Life span in individual humans is very heterogeneous.Thus, the ageing rate, measured as the decline of functional capacity and stress resistance, is different in every individual. There have been attempts made to analyse this individual age, the so-called biological age, in comparison to chronological age. Biomarkers of ageing should help to characterise this biological age and, as age is a major risk factor in many degenerative diseases,could be subsequently used to identify individuals at high risk of developing age-associated diseases or disabilities. Markers based on oxidative stress, protein glycation,inflammation, cellular senescence and hormonal deregulation are discussed.
Background: Cardiac surgery often represents the only treatment option in patients with infective endocarditis (IE). However, IE surgery may lead to a sudden release of inflammatory mediators, which is associated with the severity of postoperative organ dysfunction. We investigated the impact of hemoadsorption during IE surgery on postoperative organ dysfunction. Methods: This multi-center, randomized, non-blinded, controlled trial assigned patients undergoing cardiac surgery for IE to hemoadsorption [integration of CytoSorb® to cardiopulmonary bypass (CPB)] or control. The Primary outcome (ΔSOFA) was defined as the difference between the mean total postoperative sequential organ failure assessment score (SOFA), calculated maximally to the 9th postoperative day, and the basal SOFA score. The analysis was by modified intention-to-treat. A predefined inter-group comparison was done using a linear mixed model for ΔSOFA including surgeon and baseline SOFA as fixed effect covariates and with the surgical center as random effect. The SOFA score assesses dysfunction in six organ systems, each scored from zero to four. Higher scores indicate worsening dysfunction. Secondary outcomes were 30-day mortality, durations of mechanical ventilation, vasopressor and renal replacement therapy. Cytokines were measured in the first 50 patients. Results: Between January 17, 2018 and January 31, 2020, A total of 288 patients were randomly assigned to hemoadsorption (n=142) or control (n=146). Four patients in the hemoadsorption and two in the control group were excluded as they did not undergo surgery. The primary outcome ΔSOFA did not differ between the hemoadsorption and the control group (1.79 ± 3.75 and 1.93 ± 3.53, respectively, 95% CI: −1.30 to 0.83, p=0.6766). Mortality at 30 days (21% hemoadsorption vs 22% control, p=0.782), the durations of mechanical ventilation, vasopressor and renal replacement therapy did not differ between groups. Levels of IL-1β and IL-18 at the end of CPB were significantly lower in the hemoadsorption than in the control group. Conclusions: This randomized trial failed to demonstrate a reduction in postoperative organ dysfunction through intraoperative hemoadsorption in patients undergoing cardiac surgery for IE. Although hemoadsorption reduced plasma cytokines at the end of CPB, there was no difference in any of the clinically relevant outcome points.
Inflammatory pathways are involved in the development of atherosclerosis. Interaction of vessel wall cells and invading monocytes by cytokines may trigger local inflammatory processes. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are standard medications used in cardiovascular diseases. They are thought to have anti-inflammatory capacities, in addition to their lipid-lowering effects. We investigated the anti-inflammatory effect of statins in the cytokine-mediated-interaction-model of human vascular smooth muscle cells (SMC) and human mononuclear cells (MNC). In this atherosclerosis-related inflammatory model LPS (lipopolysaccharide, endotoxin), as well as high mobility group box 1 stimulation resulted in synergistic (i.e. over-additive) IL-6 (interleukin-6) production as measured in ELISA. Recombinant IL-1, tumour necrosis factor-α and IL-6 mediated the synergistic IL-6 production. The standard anti-inflammatory drugs aspirin and indomethacin (Indo) reduced the synergistic IL-6 production by 60%. Simvastatin, atorvastatin, fluvastatin or pravastatin reduced the IL-6 production by 53%, 50%, 64% and 60%, respectively. The inhibition by the statins was dose dependent. Combination of statins with aspirin and/or Indo resulted in complete inhibition of the synergistic IL-6 production. The same inhibitors blocked STAT3 phosphorylation, providing evidence for an autocrine role of IL-6 in the synergism. MNC from volunteers after 5 day aspirin or simvastatin administration showed no decreased IL-6 production, probably due to drug removal during MNC isolation. Taken together, the data show that anti-inflammatory functions (here shown for statins) can be sensitively and reproducibly determined in this novel SMC/MNC coculture model. These data implicate that statins have the capacity to affect atherosclerosis by regulating cytokine-mediated innate inflammatory pathways in the vessel wall.
This review addresses pharmacological, structural and functional relationships among H2-histamine receptors and H1-histamine receptors in the mammalian heart. The role of both receptors in the regulation of force and rhythm, including their electrophysiological effects on the mammalian heart, will then be discussed in context. The potential clinical role of cardiac H2-histamine-receptors in cardiac diseases will be examined. The use of H2-histamine receptor agonists to acutely increase the force of contraction will be discussed. Special attention will be paid to the potential role of cardiac H2-histamine receptors in the genesis of cardiac arrhythmias. Moreover, novel findings on the putative role of H2-histamine receptor antagonists in treating chronic heart failure in animal models and patients will be reviewed. Some limitations in our biochemical understanding of the cardiac role of H2-histamine receptors will be discussed. Recommendations for further basic and translational research on cardiac H2-histamine receptors will be offered. We will speculate whether new knowledge might lead to novel roles of H2-histamine receptors in cardiac disease and whether cardiomyocyte specific H2-histamine receptor agonists and antagonists should be developed.
