Very small embryonic-like stem cells in cardiovascular repair

Adult bone marrow (BM) harbors several small populations of cells which may contribute to cardiac and endothelial repair, such as endothelial progenitor cells (EPCs), mesenchymal stromal cells (MSCs) and very small embryonic-like cells (VSELs) expressing several markers of pluripotent stem cells (PSCs), such as Oct-4, Nanog and SSEA-1. Such cells were identified in mice bone marrow, peripheral blood and solid organs as well as in umbilical cord blood (UCB) and peripheral blood (PB) in humans. The adult BM-derived VSELs may undergo differentiation into cells derived for all three germ layers, including cardiomyocytes and vascular endothelial cells. VSELs can be isolated using a multiparameter live cell sorting technique with special gating strategy based on their small size, expression of stem cell markers (Sca-1 in mice, CXCR4 and CD133 in humans) and absence of hematopoietic lineage markers (CD45(-) Lin(-)). Experiments in murine models of myocardial infarction (MI) demonstrated population of VSELs expressed also early markers of cardiac and endothelial lineages (GATA-4, Nkx2.5/Csx, VE-cadherin, von Willebrand factor) which migrated to stromal-derived factor-1 (SDF-1) and other chemoattractant gradient and underwent rapid mobilization into peripheral blood in experimental MI mice models. Recently, we demonstrated the mobilization of VSELs expressing PSC, early cardiac and endothelial markers in patients with acute MI. In addition to BM, VSELs were also identified in several murine solid organs including the heart and brain, as well as in umbilical cord blood and peripheral blood in adult humans. We hypothesized that VSELs are quiescent progeny of epiblast-derived PSCs that are deposited during organogenesis in developing organs. In experimental MI intramyocardial injection of VSELs was more efficient than that of HSCs at improving left ventricular ejection fraction and attenuation of myocardial hypertrophy. VSELs can be useful in translational studies of cardiovascular repair.     

The Effect of Chronic Mild Stress and Imipramine on the Markers of Oxidative Stress and Antioxidant System in Rat Liver

Liver abnormalities have been reported to occur in up to 20 % of patients on a long-term therapy with the tricyclic antidepressant drug imipramine (IMI). The mechanism involved in this IMI-induced process is unknown but a contribution of oxidative stress is highly likely. Chronic mild stress (CMS) is widely used for modeling depressive-like behavior in rats. In the present study, we examined the effects of CMS and chronic IMI treatment, applied alone or in combination, on the levels of oxidative stress markers, such as reactive oxygen species (ROS), malondialdehyde (MDA), non-protein sulfhydryl groups, and sulfane sulfur as well as on activities of key antioxidant enzymes: catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase in the rat liver. Administration of IMI for 5 weeks to rats subjected to CMS resulted in a gradual significant reduction of anhedonia measured by sucrose intake, in a majority of animals (CMS IMI-reactive, CMS IMI-R), although about 20 % of rats did not respond to the IMI treatment (CMS IMI non-reactive, CMS IMI-NR). CMS-induced hepatic oxidative stress, estimated by increased ROS and MDA concentrations, was not prevented by the IMI administration, moreover, in CMS IMI-NR animals, the level of the marker of lipid peroxidation, i.e., MDA was increased in comparison to CMS-subjected rats and activity of antioxidant enzymes (GPx and CAT) was decreased compared to IMI-treated rats. The clinical significance of this observation remains to be established.     

Very small embryonic-like stem cells: characterization, developmental origin, and biological significance

Bone marrow (BM) was, for many years, primarily envisioned as the "home organ" of hematopoietic stem cells (HSC). Augmenting evidence demonstrates, however, that BM, in addition to HSC, also contains a heterogeneous population of non-HSC. Recently, our group identified in BM and other adult tissues a population of very small embryonic-like stem cells (VSELs), which express several markers characteristic for pluripotent stem cells that are characteristic for epiblast/germ line-derived stem cells. Thus, we hypothesize that VSELs are a population of epiblast-derived cells that are deposited during early gastrulation in developing tissues/organs and play an important role in turnover of tissue-specific/committed stem cells. In this context, VSELs deposited in BM can give rise to long-term repopulating HSC. VSELs could be also mobilized into peripheral blood (PB), and the number of these cells circulating in PB increases during stress and tissue/organ injuries. Finally, we envision that in pathological situations VSELs are involved in development of some malignancies (e.g., teratomas, germinal tumors).     

Phenotype of NK Cells Determined on the Basis of Selected Immunological Parameters in Children Treated due to Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most frequent pediatric malignancy. The chemotherapy for ALL is associated with a profound secondary immune deficiency.We evaluated the number and phenotype of natural killer (NK) cells at diagnosis, after the intensive chemotherapy and following the completion of the entire treatment for patients with ALL. The fraction, absolute number, and percentage of NK cells expressing interferon-γ were determined in full blood samples. The fraction of NK cells expressing CD158a, CD158b, perforin, A, B, and K granzymes was examined in isolated NK cells.We have shown that patients assessed at ALL diagnosis showed significantly lower values of the fraction of NK cells and percentage of NK cells with the granzyme A expression. Additionally, the absolute number of NK cells, the expression of CD158a, CD158b, perforin, and granzyme A were significantly lower in patients who completed intensive chemotherapy. Also, there was a significantly higher fraction of NK cells expressing granzyme K in patients who completed the therapy.Abnormalities of NK cells were found at all stages of the treatment; however, the most pronounced changes were found at the end of intensive chemotherapy.     

