Current concepts on ventricular fibrillation: A Vicious Circle of Cardiomyocyte Calcium Overload in the Initiation, Maintenance, and Termination of Ventricular Fibrillation

Based on recent experimental studies, this review article introduces the novel concept that cardiomyocyte Ca(2+) and ventricular fibrillation (VF) are mutually related, forming a self-maintaining vicious circle in the initiation, maintenance, and termination of VF. On the one hand, elevated myocyte Ca(2+) can cause delayed afterdepolarizations, triggered activity, and consequently life-threatening ventricular tachyarrhythmias in various pathological conditions such as digitalis toxicity, myocardial ischemia, or heart failure. On the other hand, VF itself directly and rapidly causes progressive myocyte Ca(2+) overload that maintains VF and renders termination of VF increasingly difficult. Accordingly, energy levels for successful electrical defibrillation (defibrillation thresholds) increase as both VF and Ca(2+) overload progress. Furthermore, VF-induced myocyte Ca(2+) overload can promote re-induction of VF after defibrillation and/or postfibrillatory myocardial dysfunction (postresuscitation stunning) due to reduced myofilament Ca(2+) responsiveness. The probability of these adverse events is best reduced by early detection and rapid termination of VF to prevent or limit Ca(2+) overload. Early additional therapy targeting transsarcolemmal Ca(2+) entry, particularly during the first 2 min of VF, may partially prevent myocyte Ca(2+) overload and thus, increase the likelihood of successful defibrillation as well as prevent postfibrillatory myocardial dysfunction

Brushing without brushing?—a review of the efficacy of powered toothbrushes in noncontact biofilm removal

Objectives: The aim of the present review was to analyze the impact of the hydrodynamic effects created by powered toothbrushes on biofilm removal in vitro. Materials and methods: A MEDLINE search was performed for publications published by 20 May 2012; this search was complemented by a manual search. The study selection, data preparation, and validity assessment were conducted by two reviewers. Results: Sixteen studies were included. The studies differed with respect to the methods of biofilm formation and brushing protocols. Eighteen different powered toothbrush models were evaluated. Toothbrushes with side-to-side action demonstrated biofilm removal without direct bristle contact to biofilms ranging from 38 to 99%. Most studies found biofilm removal exceeding 50%. Biofilm reduction using multidimensional toothbrushes was significantly lower than by those with the side-to-side mode. Detachment forces due to hydrodynamic phenomena, passing air-liquid interfaces, and acoustic energy transfer were suggested to cause reduction of the biofilm. Conclusion: Noncontact biofilm reduction was obtained by the hydrodynamic effects of some powered toothbrushes in vitro. Clinical relevance: Powered toothbrushes may have the potential to simplify self-performed oral hygiene. However, additional beneficial effects of higher amounts of noncontact biofilm removal in vitro have not been shown clinically, ye

Converbs, Medial Verbs, Clause Chaining and Related Issues

This volume grew out of a workshop on "Converbs, medial verbs, clause chaining and related issues" held at Leiden University on 8th December 2006, which was cosponsored by the Swiss National Science Fotmdation (SNF) project "Functional typology of Ethiopian languages" (no. 100012-\09306). That occasion brought together specialists working on a range of languages spoken in a circle that spans from New Caledonia via India to Ethiopia and Mozambique. All while struggling to find a common language to talk about phenomena that are so pervasive in our respective languages of investigation, our discussions greatly benefited from the pooling of experiences in fields between which scientific exchange is often obstructed by the boundaries of various traditions. Far from adhering all to one theory or perspective, we hope that bringing together the following articles in one volume will provide new data and insights for tile already lively discussion around converbs, medial verbs and related issues. We wish to thank the editorial board of the Frankfurter Afrikanistische Blatter for accepting this volume in their journal and for their willingness to publish articles that go beyond African languages. In the same vein, we wish to thank all contributors to this volume, and especially our non-Africanist colleagues that have crossed one or more continental and disciplinary divides by publishing in this journal. Special mention and thanks are due to Sascha Völlmin, who did the layout of the whole volume. Finally, we hereby gratefully acknowledge the financial and logistical support of the workshop by the Institute of African Languages and Cultures, Leiden, and the Swiss National Science Foundation

Bradykinin improves postischaemic recovery in the rat heart: role of high energy phosphates, nitric oxide, and prostacyclin

