Administration of bone marrow-derived mononuclear cells (BMC) may increase cardiac function after myocardial ischemia. However, the functional capacity of BMC derived from chronic heart failure (CHF) ...patients is significantly impaired. As modulation of the energy metabolism allows cells to match the divergent demands of the environment, we examined the regulation of energy metabolism in BMC from patients and healthy controls (HC). The glycolytic capacity of CHF-derived BMC is reduced compared to HC, whereas BMC of metabolically activated bone marrow after acute myocardial infarction reveal increased metabolism. The correlation of metabolic pathways with the functional activity of cells indicates an influence of metabolism on cell function. Reducing glycolysis without profoundly affecting ATP-production reversibly reduces invasion as well as colony forming capacity and abolishes proliferation of CD34(+) CD38(-) lin(-) hematopoietic stem and progenitor cells (HSPC). Ex vivo inhibition of glycolysis further reduced the pro-angiogenic activity of transplanted cells in a hind limb ischemia model in vivo. In contrast, inhibition of respiration, without affecting total ATP production, leads to a compensatory increase in glycolytic capacity correlating with increased colony forming capacity. Isolated CD34(+) , CXCR4(+) , and CD14(+) cells showed higher glycolytic activity compared to their negative counterparts. Metabolic activity was profoundly modulated by the composition of media used to store or culture BMC. This study provides first evidence that metabolic alterations influence the functional activity of human HSPC and BMC independent of ATP production. Changing the balance between respiration and glycolysis might be useful to improve patient-derived cells for clinical cardiac cell therapy. Stem Cells 2016;34:2236-2248.
Coronary artery disease (CAD) patients have less circulating proangiogenic cells (PACs), formerly known as endothelial progenitor cells, which exhibit impaired neovascularization properties. Inverse ...correlations were also found between PAC function and risk factors like age. Krüppel-like factor 2 (KLF2) is expressed by mature endothelial cells (ECs), is induced by both shear stress and statins, and provokes endothelial functional differentiation. The aim of this study is to identify whether KLF2 can reverse negative effects of ageing on PAC function.
We describe that progenitor cells in the bone marrow and PACs also express KLF2 at a comparable level to mature ECs and that senescence decreases KLF2 levels. To study the effects of ageing on KLF2 levels, we compared progenitor cells of 4 weeks and 16- to 18-month-old C57BL/6 mice. In addition to the three-fold reduction of circulating Sca1(+)/c-Kit(+)/Lin(-) progenitor cells and the 15% reduction of Sca1(+)/Flk1(+) endothelial-committed progenitor cells, the spleen-derived PACs and bone marrow-derived progenitor cells isolated from aged mice showed a lower level of KLF2 when compared with young mice. Lentiviral overexpression of KLF2 increased human PAC numbers and endothelial nitric oxide synthase expression by 60% during in vitro culture. Endothelial lineage-specific KLF2 overexpression in aged bone marrow-derived mononuclear cells strongly augments neovascularization in vivo in a murine hind-limb ischaemia model.
These results imply that KLF2 is an attractive novel target to rejuvenate PACs before autologous administration to CAD patients.
Chronic heart failure (CHF) is associated with a 4-fold increased risk for osteoporotic fractures. Therefore, we sought to identify the pathophysiological link between chronic heart failure and ...catabolic bone remodeling.
In a total cohort of 153 subjects (123 patients with CHF, 30 patients with coronary artery disease and preserved cardiac function) as well as mice with heart failure, bone marrow (BM) plasma levels of the catabolic receptor activator of NF-κB ligand (RANKL), and its antagonist, osteoprotegerin were measured. The osteoclast inducing activity of BM plasma was tested in cell culture. BM plasma levels of RANKL and of the ratio RANKL/osteoprotegerin were significantly elevated in patients with CHF. On multivariate regression analysis, parameters of severity and duration of heart failure were independent determinants of elevated BM plasma RANKL levels. BM plasma levels of RANKL were directly correlated with the systemic marker of bone turnover C-telopeptide of type 1 collagen (r=0.6; P<0.001). Alterations in BM plasma levels of RANKL/osteoprotegerin were confirmed in a mouse model of postinfarction heart failure. Stimulation of human mesenchymal cells with BM plasma obtained from CHF patients increased the formation of osteoclasts, and this effect was blocked by the RANKL inhibition.
CHF is associated with a profound and selective elevation of the bone resorption stimulating RANKL within the BM microenvironment. These data for the first time disclose a direct pathophysiological pathway linking CHF with catabolic bone remodeling associated with an increased osteoporotic fracture risk.
URL: http://www.clinicaltrials.gov. Unique identifiers: NCT 00289822, NCT 00284713, NCT 00326989, NCT 00962364.
