57 research outputs found
Mechanical ventilation during experimental sepsis increases deposition of advanced glycation end products and myocardial inflammation
Phenethylamine-derived new psychoactive substances 2C-E-FLY, 2C-EF-FLY, and 2C-T-7-FLY: Investigations on their metabolic fate including isoenzyme activities and their toxicological detectability in urine screenings
Psychoactive substances of the 2C-series are phenethylamine-based designer drugs that can induce psychostimulant and hallucinogenic effects. The so-called 2C-FLY series contains rigidified methoxy groups integrated in a 2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran core. The aim of the presented work was to investigate the in vivo and in vitro metabolic fate including isoenzyme activities and toxicological detectability of the three new psychoactive substances (NPS) 2C-E-FLY, 2C-EF-FLY, and 2C-T-7-FLY to allow clinical and forensic toxicologists the identification of these novel compounds. Rat urine, after oral administration, and pooled human liver S9 fraction (pS9) incubations were analyzed by liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS). By performing activity screenings, the human isoenzymes involved were identified and toxicological detectability in rat urine investigated using standard urine screening approaches (SUSAs) based on gas chromatography (GC)-MS, LC-MSn, and LC-HRMS/MS. In total, 32 metabolites were tentatively identified. Main metabolic steps consisted of hydroxylation and N acetylation. Phase I metabolic reactions were catalyzed by CYP2D6, 3A4, and FMO3 and N-acetylation by NAT1 and 2. Methoxyamine was used as a trapping agent for detection of the deaminated metabolite formed by MAO-A and B. Interindividual differences in the metabolism of the 2C-FLY drugs could be caused by polymorphisms of enzymes involved or drug-drug interactions. All three SUSAs were shown to be suitable to detect an intake of these NPS but common metabolites of 2C-E-FLY and 2C-EF-FLY have to be considered during interpretation of analytical findings
Design of the ExCersion-VCI study: The effect of aerobic exercise on cerebral perfusion in patients with vascular cognitive impairment
There is evidence for a beneficial effect of aerobic exercise on cognition, but underlying mechanisms are unclear. In this study, we test the hypothesis that aerobic exercise increases cerebral blood flow (CBF) in patients with vascular cognitive impairment (VCI). This study is a multicenter single-blind randomized controlled trial among 80 patients with VCI. Most important inclusion criteria are a diagnosis of VCI with Mini-Mental State Examination ≥22 and Clinical Dementia Rating ≤0.5. Participants are randomized into an aerobic exercise group or a control group. The aerobic exercise program aims to improve cardiorespiratory fitness and takes 14 weeks, with a frequency of three times a week. Participants are provided with a bicycle ergometer at home. The control group receives two information meetings. Primary outcome measure is change in CBF. We expect this study to provide insight into the potential mechanism by which aerobic exercise improves hemodynamic status
IFT74 variants cause skeletal ciliopathy and motile cilia defects in mice and humans
Motile and non-motile cilia play critical roles in mammalian development and health. These organelles are composed of a 1000 or more unique proteins, but their assembly depends entirely on proteins synthesized in the cell body and transported into the cilium by intraflagellar transport (IFT). In mammals, malfunction of non-motile cilia due to IFT dysfunction results in complex developmental phenotypes that affect most organs. In contrast, disruption of motile cilia function causes subfertility, disruption of the left-right body axis, and recurrent airway infections with progressive lung damage. In this work, we characterize allele specific phenotypes resulting from IFT74 dysfunction in human and mice. We identified two families carrying a deletion encompassing IFT74 exon 2, the first coding exon, resulting in a protein lacking the first 40 amino acids and two individuals carrying biallelic splice site mutations. Homozygous exon 2 deletion cases presented a ciliary chondrodysplasia with narrow thorax and progressive growth retardation along with a mucociliary clearance disorder phenotype with severely shorted cilia. Splice site variants resulted in a lethal skeletal chondrodysplasia phenotype. In mice, removal of the first 40 amino acids likewise results in a motile cilia phenotype but with little effect on primary cilia structure. Mice carrying this allele are born alive but are growth restricted and developed hydrocephaly in the first month of life. In contrast, a strong, likely null, allele of Ift74 in mouse completely blocks ciliary assembly and causes severe heart defects and midgestational lethality. In vitro studies suggest that the first 40 amino acids of IFT74 are dispensable for binding of other IFT subunits but are important for tubulin binding. Higher demands on tubulin transport in motile cilia compared to primary cilia resulting from increased mechanical stress and repair needs could account for the motile cilia phenotype observed in human and mice
