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The aim of this study is to compare two methods of interpolation, namely Kriging (a standard algorithm), mainly used in geostatistics, and the Experimental Probabilistic Hypersurface (developed by SCM SA). We study several technical points, such as their ability to take uncertainties into account, to return an uncertainty on the interpolation, the quality of the numerical procedures, etc. The Experimental Probabilistic Hypersurface (EPH) is a minimal information model, which only uses the existing data and makes as less artificial hypothesis on the data as possible. The Kriging, on the contrary, relies on an estimation of the variability of the data using a variogram.

Abstract Studies show that propolis has antimicrobial, antifungal, antiviral, anti-inflammatory, antioxidant, antitumor, and immunomodulatory properties, and may protect against diseases such as diabetes, cardiovascular disease, and cancer. We aimed to extract compounds of brown propolis with hydroalcoholic solvents and evaluate their cytotoxic activity on tumor and non-tumor cells by MTT test. We tested the solute:solvent ratio (ethanol:water) and extraction time in a Shaker incubator (710 rpm) before conducting a central composite rotational design (CCRD) to optimize time and solvent mixture. We found that a temperature of 80 °C and a solvent concentration of 90:10 were the best extraction conditions for phenolic compounds, especially pinocembrin and cinnamic acid. The extract showed antioxidant capacity, acid characteristics, low humidity, and the presence of ash, lipids, and soluble solids. The cytotoxicity test with normal kidney cells of Macaca mullata (LLC-MK2) and human lung tumor cells (A549) showed no statistical difference from the negative control. For liver tumor cells (HuH7.5), different concentrations showed cytotoxic/antiproliferative activity. Thus, the data indicate that this product deserves prominence in the search for new applications. Resumo Estudos mostram que a própolis possui propriedades antimicrobianas, antifúngicas, antivirais, anti-inflamatórias, antioxidantes, antitumorais e imunomoduladoras, podendo proteger contra doenças como diabetes, doenças cardiovasculares e câncer. O objetivo deste estudo foi extrair compostos de própolis marrom com solventes hidroalcoólicos e avaliar sua atividade citotóxica para células tumorais e não-tumorais, pelo teste MTT. A relação soluto:solvente (etanol:água) e o tempo de extração foram testados em uma incubadora Shaker (710 rpm) antes de realizar um projeto composto rotacional central (DCCR) para otimização do tempo e mistura do solvente. Verificou-se que a temperatura de 80 oC e a concentração de solvente de 90:10 foram as melhores condições de extração em termos de compostos fenólicos, especialmente pinocembrina e ácido cinâmico. O extrato apresentou capacidade antioxidante, característica ácida, baixa umidade, presença de cinzas, lipídios e sólidos solúveis. O teste de citotoxicidade com células normais de rim de Macaca mullata (LLC-MK2) e de tumor pulmonar humano (A549) não apresentou diferença estatística do controle negativo. Para os tumores hepáticos (HuH7.5), diferentes concentrações apresentaram citotoxicidade/atividade antiproliferativa. Assim, os dados do presente estudo demonstraram que este produto merece destaque na busca por novas aplicações.