Comparison of invasive and non-invasive treatment strategies in older patients with acute myocardial infarction complicated by cardiogenic shock (from the Polish Registry of Acute Coronary Syndromes - PL-ACS)

Cardiogenic shock (CS) continues to be the most important factor affecting the mortality rate of patients with acute myocardial infarctions (AMIs). However, controversy regarding the optimal treatment of older patients with AMIs complicated by CS still exists. The aim of this study was to compare the results of invasive (coronary angiography during index hospitalization) and noninvasive treatment strategies in patients aged ≥ 75 years with AMIs complicated by CS, defined as systolic blood pressure <90 mm Hg or need for hemodynamic support and end-organ hypoperfusion. A multicenter Polish registry that included data on patients with acute coronary syndromes was examined to identify patients with AMIs treated from October 2003 to May 2007. A total of 97,531 patients with AMIs were hospitalized, and 5.5% of those patients (n = 5,390) had CS on admission, including 1,976 patients aged ≥ 75 years (509 treated invasively and 1,467 treated noninvasively). In-hospital mortality was 55.4% in patients treated invasively and 69.9% in patients treated noninvasively (p <0.0001). After 6 months, the mortality rate was 65.8% in the invasive group and 80.5% in the noninvasive group (p <0.0001). Propensity score analysis, in which 499 patients of each group were analyzed after being matched for demographic and clinical data, confirmed the early and long-term benefits of the invasive strategy. In conclusion, applying the invasive strategy to patients with AMIs complicated by CS reduced in-hospital and 6-month mortality in patients aged ≥ 75 years.     

Fracture of Colvin-Galloway-Future band in a patient with mitral valve annuloplasty

Annuloplasty with various annuloplasty ring systems is a fundamental part of mitral valve repair and has been frequently performed since its introduction by Carpentier in 1969. Due to the different advantages or disadvantages of each system, some controversies exist regarding the best type of ring annuloplasty support. Here we describe, for the first time, the case of a female patient in which a fracture of a semi-rigid open annuloplasty ring occurred, leading to annular deformation and mitral regurgitation.     

Interleukin-8: more on the mechanisms of progenitor cells mobilization in acute coronary syndromes.

In the article published in the current issue of European HeartJournal, Schömig and collaborators identify new humoralfactor associated with the release of progenitor cells in acutemyocardial infarction (AMI). The article expands current knowledgewith regard to mobilization of bone-marrow progenitors in AMIby showing that parallel to already described increase of vascularendothelial growth factor, there is a marked upregulation ofinterleukin-8 (IL-8) in patients with AMI treated with primarypercutaneous coronary intervention (PCI). The increase of IL-8levels shows the similar time-course as the mobilization ofCD133+ cells, moreover plasma concentrations of IL-8 and wereshown to be an independent predictor of circulating CD133+ cellsnumber in multivariable regression model that included parametersknown to influence the progenitor cell mobilization, such ascardiovascular risk factors, infarct size,     

Serum aminoterminal peptide of type III procollagen (PIIINP) and transforming growth factor-beta1 (TGF-beta1) levels in patients with chronic hepatitis B and C

Fibrosis is the process accompanying majority of chronic diseases of liver, independent of etiological factor and leading to cirrhosis and hepatic failure. Monitoring fibrosis process by liver's biopsy is limited, so many attempts are undertaken to assess concentrations of definite proteins in blood, which could be easily accessible marker of intrahepatic process. It seems, that among others, determinations of blood concentration of aminoterminal propeptide of procollagen III--index of collagen's III synthesis and TGF-beta 1--cytokine of antiproliferative action and inhibiting hepatocytes' growth, yet inducing fibroblasts' growth and stimulating fibrosis process brings out such a possibility. The aim of the study was simultaneous determination of TGF-beta 1 and PIIINP concentration in blood of patients with chronic hepatitis B and C before interferone's therapy in comparison to healthy controls, assessment of the parameters in dependence on stage of liver fibrosis and determination of correlation between TGF-beta 1 and PIIINP. Studies were performed in 40 patients with chronic hepatitis B (CAH B) and 35 patients with chronic hepatitis C (CAH C). Significantly increased serum concentrations of TGF-beta 1 as PIIINP in both groups of patients (CAH B and CAH C; grading 2-3, staging 1-2) in comparison with control group was noted. Significant positive correlation of TGF-beta 1 and PIIINP serum concentrations in both groups of patients was observed. There was not significant changes in PIIINP serum levels in patients with hepatitis B and C in dependence on stage of liver fibrosis (staging 1 vs staging 2) but TGF-beta 1 serum levels was significantly increased in CAH B and C patients with higher stage of liver fibrosis process. On the base of obtained results, it seems that changes in TGF-beta 1 concentrations in blood reflect "grading" and "staging" and can be a marker of intensification of intrahepatic fibrosis process whereas PIIINP levels in blood have rather the relation with "grading".