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Decline in physical activity in the weeks preceding sustained ventricular arrhythmia in women
(2020)
Background: Heightened risk of cardiac arrest following physical exertion has been reported. Among patients with an implantable defibrillator, an appropriate shock for sustained ventricular arrhythmia was preceded by a retrospective self-report of engaging in mild-to-moderate physical activity. Previous studies evaluating the relationship between activity and sudden cardiac arrest lacked an objective measure of physical activity and women were often underrepresented.
Objective: To determine the relationship between physical activity, recorded by accelerometer in a wearable cardioverter-defibrillator (WCD), and sustained ventricular arrhythmia among female patients.
Methods: A dataset of female adult patients prescribed a WCD for a diagnosis of myocardial infarction or dilated cardiomyopathy was compiled from a commercial database. Curve estimation, to include linear and nonlinear interpolation, was applied to physical activity as a function of time (days before arrhythmia).
Results: Among women who received an appropriate WCD shock for sustained ventricular arrhythmia (N = 120), a quadratic relationship between time and activity was present prior to shock. Physical activity increased starting at the beginning of the 30-day period up until day -16 (16 days before the ventricular arrhythmia) when activity begins to decline.
Conclusion: For patients who received treatment for sustained ventricular arrhythmia, a decline in physical activity was found during the 2 weeks preceding the arrhythmic event. Device monitoring for a sustained decline in physical activity may be useful to identify patients at near-term risk of a cardiac arrest.
Attention-Deficit/Hyperactivity Disorder (ADHD) and obesity are frequently comorbid, genetically correlated, and share brain substrates. The biological mechanisms driving this association are unclear, but candidate systems, like dopaminergic neurotransmission and circadian rhythm, have been suggested. Our aim was to identify the biological mechanisms underpinning the genetic link between ADHD and obesity measures and investigate associations of overlapping genes with brain volumes. We tested the association of dopaminergic and circadian rhythm gene sets with ADHD, body mass index (BMI), and obesity (using GWAS data of N = 53,293, N = 681,275, and N = 98,697, respectively). We then conducted genome-wide ADHD–BMI and ADHD–obesity gene-based meta-analyses, followed by pathway enrichment analyses. Finally, we tested the association of ADHD–BMI overlapping genes with brain volumes (primary GWAS data N = 10,720–10,928; replication data N = 9428). The dopaminergic gene set was associated with both ADHD (P = 5.81 × 10−3) and BMI (P = 1.63 × 10−5); the circadian rhythm was associated with BMI (P = 1.28 × 10−3). The genome-wide approach also implicated the dopaminergic system, as the Dopamine-DARPP32 Feedback in cAMP Signaling pathway was enriched in both ADHD–BMI and ADHD–obesity results. The ADHD–BMI overlapping genes were associated with putamen volume (P = 7.7 × 10−3; replication data P = 3.9 × 10−2)—a brain region with volumetric reductions in ADHD and BMI and linked to inhibitory control. Our findings suggest that dopaminergic neurotransmission, partially through DARPP-32-dependent signaling and involving the putamen, is a key player underlying the genetic overlap between ADHD and obesity measures. Uncovering shared etiological factors underlying the frequently observed ADHD–obesity comorbidity may have important implications in terms of prevention and/or efficient treatment of these conditions.
Inhibitors against the NS3-4A protease of hepatitis C virus (HCV) have proven to be useful drugs in the treatment of HCV infection. Although variants have been identified with mutations that confer resistance to these inhibitors, the mutations do not restore replicative fitness and no secondary mutations that rescue fitness have been found. To gain insight into the molecular mechanisms underlying the lack of fitness compensation, we screened known resistance mutations in infectious HCV cell culture with different genomic backgrounds. We observed that the Q41R mutation of NS3-4A efficiently rescues the replicative fitness in cell culture for virus variants containing mutations at NS3-Asp168. To understand how the Q41R mutation rescues activity, we performed protease activity assays complemented by molecular dynamics simulations, which showed that protease-peptide interactions far outside the targeted peptide cleavage sites mediate substrate recognition by NS3-4A and support protease cleavage kinetics. These interactions shed new light on the mechanisms by which NS3-4A cleaves its substrates, viral polyproteins and a prime cellular antiviral adaptor protein, the mitochondrial antiviral signaling protein MAVS. Peptide binding is mediated by an extended hydrogen-bond network in NS3-4A that was effectively optimized for protease-MAVS binding in Asp168 variants with rescued replicative fitness from NS3-Q41R. In the protease harboring NS3-Q41R, the N-terminal cleavage products of MAVS retained high affinity to the active site, rendering the protease susceptible for potential product inhibition. Our findings reveal delicately balanced protease-peptide interactions in viral replication and immune escape that likely restrict the protease adaptive capability and narrow the virus evolutionary space.
Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis
(2020)
Highlights
• Hypoxia decreases NCOA4 transcription in primary human macrophages.
• NCOA4 mRNA is a target of miR-6862-5p.
