Myocardial ATP catabolism and its pharmacological prevention

This thesis deals with high-energy phosphate metabolism during myocardial ischemia. describes the effects of some pharmacological interventions on the energy metabolism of ischemic myocardium. The chapters of this thesis are based on 11 published papers, added as appendices

Ischemic nucleotide breakdown increases during cardiac development due to drop in adenosine anabolism/catabolism ratio

Abstract Our earlier work on reperfusion showed that adult rat hearts released almost twice as much purine nucleosides and oxypurines as newborn hearts did [Am J Physiol 254 (1988) H1091]. A change in the ratio anabolism/catabolism of adenosine could be responsible for this effect. We therefore measured the activity of adenosine kinase, adenosine deaminase, nucleoside phosphorylase and xanthine oxidoreductase in homogenates of hearts and myocytes from neonatal and adult rats. In hearts the activity of adenosine deaminase and nucleoside phosphorylase (10–20 U/g protein) changed relatively little. However, adenosine kinase activity decreased from 1.3 to 0.6 U/g (P < 0.025), and xanthine oxidoreductase activity increased from 0.02 to 0.85 U/g (P < 0.005). Thus the ratio in activity of these rate-limiting enzymes for anabolism and catabolism dropped from 68 to 0.68 during cardiac development. In contrast, the ratio in myocytes remained unchanged (about 23). The large difference in adenosine anabolism/catabolism ratio, observed in heart homogenates, could explain why ATP breakdown due to hypoxia is lower in neonatal than in adult heart. Because this change is absent in myocytes, we speculate that mainly endothelial activities of adenosine kinase and xanthine oxidoreductase are responsible for this shift in purine metabolism during development

Delivering Live Multimedia Streams to Mobile Hosts in a Wireless Internet with Multiple Content Aggregators

We consider the distribution of channels of live multimedia content (e.g., radio or TV broadcasts) via multiple content aggregators. In our work, an aggregator receives channels from content sources and redistributes them to a potentially large number of mobile hosts. Each aggregator can offer a channel in various configurations to cater for different wireless links, mobile hosts, and user preferences. As a result, a mobile host can generally choose from different configurations of the same channel offered by multiple alternative aggregators, which may be available through different interfaces (e.g., in a hotspot). A mobile host may need to handoff to another aggregator once it receives a channel. To prevent service disruption, a mobile host may for instance need to handoff to another aggregator when it leaves the subnets that make up its current aggregator�s service area (e.g., a hotspot or a cellular network).\ud In this paper, we present the design of a system that enables (multi-homed) mobile hosts to seamlessly handoff from one aggregator to another so that they can continue to receive a channel wherever they go. We concentrate on handoffs between aggregators as a result of a mobile host crossing a subnet boundary. As part of the system, we discuss a lightweight application-level protocol that enables mobile hosts to select the aggregator that provides the �best� configuration of a channel. The protocol comes into play when a mobile host begins to receive a channel and when it crosses a subnet boundary while receiving the channel. We show how our protocol can be implemented using the standard IETF session control and description protocols SIP and SDP. The implementation combines SIP and SDP�s offer-answer model in a novel way

Preconditioning in globally ischemic isolated rat hearts: effect on function and metabolic indices of myocardial damage

We assessed the effects of ischemic preconditioning on heart recovery and metabolic indices of damage following global ischemia and reperfusion, in relationship to post-ischemic lactate release. Three groups of Langendorff rat hearts were studied: (1) A control group of 40 min global ischemia and 45 min reperfusion; (2) preconditioning by 5 min global ischemia and 15 min reperfusion prior to sustained ischemia and reperfusion; (3) Preconditioning by three episodes of brief ischemia-re

Absence of beneficial effect of intravenous metoprolol given during angioplasty in patients with single-vessel coronary artery disease

In a double-blind, randomized, placebo-controlled trial, the possible antiischemic effect of metoprolol during percutaneous transluminal coronary angioplasty was tested. Electrocardiograms, hemodynamics, and metabolism were studied in 27 patients with a stenosis in the left anterior descending coronary artery. Measurements took place before angioplasty, after each of four 1-minute occlusions and 15 minutes after the last balloon deflation. Patients were randomly given placebo or metoprolol (15 mg as a bolus intravenously, followed by an infusion 0.04 mg/kg/hr). At the end of the procedure, the rate-pressure product had decreased by 15% (NS) and 23% (p=0.001) in the placebo and metoprolol groups, respectively, mainly due to similar decreases in heart rate. Metoprolol tended to lower chest pain and reduce precordial ST-segment elevation due to angioplasty, but the effects were not statistically significant. Lactate, hypoxanthine, and urate release immediately after deflation was similar in both groups. Metoprolol reduced arterial plasma hypoxanthine throughout the procedure by about 30% (p ≦ 0.02 vs. placebo). Thus, intravenous infusion of metoprolol did not significantly attenuate chest pain and ST-segment elevation, and failed to decrease cardiac lactate and oxypurine release. It did, however, reduce arterial hypoxanthine concentrations during angioplasty, possibly indicating that the beta-blocker inhibits extracardiac ATP catabolism. Cardiovascular Drugs and Therapy Cardiovascular Drugs and Therapy Look Inside 1 Citation Other actions Export citation Register for Journal Updates About This Journal Reprints and Permissions Add to Papers Share Share this content on Facebook Share this content on Twitter Share this content on LinkedI

