Higher serum urate levels are associated with an increased risk of diabetic kidney disease. Lowering of the serum urate level with allopurinol may slow the decrease in the glomerular filtration rate ...(GFR) in persons with type 1 diabetes and early-to-moderate diabetic kidney disease.
In a double-blind trial, we randomly assigned participants with type 1 diabetes, a serum urate level of at least 4.5 mg per deciliter, an estimated GFR of 40.0 to 99.9 ml per minute per 1.73 m
of body-surface area, and evidence of diabetic kidney disease to receive allopurinol or placebo. The primary outcome was the baseline-adjusted GFR, as measured with iohexol, after 3 years plus a 2-month washout period. Secondary outcomes included the decrease in the iohexol-based GFR per year and the urinary albumin excretion rate after washout. Safety was also assessed.
A total of 267 patients were assigned to receive allopurinol and 263 to receive placebo. The mean age was 51.1 years, the mean duration of diabetes 34.6 years, and the mean glycated hemoglobin level 8.2%. The mean baseline iohexol-based GFR was 68.7 ml per minute per 1.73 m
in the allopurinol group and 67.3 ml per minute per 1.73 m
in the placebo group. During the intervention period, the mean serum urate level decreased from 6.1 to 3.9 mg per deciliter with allopurinol and remained at 6.1 mg per deciliter with placebo. After washout, the between-group difference in the mean iohexol-based GFR was 0.001 ml per minute per 1.73 m
(95% confidence interval CI, -1.9 to 1.9; P = 0.99). The mean decrease in the iohexol-based GFR was -3.0 ml per minute per 1.73 m
per year with allopurinol and -2.5 ml per minute per 1.73 m
per year with placebo (between-group difference, -0.6 ml per minute per 1.73 m
per year; 95% CI, -1.5 to 0.4). The mean urinary albumin excretion rate after washout was 40% (95% CI, 0 to 80) higher with allopurinol than with placebo. The frequency of serious adverse events was similar in the two groups.
We found no evidence of clinically meaningful benefits of serum urate reduction with allopurinol on kidney outcomes among patients with type 1 diabetes and early-to-moderate diabetic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171.).
Gout is a common autoinflammatory joint diseases characterized by deposition of monosodium urate (MSU) crystals which trigger an innate immune response mediated by inflammatory cytokines. IGF1R is ...one of the loci associated with both urate levels and gout susceptibility in GWAS to date, and IGF-1-IGF-1R signaling is implicated in urate control. We investigate the role of IGF-1/IGF1R signaling in the context of gouty inflammation. Also, we test the gout and urate-associated IGF1R rs6598541 polymorphism for association with the inflammatory capacity of mononuclear cells. For this, freshly isolated human peripheral blood mononuclear cells (PBMCs) were exposed to recombinant IGF-1 or anti-IGF1R neutralizing antibody in the presence or absence of solubilized urate, stimulated with LPS/MSU crystals. Also, the association of rs6598541 with IGF1R and protein expression and with ex vivo cytokine production levels after stimulation with gout specific stimuli was tested. Urate exposure was not associated with IGF1R expression in vitro or in vivo. Modulation of IGF1R did not alter urate-induced inflammation. Developing urate-induced trained immunity in vitro was not influenced in cells challenged with IGF-1 recombinant protein. Moreover, the IGF1R rs6598541 SNP was not associated with cytokine production. Our results indicate that urate-induced inflammatory priming is not regulated by IGF-1/IGF1R signaling in vitro. IGF1R rs6598541 status was not asociated with IGF1R expression or cytokine production in primary human PBMCs. This study suggests that the role of IGF1R in gout is tissue-specific and may be more relevant in the control of urate levels rather than in inflammatory signaling in gout.
