) e proteína precursora de beta amilóide (APP; P=0,006) em doentes com DA comparativamente com os voluntários saudáveis. Estas observações apontam para uma diminuição significativa da expressão dos genes associados com a exportação de Fe celular mediada pela ferroportina na DA. Assim, o presente estudo reforça resultados anteriores que mostram alterações no metabolismo do Fe e podem estar na origem da retenção intracelular deste metal e aumento de stress oxidativo caraterísticos desta patologia.A dysregulation of iron (Fe) metabolism in Alzheimer’s disease (AD) has been suggested previously. Herein, we intended to further clarify the molecular mechanisms underlying Fe homeostasis in AD particularly at the level of cellular iron efflux. Thus, the expression of specific Fe metabolism-related genes directly involved in Fe regulation and export was assessed by quantitative PCR in peripheral blood mononuclear cells (PBMCs) from 73 AD patients and 74 controls. A significant decrease in the expression of aconitase 1 (ACO1; P=0.007); ceruloplasmin (CP; P<0.001) and amyloid peptide precursor (APP; P=0.006) genes was fund in AD patients compared with healthy volunteers. These observations point out to a significant downregulation of the expression of genes associated with ferroportin-mediated cellular Fe export in PBMCs from AD patients. The present findings support previous studies suggesting impairment of Fe homeostasis in AD, which may lead to cellular Fe retention and oxidative stress, a typical feature of this disease

The effects of melatonin on the descending pain inhibitory system and neural plasticity markers in breast cancer patients receiving chemotherapy : randomized, double-blinded, placebo-controlled trial

Background: Adjuvant chemotherapy for breast cancer (ACBC) has been associated with fatigue, pain, depressive symptoms, and disturbed sleep. And, previous studies in non-cancer patients showed that melatonin could improve the descending pain modulatory system (DPMS). We tested the hypothesis that melatonin use before and during the first cycle of ACBC is better than placebo at improving the DPMS function assessed by changes in the 0–10 Numerical Pain Scale (NPS) during the conditioned pain modulating task (CPM-task) (primary outcome). The effects of melatonin were evaluated in the following secondary endpoints: heat pain threshold (HPT), heat pain tolerance (HPTo), and neuroplasticity state assessed by serum brain-derived neurotrophic factor (BDNF), tropomyosin kinase receptor B, and S100B-protein and whether melatonin’s effects on pain and neuroplasticity state are due more so to its impact on sleep quality. Methods: Thirty-six women, ages 18 to 75 years old, scheduled for their first cycle of ACBC were randomized to receive 20mg of oral melatonin (n = 18) or placebo (n = 18). The effect of treatment on the outcomes was analyzed by delta (Δ)-values (from pre to treatment end). Results: Multivariate analyses of covariance revealed that melatonin improved the function of the DPMS. The Δ-mean (SD) on the NPS (0–10) during the CPM-task in the placebo group was −1.91 [−1.81 (1.67) vs. −0.1 (1.61)], and in the melatonin group was −3.5 [−0.94 (1.61) vs. −2.29 (1.61)], and the mean difference (md) between treatment groups was 1.59 [(95% CI, 0.50 to 2.68). Melatonin’s effect increased the HPTo and HPT while reducing the (Δ)-means of the serum neuroplasticity marker in placebo vs.melatonin. The Δ-BDNF is 1.87 (7.17) vs. −20.44 (17.17), respectively, and the md = 22.31 [(95% CI = 13.40 to 31.22)]; TrKB md = 0.61 [0.46 (0.17) vs. −0.15 (0.18); 95% CI = 0.49 to 0.73)] and S00B-protein md = −8.27[(2.89 (11.18) vs. −11.16 (9.75); 95% CI = −15.38 to −1.16)]. However, melatonin’s effect on pain and the neuroplastic state are not due to its effect on sleep quality. Conclusions: These results suggest that oral melatonin, together with the first ACBC counteracts the dysfunction in the inhibitory DPMS and improves pain perception measures. Also, it shows that changes in the neuroplasticity state mediate the impact of melatonin on pain