Urate production by human heart

Xanthine oxidoreductase has been demonstrated in the heart of various species. However, its presence in human heart is still debated. In the literature, high to undetectable levels have been reported. We studied the arterial-venous urate difference across the heart of patients undergoing both routine cardiac catheterization and percutaneous transluminal coronary angioplasty. Urate is the end product of the reaction catalysed by xanthine oxidoreductase. In 10 patients, studied before angioplasty, the plasma urate level in the great cardiac vein exceeded the arterial one by 26 +/- 10 nmol/ml (P = 0.028). In a further 13 patients, urate production was maximal immediately after the last of four consecutive occlusions (23 +/- 8 nmol/ml, P = 0.018) and concomitant with increased coronary sinus hypoxanthine levels. We conclude that xanthine oxidoreductase is probably present in the heart of patients, suffering from ischemic heart disease, and responsible for the increase in urate production during transient myocardial ischemia

Simulation of cell-substrate traction force dynamics in response to soluble factors

Finite element (FE) simulations of contractile responses of vascular muscular thin films (vMTFs) and endothelial cells resting on an array of micro-posts under stimulation of soluble factors were conducted in comparison with experimental measurements reported in literature. Two types of constitutive models were employed in the simulations, i.e. smooth muscle cell type and non-smooth muscle cell type. The time histories of the effects of soluble factors were obtained via calibration against experimental measurements of contractile responses of tissues or cells. The numerical results for vMTFs with micropatterned tissues suggest that the radius of curvature of vMTFs under stimulation of soluble factors is sensitive to width of the micropatterned tissue, i.e. the radius of curvature increases as the tissue width decreases. However, as the tissue response is essentially isometric, the time history of the maximum principal stress of the micropatterned tissues is not sensitive to tissue width. Good agreement has been achieved for predictions of the vasoconstrictor endothelin-1 (ET-1) induced contraction stress between the FE numerical simulation and the experiment based approach of Alford, et al. (2011) for the vMTFs with 40, 60, 80 and 100 μm width patterns. This may suggest the contraction stress is weakly sensitive to the tissue width for these patterns. However, for 20 μm width tissue patterning, the numerical simulation result for contraction stress is less than the average value of experimental measurements, which may suggest the thinner and more elongated spindle-like cells within the 20 μm width tissue patterning have higher contractile output. The constitutive model for non-smooth muscle cells was used to simulate the contractile response of the endothelial cells. The substrate was treated as an effective continuum. For agonists such as Lysophosphatidic acid (LPA) and vascular endothelial growth factor (VEGF), the deformation of the cell diminishes from edge to centre and the central part of the cell is essentially under isometric state. Numerical studies demonstrated the scenarios that cell polarity can be triggered via manipulation of the effective stiffness and Possion’s ratio of the substrate

Tagged IDS causes efficient and engraftment-independent prevention of brain pathology during lentiviral gene therapy for Mucopolysaccharidosis type II

Mucopolysaccharidosis type II (OMIM 309900) is a lysosomal storage disorder caused by iduronate 2-sulfatase (IDS) deficiency and accumulation of glycosaminoglycans, leading to progressive neurodegeneration. As intravenously infused enzyme replacement therapy cannot cross the blood-brain barrier (BBB), it fails to treat brain pathology, highlighting the unmet medical need to develop alternative therapies. Here, we test modified versions of hematopoietic stem and progenitor cell (HSPC)-mediated lentiviral gene therapy (LVGT) using IDS tagging in combination with the ubiquitous MND promoter to optimize efficacy in brain and to investigate its mechanism of action. We find that IDS tagging with IGF2 or ApoE2, but not RAP12x2, improves correction of brain heparan sulfate and neuroinflammation at clinically relevant vector copy numbers. HSPC-derived cells engrafted in brain show efficiencies highest in perivascular areas, lower in choroid plexus and meninges, and lowest in parenchyma. Importantly, the efficacy of correction was independent of the number of brain-engrafted cells. These results indicate that tagged versions of IDS can outperform untagged IDS in HSPC-LVGT for the correction of brain pathology in MPS II, and they imply both cell-mediated and tag-mediated correction mechanisms, including passage across the BBB and increased uptake, highlighting their potential for clinical translation.</p

What is the prevalence of fear of cancer recurrence in cancer survivors and patients? A systematic review and individual participant data meta-analysis

This study was supported by the Dutch Cancer Society (KWF) grant number 10936.Objective Care for fear of cancer recurrence (FCR) is considered the most common unmet need among cancer survivors. Yet the prevalence of FCR and predisposing factors remain inconclusive. To support targeted care, we provide a comprehensive overview of the prevalence and severity of FCR among cancer survivors and patients, as measured using the short form of the validated Fear of Cancer Recurrence Inventory (FCRI-SF). We also report on associations between FCR and clinical and demographic characteristics. Methods This is a systematic review and individual participant data (IPD) meta-analysis on the prevalence of FCR. In the review, we included all studies that used the FCRI-SF with adult (≥18 years) cancer survivors and patients. Date of search: 7 February 2020. Risk of bias was assessed using the Joanna Briggs Institute critical appraisal tool. Results IPD were requested from 87 unique studies and provided for 46 studies comprising 11,226 participants from 13 countries. 9311 respondents were included for the main analyses. On the FCRI-SF (range 0–36), 58.8% of respondents scored ≥13, 45.1% scored ≥16 and 19.2% scored ≥22. FCR decreased with age and women reported more FCR than men. FCR was found across cancer types and continents and for all time periods since cancer diagnosis. Conclusions FCR affects a considerable number of cancer survivors and patients. It is therefore important that healthcare providers discuss this issue with their patients and provide treatment when needed. Further research is needed to investigate how best to prevent and treat FCR and to identify other factors associated with FCR. The protocol was prospectively registered (PROSPERO CRD42020142185).Publisher PDFPeer reviewe