Autoimmune hepatitis (AIH) is characterized by immune-mediated hepatocyte injury resulting in the destruction of liver cells, causing inflammation, liver failure, and fibrosis. Pediatric (AIH) is an ...autoimmune inflammatory disease that usually requires immunosuppression for an extended period. Frequent relapses after treatment discontinuation demonstrate that current therapies do not control intrahepatic immune processes. This study describes targeted proteomic profiling data in patients with AIH and controls. A total of 92 inflammatory and 92 cardiometabolic plasma markers were assessed for (i) pediatric AIH versus controls, (ii) AIH type 1 versus type 2, (iii) AIH and AIH-autoimmune sclerosing cholangitis overlapping syndrome and (iv) correlations with circulating vitamin D levels in AIH. A total of 16 proteins showed a nominally significant differential abundance in pediatric patients with AIH compared to controls. No clustering of AIH subphenotypes based on all protein data was observed, and no significant correlation of vitamin D levels was observed for the identified proteins. The proteins that showed variable expression include CA1, CA3, GAS6, FCGR2A, 4E-BP1 and CCL19, which may serve as potential biomarkers for patients with AIH. CX3CL1, CXCL10, CCL23, CSF1 and CCL19 showed homology to one another and may be coexpressed in AIH. CXCL10 seems to be the central intermediary link for the listed proteins. These proteins were involved in relevant mechanistic pathways for liver diseases and immune processes in AIH pathogenesis. This is the first report on the proteomic profile of pediatric AIH. The identified markers could potentially lead to new diagnostic and therapeutic tools. Nevertheless, considering the complex pathogenesis of AIH, more extensive studies are warranted to replicate and validate the present study's findings.
Soluble urate leads to a pro-inflammatory phenotype in human monocytes characterized by increased production of IL-1β and downregulation of IL-1 receptor antagonist, the mechanism of which remains to ...be fully elucidated. Previous transcriptomic data identified differential expression of genes in the transforming growth factor (TGF)-β pathway in monocytes exposed to urate in vitro. In this study, we explore the role of TGF-β in urate-induced hyperinflammation in peripheral blood mononuclear cells (PBMCs).
TGF-β mRNA in unstimulated PBMCs and protein levels in plasma were measured in individuals with normouricemia, hyperuricemia and gout. For in vitro validation, PBMCs of healthy volunteers were isolated and treated with a dose ranging concentration of urate for assessment of mRNA and pSMAD2. Urate and TGF-β priming experiments were performed with three inhibitors of TGF-β signalling: SB-505124, 5Z-7-oxozeaenol and a blocking antibody against TGF-β receptor II.
TGF-β mRNA levels were elevated in gout patients compared to healthy controls. TGF-β-LAP levels in serum were significantly higher in individuals with hyperuricemia compared to controls. In both cases, TGF-β correlated positively to serum urate levels. In vitro, urate exposure of PBMCs did not directly induce TGF-β but did enhance SMAD2 phosphorylation. The urate-induced pro-inflammatory phenotype of monocytes was partly reversed by blocking TGF-β.
TGF-β is elevated in individuals with hyperuricemia and correlated to serum urate concentrations. In addition, the urate-induced pro-inflammatory phenotype in human monocytes is mediated by TGF-β signalling. Future studies are warranted to explore the intracellular pathways involved and to assess the clinical significance of urate-TGF-β relation.
Abstract
Parts machined by high cutting speeds can often exhibit high fatigue strength, increased micro-hardness in the surface layers and plastic deformations, due to the tool cutting edge radius ...associated with the induced stresses. The changing of rake and clearance angles has an important influence on the chip formation, cutting forces, residual stresses, temperatures in both the workpiece and the tool. International research on the influence of geometric parameters of the tool on the entire cutting process, are of particular importance to understand this process development. The approach of this study, considers the parametric realization of the cutting tool profile - a coated TiC turning chisel, which will be used in the finite element simulation of the orthogonal turning process. Deform 2D application, which is a powerful simulation engine was chosen and allows the correct simulation of the cutting process in real machining conditions. Deform 2D enables the automatically meshing and remeshing generation and also the optimization whenever needed and wherever is required a high accuracy, thereby reducing the overall difficulty of the problem and the computational requirements. Using Lagrangian discretization, the machining process was simulated and made possible to observe and present a series of conclusions and own points of view regarding the temperature distribution at the tool tip and in the workpiece, the effective stresses distribution and the cutting force variation under the rake and clearance angles influences.