My dissertation shows that the ideology concept developed by Karl Marx was first and foremost a critique of mental labor in bourgeois society, rather than a philosophy of consciousness, as is ...commonly assumed. Marx's theory of ideology constituted a pivotal moment in the formation of his critique of political economy insofar as it offered a solution to the problem of idealist metaphysics, discussed among the Left Hegelian philosophers in the late 1830's and early 1840's, by explaining it in terms of its origin in the class structure of capitalist society. I interpret Marx's texts using the approach of the "Cambridge School" of the history of political thought (Quentin Skinner), which has stressed the importance of examining classical texts in terms of their authors' explicit objectives, the polemical function of philosophical language as individual speech acts, and the contextual nature of particular ideas and concepts. Based on a close study and analysis of one of Marx's so-called "works of the break," my investigation focuses on establishing the original meaning of "ideology" in relation to the Young Hegelian case for the "end of philosophy." While it is generally recognized that The German Ideology, written in 1845/46 by Marx and Engels, is a key text in nineteenth century intellectual history, few attempts have been made to subject this complicated manuscript to a comprehensive analysis. Consequently, the connection between ideology and the capitalist division of labor has not been duly recognized. Most broadly, then, the goal of this dissertation is to reconstruct Marx's effort to fully secularize post-Enlightenment critical philosophy by applying the tools of political economy to the question that animated the intellectual debate at the time: the question of how to come to terms with, and overcome, Hegel's metaphysical idealism. The significance of my dissertation lies in its contribution to nineteenth-century intellectual history, to the study of critical social theory, and to contemporary discussions of the Marxist tradition. Because exegetical projects have typically converged on just the first hundred pages, one quarter of the complete manuscripts, this section, titled "I. Feuerbach," has gained misleading prominence in readings of The German Ideology. "I Feuerbach" resembles a discourse on method because of its general comments on "the correct manner of approach," but its importance within the work as a whole is questionable due to its fragmented and unfinished state. In order to shift our understanding of The German Ideology toward a better appreciation of Marx's concrete analysis of the typical (because characteristically bourgeois) yet peculiar (because uniquely passive) expressions of the German intelligentsia, I privilege instead the longest part of the manuscript, "III. Saint Max," Marx and Engels's exhaustive settling of accounts with Max Stirner's 1844 book The Ego and Its Own. This book was then the most radical attempt to break with the Left Hegelian critique of religion and prompted Marx to subject his own Feuerbachian assumptions to thorough scrutiny. Revealing Stirner's "Ego" – the singular, separate, fully sovereign individual – to be no alternative to Feuerbach's "Man" but rather another humanist abstraction from the real relations that define people in their particular social situations, Marx took the decisive step to produce a materialist, i.e. economic, account of ideology. By focusing my inquiry on Marx's response to Stirner, which remained unpublished until 1932, I reread The German Ideology in terms of its specific arguments against the Young Hegelian idealist distortion of particular historical events, social transformations, and contradictions. However, by situating the work squarely within the context of the early nineteenth-century debates over how to successfully "world" Hegel's dialectic, I also recover Marx's particular intervention in these debates. Marx, I show, was able to overcome the idealism of his former friends and allies by grounding the critique of philosophy in a theory of the intricate connection between labor, class, and practice. (Abstract shortened by UMI.)
Invasive listeriosis is a severe foodborne infection in humans and is difficult to control. Listeriosis incidence is increasing worldwide, but some countries have implemented molecular surveillance ...programs to improve recognition and management of listeriosis outbreaks. In Germany, routine whole-genome sequencing, core genome multilocus sequence typing, and single nucleotide polymorphism calling are used for subtyping of Listeria monocytogenes isolates from listeriosis cases and suspected foods. During 2018-2019, an unusually large cluster of L. monocytogenes isolates was identified, including 134 highly clonal, benzalkonium-resistant sequence type 6 isolates collected from 112 notified listeriosis cases. The outbreak was one of the largest reported in Europe during the past 25 years. Epidemiologic investigations identified blood sausage contaminated with L. monocytogenes highly related to clinical isolates; withdrawal of the product from the market ended the outbreak. We describe how epidemiologic investigations and complementary molecular typing of food isolates helped identify the outbreak vehicle.
To compare long-term outcome of children and young adults with arterial ischemic stroke (AIS) from 2 large registries.
Prospective cohort study comparing functional and psychosocial long-term outcome ...(≥2 years after AIS) in patients who had AIS during childhood (1 month-16 years) or young adulthood (16.1-45 years) between January 2000 and December 2008, who consented to follow-up. Data of children were collected prospectively in the Swiss Neuropediatric Stroke Registry, young adults in the Bernese stroke database.
Follow-up information was available in 95/116 children and 154/187 young adults. Median follow-up of survivors was 6.9 years (interquartile range 4.7-9.4) and did not differ between the groups (p = 0.122). Long-term functional outcome was similar (p = 0.896): 53 (56%) children and 84 (55%) young adults had a favorable outcome (modified Rankin Scale 0-1). Mortality in children was 14% (13/95) and in young adults 7% (11/154) (p = 0.121) and recurrence rate did not differ (p = 0.759). Overall psychosocial impairment and quality of life did not differ, except for more behavioral problems among children (13% vs 5%, p = 0.040) and more frequent reports of an impact of AIS on everyday life among adults (27% vs 64%, p < 0.001). In a multivariate regression analysis, low Pediatric NIH Stroke Scale/NIH Stroke Scale score was the most important predictor of favorable outcome (p < 0.001).
There were no major differences in long-term outcome after AIS in children and young adults for mortality, disability, quality of life, psychological, or social variables.
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