Noninvasive diagnosis of vulnerable coronary plaque

Myocardial infarction and sudden cardiac death are frequently the first manifestation of coronary artery disease.For this reason,screening of asymptomatic coronary atherosclerosis has become an attractive field of research in cardiovascular medicine.Necropsy studies have described histopathological changes associated with the development of acute coronary events.In this regard,thin-cap fibroatheroma has been identified as the main vulnerable coronary plaque feature.Hence,many imaging techniques,such as coronary computed tomography,cardiac magnetic resonance or positron emission tomography,have tried to detect noninvasively these histomorphological characteristics with different approaches.In this article,we review the role of these diagnostic tools in the detection of vulnerable coronary plaque with particular interest in their advantages and limitations as well as the clinical implications of the derived findings.

Interplay between post-translational cyclooxygenase-2 modifications and the metabolic and proteomic profile in a colorectal cancer cohort

BACKGROUND Colorectal cancer(CRC) is the second most common cause of cancer death worldwide. It is broadly described that cyclooxygenase-2(COX-2) is mainly overexpressed in CRC but less is known regarding post-translational modifications of this enzyme that may regulate its activity, intracellular localization and stability. Since metabolic and proteomic profile analysis is essential for cancer prognosis and diagnosis, our hypothesis is that the analysis of correlations between these specific parameters and COX-2 state in tumors of a high number of CRC patients could be useful for the understanding of the basis of this cancer in humans.AIM To analyze COX-2 regulation in colorectal cancer and to perform a detailed analysis of their metabolic and proteomic profile.METHODS Biopsies from both healthy and pathological colorectal tissues were taken under informed consent from patients during standard colonoscopy procedure in the University Hospital of Bellvitge(Barcelona, Spain) and Germans Trias i Pujol University Hospital(Campus Can Ruti)(Barcelona, Spain). Western blot analysis was used to determine COX-2 levels. Deglycosylation assays were performed in both cells and tumor samples incubating each sample with peptide N-glycosidase F(PNGase F). Prostaglandin E2(PGE2) levels were determined using a specific ELISA. 1 H high resolution magic angle spinning(HRMAS) analysis was performed using a Bruker AVIII 500 MHz spectrometer and proteomic analysis was performed in a nano-liquid chromatography-tandem mass spectrometer(nano LC-MS/MS) using a QExactive HF orbitrap MS.RESULTS Our data show that COX-2 has a differential expression profile in tumor tissue of CRC patients vs the adjacent non-tumor area, which correspond to a glycosylated and less active state of the protein. This fact was associated to a lesser PGE2 production in tumors. These results were corroborated in vitro performing deglycosylation assays in HT29 cell line where COX-2 protein profile was modified after PNGase F incubation, showing higher PGE2 levels. Moreover,HRMAS analysis indicated that tumor tissue has altered metabolic features vs non-tumor counterparts, presenting increased levels of certain metabolites such as taurine and phosphocholine and lower levels of lactate. In proteomic experiments, we detected an enlarged number of proteins in tumors that are mainly implicated in basic biological functions like mitochondrial activity,DNA/RNA processing, vesicular trafficking, metabolism, cytoskeleton and splicing.CONCLUSION In our colorectal cancer cohort, tumor tissue presents a differential COX-2 expression pattern with lower enzymatic activity that can be related to an altered metabolic and proteomic profile.

Beta-blocker therapy in elderly patients with renal dysfunction and heart failure

