Increased risk of cognitive and functional decline in patients with atrial fibrillation: results of the ONTARGET and TRANSCEND studies

Background:

The role of atrial fibrillation in cognitive impairment and dementia, independent of stroke, is uncertain. We sought to determine the association of atrial fibrillation with cognitive and physical impairment in a large group of patients at high cardiovascular risk.

Methods:

We conducted a post-hoc analysis of two randomized controlled trials involving 31 546 patients, the aims of which were to evaluate the efficacy of treatment with ramipril plus telmisartan (ONTARGET) or telmisartan alone (TRANSCEND) in reducing cardiovascular disease. We evaluated the cognitive function of participants at baseline and after two and five years using the Mini–Mental State Examination (MMSE). In addition, we recorded incident dementia, loss of independence in activities of daily living and admission to long-term care facilities. We used a Cox regression model adjusting for main confounders to determine the association between atrial fibrillation and our primary outcomes: a decrease of three or more points in MMSE score, incident dementia, loss of independence in performing activities of daily living and admission to long-term care.

Results:

We enrolled 31 506 participants for whom complete information on atrial fibrillation was available, 70.4% of whom were men. The mean age of participants was 66.5 years, and the mean baseline MMSE score was 27.7 (standard deviation 2.9) points. At baseline, 1016 participants (3.3%) had atrial fibrillation, with the condition developing in an additional 2052 participants (6.5%) during a median follow-up of 56 months. Atrial fibrillation was associated with an increased risk of cognitive decline (hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.03–1.26), new dementia (HR 1.30, 95% CI 1.14–1.49), loss of independence in performing activities of daily living (HR 1.35, 95% CI 1.19–1.54) and admission to long-term care facilities (HR 1.53, 95% CI 1.31–1.79). Results were consistent among participants with and without stroke or receiving antihypertensive drugs.

Interpretation:

Cognitive and functional decline are important consequences of atrial fibrillation, even in the absence of overt stroke.A trial fibrillation is an important and modifiable cause of ischemic stroke, which may result in considerable physical and cognitive disability.¹ In addition, atrial fibrillation is associated with an increased risk of covert cerebral infarction, which is reported in about one-quarter of patients with atrial fibrillation who undergo magnetic resonance imaging of the brain.² Thus, atrial fibrillation may be an important determinant of cognitive and functional decline, even in the absence of clinical ischemic stroke. However, previous epidemiologic studies evaluating atrial fibrillation’s association with cognitive function have been inconsistent,^3–13 and very few have evaluated its association with functional outcomes.¹⁴A recent systematic review showed convincing evidence of an association between atrial fibrillation and dementia in patients with a history of stroke, but it concluded that there was considerable uncertainty of a link between atrial fibrillation and dementia in patients with no history of stroke.¹⁵ Large prospective cohort studies are required to determine a true association between atrial fibrillation and cognitive outcomes.In this study, we sought to determine the prospective association between atrial fibrillation and cognitive decline, loss of independence in activities of daily living and admission to long-term care facilities, using data from a large group of patients included in the ONTARGET and TRANSCEND trials.^16,17     

A ratiometric fluorescent probe for assessing mitochondrial phospholipid peroxidation within living cells

Mitochondrial oxidative damage contributes to a wide range of pathologies, and lipid peroxidation of the mitochondrial inner membrane is a major component of this disruption. However, despite its importance, there are no methods to assess mitochondrial lipid peroxidation within cells specifically. To address this unmet need we have developed a ratiometric, fluorescent, mitochondria-targeted lipid peroxidation probe, MitoPerOx. This compound is derived from the C11-BODIPY(581/591) probe, which contains a boron dipyromethane difluoride (BODIPY) fluorophore conjugated via a dienyl link to a phenyl group. In response to lipid peroxidation the fluorescence emission maximum shifts from ～590 to ～520nm. To target this probe to the matrix-facing surface of the mitochondrial inner membrane we attached a triphenylphosphonium lipophilic cation, which leads to its selective uptake into mitochondria in cells, driven by the mitochondrial membrane potential. Here we report on the development and characterization of MitoPerOx. We found that MitoPerOx was taken up very rapidly into mitochondria within cells, where it responded to changes in mitochondrial lipid peroxidation that could be measured by fluorimetry, confocal microscopy, and epifluorescence live cell imaging. Importantly, the peroxidation-sensitive change in fluorescence at 520nm relative to that at 590nm enabled the use of the probe as a ratiometric fluorescent probe, greatly facilitating assessment of mitochondrial lipid peroxidation in cells.     