The experimental fusion reactor ITER will feature two (or three) heating neutral beam injectors (NBI) capable of delivering 33(or 50) MW of power into the plasma. A NBI consists of a plasma source for production of negative ions (extracted negative ion current up to 329 A/m 2 in H and 285 A/m 2 in D) then accelerated up to 1 MeV for one hour. The negative ion beam is neutralized, and the residual ions are electrostatically removed before injection. The beamline was designed for a beam divergence between 3 and 7 mrad. The ion source in ITER NBIs relies on RF-driven, Inductively-Coupled Plasmas (ICP), based on the prototypes developed at IPP Garching; RF-driven negative-ion beam sources have never been employed in fusion devices up to now. The recent results of SPIDER, the full size ITER NBI ion source operating at NBTF in Consorzio RFX, Padova, measure a beamlet divergence minimum of 12mrad and highlighted beam spatial non-uniformity. SPIDER results confirmed the experimental divergence found in smaller prototype sources, which is larger compared to filament-arc ion sources. Although prototype experiments have shown that the extracted current requirement can be achieved with minor design improvements, the beamlet divergence is expected to marginally achieve the design value of 7 mrad, which in multi-grid long accelerators results in unexpected heat loads over the accelerator grids. A contributor to the beam divergence is the energy/temperature of the extracted negative ions, so it is believed that plasma differences between the two source types play a role. Research is focused on the plasma parameters in the ion source. One RF driver, identical to the ones used in SPIDER, installed in a relatively small-scale experimental set-up, inherently more flexible than large devices, is starting operations devoted to the investigation of the properties of RF-generated plasmas, so as to contribute to the assessment of negative ion precursors, and of their relationship with the plasma parameters, particularly when enhancing plasma confinement. The scientific questions, that have arisen from the preliminary results of SPIDER, guided the design of the test stand, which are described in this contribution, together with the diagnostic systems and related simulation tools. The test stand, which shares with the larger experiment all the geometrical features and constraints, will allow technological developments and optimized engineering solutions related to the ICP design for the ITER NBIs.

Src-family kinases (SFKs) regulate different granulocyte and monocyte/macrophage responses. Accumulating evidence suggests that members of this family are implicated in signal transduction pathways regulating phagocytic cell migration and recruitment into inflammatory sites. Macrophages with a genetic deficiency of SFKs display marked alterations in cytoskeleton dynamics, polarization and migration. This same phenotype is found in cells with either a lack of SFK substrates and/or interacting proteins such as Pyk2/FAK, c-Cbl and p190RhoGAP. Notably, SFKs and their downstream targets also regulate monocyte recruitment into inflammatory sites. Depending on the type of assay used, neutrophil migration in vitro may be either dependent on or independent of SFKs. Also neutrophil recruitment in in vivo models of inflammation may be regulated differently by SFKs depending on the tissue involved. In this review we will discuss possible mechanisms by which SFKs may regulate phagocytic cell migratory abilities.

The main reason for the unfavorable clinical outcome of BCR–ABL1 -positive acute lymphoblastic leukemia (ALL) is genetic instability. However, how normal B-cell precursors acquire the genetic changes that lead to transformation has not yet been completely defined. We investigated the expression of the activation-induced cytidine deaminase (AID) and its role in clinical outcome in 61 adult BCR–ABL1 -positive ALL patients. AID expression was detected in 36 patients (59%); it correlated with the BCR–ABL1 transcript levels and disappeared after treatment with tyrosine kinase inhibitors. Different AID splice variants were identified: full-length isoform; AIDΔE4a, with a 30-bp deletion of exon 4; AIDΔE4, with the exon 4 deletion; AIDins3, with the retention of intron 3; AIDΔE3-E4 isoform without deaminase activity. AID-FL predominantly showed cytoplasmic localization, as did the AID-ΔE4a and AID-ΔE3E4 variants, whereas the C-terminal-truncated AID-ΔE4 showed a slightly increased nuclear localization pattern. AID expression correlated with a higher number of copy number alterations identified in genome-wide analysis using a single-nucleotide polymorphism array. However, the expression of AID at diagnosis was not associated with a worse prognosis. In conclusion, BCR–ABL1 -positive ALL cells aberrantly express different isoforms of AID that may act as mutators outside the immunoglobulin (Ig) gene loci in promoting genetic instability.

