Immunotherapy with Interferon-beta (IFNβ) results in remarkably beneficial effects in patients with relapsing-remitting multiple sclerosis (MS), although the mechanisms by which it exerts these ...beneficial effects remain poorly understood. An investigation was made of the effects of IFNβ on pro-inflammatory and anti-inflammatory cytokine production in peripheral blood cells in MS patients, both untreated and those undergoing immunotherapy, as well as in healthy controls.
Results show a significant increase in the production of pro-inflammatory cytokines such as TNFα, IFNγ and IL-12 in the plasma and in the supernatant of leukocyte cultures from MS patients with the untreated disease; IFNβ administration significantly reduced the levels of TNFα and IFNγ, with no changes in the level of IL-12. The Interferon-beta therapy also led to a significant increase in the production of IL-10, as well as a slight increase in that of TGFβ.
The reduction in pro-inflammatory cytokine production in the treated MS patient group, accompanied by a simultaneous increase in the production of anti-inflammatory cytokines and the reduction of relapse rates suggests that the beneficial effects of IFNβ immunotherapy result, at least in part, from the modulation of cytokine patterns.
•Pitavastatin reduces EAE development.•Pitavatatin modulates Treg and Th17 cell differentiation.•Pitavastatin regulates T cell differentiation by inhibiting mevalonate metabolism.
While Treg cells ...are responsible for self-tolerance and immune homeostasis, pathogenic autoreactive Th17 cells produce pro-inflammatory cytokines that lead to tissue damage associated with autoimmunity, as observed in multiple sclerosis. Therefore, the immunological balance between Th17 and Treg cells may represent a promising option for immune therapy. Statin drugs are used to treat dyslipidemia; however, besides their effects on preventing cardiovascular diseases, statins also have anti-inflammatory effects. Here, we investigated the role of pitavastatin on experimental autoimmune encephalomyelitis (EAE) and the differentiation of Treg and Th17 cells. EAE was induced by immunizing C57BL/6 mice with MOG35-55. EAE severity was determined by analyzing the clinical score and inflammatory parameters in the spinal cord. Naive CD4 T cells were cultured under Treg and Th17-skewing conditions in vitro in the presence of pitavastatin. We found that pitavastatin decreased EAE development, which was accompanied by a reduction of all parameters investigated. Pitavastatin also reduced the expression of IBA1 and pSTAT3 (Y705 and S727) in the spinal cords of EAE mice. Interestingly, the reduction of Th17 cell frequency in the draining lymph nodes of EAE mice treated with pitavastatin was followed by an increase of Treg cells. Indeed, pitavastatin directly affects T cell differentiation in vitro by decreasing Th17 and increasing Treg cell differentiation. Mechanistically, pitavastatin effects are dependent on mevalonate synthesis. Thus, our data show the potential anti-inflammatory effect of pitavastatin on the pathogenesis of the experimental neuroinflammation by modulating the Th17/Treg axis.
The immunomodulador glatiramer acetate (GA) has been shown to significantly reduce the severity of symptoms during the course of multiple sclerosis and in its animal model--experimental autoimmune ...encephalomyelitis (EAE). Since GA may influence the response of non-neuronal cells in the spinal cord, it is possible that, to some extent, this drug affects the synaptic changes induced during the exacerbation of EAE. In the present study, we investigated whether GA has a positive influence on the loss of inputs to the motoneurons during the course of EAE in rats. Lewis rats were subjected to EAE associated with GA or placebo treatment. The animals were sacrificed after 15 days of treatment and the spinal cords processed for immunohistochemical analysis and transmission electron microscopy. A correlation between the synaptic changes and glial activation was obtained by performing labeling of synaptophysin and glial fibrillary acidic protein using immunohistochemical analysis. Ultrastructural analysis of the terminals apposed to alpha motoneurons was also performed by electron transmission microscopy. Interestingly, although the GA treatment preserved synaptophysin labeling, it did not significantly reduce the glial reaction, indicating that inflammatory activity was still present. Also, ultrastructural analysis showed that GA treatment significantly prevented retraction of both F and S type terminals compared to placebo. The present results indicate that the immunomodulator GA has an influence on the stability of nerve terminals in the spinal cord, which in turn may contribute to its neuroprotective effects during the course of multiple sclerosis.