Low heritabilities, but genetic and maternal correlations between red squirrel behaviours

Consistent individual differences in behaviour, and behavioural correlations within and across contexts, are referred to as animal personalities. These patterns of variation have been identified in many animal taxa and are likely to have important ecological and evolutionary consequences. Despite their importance, genetic and environmental sources of variation in personalities have rarely been characterized in wild populations. We used a Bayesian animal model approach to estimate genetic parameters for aggression, activity and docility in North American red squirrels (Tamiasciurus hudsonicus). We found support for low heritabilities (0.08-0.12), and cohort effects (0.07-0.09), as well as low to moderate maternal effects (0.07-0.15) and permanent environmental effects (0.08-0.16). Finally, we found evidence of a substantial positive genetic correlation (0.68) and maternal effects correlation (0.58) between activity and aggression providing evidence of genetically based behavioural correlations in red squirrels. These results provide evidence for the presence of heritable variation in red squirrel behaviour, but also emphasize the role of other sources of variation, including maternal effects, in shaping patterns of variation and covariation in behavioural traits.     

Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis

Identification of the factors critical to the tumor-initiating cell (TIC) state may open new avenues in cancer therapy. Here we show that the metabolic enzyme glycine decarboxylase (GLDC) is critical for TICs in non-small cell lung cancer (NSCLC). TICs from primary NSCLC tumors express high levels of the oncogenic stem cell factor LIN28B and GLDC, which are both required for TIC growth and tumorigenesis. Overexpression of GLDC and other glycine/serine enzymes, but not catalytically inactive GLDC, promotes cellular transformation and tumorigenesis. We found that GLDC induces dramatic changes in glycolysis and glycine/serine metabolism, leading to changes in pyrimidine metabolism to regulate cancer cell proliferation. In the clinic, aberrant activation of GLDC correlates with poorer survival in lung cancer patients, and aberrant GLDC expression is observed in multiple cancer types. This link between glycine metabolism and tumorigenesis may provide novel targets for advancing anticancer therapy.     

Survival and Germination of Bacillus cereus Spores without Outgrowth or Enterotoxin Production during In Vitro Simulation of Gastrointestinal Transit

To study the gastrointestinal survival and enterotoxin production of the food-borne pathogen Bacillus cereus, an in vitro simulation experiment was developed to mimic gastrointestinal passage in 5 phases: (i) the mouth, (ii) the stomach, with gradual pH decrease and fractional emptying, (iii) the duodenum, with high concentrations of bile and digestive enzymes, (iv) dialysis to ensure bile reabsorption, and (v) the ileum, with competing human intestinal bacteria. Four different B. cereus strains were cultivated and sporulated in mashed potato medium to obtain an inoculum of 7.0 log spores/ml. The spores showed survival and germination during the in vitro simulation of gastrointestinal passage, but vegetative outgrowth of the spores was suppressed by the intestinal bacteria during the final ileum phase. No bacterial proliferation or enterotoxin production was observed, despite the high inoculum levels. Little strain variability was observed: except for the psychrotrophic food isolate, the spores of all strains survived well throughout the gastrointestinal passage. The in vitro simulation experiments investigated the survival and enterotoxin production of B. cereus in the gastrointestinal lumen. The results obtained support the hypothesis that localized interaction of B. cereus with the host''s epithelium is required for diarrheal food poisoning.     

Chemically inhibited ATP synthesis promoted detachment of different-age biofilms from membrane surface

This study investigated the response of different-age biofilms developed on membrane surface to a chemical uncoupler 3, 3', 4', 5-tetrachlorosalicylanilide (TCS). Results showed that adenosine triphosphate (ATP) dissipation caused by TCS would promote different-age biofilms detachment, whereas chemically inhibited cellular ATP synthesis subsequently suppressed autoinducer-2 (AI-2) and extracellular polymeric substances (EPS) production. The extent of biofilm detachment was found to be closely related to AI-2-regulated EPS contents of bacteria. It was revealed that energy dissipation induced biofilm detachability was controlled by AI-2 regulated cellular communication via AI-2-mediated EPS secretion. This study would lead to a new cleaning strategy of biologically fouled membrane.     