• Lowering NCOA4 increases FTMT abundance under hypoxia.
• FTMT and FTH protect from ferroptosis.
• Tumor cells lack the hypoxic decrease of NCOA4 and fail to stabilize FTMT.
Abstract
Cellular iron, at the physiological level, is essential to maintain several metabolic pathways, while an excess of free iron may cause oxidative damage and/or provoke cell death. Consequently, iron homeostasis has to be tightly controlled. Under hypoxia these regulatory mechanisms for human macrophages are not well understood. Hypoxic primary human macrophages reduced intracellular free iron and increased ferritin expression, including mitochondrial ferritin (FTMT), to store iron. In parallel, nuclear receptor coactivator 4 (NCOA4), a master regulator of ferritinophagy, decreased and was proven to directly regulate FTMT expression. Reduced NCOA4 expression resulted from a lower rate of hypoxic NCOA4 transcription combined with a micro RNA 6862-5p-dependent degradation of NCOA4 mRNA, the latter being regulated by c-jun N-terminal kinase (JNK). Pharmacological inhibition of JNK under hypoxia increased NCOA4 and prevented FTMT induction. FTMT and ferritin heavy chain (FTH) cooperated to protect macrophages from RSL-3-induced ferroptosis under hypoxia as this form of cell death is linked to iron metabolism. In contrast, in HT1080 fibrosarcome cells, which are sensitive to ferroptosis, NCOA4 and FTMT are not regulated. Our study helps to understand mechanisms of hypoxic FTMT regulation and to link ferritinophagy and macrophage sensitivity to ferroptosis.
Aims: Acetylsalicylic acid (ASA) is widely used for the prevention of atherothrombotic events in patients with chronic coronary artery disease (CAD) and peripheral artery disease (PAD), but the risk of vascular events remains high. We aimed at identifying randomised controlled trials (RCTs) on antithrombotic treatments in patients with chronic CAD or PAD.
Methods: Searches were conducted on MEDLINE, EMBASE, and CENTRAL on March 1st, 2018. This systematic review (SR) uses a narrative synthesis to summarize the evidence for the efficacy and safety of antiplatelet and anticoagulant therapies in the population of both chronic CAD or PAD patients.
Results: Four RCTs from 27 publications were included. Study groups included 15,603 to 27,395 patients. ASA alone was the most extensively studied (n = 3); other studies included rivaroxaban with or without ASA (n = 1), vorapaxar alone (n = 1), and clopidogrel with (n = 1) or without ASA (n = 1). Clopidogrel alone and clopidogrel plus ASA compared to ASA presented similar efficacy with comparable safety profile. Rivaroxaban plus ASA significantly reduced the risk of the composite of cardiovascular death, myocardial infarction, and stroke compared to ASA alone, although major bleeding with rivaroxaban plus ASA increased.
Conclusion: There is limited and heterogeneous evidence on the prevention of atherothrombotic events in patients with chronic CAD or PAD. Clopidogrel alone and clopidogrel plus ASA did not demonstrate superiority over ASA alone. A combination of rivaroxaban plus ASA may offer significant additional benefit in reducing cardiovascular outcomes, yet it may increase the risk of bleeding, compared to ASA alone.
Determination of a minimal postmortem interval via age estimation of necrophagous diptera has been restricted to the juvenile stages and the time until emergence of the adult fly, i.e. up until 2–6 weeks depending on species and temperature. Age estimation of adult flies could extend this period by adding the age of the fly to the time needed for complete development. In this context pteridines are promising metabolites, as they accumulate in the eyes of flies with increasing age. We studied adults of the blow fly Lucilia sericata at constant temperatures of 16 °C and 25 °C up to an age of 25 days and estimated their pteridine levels by fluorescence spectroscopy. Age was given in accumulated degree days (ADD) across temperatures. Additionally, a mock case was set up to test the applicability of the method. Pteridine increases logarithmically with increasing ADD, but after 70–80 ADD the increase slows down and the curve approaches a maximum. Sex had a significant impact (p < 4.09 × 10−6) on pteridine fluorescence level, while body-size and head-width did not. The mock case demonstrated that a slight overestimation of the real age (in ADD) only occurred in two out of 30 samples. Age determination of L. sericata on the basis of pteridine levels seems to be limited to an age of about 70 ADD, but depending on the ambient temperature this could cover an extra amount of time of about 5–7 days after completion of the metamorphosis.
Cabozantinib (Cabometyx®) is a potent multikinase inhibitor targeting the vascular endothelial growth factor (VEGF) receptor 2, the mesenchymal-epithelial transition factor (MET) receptor, and the “anexelekto” (AXL) receptor tyrosine kinase. It is approved for the treatment of advanced hepatocellular carcinoma (HCC) after failure of sorafenib in Europe (since November 2018) and in the USA (since January 2019). The approval of cabozantinib was based on results of the randomized, placebo-controlled, phase 3 CELESTIAL trial in patients with unresectable HCC, who received one or two prior lines of treatment including sorafenib. At the second planned interim analysis, the trial was stopped, because the primary end point overall survival was clearly in favor for cabozantinib. Additionally, median progression-free survival was superior to placebo. The most common ≥ grade 3 relevant adverse events in patients with HCC treated with cabozantinib were palmar–plantar erythrodysesthesia, hypertension, fatigue, and diarrhea. In this review, current data on cabozantinib for the treatment of patients with advanced HCC, with a focus on the management of common adverse events and ongoing clinical trials, are discussed.