Brazilian tracheotomy speech valve: diaphragm pressure standardization

Tracheotomy is performed in cases of upper airway obstruction or chronic pulmonary disorders. The Tracheotomy Speech Valves (TSV) improve communication and airway hygiene and humidification of tracheotomized patients. AIM: To show the low cost Brazilian TSV and its use in speech rehabilitation of tracheotomized patients, to evaluate diaphragm opening resistance and comfort to the patient. Study Design: Experimental, contemporary cohort. MATERIALS AND METHODS: The TSV was used in 32 patients. The valve has a diaphragm within a stainless steel body with plastic fittings. We studied the level of respiratory comfort according to the degree of valve diaphragm resistance, 40, 50 and 60 shores. RESULTS: All the patients used the TSV coupled to the cannula in a regular basis, 26 of them did it for more than 12 hours daily and from these, 14 used it for 24h daily. The diaphragm pressure obtained was that of 40 shores for 13 patients and 50 shores for 19 patients. 60 shores was never used. CONCLUSION: the metal TSV helps with speech without the need for closing the cannula with one's finger, and breathing was comfortable. We achieved standard diaphragm resistance. Currently all the patients from this study use this TSV with speech and 43.75% use it full time.A traqueotomia está indicada em condições com obstrução respiratória alta ou doença pulmonar obstrutiva crônica. As Válvulas Fonatórias (VF) melhoram a comunicação, higienização e umidificação das vias aéreas dos pacientes traqueotomizados. OBJETIVO: Demonstrar a VF nacional, de menor custo, e sua utilização na reabilitação fonatória desses pacientes, avaliar resistência de abertura pelo diafragma, o que confere melhor conforto ao paciente. Forma de Estudo: Experimental, coorte contemporâneo. MATERIAL E MÉTODO: A VF foi utilizada em 32 pacientes. A válvula tem diafragma dentro de um corpo em aço inox com encaixes de plástico. Estudou-se grau de conforto respiratório de acordo com a resistência do diafragma da válvula, 40, 50 e 60 shores. RESULTADOS: Obteve-se uso regular da VF acoplada à cânula por todos os pacientes, 26 o fizeram por mais de 12h diárias e destes 14 por 24h diárias. A pressão do diafragma obtida foi de 40 shores para 13 pacientes e 50 shores para 19 pacientes, sem utilização de 60 shores. CONCLUSÃO: A VF metálica permite fonação, sem a oclusão digital da cânula, e respiração sob conforto. Obteve-se resistência padronizada do diafragma. Atualmente todos os pacientes do estudo utilizam estas VF com fonação e 43,75% período integral.10711

FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation

SARS-CoV-2 can cause acute respiratory distress and death in some patients1. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood2. Monocytes and macrophages are sentinel cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D (GSDMD), leading to inflammatory death (pyroptosis) and release of potent inflammatory mediators3. Here we show that about 6% of blood monocytes in COVID-19 patients are infected with SARS-CoV-2. Monocyte infection depends on uptake of antibody-opsonized virus by Fcγ receptors. Vaccine recipient plasma does not promote antibody-dependent monocyte infection. SARS-CoV-2 begins to replicate in monocytes, but infection is aborted, and infectious virus is not detected in infected monocyte culture supernatants. Instead, infected cells undergo inflammatory cell death (pyroptosis) mediated by activation of NLRP3 and AIM2 inflammasomes, caspase-1 and GSDMD. Moreover, tissue-resident macrophages, but not infected epithelial and endothelial cells, from COVID-19 lung autopsies have activated inflammasomes. These findings taken together suggest that antibody-mediated SARS-CoV-2 uptake by monocytes/macrophages triggers inflammatory cell death that aborts production of infectious virus but causes systemic inflammation that contributes to COVID-19 pathogenesis

Serological response and breakthrough infection after COVID-19 vaccination in patients with cirrhosis and post-liver transplant