Background: The role of echocardiography in the risk stratification of acute heart failure (HF) is unknown. Some small studies and retrospective analyses have found little change in echocardiographic ...variables during admission for acute HF and some echocardiographic parameters were not found to be associated with outcomes. It is unknown which echocardiographic variables will predict outcomes in sub-Saharan African patients admitted with acute HF. Using echocardiograms, this study aimed to determine the predictors of death and re-admissions within 60 days and deaths up to 180 days in patients with acute heart failure.Methods: Out of the 1 006 patients in the THESUS-HF registry, 954 had had an echocardiogram performed within a few weeks of admission. Echocardiographic measurements were performed according to the American Society of Echocardiography guidelines. We examined the associations between each echocardiographic predictor and outcome using regression models.Results: Heart rate and left atrial size predicted death within 60 days or re-admission. Heart rate, left ventricular posterior wall thickness in diastole (PWTd), and presence of aortic stenosis were associated with the risk of death within 180 days. PTWd added to clinical variables in predicting 180-day mortality rates.Conclusions: Echocardiographic variables, especially those of left ventricular size and function, were not found to have additional predictive value in patients admitted for acute HF. Left atrial size, aortic stenosis, heart rate and measures of hypertrophy (LV PWTd) had some predictive value, suggesting the importance of early treatment of hypertension and severe valvular heart disease.
Evidence from nationally representative studies in low-income and middle-income countries (LMICs) on where in the hypertension care continuum patients are lost to care is sparse. This information, ...however, is essential for effective targeting of interventions by health services and monitoring progress in improving hypertension care. We aimed to determine the cascade of hypertension care in 44 LMICs—and its variation between countries and population groups—by dividing the progression in the care process, from need of care to successful treatment, into discrete stages and measuring the losses at each stage.
In this cross-sectional study, we pooled individual-level population-based data from 44 LMICs. We first searched for nationally representative datasets from the WHO Stepwise Approach to Surveillance (STEPS) from 2005 or later. If a STEPS dataset was not available for a LMIC (or we could not gain access to it), we conducted a systematic search for survey datasets; the inclusion criteria in these searches were that the survey was done in 2005 or later, was nationally representative for at least three 10-year age groups older than 15 years, included measured blood pressure data, and contained data on at least two hypertension care cascade steps. Hypertension was defined as a systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, or reported use of medication for hypertension. Among those with hypertension, we calculated the proportion of individuals who had ever had their blood pressure measured; had been diagnosed with hypertension; had been treated for hypertension; and had achieved control of their hypertension. We weighted countries proportionally to their population size when determining this hypertension care cascade at the global and regional level. We disaggregated the hypertension care cascade by age, sex, education, household wealth quintile, body-mass index, smoking status, country, and region. We used linear regression to predict, separately for each cascade step, a country's performance based on gross domestic product (GDP) per capita, allowing us to identify countries whose performance fell outside of the 95% prediction interval.
Our pooled dataset included 1 100 507 participants, of whom 192 441 (17·5%) had hypertension. Among those with hypertension, 73·6% of participants (95% CI 72·9–74·3) had ever had their blood pressure measured, 39·2% of participants (38·2–40·3) had been diagnosed with hypertension, 29·9% of participants (28·6–31·3) received treatment, and 10·3% of participants (9·6–11·0) achieved control of their hypertension. Countries in Latin America and the Caribbean generally achieved the best performance relative to their predicted performance based on GDP per capita, whereas countries in sub-Saharan Africa performed worst. Bangladesh, Brazil, Costa Rica, Ecuador, Kyrgyzstan, and Peru performed significantly better on all care cascade steps than predicted based on GDP per capita. Being a woman, older, more educated, wealthier, and not being a current smoker were all positively associated with attaining each of the four steps of the care cascade.
Our study provides important evidence for the design and targeting of health policies and service interventions for hypertension in LMICs. We show at what steps and for whom there are gaps in the hypertension care process in each of the 44 countries in our study. We also identified countries in each world region that perform better than expected from their economic development, which can direct policy makers to important policy lessons. Given the high disease burden caused by hypertension in LMICs, nationally representative hypertension care cascades, as constructed in this study, are an important measure of progress towards achieving universal health coverage.
Harvard McLennan Family Fund, Alexander von Humboldt Foundation.
•Nerolidol is a sesquiterpene present in the essential oil of Piper gaudichaudianum.•Essential oil and nerolidol led to cytotoxicity in XV185-14c and N123 strains.•BER defective strains showed ...pronounced sensitivity to essential oil and nerolidol.•Superoxide dismutase absence increases the sensitivity to the essential oil and nerolidol.•P. gaudichaudianum essential oil and nerolidol induce the ROS production.