Objective: The aim was to define: (1) whether bradykinin administration during reperfusion improves postischaemic myocardial recovery; (2) whether high energy phosphate compounds are involved in the protective effects of bradykinin; and (3) whether bradykinin-induced release of prostacyclin and nitric oxide mediate the protective effects of bradykinin. Methods: In the Langendorff rat heart preparation, coronary flow, left ventricular developed pressure, and, using 31P magnetic resonance spectroscopy, the high energy phosphate compounds phosphocreatine and β-ATP were assessed during 15 min of global ischaemia and 30 min of reperfusion. Administration of 10−7 M bradykinin was started before ischaemia and maintained throughout the experiment (BK-pre). This was compared to 10−7 M bradykinin given exclusively with reperfusion (BK-post). Then 10−7 M bradykinin was given simultaneously with 10−4 M Nω-nitro-L-arginine-methyl ester (BK-LNAME) or 10−5 M indomethacin (BK-indo). Results: In comparison to control hearts, BK-pre exerted a significant protective effect on the postischaemic recovery of coronary flow [71(5)% v 43(4)%, P < 0.05], left ventricular pressure [81(8)% v 42(5)%, P < 0.05], phosphocreatine [105(4)% v 67(8)%, P < 0.05], and β-ATP [78(9)% v 48(7)%, P < 0.05]. With BK-post, recovery of coronary flow [71(4)% v 43(4)%, P < 0.05] and left ventricular pressure [78(4)% v 42(5)%, P < 0.05] significantly improved; however the recovery of phosphocreatine [70(4)% v 67(8)%, NS] and β-ATP [58(2)% v 48(7)%, NS] was not different from control. When bradykinin and L-NAME or indomethacin was given the beneficial effects of bradykinin on ischaemic hearts were abolished. Conclusions: (1) Bradykinin improved postischaemic myocardial recovery when given before ischaemia or starting exclusively with reperfusion; (2) this was only partially related to a protective action on the high energy phosphate compounds during ischaemia; (3) the beneficial effects of bradykinin on ischaemic hearts are dependent from an unrestrained action of prostacyclin and nitric oxid

Antiarrhythmic effect of ischemic preconditioning during low-flow ischemia: The role of bradykinin and sarcolemmal versus mitochondrial ATP-sensitive K+ channels

Abstract. : Short episodes of ischemia (ischemic preconditioning) protect the heart against ventricular arrhythmias during zero-flow ischemia and reperfusion. However, in clinics, many episodes of ischemia present a residual flow (low-flow ischemia). Here we examined whether ischemic preconditioning protects against ventricular arrhythmias during and after a low-flow ischemia and, if so, by what mechanism(s). Isolated rat hearts were subjected to 60 min of low-flow ischemia (12% residual coronary flow) followed by 60 min of reperfusion. Ischemic preconditioning was induced by two cycles of 5 min of zero-flow ischemia followed by 5 and 15 min of reperfusion, respectively. Arrhythmias were evaluated as numbers of ventricular premature beats (VPBs) as well as incidences of ventricular tachycardia (VT) and ventricular .brillation (VF) during low-flow ischemia and reperfusion. Ischemic preconditioning significantly reduced the number of VPBs and the incidence of VT and of VF during low-flow ischemia. This antiarrhythmic effect of preconditioning was abolished by HOE 140 (100 nM), a bradykinin B2 receptor blocker. Similar to preconditioning, exogenous bradykinin (10 nM) reduced the number of VPBs and the incidence of VT and of VF during low-flow ischemia. Furthermore, the antiarrhythmic effects of both ischemic preconditioning and bradykinin were abolished by glibenclamide (1 µM), a non-specific blocker of ATP-sensitive K+ (KATP) channels. Finally, the antiarrhythmic effects of both ischemic preconditioning and bradykinin were abolished by HMR 1098 (10 µM), a sarcolemmal KATP channel blocker but not by 5-hydroxydecanoate (100 µM), a mitochondrial KATP channel blocker. In conclusion, ischemic preconditioning protects against ventricular arrhythmias induced by low-flow ischemia, and this protection involves activation of bradykinin B2 receptors and subsequent opening of sarcolemmal but not of mitochondrial KATP channel

Intracellular calcium transients underlying interval-force relationship in whole rat hearts: effects of calcium antagonists

Objectives: Much of the understanding about the cardiac interval-force relationship of the whole heart, including mechanical restitution and postextrasystolic potentiation (PESP), has been inferred from isolated muscle studies. We tested whether results from isolated muscles about intracellular Ca2+([Ca2+]i) transients underlying the interval-force relationship can be substantiated in whole hearts. Additionally, we investigated whether Ca2+ antagonists could alter [Ca2+]i transients underlying mechanical restitution and postextrasystolic potentiation. Methods: [Ca2+]i transients were studied in isolated perfused rat hearts by surface fluorometry and Indo-1. Using computer-controlled pacing protocols, we performed restitution curves for left ventricular developed pressure and [Ca2+]i (developed pressure and [Ca2+]i plotted as a function of extrasystolic intervals). To quantify restitution curves, we fitted monoexponential functions to plots and analyzed their shift and slope. Then, we used Ca2+ antagonists, low extracellular Ca2+([Ca2+]o) and PESP to modify restitution curves. [Ca2+]i transients in isolated rat hearts were interpreted as Ca2+ released from the sarcoplasmic reticulum. Results: Interval-dependent changes in developed pressure were strongly correlated to interval-dependent changes in the amplitude of [Ca2+]i transients in isolated whole rat hearts. Additionally, nifedipine and low [Ca2+]o led to similar downward shifts but not to a changed slope of restitution curves for [Ca2+]i. On the other hand, PESP increased the slope of restitution curves for [Ca2+]i. Furthermore, the effect of PESP on developed pressure was blunted by high concentrations of Ca2+ antagonists. Conclusions: The results from isolated muscles about [Ca2+]i transients underlying the interval-force relationship could be substantiated in whole hearts. Additionally, low [Ca2+]i (induced by nifedipine or low [Ca2+]o) decreased the maximal Ca2+ release of the sarcoplasmic reticulum but did not change the release kinetics. On the other hand, PESP presumably accelerated Ca2+ release kinetics of the sarcoplasmic reticulu

