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Bobbert P.,Charite - Medical University of Berlin | Jenke A.,Charite - Medical University of Berlin | Bobbert T.,Charite - Medical University of Berlin | Kuhl U.,Charite - Medical University of Berlin | And 6 more authors.
European Journal of Heart Failure | Year: 2012

AimThe expression of leptin and resistin is known to be positively correlated with the incidence of chronic heart failure (CHF). Both adipokines have been implicated in immunomodulation and cardiac remodelling. Therefore, we performed for the first time a clinical study to elucidate the effects of leptin and resistin on progression of CHF in patients with non-ischaemic dilated (DCM) and inflammatory (DCMi) cardiomyopathy.Methods and resultsFor the clinical study 120 patients were divided into a control (n 16), DCM (n 52), and DCMi (n 52) group to determine the effect of leptin and resistin on CHF progression. Nuclear factor-κB (NF-κB) activation, reactive oxygen species generation, and tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) expression following adipokine exposition were determined in vitro in cardiomyocytes. Leptin and resistin systemic plasma levels and not cardiac expression were significantly elevated in patients with DCM (leptin, 13.12 ± 17.2 ng/mL, P < 0.05; resistin, 6.87 ± 2.25 ng/mL, P < 0.05) and DCMi (leptin, 13.63 ± 16 ng/mL, P < 0.05; resistin, 7.27 ± 2.2 ng/mL, P < 0.05) compared with the control group (leptin, 7.34 ± 5.7 ng/mL; resistin, 4.4 ± 1.18 ng/mL). A multivariate linear regression model revealed low leptin and resistin plasma levels as contributors for favourable cardiac functional parameters at 6-month follow-up independent of inflammatory conditions. Cell culture experiments in vitro showed leptin and resistin to be potent regulators of TNF-α and IL-6 expression in cardiomyocytes, leading to significantly increased redox stress in cardiac cells.ConclusionsHigh leptin and resistin expression in patients with DCM and DCMi is associated with CHF progression, i.e. severe cardiac dysfunction, independent of immune responses. © 2012 The Author.

Tweedy J.,London School of Hygiene and Tropical Medicine | Spyrou M.A.,London School of Hygiene and Tropical Medicine | Spyrou M.A.,University of Tubingen | Hubacek P.,Motol University Hospital | And 3 more authors.
Journal of General Virology | Year: 2015

Human herpesvirus-6A (HHV-6A) is rarer than HHV-6B in many infant populations. However, they are similarly prevalent as germline, chromosomally integrated genomes (ciHHV-6A/B). This integrated form affects 0.1–1% of the human population, where potentially virus gene expression could be in every cell, although virus relationships and health effects are not clear. In a Czech/ German patient cohort ciHHV-6A was more common and diverse than ciHHV-6B. Quantitative PCR, nucleotide sequencing and telomeric integration site amplification characterized ciHHV-6 in 44 German myocarditis/cardiomyopathy and Czech malignancy/inflammatory disease (MI) patients plus donors. Comparisons were made to sequences from global virus reference strains, and blood DNA from childhood-infections from Zambia (HHV-6A mainly) and Japan (HHV-6B). The MI cohort were 86% (18/21) ciHHV-6A, the cardiac cohort 65% (13/20) ciHHV-6B, suggesting different disease links. Reactivation was supported by findings of 1) recombination between ciHHV-6A and HHV-6B genes in 20% (4/21) of the MI cohort; 2) expression in a patient subset, of early/late transcripts from the inflammatory mediator genes chemokine receptor U51 and chemokine U83, both identical to ciHHV-6A DNA sequences; and 3) superinfection shown by deep sequencing identifying minor virus-variants only in ciHHV-6A, which expressed transcripts, indicating virus infection reactivates latent ciHHV-6A. Half the MI cohort had more than two copies per cell, median 5.2, indicative of reactivation. Remarkably, the integrated genomes encoded the secreted-active form of virus chemokines, rare in virus from childhoodinfections. This shows integrated virus genomes can contribute new human genes with links to inflammatory pathology and supports ciHHV-6A reactivation as a source for emergent infection. © 2015 The Authors.

Chattha K.S.,Ohio State University | Vlasova A.N.,Ohio State University | Kandasamy S.,Ohio State University | Esseili M.A.,Ohio State University | And 4 more authors.
Vaccine | Year: 2013

Breast milk (colostrum [col]/milk) components and gut commensals play important roles in neonatal immune maturation, establishment of gut homeostasis and immune responses to enteric pathogens and oral vaccines. We investigated the impact of colonization by probiotics, Lactobacillus rhamnosus GG (LGG) and Bifidobacterium lactis Bb12 (Bb12) with/without col/milk (mimicking breast/formula fed infants) on B lymphocyte responses to an attenuated (Att) human rotavirus (HRV) Wa strain vaccine in a neonatal gnotobiotic pig model. Col/milk did not affect probiotic colonization in AttHRV vaccinated pigs. However, unvaccinated pigs fed col/milk shed higher numbers of probiotic bacteria in feces than non-col/milk fed colonized controls. In AttHRV vaccinated pigs, col/milk feeding with probiotic treatment resulted in higher mean serum IgA HRV antibody titers and intestinal IgA antibody secreting cell (ASC) numbers compared to col/milk fed, non-colonized vaccinated pigs. In vaccinated pigs without col/milk, probiotic colonization did not affect IgA HRV antibody titers, but serum IgG HRV antibody titers and gut IgG ASC numbers were lower, suggesting that certain probiotics differentially impact HRV vaccine responses. Our findings suggest that col/milk components (soluble mediators) affect initial probiotic colonization, and together, they modulate neonatal antibody responses to oral AttHRV vaccine in complex ways. © 2013 Elsevier Ltd.

Schmidt-Lucke C.,Franklin University | Escher F.,Charite - Medical University of Berlin | Escher F.,German Center for Cardiovascular Research | Escher F.,Institute of Cardiac Diagnostics and Therapy IKDT | And 8 more authors.
Mediators of Inflammation | Year: 2015

Introduction. Mesenchymal stromal cells (MSC) have immunomodulatory features. The aim of this study was to investigate the migration and homing potential of endogenous circulating MSC in virus negative inflammatory cardiomyopathy (CMi). Methods. In 29 patients with n=23 or without n=6 CMi undergoing endomyocardial biopsies (EMB), transcardiac gradients (TCGs) of circulating MSC were measured by flow cytometry from blood simultaneously sampled from aorta and coronary sinus. The presence of MSC in EMB, cardiac inflammation, and SDF-1α mRNA expression were detected via immunohistochemistry and real-time PCR. Results. MSC defined as CD45-CD34-CD11b-CD73+CD90+ cells accounted for 0.010 [0.0025-0.048]%/peripheral mononuclear cell (PMNC) and as CD45-CD34-CD11b-CD73+CD105+ cells for 0.019 [0.0026-0.067]%/PMNC, both with similar counts in patients with or without cardiac inflammation. There was a 29.9% P<0.01 transcardiac reduction of circulating MSC in patients with CMi, correlating with the extent of cardiac inflammation (P<0.05, multivariate analysis). A strong correlation was found between the TCG of circulating MSC and numbers of MSC (CD45-CD34-CD90+CD105+) in EMB (r=-0.73, P<0.005). SDF-1α was the strongest predictor for increased MSC in EMB (P<0.005, multivariate analysis). Conclusions. Endogenous MSC continuously migrate to the heart in patients with CMi triggered by cardiac inflammation. © 2015 Caroline Schmidt-Lucke et al.

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