Diabetes mellitus is associated with increased mortality in subjects with acute myocardial infarction (AMI). We aimed to estimate the risk of mortality in AMI patients with and without diabetes using the urinary albumin : creatinine ratio (ACR). This is a prospective study of 121 consecutive, non-selected diabetic AMI patients, 121 age- and sex-matched non-diabetic AMI patients and 61 diabetic non-AMI outpatients as control subjects. All data were obtained during the first 7 days of hospitalisation and each AMI patient was followed for a period of exactly 3 years. Baseline ACR RIA measurements were made on the 1st, 3rd and 7th days of admission. Adjusted ACR values were significantly higher in the diabetic AMI patients than in the diabetic control outpatients ( p<0.0001), and a significant difference was observed between the weekly ACR slopes for these two groups ( p<0.0001). Microalbuminuria was more prevalent in the diabetic AMI patients than in the non-diabetic AMI patients on the 1st day (62% vs 46%, p=0.01) and 3rd day (41% vs 29%, p=0.04). Among the AMI patients with normoalbuminuria (ACR <30 microg/mg), the mortality rate was 11.6% for the patients without diabetes and 33.8% for those with diabetes ( p=0.001). The mortality rate was much higher among the AMI patients with microalbuminuria (ACR >/=30 microg/mg) and similar for the diabetic (68.0%) and non-diabetic patients (74.3%). In a multivariable Cox model, ACR ( p<0.0001) and diabetes status ( p=0.01) were associated with adverse outcome even when several other clinical variables were included in the model. Furthermore, a negative interaction was found between diabetes and ACR ( p=0.01). Microalbuminuria frequently occurs in diabetic and non-diabetic AMI patients during the first 3 days of admission to hospital and can be used to identify subjects at high risk of mortality.

In addition to the treatment of specific cardiovascular risk factors, intervention which interferes with the general mechanisms of atherosclerosis could further reduce the incidence of cardiovascular events. We aimed to investigate in general practice the efficacy of antiplatelets and antioxidants in primary prevention of cardiovascular events in people with one or more major cardiovascular risk factors. We did a randomised controlled open 2·2 factorial trial to investigate low-dose aspirin (100 mg/day) and vitamin E (300 mg/day) in the prevention of cardiovascular events, in people with one or more of the following: hypertension, hypercholesterolaemia, diabetes, obesity, family history of premature myocardial infarction, or individuals who were elderly. 4495 people (2583 female, mean age 64·4 years) were included in the trial. After a mean follow-up of 3·6 years the trial was prematurely stopped on ethical grounds when newly available evidence from other trials on the benefit of aspirin in primary prevention was strictly consistent with the results of the second planned interim analysis. Aspirin lowered the frequency of all the endpoints, being significant for cardiovascular death (from 1·4 to 0·8%; relative risk 0·56 [95% CI 0·31–0·99]) and total cardiovascular events (from 8·2 to 6·3%; 0·77 [0·62–0·95]). Severe bleedings were more frequent in the aspirin group than the no-aspirin group (1·1% vs 0·3%; p<0·0008). Vitamin E showed no effect on any prespecified endpoint. Analyses were by intention-to-treat. In women and men at risk of having a cardiovascular event because of the presence of at least one major risk factor, low-dose aspirin given in addition to treatment of specific risk factors contributes an additional preventive effect, with an acceptable safety profile. The results on vitamin E's cardiovascular primary preventive efficacy are not conclusive per se, although our results are consistent with the negative results of other large published trials on secondary prevention.

High C-reactive protein (CRP) levels have been associated with higher mortality rate in patients with acute myocardial infarction (AMI). However, it is not known whether inflammation plays a role in the time-course of heart failure (HF) in this clinical setting. Our aim was to study the nature of the relationship between CRP and HF during AMI. This prospective study was carried out in 269 subjects admitted to the hospital for suspected AMI. Of these, 220 had evidence of AMI. The other 49 subjects were studied as controls. CRP was assessed on the first, third, and seventh day after admission. CRP was significantly higher in the patients with AMI than in the control patients ( P = .001) and peaked on the third day. Among the patients with AMI, CRP was higher in patients with HF than in patients without HF (adjusted P = .008, P = .02 and P = .03 on 1st, 3rd, and 7th day, respectively). Prevalence of HF on admission was slightly higher in the subjects with first-day CRP ≥15 mg/L than in those with CRP <15 mg/L, and the between-group difference progressively increased from the first to the seventh day ( P < .0001). At multivariable regression analysis, first-day log-CRP was shown to be a strong independent predictor of both HF progression ( P < .0001) and left ventricular ejection fraction ( P < .0001). One-year total mortality and HF-mortality rates turned out to be higher in the patients with CRP ≥85 mg/L than in those with CRP below that level ( P < .0001), and log–third-day CRP was independently associated with 1-year mortality at multivariable analysis ( P = .0001). CRP on admission to hospital is suitable for predicting the time-course of HF in patients with AMI. Peak CRP value is a strong independent predictor of global and HF-mortality during the following year.