Piper gaudichaudianum Kunth is used in popular medicine as anti-inflamatory and against liver disorders. One of the most studied components of the plant is the essential oil for which chemical analysis revealed (E)-nerolidol as major compound. Recently, we have shown that P. gaudichaudianum essential oil possesses strong cytotoxic effects in mammalian V79 cells. The aim of this study was to analyze the cytotoxicity and mutagenicity of P. gaudichaudianum essential oil and nerolidol using Saccharomyces cerevisiae as model study. Treatment of the XV185-14c and N123 strains with essential oil and nerolidol led to cytotoxicity but did not induce mutagenicity. Our results revealed an important role of base excision repair (BER) as the ntg1, ntg2, apn1 and apn2 mutants showed pronounced sensitivity to essential oil and nerolidol. In the absence of superoxide dismutase (in sod1Δ mutant strain) sensitivity to the essential oil and nerolidol increased indicating that this oil and nerolidol are generating reactive oxygen species (ROS). The ROS production was confirmed by DCF-DA probing assay in Sod-deficient strains. From this, we conclude that the observed cytotoxicity to P. gaudichaudianum essential oil and nerolidol is mainly related to ROS and DNA single strand breaks generated by the presence of oxidative lesions.
Digging deeper into the plant cell wall proteome Lee, Sang-Jik; Saravanan, Ramu S.; Damasceno, Cynthia M.B. ...
Plant physiology and biochemistry,
12/2004, Letnik:
42, Številka:
12
Journal Article
Recenzirano
The proteome of the plant cell wall/apoplast is less well characterized than those of other subcellular compartments. This largely reflects the many technical challenges involved in extracting and ...identifying extracellular proteins, many of which resist isolation and identification, and in capturing a population that is both comprehensive and relatively uncontaminated with intracellular proteins. However, a range of disruptive techniques, involving tissue homogenization and subsequent sequential extraction and non-disruptive approaches has been developed. These approaches have been complemented more recently by other genome-scale screens, such as secretion traps that reveal the genes encoding proteins with N-terminal signal peptides that are targeted to the secretory pathway, many of which are subsequently localized in the wall. While the size and complexity of the wall proteome is still unresolved, the combination of experimental tools and computational prediction is rapidly expanding the catalog of known wall-localized proteins, suggesting the unexpected extracellular localization of other polypeptides and providing the basis for further exploration of plant wall structure and function.
Indigenous people have been managing fire‐prone landscapes for millennia, especially in tropical savannas, thereby maintaining carbon stocks and pyrodiversity and ensuring food security. In some ...indigenous lands in Brazil, fire brigades are composed of indigenous people, integrating their traditional knowledge in Brazilian fire management policies; however, the effectiveness of their management is largely undocumented. Nevertheless, we need to know the effectiveness of indigenous fire brigades and their influence on fire patterns.
Here, we evaluate an 18‐year historical series of fire patterns and burn scars, comparing periods with and without indigenous brigade activity, to describe the role of indigenous fire brigades in the Kadiwéu Indigenous Territory. In this Indigenous Territory, fire brigades composed of indigenous people have been instituted, trained and maintained by the National Center of Prevention and Combat of Wildfire (PREVFOGO/IBAMA) since 2009. These brigades are responsible for fire management throughout the Kadiwéu Indigenous Territory using controlled burning, prescribed burning and combating wildfires.
We found that fire management by the indigenous brigades has reduced fire frequency by 80% in the areas with high fire frequency (over 70% of the analysed time). Management also reduced the size of the area burned by 53% and the influence of climate over the total area burned. According to our models, the area affected by fires is mainly influenced by annual rainfall in the absence of indigenous brigades; in contrast, climatic factors could not explain the variation in the burned area in the period without indigenous brigades.
Synthesis and applications. The fire management realized by the indigenous brigades can modify the fire regime. These changes in the fire regime can include: changes in spatial patterns, the magnitude of fires and reduction in the influence of climate on fire regimes. Hence, the management carried out by the indigenous brigades can be considered an important tool for fire management. In addition to demonstrating the importance of programs that integrate traditional indigenous knowledge with fire management policies, such as the Integrated Fire Management (IFM), to construct effective management strategies.
Resumo
Os povos indígenas vêm gerindo paisagens propensas ao fogo há milênios, especialmente nas savanas tropicais, mantendo assim os estoques de carbono e a pirodiversidade e garantindo a segurança alimentar. Em algumas terras indígenas no Brasil, as brigadas de incêndio são compostas por indígenas, integrando seus conhecimentos tradicionais nas políticas de manejo de incêndios; no entanto, a eficácia da sua gestão é em grande parte não documentada. Deste modo, precisamos conhecer a eficácia das brigadas de incêndio indígenas e sua influência nos padrões de incêndio.
Neste estudo, avaliamos uma série histórica de 18 anos de padrões de incêndio e cicatrizes de queimadas, comparando períodos com e sem atividade de brigada indígena, para descrever o papel das brigadas indígenas na Terra Indígena Kadiwéu. Neste Território Indígena, desde 2009, brigadas de incêndio compostas por indígenas são instituídas, treinadas e mantidas pelo Centro Nacional de Prevenção e Combate a Incêndios (PREVFOGO/IBAMA). Estas brigadas são responsáveis pelo manejo do fogo em todo o território Kadwéu, utilizando técnicas como a queima prescrita, queima controlada e o combate a incêndios.