Rationale and design of a proof-of-concept trial investigating the effect of uninterrupted perioperative (par)enteral nutrition on amino acid profile, cardiomyocytes structure, and cardiac perfusion and metabolism of patients undergoing coronary artery bypass grafting
<p>Abstract</p> <p>Background</p> <p>Malnutrition is very common in patients undergoing cardiac surgery. Malnutrition can change myocardial substrate utilization which can induce adverse effects on myocardial metabolism and function. We aim to investigate the hypothesis that there is a disturbed amino acids profile in the cardiac surgical patient which can be normalized by (par)enteral nutrition before, during and after surgery, subsequently improving cardiomyocyte structure, cardiac perfusion and glucose metabolism.</p> <p>Methods/Design</p> <p>This randomized controlled intervention study investigates the effect of uninterrupted perioperative (par)enteral nutrition on cardiac function in 48 patients undergoing coronary artery bypass grafting. Patients are given enteral nutrition (n = 16) or parenteral nutrition (n = 16), at least two days before, during, and two days after coronary artery bypass grafting, or are treated according to the standard guidelines (control) (n = 16). We will illustrate the effect of (par)enteral nutrition on differences in concentrations of amino acids and asymmetric dimethylarginine and in activity of dimethylarginine dimethylaminohydrolase and arginase in cardiac tissue and blood plasma. In addition, cardiomyocyte structure by histological, immuno-histochemical and ultrastructural analysis will be compared between the (par)enteral and control group. Furthermore, differences in cardiac perfusion and global left ventricular function and glucose metabolism, and their changes after coronary artery bypass grafting are evaluated by electrocardiography-gated myocardial perfusion scintigraphy and <sup>18</sup>F-fluorodeoxy-glucose positron emission tomography respectively. Finally, fat free mass is measured before and after intervention with bioelectrical impedance spectrometry in order to evaluate nutritional status.</p> <p>Trial registration</p> <p>Netherlands Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2183">NTR2183</a></p
Effect of additional treatment with EXenatide in patients with an Acute Myocardial Infarction (EXAMI): study protocol for a randomized controlled trial
<p>Abstract</p> <p>Background</p> <p>Myocardial infarction causes irreversible loss of cardiomyocytes and may lead to loss of ventricular function, morbidity and mortality. Infarct size is a major prognostic factor and reduction of infarct size has therefore been an important objective of strategies to improve outcomes. In experimental studies, glucagon-like peptide 1 and exenatide, a long acting glucagon-like peptide 1 receptor agonist, a novel drug introduced for the treatment of type 2 diabetes, reduced infarct size after myocardial infarction by activating pro-survival pathways and by increasing metabolic efficiency.</p> <p>Methods</p> <p>The EXAMI trial is a multi-center, prospective, randomized, placebo controlled trial, designed to evaluate clinical outcome of exenatide infusion on top of standard treatment, in patients with an acute myocardial infarction, successfully treated with primary percutaneous coronary intervention. A total of 108 patients will be randomized to exenatide (5 μg bolus in 30 minutes followed by continuous infusion of 20 μg/24 h for 72 h) or placebo treatment. The primary end point of the study is myocardial infarct size (measured using magnetic resonance imaging with delayed enhancement at 4 months) as a percentage of the area at risk (measured using T2 weighted images at 3-7 days).</p> <p>Discussion</p> <p>If the current study demonstrates cardioprotective effects, exenatide may constitute a novel therapeutic option to reduce infarct size and preserve cardiac function in adjunction to reperfusion therapy in patients with acute myocardial infarction.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01254123">NCT01254123</a></p
Intralesional injection of adipose-derived stem cells reduces hypertrophic scarring in a rabbit ear model
Adipose tissue-derived stem cells suppress hypertrophic scar fibrosis via the p38/MAPK signaling pathway
EMT and stemness: flexible processes tuned by alternative splicing in development and cancer progression
Liquid chromatography-electrospray tandem mass spectrometry of acidic monoamine metabolites
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