BackgroundRegular exercise training is an important factor in prevention of myocardial infarction (MI). However, little is known whether exercise engagement prior to MI is related to the magnitude of ...post-MI cardiac biomarker concentrations and clinical outcomes.ObjectivesWe tested the hypothesis that exercise engagement in the week prior MI is related to lower cardiac biomarker concentrations following ST-elevated MI (STEMI).MethodsWe recruited hospitalised STEMI patients and assessed the amount of exercise engagement in the 7 days preceding MI onset using a validated questionnaire. Patients were classified as ‘exercise’ if they performed any vigorous exercise in the week prior MI, or as ‘control’ if they did not. Post-MI peak concentrations of high-sensitive cardiac troponin T (peak-hs-cTnT) and creatine kinase (peak-CK) were examined. We also explored whether exercise engagement prior MI is related to the clinical course (duration of hospitalisation and incidence of in-hospital, 30-day and 6-month major adverse cardiac events (reinfarction, target vessel revascularisation, cardiogenic shock or death)).ResultsIn total, 98 STEMI patients were included, of which 16% (n=16) was classified as ‘exercise’, and 84% (n=82) as ‘control’. Post-MI peak-hs-cTnT and peak-CK concentrations were lower in the exercise group (941 (645–2925) ng/mL; 477 (346–1402) U/L, respectively) compared with controls (3136 (1553–4969) ng/mL, p=0.010; 1055 (596–2019) U/L, p=0.016, respectively). During follow-up, no significant differences were found between both groups.ConclusionEngagement in exercise is associated with lower cardiac biomarker peak concentrations following STEMI. These data could provide further support for the cardiovascular health benefits of exercise training.
The purpose of this paper is to identify based on the composite central factorial experiment, the mathematical model between the arithmetic mean deviation of the surface profile and the cutting ...process parameters (cutting speed, cutting depth and feed per tooth), which describes the studied system in any point of the chosen experimental domain. The coefficients of these equations represent the influence of the variables on the response. The analysis of the variance ANOVA is focused on estimating the different types of variability of the response and the estimations made with the Fisher test. This test analyses the coefficients significance of the regression equation, by comparing the ratio of two variants. The Fisher test indicate the probability to be a statistical difference between them or not. In any case, the experimental results are associated with experimental errors. It is essential to find the prediction accuracy of the coefficient's values, and not only their absolute value. In the end, will be determined the arithmetic mean deviation of the surface profile Ra, based on the mathematical model, and will be compared with the experimental results.
In the aerospace industry, the milling of aluminum alloy parts is a machining process with the primary purpose of removing high volumes of material. Aluminum alloys are materials that have relatively ...good machinability, which helps the process because many of the components of the aircraft are of high dimensions. These parts have many pockets more or less deep, and the removal by cutting off about 90% of the initial volume of the workpiece is a matter of consideration. The manufacturing process is protracted and involves long semi-finishing and finishing operations, so it is recommended that any researcher who begins and finishes an experimental study should do it base on a specific experimental plan. Mathematical statistics techniques and methods are used, but also optimization methods that lead to a rational choice of process parameters, process input data and objective functions that need to be improved. This scientific paper presents applied research based on an extremely pertinent active experiment that has led to some practical solutions applied in the aerospace industry worldwide. The dedicated objective function on which the study conducted in this case was the mean arithmetic deviation of the surface profile. The independent variables were chosen by the concrete application of a dispersion analysis applied to the milling process, namely the cutting speed, the cutting depth and the feed per tooth. Interpretation of the results was performed by a graphical evaluation of the normality of the data distribution, by presenting the histogram responses as well as by the dispersion diagrams. It was used for a better correlation a 3D graphical analysis that followed the Ra variation of the mean arithmetic deviation of the machined surface profile under the influence of the cutting parameters and the independent variables respectively. The obtained conclusions led to the validation of the experimental model and the application of the research presented within an aerospace industry organization with important global valences.
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