Background Localized stress and cell death in chronic inflammatory diseases may release tissue-specific lipids into the circulation causing the blood plasma lipidome to reflect the type of inflammation. However, deep lipid profiles of major chronic inflammatory diseases have not been compared. Methods Plasma lipidomes of patients suffering from two etiologically distinct chronic inflammatory diseases, atherosclerosis-related vascular disease, including cardiovascular (CVD) and ischemic stroke (IS), and systemic lupus erythematosus (SLE), were screened by a top-down shotgun mass spectrometry-based analysis without liquid chromatographic separation and compared to each other and to age-matched controls. Lipid profiling of 596 lipids was performed on a cohort of 427 individuals. Machine learning classifiers based on the plasma lipidomes were used to distinguish the two chronic inflammatory diseases from each other and from the controls. Findings Analysis of the lipidomes enabled separation of the studied chronic inflammatory diseases from controls based on independent validation test set classification performance (CVD vs control - Sensitivity: 0.94, Specificity: 0.88; IS vs control - Sensitivity: 1.0, Specificity: 1.0; SLE vs control – Sensitivity: 1, Specificity: 0.93) and from each other (SLE vs CVD ‒ Sensitivity: 0.91, Specificity: 1; IS vs SLE - Sensitivity: 1, Specificity: 0.82). Preliminary linear discriminant analysis plots using all data clearly separated the clinical groups from each other and from the controls, and partially separated CVD severities, as classified into five clinical groups. Dysregulated lipids are partially but not fully counterbalanced by statin treatment. Interpretation Dysregulation of the plasma lipidome is characteristic of chronic inflammatory diseases. Lipid profiling accurately identifies the diseases and in the case of CVD also identifies sub-classes. Funding Full list of funding sources at the end of the manuscript.
One in four patients with systolic HF followed in a heart failure outpatient clinic would fulfill the reference study criteria for treatment with the new drug, sacubitril/valsartan.
The aim of this study was to determine among nine temperature-humidity index (THI) equations, the one that best represents the effects of heat stress on crossbred dairy calves reared in a tropical environment. Twelve male and female calves, aged 20 to 60 days, and raised in a tropical pen were evaluated. Respiratory (RR) and heart rates (HR), rectal (RT), body surface (BST), dry bulb (Tdb) and wet bulb (Tbw) temperatures, partial vapor pressure (Pv), relative humidity (RH) and dew point temperature (Tpo) were quantified in the morning and afternoon. Nine THI equations were calculated. The highest correlation between physiological variables and this was used to select the best THI equation. Averages for nine THI equations, Tdb, Twb, Pv, Tdp, RR, HR, RT, and BST were higher in the afternoon than in the morning, whereas that for RH was the opposite. The highest values for RT occurred at temperatures above 26.4°C and when humidity was below 55.5%. The Tdb and Pv correlations with RR (0.697 and 0.707), RT (0.703 and 0.706) and BST (0.818 and 0.817) were significant and positive, whereas the RH correlations with the same physiological variables were significant and negative (-0.622, -0.590 and -0.638, respectively). The best index was the THI sensible heat-based ( T H I = 3.43 + 1.058 x T d b - 0.293 x R H + 0.0164 x T d b x R H + 35.7), which was significantly correlated with RR (r=0.668 and r²=0.446), HR (r=0.259 and r²=0.067), RT (r=0.693 and r²=0.479) and BST (r=0.807 and r²=0.650). In conclusion, the THI sensible heat-based equation best represents the effects of heat stress on crossbred dairy calves reared in a tropical environment.
OBJECTIVEA key event in atherogenesis is the formation of lipid-loaded macrophages, lipidotic cells, which exhibit irreversible accumulation of undigested modified low-density lipoproteins in lysosomes. This event culminates with the loss of cell homeostasis, inflammation and cell death. In this study we propose to identify the chemical etiological factors and understanding the molecular and cellular mechanisms responsible for the impairment of lysosome function in macrophages.APPROACH AND RESULTSUsing shotgun lipidomics we have discovered that a family of oxidized lipids (cholesteryl hemiesters, ChE), end products of oxidation of polyunsaturated cholesteryl esters, occurs at higher concentrations in the plasma of two cohorts of cardiovascular disease patients than in the plasma of a control cohort. Macrophages exposed to the most prevalent ChE, cholesteryl hemiazelate (ChA) exhibit lysosome enlargement, peripheral lysosomal positioning, lysosome dysfunction and lipidosis which are irreversible. The transcriptomic profile of macrophages exposed to ChA indicates that the lysosome pathway is deeply affected and is well correlated with lysosome phenotypic and functional changes. Interestingly, the dysfunctional peripheral lysosomes are more prone to fuse with the plasma membrane, secreting their undigested luminal content into the extracellular milieu with potential consequences to the pathology.CONCLUSIONWe identify ChA not only as one of the molecules involved in the etiology of irreversible lysosome dysfunction culminating with lipidosis but also as a promoter of exocytosis of the dysfunctional lysosomes. The latter event is a new mechanism that may be important in the pathogenesis of atherosclerosis.
ao Programa de Pós-graduação em Ciências Veterinárias (PPGCV), a todos os seus docentes e colaborados pela oportunidade concedida, pelo serviço que prestam a educação e a ciência. Agradeço aos coordenadores do PPGCV com os quais convivi, a Prof. Dra Ricarda Maria dos Santos e Prof. Dr. João Paulo Elsen Saut pela presteza e orientações, bem como a secretária do programa Célia Regina de Oliveira Macedo pela cordialidade no atendimento. Ao Prof. Dr. Ednaldo Carvalho Guimarães da Faculdade de Matemática da UFU pelas análises estatísticas e solicitude com que me instruiu. À equipe do Laboratório de Ensino e Pesquisa em Animais Silvestres (LAPAS), agradeço pela honra de ter podido conviver com cada qual. Ao Sr. Vicente e Dona Fátima pela acolhida e cuidados. A Lucélia Vieira, exemplo de pesquisadora, pelos ensinamentos e ajuda. Aos colegas Mariana Lima, Priscila Rosa, Juliana Mendonça e Evandro, pelos bons momentos partilhados. Agradeço aos amigos e médicos veterinários do LAPAS, Liliane Rangel, Rafael Ferraz e Thais Carneiro por participarem dessa pesquisa, pelo cuidado com os jabutis e por tudo que me ensinaram a respeito deles. Aos Professores Hugo Cristiano Melo e Marilda Pereira Caixeta pela conspícua contribuição e valiosas sugestões. À Faculdade Patos de Minas (FPM), seus docentes, colaboradores e alunos, com os quais tive e ainda tenho a oportunidade de conviver, por ser minha segunda família. Gostaria de agradecer aos amigos do Laboratório de Análises Clínicas da FPM pela convivência diária; um especial obrigado a Dra. Nádia Kappes, Guilherme Romão e Poliana Barcelos, Washington e Nayara por tudo que me ensinam, pela colaboração e dedicada amizade.
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