Signal transduction through the leukocyte integrins is required for the processes of firm adhesion, activation, and chemotaxis of neutrophils during inflammatory reactions. Neutrophils isolated from knockout mice that are deficient in the expression of p59/61hck(Hck) and p58c-fgr(Fgr), members of the Src-family of protein tyrosine kinases, have been shown to be defective in adhesion mediated activation. Cells from these animals have impaired induction of respiratory burst and granule secretion following plating on surfaces that crosslink β2and β3integrins. To determine if the defective function of hck-/-fgr-/-neutrophils observed in vitro also results in impaired inflammatory responses in vivo, we examined responses induced by lipopolysaccharide (LPS) injection in these animals. The hck-/-fgr-/-mice showed marked resistance to the lethal effects of high-dose LPS injection despite the fact that high levels of serum tumor necrosis factor α and interleukin 1α were detected. Serum chemistry analysis revealed a marked reduction in liver and renal damage in mutant mice treated with LPS, whereas blood counts showed a marked neutrophilia that was not seen in wild-type animals. Direct examination of liver sections from mutant mice revealed reduced neutrophil migration into the tissue. These data demonstrate that defective integrin signaling in neutrophils, caused by loss of Hck and Fgr tyrosine kinase activity, results in impaired inflammation-dependent tissue injury in vivo.

Survival after acute myocardial infarction has been enhanced by treatment with thrombolytic agents, aspirin, and β-adrenoceptor blockade. However, there remains a substantial subgroup of patients who manifest clinical evidence of heart failure despite the first two of these treatments, and for whom β-adrenoceptor antagonists are relatively or absolutely contraindicated. These patients have a greatly increased risk of fatal and non-fatal ischaemic, arrhythmic, and haemodynamic events. In this selected high-risk subset of patients we investigated the effect of therapy with the angiotensin converting enzyme (ACE) inhibitor ramipril, postulating that it would lengthen survival. 2006 patients who had shown clinical evidence of heart failure at any time after an acute myocardial infarction (AMI) were recruited from 144 centres in 14 countries. Patients were randomly allocated to double-blind treatment with either placebo (992 patients) or ramipril (1014 patients) on day 3 to day 10 after AMI (day 1). Patients with severe heart failure resistant to conventional therapy, in whom the attending physician considered the use of an ACE inhibitor to be mandatory, were excluded. Follow-up was continued for a minimum of 6 months and an average of 15 months. On intention-to-treat analysis mortality from all causes was significantly lower for patients randomised to receive ramipril (170 deaths; 17%) than for those randomised to receive placebo (222 deaths; 23%). The observed risk reduction was 27% (95% Cl 11% to 40%; p=0·002). Analysis of prespecified secondary outcomes revealed a risk reduction of 19% for the first validated outcome (ie, first event in an individual patient)—namely, death, severe/resistant heart failure, myocardial infarction, or stroke (95% CI 5% to 31%; p=0·008). Oral administration of ramipril to patients with clinical evidence of either transient or ongoing heart failure, initiated between the second and ninth day after myocardial infarction, resulted in a substantial reduction in premature death from all causes. This benefit was apparent as early as 30 days and was consistent across a range of subgroups.