BACKGROUND: Vaccine hesitancy and lack of access remain major issues in disseminating COVID-19 vaccination to liver patients globally. Factors predicting poor response to vaccination and risk of breakthrough infection are important data to target booster vaccine programs. The primary aim of the current study was to measure humoral responses to 2 doses of COVID-19 vaccine. Secondary aims included the determination of factors predicting breakthrough infection. METHODS: COVID-19 vaccination and Biomarkers in cirrhosis And post-Liver Transplantation is a prospective, multicenter, observational case-control study. Participants were recruited at 4-10 weeks following first and second vaccine doses in cirrhosis [n = 325; 94% messenger RNA (mRNA) and 6% viral vaccine], autoimmune liver disease (AILD) (n = 120; 77% mRNA and 23% viral vaccine), post-liver transplant (LT) (n = 146; 96% mRNA and 3% viral vaccine), and healthy controls (n = 51; 72% mRNA, 24% viral and 4% heterologous combination). Serological end points were measured, and data regarding breakthrough SARS-CoV-2 infection were collected. RESULTS: After adjusting by age, sex, and time of sample collection, anti-Spike IgG levels were the lowest in post-LT patients compared to cirrhosis (p < 0.0001), AILD (p < 0.0001), and control (p = 0.002). Factors predicting reduced responses included older age, Child-Turcotte-Pugh B/C, and elevated IL-6 in cirrhosis; non-mRNA vaccine in AILD; and coronary artery disease, use of mycophenolate and dysregulated B-call activating factor, and lymphotoxin-α levels in LT. Incident infection occurred in 6.6%, 10.6%, 7.4%, and 15.6% of cirrhosis, AILD, post-LT, and control, respectively. The only independent factor predicting infection in cirrhosis was low albumin level. CONCLUSIONS: LT patients present the lowest response to the SARS-CoV-2 vaccine. In cirrhosis, the reduced response is associated with older age, stage of liver disease and systemic inflammation, and breakthrough infection with low albumin level

Characterization of KIR2DS1+ decidual Natural Killer cells in healthy and viral/bacterial – infected human pregnancy