OBJECTIVE To assess the role of beta-blockers(BB)in patients with chronic kidney disease(CKD)aged≥75 years.METHODS AND RESULTS From January 2008 to July 2014,we included 390 consecutive patients≥75 years of age with ejection fraction≤35%and glomerular filtration rate(GFR)≤60 m L/min per 1.73 m^2.We analyzed the relationship between treatment with BB and mortality or cardiovascular events.The mean age of our population was 82.6±4.1 years.Mean ejection fraction was 27.9%±6.5%.GFR was 60-45 m L/min per 1.73 m^2 in 50.3%of patients,45-30 m L/min per 1.73 m^2 in 37.4%,and<30 m L/min per 1.73 m^2 in 12.3%.At the conclusion of follow-up,67.4%of patients were receiving BB.The median follow-up was28.04(IR:19.41-36.67)months.During the study period,211 patients(54.1%)died and 257(65.9%)had a major cardiovascular event(death or hospitalization for heart failure).BB use was significantly associated with a reduced risk of death(HR=0.51,95%CI:0.35-0.74;P<0.001).Patients receiving BB consistently showed a reduced risk of death across the different stages of CKD:stage IIIa(GFR=30-45 m L/min per 1.73 m^2;HR=0.47,95%CI:0.26-0.86,P<0.0001),stage IIIb(GFR 30-45 m L/min per 1.73 m^2;HR=0.55,95%CI:0.26-1.06,P=0.007),and stages IV and V(GFR<30 m L/min per 1.73 m~2;HR=0.29,95%CI:0.11-0.76;P=0.047).CONCLUSIONS The use of BB in elderly patients with HFr EF and renal impairment was associated with a better prognosis.Use of BB should be encouraged when possible.

Clinical and prognostic implications of delirium in elderly patients with non–ST-segment elevation acute coronary syndromes

Background Elderly patients with non-ST-segment elevation acute coronary syndromes(NSTE-ACS)may present delirium but its clinical relevance is unknown.This study aimed at detennining the clinical associated factors,and prognostic implications of delirium in old-aged patients admitted for NSTE-ACS.Methods LONGEVO-SCA is a prospective multicenter registry including unselected patients with NSTE-ACS aged>80 years.Clinical variables and a complete geriatric evaluation were assessed during hospitalization.The association between delirium and 6-month mortality was assessed by a Cox regression model weighted for a propensity score including the potential confounding variables.We also analysed its association with 6-month bleeding and cognitive or functional decline.Results Among 527 patients included,thirty-seven(7%)patients presented delirium during the hospitalization.Delirium was more frequent in patients with dementia or depression and in those from nursing homes(27.0%vs.3.1%,24.3%vs.11.6%,and 11.1%V5.2.2%,respectively;all P<0.05).Delirium was significantly associated with in-hospital infections(27.0%vs.5.3%,P<0.001)and usage of diuretics(70.3%vs.49.8%,P=0.02).Patients with delirium had longer hospitalizations[median 8.5(5.5-14)vs.6.0(4.0-10)days,P=0.02]and higher incidence of 6-month bleeding and mortality(32.3%vs.10.0%and 24.3%vs.10.8%,respectively;both P<0.05)but similar cognitive or functional decline.Delirium was independently associated with 6-month mortality(HR=1.47,95%CI:1.02-2.13,P=0.04)and 6-month bleeding events(OR=2.87;95%CI:1.98-4」6,P<0.01).Conclusions In-hospital delirium in elderly patients with NSTE-ACS is associated with some preventable risk factors and it is an independent predictor of 6-month mortality.

Metabolism of tissue macrophages in homeostasis and pathology

Cellular metabolism orchestrates the intricate use of tissue fuels for catabolism and anabolism to generate cellular energy and structural components.The emerging field of immunometabolism highlights the importance of cellular metabolism for the maintenance and activities of immune cells.Macrophages are embryo-or adult bone marrow-derived leukocytes that are key for healthy tissue homeostasis but can also contribute to pathologies such as metabolic syndrome,atherosclerosis,fibrosis or cancer.Macrophage metabolism has largely been studied in vitro.However,different organs contain diverse macrophage populations that specialize in distinct and often tissue-specific functions.This context specificity creates diverging metabolic challenges for tissue macrophage populations to fulfill their homeostatic roles in their particular microenvironment and conditions their response in pathological conditions.Here,we outline current knowledge on the metabolic requirements and adaptations of macrophages located in tissues during homeostasis and selected diseases.