Die Gattungen Nicotiana tabacum und Nicotiana rustica der Tabakpflanze sind von großer wirtschaftlicher Bedeutung. Aus ihnen wird Tabak hergestellt, der mit Alkohol zur weltweit am häufigsten konsumierten Genussdroge zählt. Aufgrund seiner Legalität wird die Toxizität trotz steigender Warnung und Aufklärung immer noch unterschätzt. Die Toxizität der Tabakpflanze ist vor allem auf das Alkaloid Nikotin zurückzuführen. Dass es selten zu einer Vergiftung durch die reine Pflanze kommt, liegt daran, dass sie optisch kaum zum Verzehr anregt. Häufiger dagegen ist eine Vergiftung durch z. B. verschluckte Zigarettenstummel, die vor allem für Kinder sehr gefährlich sein kann. Eine weitere Gefahr der Vergiftung entsteht bei der Tabakernte. Nikotin wird auch über die Haut aufgenommen und kann so zu der Green Tobacco Sickness bei Tabakplantagenarbeitern führen. Im Ernstfall existiert kein Antidot. Aktivkohle sollte so schnell wie möglich gegeben werden, um die Resorption zu vermindern. Ansonsten muss das Nikotin mit einer Magenwäsche aus dem Körper gefiltert werden. Präventiv sollten deshalb verstärkt auf die Gefahren des Tabaks aufmerksam gemacht werden.
Deubiquitinases (DUBs) are vital for the regulation of ubiquitin signals, and both catalytic activity of and target recruitment by DUBs need to be tightly controlled. Here, we identify asparagine hydroxylation as a novel posttranslational modification involved in the regulation of Cezanne (also known as OTU domain–containing protein 7B (OTUD7B)), a DUB that controls key cellular functions and signaling pathways. We demonstrate that Cezanne is a substrate for factor inhibiting HIF1 (FIH1)- and oxygen-dependent asparagine hydroxylation. We found that FIH1 modifies Asn35 within the uncharacterized N-terminal ubiquitin-associated (UBA)-like domain of Cezanne (UBACez), which lacks conserved UBA domain properties. We show that UBACez binds Lys11-, Lys48-, Lys63-, and Met1-linked ubiquitin chains in vitro, establishing UBACez as a functional ubiquitin-binding domain. Our findings also reveal that the interaction of UBACez with ubiquitin is mediated via a noncanonical surface and that hydroxylation of Asn35 inhibits ubiquitin binding. Recently, it has been suggested that Cezanne recruitment to specific target proteins depends on UBACez. Our results indicate that UBACez can indeed fulfill this role as regulatory domain by binding various ubiquitin chain types. They also uncover that this interaction with ubiquitin, and thus with modified substrates, can be modulated by oxygen-dependent asparagine hydroxylation, suggesting that Cezanne is regulated by oxygen levels.
Assessment of individual therapeutic responses provides valuable information concerning treatment benefits in individual patients. We evaluated individual therapeutic responses as determined by the Disease Activity Score-28 joints critical difference for improvement (DAS28-dcrit) in rheumatoid arthritis (RA) patients treated with intravenous tocilizumab or comparator anti-tumor necrosis factor (TNF) agents. The previously published DAS28-dcrit value [DAS28 decrease (improvement) ≥ 1.8] was retrospectively applied to data from two studies of tocilizumab in RA, the 52-week ACT-iON observational study and the 24-week ADACTA randomized study. Data were compared within (not between) studies. DAS28 was calculated with erythrocyte sedimentation rate as the inflammatory marker. Stability of DAS28-dcrit responses and European League Against Rheumatism (EULAR) good responses was determined by evaluating repeated responses at subsequent timepoints. A logistic regression model was used to calculate p values for differences in response rates between active agents. Patient-reported outcomes (PROs; pain, global health, function, and fatigue) in DAS28-dcrit responder versus non-responder groups were compared with an ANCOVA model. DAS28-dcrit individual response rates were 78.2% in tocilizumab-treated patients and 58.2% in anti-TNF-treated patients at week 52 in the ACT-ion study (p = 0.0001) and 90.1% versus 59.1% at week 24 in the ADACTA study (p < 0.0001). DAS28-dcrit responses showed greater stability over time (up to 52 weeks) than EULAR good responses. For both active treatments, DAS28-dcrit responses were associated with statistically significant improvements in mean PRO values compared with non-responders. The DAS28-dcrit response criterion provides robust assessments of individual responses to RA therapy and may be useful for discriminating between active agents in clinical studies and guiding treat-to-target decisions in daily practice.