Tese de doutoramento em Biociências, na área de especialização de Biologia Celular e Molecular, apresentada ao Departamento de Ciências da Vida da Faculdade de Ciências e Tecnologia da Universidade de CoimbraHuman pregnancy is a challenge for the maternal immune system, which must maintain tolerance to a semi-foreign entity (the fetus) while keeping immunity against viral, bacterial and parasite infections. While the mechanisms involved in placental immune tolerance have been addressed for the last thirty years, very little attention has been given to the maternal immune system role in the elimination of infections. In preparation for implantation, the uterine endometrium undergoes modifications known as decidualization. The placental cells (trophoblast) invade the decidua to facilitate nutrient and gas exchanges. In particular, the extravillous trophoblast (EVT) of fetal origin detaches from placental villi, migrates into the decidual tissue and contacts directly with maternal immune cells such as decidual natural killer cells (dNK). dNK are the most abundant leukocyte type in decidua and have a different phenotype from peripheral NK cells (pNK). dNK have lower cytotoxicity in response to MHC-Class I – negative targets and secrete more cytokines and growth factors than pNK. dNK express high levels of killer cell immunoglobulin-like receptors (KIR) that recognize MHC Class I in maternal tissue and EVT. EVT express HLA-E and HLA-G, in addition to polymorphic HLA-C. Recently, women who lack the gene for the activating receptor KIR2DS1 and carry a fetus expressing HLA-C2 (the ligand for KIR2DS1) were found to be at increased risk of recurrent miscarriage, fetal growth restriction and preeclampsia. The molecular and cellular mechanisms involved are unknown. The current hypothesis suggests that absence of activating KIR2DS1 and expression of KIR2DL1 (inhibitory receptor for HLA-C2) results in stronger inhibition of dNK upon interaction with fetal HLA-C2. This inhibition dampens dNK secretion of growth factors involved in placentation and vessel remodeling, leading to pregnancy complications. Particular combinations of KIR haplotypes and HLA allotypes are also associated with improved clearance of viral infection. Therefore we hypothesized that the protective effect of KIR2DS1 lies in a more efficient clearance of infections during early pregnancy. This may prevent virus-induced placental pathology and subsequent fetal and maternal complications. Both hypotheses are tested in the present work. In this thesis, human dNK phenotype and function in healthy pregnancy and viral/bacterial infections are characterized, focusing on the role of KIR2DS1. Chapter 1 of this thesis provides a general introduction to contextualize the data presented in the following chapters. Chapter 2 presents a characterization of KIR2DS1+ (S1+) dNK in healthy pregnancy. dNK are shown to express receptors for MHC Class I in higher frequencies than pNK, specifically KIR2DL1 and KIR2DS1, KIR2DL2/3 (inhibitory HLA-C1 receptors) and NKG2A/NKG2C (respectively, inhibitory and activating HLA-E receptors). dNK express similar levels of the cytolytic molecules granzyme A and B as pNK, but lower levels of the pore forming protein perforin. Strikingly, dNK express much higher levels of the antimicrobial peptide granulysin than pNK. In addition, the expression of granzyme B, perforin and granulysin are increased in S1+ dNK. These observations point to a higher cytolytic potential of S1+ dNK. In fact, cytotoxicity of dNK from KIR2DS1+¬ women was not as efficiently inhibited by HLA-C2+ target cells as dNK from KIR2DS1- women and pNK from all donors. S1+ dNK also displayed the highest levels of degranulation of all 4 subsets (L1+, S1+, L1+S1+, L1-S1-) in response to HLA-C2+ target cells. Although dNK degranulated and secreted cytokines in response to MHC Class I-negative or HLA-C2+ cell lines, co-culture with EVT did not elicit secretion of IFN-γ, VEGF or GM-CSF. The failure of KIR2DS1+ dNK to secrete cytokines in response to HLA-C2+ EVT led to the hypothesis that the higher cytotoxic potential of KIR2DS1+ dNK contributes to an increased clearance of placental viral infections, a possibility explored in chapter 3. Human cytomegalovirus (HCMV) is the most common congenital viral infection and can lead to miscarriages, fetal growth restriction and permanent hearing damage. In chapter 3, dNK were shown to degranulate and secrete pro-inflammatory cytokines in response to HCMV-infected decidual stromal cells (DSC). However, dNK did not respond to HCMV-infected choriocarcinoma cell line (JEG3) and sample-matched primary EVT. This demonstrates the high resistance to death by trophoblast and highlights the difficulties the maternal immune system faces to clear infections in the tolerogenic compartment of the placenta. Furthermore, KIR2DS1+ dNK were demonstrated to deliver an increased cytolytic response to HCMV-infected DSC expressing HLA-C2. This observation may explain the protective effect of KIR2DS1 in human pregnancy by limiting viral infection in the placenta. KIR2DS1+ dNK may control the spread of infection and reduce the risk for virus-induced pregnancy complications. Finally, in chapter 4, the role of dNK in the elimination of bacterial infections was investigated. The high expression of antimicrobial peptide granulysin by dNK was the basis for this study. dNK constitutively secreted high levels of granulysin. In addition, dNK cells and dNK supernatants were able to kill both extracellular and intracellular bacteria in JEG3 without killing the host cell. This effect was independent of degranulation. This striking result reveals a novel function for dNK and strengthens their