Inflammatory mechanisms contribute to atherogenesis. Monocyte chemoattractant protein (MCP)-1 and IL-6 are potent mediators of inflammation. Both contribute to early atherogenesis by luring monocytes and regulating cell functions in the vessel wall. MCP-1 and IL-6 production resulting from the interaction of invading monocytes with local vessel wall cells may accelerate atherosclerosis. We investigated the influence of the interaction of human vascular smooth muscle cells (SMCs) with human mononuclear cells (MNCs) or monocytes on IL-6 and MCP-1 production in a coculture model. Interaction synergistically enhanced IL-6 and MCP-1 production (up to 30- and 10-fold, respectively) compared with separately cultured cells. This enhancement was mediated by CD14-positive monocytes. It was dependent on the SMC-to-MNC/monocyte ratio, and as few as 0.2 monocytes/SMC induced the synergism. Synergistic IL-6 production was observed at the protein, mRNA, and functional level. It was mediated by soluble factors, and simultaneous inhibition of IL-1, TNF-alpha, and IL-6 completely blocked the synergism. IL-1, TNF-alpha, and IL-6 were present in the cultures. Blockade of the synergism by soluble glycoprotein 130Fc/soluble IL-6 receptor, as well as the induction of synergistic IL-6 production by costimulation of SMCs with IL-1, TNF-alpha, and hyper-IL-6, suggested the involvement of IL-6 trans-signaling. The contribution of IL-6 was consistent with enhanced STAT3 phosphorylation. The present data suggest that SMC/monocyte interactions may augment the proinflammatory status in the tissue, contributing to the acceleration of early atherogenesis.
Previous studies have demonstrated that exposure to psychostimulant drugs can produce a lasting crosssensitization to the behavioral effects of stress. The main purpose the present study was, therefore, to determine the effects of psychostimulant cross-sensitization on the stressinduced release of adrenocorticotropic hormone (ACTH) and corticosterone (CORT). Rats were given a series of injections of d -amphetamine or vehicle in a regimen (Goldstein 1990;Henry 1992;Folkow 1997;Sapolsky et al. 2000). Consequently, a complex set of homeostatic mechanisms, which include endocrine, metabolic, immune and neural defensive reactions, has evolved to ensure that the harmful effects of most stressors rarely exceed an organism's capacity to cope with them (Johnson et al. 1992;McEwen 1998). In certain instances, however, these homeostatic mechanisms become compromised, such as after chronic hypothalamicpituitary-adrenal (HPA) axis activation or prolonged stress, and the noxious effects of stressors then become exaggerated (McEwen 1998;Brown et al. 1999). The emerging concept of a physiological and psychological cost involved with chronically heightened neuroendocrine arousal to environmental stimuli, often referred to as "allostatic load", is seeing increased interest as an imporDepartment of Psychology (AMB, CEH, JW, AGP), Department of Anatomy (CEH, JW), Department of Psychiatry (AGP), University of British Columbia, Vancouver, Canada Address correspondence to: Anthony G. Phillips, Department of Psychology, 2136 West Mall, University of British Columbia, Vancouver, Canada, V6T1Z4, Tel.: 604-822-3245, Fax: 604-822-6923, E-mail: aphillips@cortex.psych.ubc.ca Received August 31, 2000; revised March 28, 2001; accepted June 5, 2001.Online publication: 6/6/01 at www.acnp.org/citations/Npp 060601130 N EUROPSYCHOPHARMACOLOGY 2002 -VOL . 26 , NO . 3 D -amphetamine Induces Sensitization of HPA Axis 287 tant factor in the development of many forms of human disease (McEwen 2000;Koob and Le Moal 2001). A wealth of evidence suggests that an increased reactivity to stressors and/or the inability to respond effectively and appropriately to stressors plays an important role in the development and expression of many forms of mental illness (Ehlert and Straub 1998;Kreek and Koob 1998;Dohrenwend 2000;Heim et al. 2000). Clearly, a better understanding of the underlying neurobiology of this sensitivity to stressors may help in the prophylaxis and treatment of these disorders.Animal and human studies have demonstrated that environmental manipulation, such as exposure to alcohol or stress during the pre-and early postnatal period (Liang and Boyce 1993;Weinberg et al. 1996;Day et al. 1998), can modify an organism's response to stressors. Such manipulations may lead to an increased reactivity to stressors ("sensitization"), which can be expressed both behaviourally and neurochemically (Pitman et al. 1990;Badiani et al. 1996;Pani et al. 2000). One form of sensitization involves the capacity of psychostimulant drugs, such as cocaine and d -amp...
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