Constatamos que o manejo de incêndios realizado pelas brigadas indígenas reduziu a frequência de incêndios em 80% nas áreas com alta frequência de incêndios (mais de 70% do tempo analisado). O manejo também reduziu em 53% o tamanho da área anual queimada e a influência do clima sobre a área total queimada. De acordo com nossos modelos, a área afetada pelos incêndios é influenciada principalmente pelas chuvas anuais na ausência de brigadas indígenas; em contrapartida, os fatores climáticos não puderam explicar a variação da área queimada no período sem brigadas indígenas.
Síntese e aplicações. O manejo do fogo realizado pelas brigadas indígenas pode modificar o regime de fogo. Essas alterações no regime de fogo podem incluir: mudanças nos padrões espaciais, na magnitude dos incêndios e redução na influência do clima sobre os regimes de fogo. Assim, o manejo realizado pelas brigadas indígenas pode ser considerado uma importante ferramenta para o manejo do fogo. Além disso, demonstra a importância de programas que integrem o conhecimento tradicional indígena com políticas de manejo do fogo, como o Manejo Integrado do Fogo (MFI), para a construção de estratégias de manejo eficazes.
The fire management realized by the indigenous brigades can modify the fire regime. These changes in the fire regime can include: changes in spatial patterns, the magnitude of fires and reduction in the influence of climate on fire regimes. Hence, the management carried out by the indigenous brigades can be considered an important tool for fire management. In addition, demonstrates the importance of programs that integrate traditional indigenous knowledge with fire management policies, such as the Integrated Fire Management (IFM), to construct effective management strategies.
Adaptive teaching, mediated by technology, has become a reality and a great ally in distance teaching and learning. Artificial intelligence, through machine learning, has been an important tool for ...the development of innovative solutions for education. One of the approaches for adaptive teaching has been the student emotion analysis in distance learning to propose didactic solutions that best fit the profile of each student. In this sense, this work aims to present the preliminary studies carried out with SVM models and the AffectNet database in order to propose a solution for the analysis of emotions in the context of distance learning. As a result of this study, it is expected to propose an additional resource for the Homero platform (A Learning Management System) capable of adapting content based on information about the students' emotional states. In addition, this information can also be used to predict potential evasion risks. The development and preliminary tests point to a result with an average accuracy of 73% for emotion recognition based on video. With the tests, it was also possible to verify some necessary adjustments for the development of an efficient model for the recognition and analysis of emotions.
Testing of factor Xa inhibitors for the prevention of cardiovascular events in patients with rheumatic heart disease-associated atrial fibrillation has been limited.
We enrolled patients with atrial ...fibrillation and echocardiographically documented rheumatic heart disease who had any of the following: a CHA
DS
VASc score of at least 2 (on a scale from 0 to 9, with higher scores indicating a higher risk of stroke), a mitral-valve area of no more than 2 cm
, left atrial spontaneous echo contrast, or left atrial thrombus. Patients were randomly assigned to receive standard doses of rivaroxaban or dose-adjusted vitamin K antagonist. The primary efficacy outcome was a composite of stroke, systemic embolism, myocardial infarction, or death from vascular (cardiac or noncardiac) or unknown causes. We hypothesized that rivaroxaban therapy would be noninferior to vitamin K antagonist therapy. The primary safety outcome was major bleeding according to the International Society of Thrombosis and Hemostasis.
Of 4565 enrolled patients, 4531 were included in the final analysis. The mean age of the patients was 50.5 years, and 72.3% were women. Permanent discontinuation of trial medication was more common with rivaroxaban than with vitamin K antagonist therapy at all visits. In the intention-to-treat analysis, 560 patients in the rivaroxaban group and 446 in the vitamin K antagonist group had a primary-outcome event. Survival curves were nonproportional. The restricted mean survival time was 1599 days in the rivaroxaban group and 1675 days in the vitamin K antagonist group (difference, -76 days; 95% confidence interval CI, -121 to -31; P<0.001). A higher incidence of death occurred in the rivaroxaban group than in the vitamin K antagonist group (restricted mean survival time, 1608 days vs. 1680 days; difference, -72 days; 95% CI, -117 to -28). No significant between-group difference in the rate of major bleeding was noted.
Among patients with rheumatic heart disease-associated atrial fibrillation, vitamin K antagonist therapy led to a lower rate of a composite of cardiovascular events or death than rivaroxaban therapy, without a higher rate of bleeding. (Funded by Bayer; INVICTUS ClinicalTrials.gov number, NCT02832544.).
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