role as immune effector cells.A gravidez humana é um desafio para o sistema imunitário materno, o qual deve garantir tolerância a um feto semi-incompatível enquanto mantém imunidade contra infeções. Os mecanismos envolvidos na tolerância têm sido bastante explorados, mas o estudo da imunidade a infeções congénitas tem sido negligenciado. A implantação do embrião exige que o endométrio uterino sofra modificações profundas (decidualização). As células fetais da placenta (trofoblastos) invadem a decidua para permitir trocas eficientes de gases e nutrientes. Em especial, os trofoblastos extravilosos (EVT) migram para o tecido decidual, contatando directamente com linfócitos maternos como as células Natural Killer deciduais (dNK). As dNK são os leucócitos mais abundantes na decidua, mas são menos citotóxicas em resposta a células alvo que não expressam MHC Classe I que as NK do sangue (periféricas, pNK), e secretam mais citocinas e fatores de crescimento. As dNK expressam níveis elevados de recetores KIR (killer cell immunoglobulin-like receptors) que reconhecem proteínas MHC Classe I nos tecidos maternos e EVT. Os EVT expressam HLA-E e HLA-G e também HLA-C, que é polimórfico. Recentemente, foi encontrada uma associação prejudicial entre genes KIR maternos e alelos HLA-C do feto. As grávidas que não possuem o gene para o recetor ativador KIR2DS1 e cujo feto expressa HLA-C2 têm um risco elevado de aborto espontâneo, restrição de crescimento fetal e pré-eclâmpsia. Os mecanismos moleculares e celulares envolvidos não são conhecidos. A hipótese proposta atualmente sugere que a ausência de KIR2DS1 ativador e expressão de KIR2DL1 (recetor inibidor de HLA-C2) leva a uma inibição mais pronunciada das dNK aquando da interação com HLA-C2 fetal. Esta inibição reduz a secreção pelas dNK de fatores de crescimento envolvidos na placentação e remodelação de artérias uterinas, resultando em complicações na gravidez. São também conhecidas combinações de haplótipos de KIR com alelos de HLA que estão associadas a um melhor combate a infeções virais. Estes dados levaram à nossa hipótese de que o efeito protetor de KIR2DS1 está relacionado com uma resposta imunitária mais eficiente a infeções congénitas. Este fenómeno pode prevenir danos induzidos por vírus na placenta e consequentes complicações na gravidez. Ambas as hipóteses foram testadas no trabalho aqui apresentado. Nesta tese, é apresentada uma caraterização do fenótipo e função das dNK humanas em gravidezes saudáveis e afetadas por infeções virais ou bacterianas, com foco no papel de KIR2DS1. O capítulo 1 desta tese fornece uma introdução geral para contextualizar os dados apresentados nos capítulos seguintes. O capítulo 2 apresenta uma caraterização das dNK que expressam KIR2DS1 (S1+) em gravidezes saudáveis. A frequência de expressão de recetores para MHC Classe I nas dNK é mais elevada que nas pNK, em especial KIR2DL1 e KIR2DS1, KIR2DL2/3 (recetores inibidores de HLA-C1) e NKG2A/NKG2C (recetor inibidor e ativador, respetivamente, de HLA-E). As dNK contêm níveis semelhantes das proteínas citolíticas granzima A e B aos das pNK, mas níveis mais reduzidos de perforina, que forma poros nas membranas das células alvo. Em especial, as dNK contêm muito mais proteína anti-microbiana granulisina que as pNK. Ainda, a expressão de granzima B, perforina e granulisina é mais elevada em dNK S1+. Estas observações revelam um potencial citolítico elevado das dNK S1+. De facto, a citotoxicidade das dNK isoladas de grávidas que possuem o gene KIR2DS1 não foi inibida por células alvo HLA-C2+ com a mesma eficiência que dNK isoladas de grávidas sem KIR2DS1 ou pNK de todos os indivíduos da amostra. As dNK S1+ também demonstraram possuir a mais elevada citotoxicidade dos 4 subgrupos (L1+, S1+, L1+S1+ e L1-S1-) em resposta a células-alvo HLA-C2+. As dNK desgranularam (libertaram moléculas citolíticas) e secretaram citocinas em resposta a células alvo MHC- ou HLA-C2+, mas não secretaram IFN-γ, VEGF ou GM-CSF após cultura com EVT. A falta de resposta das dNK à interação com EVT levou à hipótese de que o potencial citotóxico das dNK S1+ contribui para um combate mais eficiente às infeções virais na placenta. O vírus humano citomegalovírus (CMV) provoca a infeção congénita mais comum e pode levar a aborto espontâneo, restrição do crescimento fetal e danos auditivos permanentes. No capítulo 3, mostrou-se que as dNK desgranulam e secretam citocinas pró-inflamatórias em resposta a células do estroma da decidua (DSC) infetadas com CMV. No entanto, as dNK não responderam a células de coriocarcinoma (JEG3) ou EVT primários infetados com CMV. Estas observações demonstram a resistência à morte dos trofoblastos e sublinham a dificuldade que o sistema imunitário materno enfrenta para eliminar infeções na placenta. Em especial, mostrou-se que as dNK S1+ são mais citolíticas em resposta a DSC HLA-C2+ infetadas com CMV. Esta observação pode explicar o efeito protetor de KIR2DS1 na gravidez humana ao limitar a infeção viral na placenta. As dNK S1+ podem controlar a disseminação da infeção e reduzir o risco de complicações da gravidez induzidas por vírus. Finalmente, no capítulo 4, investigou-se o papel das dNK na eliminação de infeções bacterianas. A expressão elevada do péptido anti-microbiano granulisina em dNK constituiu a base para este estudo. As dNK secretam granulisina constitutivamente, e as células dNK e sobrenadantes das suas culturas conseguiram eliminar bactérias extracelulares e intracelulares em JEG3 sem matar as células hospedeiras. Este efeito foi independente de desgranulação. Este importante resultado revela uma nova função das dNK e reforça o seu papel como células imunitárias efetoras.FCT - SFRH/BD/33885/200