B2-kinin receptor plays a key role in B1-, angiotensin converting enzyme inhibitor-, and vascular endothelial growth factor-stimulated in vitro angiogenesis in the hypoxic mouse heart

Aims Angiotensin converting enzyme (ACE) inhibition reduces heart disease and vascular stiffness in hypertension and leads to kinin accumulation. In this study, we analysed the role and importance of two kinin receptor subtypes in angiogenesis during ACE inhibition in an in vitro model of angiogenesis of the mouse heart. Methods and results First, we analysed the angiogenic properties of bradykinin and enalapril on wild-type C57Bl/6 and B2 receptor−/− mouse heart under normoxia (21% O2) and hypoxia (1% O2) in vitro and the contribution of B1 and B2 kinin receptors to this effect. Bradykinin induced dose-dependent endothelial sprout formation in vitro in adult mouse heart only under hypoxia (1.7 fold, n = 6, P < 0.05). The B2 receptor mediated sprouting that was induced by bradykinin and vascular endothelial growth factor (VEGF164; n = 6, P < 0.05), but did not mediate sprouting that was induced by growth factors bFGF or PDGF-BB. Enalapril induced sprouting through both the B1 and B2 kinin receptors, but it required the presence of the B2 receptor in both scenarios and was dependent on BK synthesis. B1-receptor agonists induced sprout formation via the B1 receptor (2.5 fold, n = 6, P < 0.05), but it required the presence of the B2 receptor for them to do so. Both B2-receptor and B1-receptor agonist-induced angiogenesis required nitric oxide biosynthesis. Conclusion The kinin B2 receptor plays a crucial role in angiogenesis that is induced by different vasoactive molecules, namely bradykinin, ACE inhibitors, B1-stimulating kinin metabolites, and VEGF164 in an in vitro model of angiogenesis of mouse heart under hypoxia. Therapeutic treatment of hypertensive patients by using ACE inhibitors may potentially benefit the ischaemic heart through inducing B2-dependent heart neovascularizatio

Cytotoxic CD8+ Temra cells show loss of chromatin accessibility at genes associated with T cell activation

As humans age, their memory T cell compartment expands due to the lifelong exposure to antigens. This expansion is characterized by terminally differentiated CD8+ T cells (Temra), which possess NK cell-like phenotype and are associated with chronic inflammatory conditions. Temra cells are predominantly driven by the sporadic reactivation of cytomegalovirus (CMV), yet their epigenomic patterns and cellular heterogeneity remain understudied. To address this gap, we correlated their gene expression profiles with chromatin openness and conducted single-cell transcriptome analysis, comparing them to other CD8+ subsets and CMV-responses. We confirmed that Temra cells exhibit high expression of genes associated with cytotoxicity and lower expression of costimulatory and chemokine genes. The data revealed that CMV-responsive CD8+ T cells (Tcmv) were predominantly derived from a mixed population of Temra and memory cells (Tcm/em) and shared their transcriptomic profiles. Using ATAC-seq analysis, we identified 1449 differentially accessible chromatin regions between CD8+ Temra and Tcm/em cells, of which only 127 sites gained chromatin accessibility in Temra cells. We further identified 51 gene loci, including costimulatory CD27, CD28, and ICOS genes, whose chromatin accessibility correlated with their gene expression. The differential chromatin regions Tcm/em cells were enriched in motifs that bind multiple transcriptional activators, such as Jun/Fos, NFkappaB, and STAT, whereas the open regions in Temra cells mainly contained binding sites of T-box transcription factors. Our single-cell analysis of CD8+CCR7loCD45RAhi sorted Temra population showed several subsets of Temra and NKT-like cells and CMC1+ Temra populations in older individuals that were shifted towards decreased cytotoxicity. Among CD8+CCR7loCD45RAhi sorted cells, we found a decreased proportion of IL7R+ Tcm/em-like and MAIT cells in individuals with high levels of CMV antibodies (CMVhi). These results shed new light on the molecular and cellular heterogeneity of CD8+ Temra cells and their relationship to aging and CMV infection