A high-throughput screen to identify inhibitors of ATP homeostasis in non-replicating Mycobacterium tuberculosis

Growing evidence suggests that the presence of a subpopulation of hypoxic non-replicating, phenotypically drug-tolerant mycobacteria is responsible for the prolonged duration of tuberculosis treatment. The discovery of new antitubercular agents active against this subpopulation may help in developing new strategies to shorten the time of tuberculosis therapy. Recently, the maintenance of a low level of bacterial respiration was shown to be a point of metabolic vulnerability in Mycobacterium tuberculosis. Here, we describe the development of a hypoxic model to identify compounds targeting mycobacterial respiratory functions and ATP homeostasis in whole mycobacteria. The model was adapted to 1,536-well plate format and successfully used to screen over 600,000 compounds. Approximately 800 compounds were confirmed to reduce intracellular ATP levels in a dose-dependent manner in Mycobacterium bovis BCG. One hundred and forty non-cytotoxic compounds with activity against hypoxic non-replicating M. tuberculosis were further validated. The resulting collection of compounds that disrupt ATP homeostasis in M. tuberculosis represents a valuable resource to decipher the biology of persistent mycobacteria.     

Expanding the zebrafish embryo proteome using multiple fractionation approaches and tandem mass spectrometry

The proteome of zebrafish, Danio rerio, embryos has not been studied in great detail mainly due to the presence of high abundance yolk proteins in embryos. Here we report the highest number of the zebrafish embryo proteins identified so far to our knowledge, through a combination of a protein-level fractionation approach (1D SDS-PAGE) and two different peptide-level fractionation approaches (IEF and strong anion exchange (SAX)) of deyolked zebrafish embryos followed by LC-MS/MS. We detected 5267 proteins in total of which 3464 proteins were identified with at least two peptides (less than 1% peptide false discovery rate). The analysis of proteome coverage from each method showed that 56% of detected proteins were common to all approaches and 95% of the detected proteome was obtained from 1D SDS-PAGE approach alone. Bioinformatics analysis of the detected proteome demonstrated that nucleocytoplasmic transport (biological process) and ribosomal proteins (cellular component) were the most over-represented proteins, whereas cell-cell signaling (biological process) and extracellular space proteins (cellular component) were the most under-represented proteins in the identified proteome.     

Emerging roles of angiopoietin-like 4 in human cancer

Angiopoietin-like 4 (ANGPTL4) is best known for its role as an adipokine involved in the regulation of lipid and glucose metabolism. The characterization of ANGPTL4 as an adipokine is largely due to our limited understanding of the interaction partners of ANGPTL4 and how ANGPTL4 initiates intracellular signaling. Recent findings have revealed a critical role for ANGPTL4 in cancer growth and progression, anoikis resistance, altered redox regulation, angiogenesis, and metastasis. Emerging evidence suggests that ANGPTL4 function may be drastically altered depending on the proteolytic processing and posttranslational modifications of ANGPTL4, which may clarify several conflicting roles of ANGPTL4 in different cancers. Although the N-terminal coiled-coil region of ANGPTL4 has been largely responsible for the endocrine regulatory role in lipid metabolism, insulin sensitivity, and glucose homeostasis, it has now emerged that the COOH-terminal fibrinogen-like domain of ANGPTL4 may be a key regulator in the multifaceted signaling during cancer development. New insights into the mechanistic action of this functional domain have opened a new chapter into the possible clinical application of ANGPTL4 as a promising candidate for clinical intervention in the fight against cancer. This review summarizes our current understanding of ANGPTL4 in cancer and highlights areas that warrant further investigation. A better understanding of the underlying cellular and molecular mechanisms of ANGPTL4 will reveal novel insights into other aspects of tumorigenesis and the potential therapeutic value of ANGPTL4.