Arabidopsis SWC4 Binds DNA and Recruits the SWR1 Complex to Modulate Histone H2A.Z Deposition at Key Regulatory Genes

Deposition of the H2A.Z histone variant by the SWR1 complex （SWRI-C） in regulatory regions of specific loci modulates transcription. Characterization of mutations in Arabidopsis thaliana homologs of yeast SWRI-C has revealed a role for H2A.Z exchange in a variety of developmental processes. Nevertheless, the exact composition of plant SWRI-C and how it is recruited to target genes remains to be established. Here we show that SWC4, the Arabidopsis homolog of yeast SANT domain protein Swc4/Eaf2, is a DNA-binding protein that interacts with SWR1-C subunits. We demonstrate that the swc4-1 knockout mutant is embryo- lethal, while SWC4 RNAi knockdown lines display pleiotropic phenotypic alterations in vegetative and repro- ductive traits, including acceleration of flowering time, indicating that SWC4 controls post-embryonic processes. Transcriptomic analyses and genome-wide profiling of H2A.Z indicate that SWC4 represses tran- scription of a number of genes, including the floral integrator FT and key transcription factors, mainly by modulating H2A.Z deposition. Interestingly, SWC4 silencing does not affect H2A.Z deposition at the FLC locus nor expression of this gene, a master regulator of flowering previously shown to be controlled by SWR1-C. Importantly, we find that SWC4 recognizes specific AT-rich DNA elements in the chromatin regions of target genes and that SWC4 silencing impairs SWRI-C binding at FT. Collectively, our data suggest that SWC4 regulates plant growth and development by aiding SWR1-C recruitment and modulating H2A.Z deposition.

Conventional type 1 dendritic cells protect against age-related adipose tissue dysfunction and obesity

Conventional dendritic cells(cDCs)scan and integrate environmental cues in almost every tissue,including exogenous metabolic signals.While cDCs are critical in maintaining immune balance,their role in preserving energy homeostasis is unclear.Here,we showed that Batf3-deficient mice lacking conventional type 1 DCs(cDC1s)had increased body weight and adiposity during aging.This led to impaired energy expenditure and glucose tolerance,insulin resistance,dyslipidemia,and liver steatosis.cDC1 deficiency caused adipose tissue inflammation that was preceded by a paucity of NK1.1+invariant NKT(iNKT)cells.Accordingly,among antigen-presenting cells,cDC1s exhibited notable induction of IFN-γproduction by iNKT cells,which plays a metabolically protective role in lean adipose tissue.Flt3L treatment,which expands the dendritic cell(DC)compartment,mitigated diet-induced obesity and hyperlipidemia in a Batf3-dependent manner.This effect was partially mediated by NK1.1+cells.These results reveal a new critical role for the cDC1-iNKT cell axis in the regulation of adipose tissue homeostasis.

Novel human immunomodulatory T cell receptors and their double-edged potential in autoimmunity,cardiovascular disease and cancer

In the last decade,approaches based on T cells and their immunomodulatory receptors have emerged as a solid improvement in treatments for various types of cancer.However,the roles of these molecules in the therapeutic context of autoimmune and cardiovascular diseases are still relatively unexplored.Here,we review the best known and most com m only used immunomodulatory T cell receptors in clinical practice(PD-1 and CTLA-4),along with the rest of the receptors with known functions in animal models,which have great potential as modulators in human pathologies in the medium term.Am ong these other receptors is the receptor CD69,which has recently been described to be expressed in mouse and human T cells in autoimmune and cardiovascular diseases and cancer.However,inhibition of these receptors individually or in combination by drugs or monoclonal antibodies generates a loss of immunological tolerance and can trigger multiple autoimmune disorders in different organs and immune-related adverse effects.In the coming decades,knowledge on the functions of different immunomodulatory receptors will be pivotal for the development of new and better therapies with less harmful side effects.In this review,we discuss the roles of these receptors in the control of immunity from a perspective focused on therapeutic potential in not only cancer but also autoimmune diseases,such as systemic lupus erythematosus,autoimmune diabetes and rheumatoid arthritis,and cardiovascular diseases,such as atherosclerosis,acute myocardial infarction,and myocarditis.

个体化营养与健康

Jose Ordovas及其同事认为,根据个体特征和行为进行个体化营养干预具有前景,但在实施之前还需要做更多的工作。膳食因素公认是导致心脏病、卒中、2型糖尿病、癌症等常见疾病的主要因素之一1-3。尽管已知疾病与膳食模式相关联.试图改变膳食习惯进而影响公众健康和福祉的干预措施仍收效甚微。对于能够影响健康结果的行为,将干预措施个体化可能更凑效4-5,在本文中我们考量了个体化营养的相关证据。