New derivative of staphylokinase SAK-RGD-K2-Hirul exerts thrombolytic effects in the arterial thrombosis model in rats

SAK-RGD-K2-Hir and SAK-RGD-K2-Hirul are recombinant proteins that are derivatives of r-SAK (recombinant staphylokinase). They are characterized by their fibrin-specific plasminogen activation properties and their antithrombin and antiplatelet activities. The difference between these proteins is the presence of the antithrombotic fragment (hirudin or hirulog) in the C-terminal portion of the r-SAK. The aim of the present study was to examine the thrombolytic potentials of SAK-RGD-K2-Hir and SAK-RGD-K2-Hirul in an electrically induced carotid artery thrombosis model in rats and to compare the potentials to that of r-SAK. We determined that a bolus injection of SAK-RGD-K2-Hirul was more effective than one of r-SAK in the improvement and maintenance of carotid patency and in arterial thrombus weight reduction; however, it had the same potency as SAK-RGD-K2-Hir. The bleeding time, prothrombin time and activated partial thromboplastin time were significantly prolonged in the animals that were treated with either dose (1.5 or 3.0 mg/kg) of SAK-RGD-K2-Hir or SAK-RGD-K2-Hirul, whereas no changes were observed in the plasma fibrinogen concentration or the α2 plasmin inhibitor level. r-SAK alone did not change the bleeding time or coagulation parameters. In conclusion, our findings demonstrate the thrombolytic activity of intravenous bolus injection of the novel thrombolytic agent SAK-RGD-K2-Hirul in rats. Although this protein compares favorably with r-SAK, we were unable to show the presence of any beneficial effects of SAK-RGD-K2-Hirul over those of SAK-RGD-K2-Hir. Furthermore, our results suggest that high doses of SAK-RGD-K2-Hirul bear the risk of bleeding.     

Role of IL-6 and neopterin in the pathogenesis of herpetic encephalitis

Herpetic encephalitis (HSE) is one of the most severe infection of the central nervous system (CNS), connected with high mortality rate, even when appropriate therapy has been introduced. Better understanding of pathomechanisms responsible for neuronal injury during the course of the disease can be useful in the assessment of the risk of the occurrence of severe complications, as well as in potential introduction of additional therapeutic methods. The purpose of this study is to assess the correlation between concentration of neopterin and IL-6 in the CSF and serum, and the course of HSE. In this study, 36 patients with HSE were investigated, and the control group consisted of 32 patients in whom the infection of the CNS was excluded. We observed significantly higher concentration of neopterin and IL-6 in the CSF of patients with HSV as compared with the control group. Neopterin and IL-6 levels in the CSF correlated with the course of HSE. Higher values were connected with the risk of respiratory failure, development of permanent neurologic complications and patient death. Negative correlations between concentration of IL-6 and neopterin and patient condition assessed by Glasgow Coma Scale (GCS) were observed. Neopterin with high sensitivity and specificity allowed to predict the risk of death or severe neurological complications. Increased concentration of neopterin and IL-6 in the CSF and serum revealed reciprocal positive correlation. Assessment of the concentration of IL-6 and neopterin in the serum was not useful to predict the course of HSE.     

Self-assembling peptides and their potential applications in biomedicine

For many years, peptides have been known to self-assemble to form nano- and micro-scale structures. Their nature of assembly and assembled morphology has since been investigated as this area of research has important implications for the development of both drug delivery and tissue regeneration. In this article, we explore the process of peptide self-assembly in vivo, and experiments that exploit the structures formed. Particular focus is directed towards diphenylalanine, the simplest self-assembling peptide, which generally forms tube-like structures on assembly. In addition, different peptides that may assemble into a range of other morphologies are highlighted and potential applications in regenerative medicine and drug delivery discussed.     

Imatinib sensitivity in BCR-ABL1-positive chronic myeloid leukemia cells is regulated by the remaining normal ABL1 allele

Chronic myeloid leukemia in chronic phase (CML-CP) cells that harbor oncogenic BCR-ABL1 and normal ABL1 allele often become resistant to the ABL1 kinase inhibitor imatinib. Here, we report that loss of the remaining normal ABL1 allele in these tumors, which results from cryptic interstitial deletion in 9q34 in patients who did not achieve a complete cytogenetic remission (CCyR) during treatment, engenders a novel unexpected mechanism of imatinib resistance. BCR-ABL1-positive Abl1(-/-) leukemia cells were refractory to imatinib as indicated by persistent BCR-ABL1-mediated tyrosine phosphorylation, lack of BCR-ABL1 protein degradation, increased cell survival, and clonogenic activity. Expression of ABL1 kinase, but not a kinase-dead mutant, restored the antileukemic effects of imatinib in ABL1-negative chronic myelogenous leukemia (CML) cells and in BCR-ABL1-positive Abl1(-/-) murine leukemia cells. The intracellular concentration of imatinib and expression of its transporters were not affected, although proteins involved in BCR-ABL1 degradation were downregulated in Abl1(-/-) cells. Furthermore, 12 genes associated with imatinib resistance were favorably deregulated in Abl1(-/-) leukemia. Taken together, our results indicate that loss of the normal ABL1 kinase may serve as a key prognostic factor that exerts major impact on CML treatment outcomes.     

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 CEM-NET initiative: molecular biology and epidemiology in alliance--tracking antibiotic-resistant staphylococci and pneumococci in hospitals and in the community

In this brief report, we provide a portrait of the CEM-NET initiative and review studies that highlight contributions of this molecular epidemiological network to the understanding of the molecular mechanisms of drug resistance in Staphylococcus aureus and Streptococcus pneumoniae clones as well as their routes and modes of geographic expansion.     

Preparations of intravenous immunoglobulins diminish the number and proinflammatory response of CD14+CD16++ monocytes in common variable immunodeficiency (CVID) patients

We have studied the effect of intravenous immunoglobulins (IVIG) on monocyte subpopulations and cytokine production in patients with CVID. The absolute number of CD14(+)CD16(++) monocytes decreased on average 2.5-fold 4h after IVIG and after 20h returned to the baseline. The cytokine level in the supernatants of peripheral blood mononuclear cells (PBMC) after ex vivo LPS stimulation demonstrated the >2-fold decrease in TNF production 4h after IVIG. The TNF expression, which is higher in the CD14(+)CD16(++) monocytes, was decreased in these cells by IVIG in 4/7 CVID cases. In vitro exposure of the healthy individuals' monocytes to the IVIG preparation resulted in reduced TNF production, which was overcome by blockade of the FcγRIIB in the CD14(+)CD16(++) CD32B(high) monocytes. Our data suggest that reduction in the number of CD14(+)CD16(++) monocytes and the blockade of their cytokine production via triggering CD32B can contribute to the anti-inflammatory action of IVIG.     

Behavioural genetics of Alzheimer's disease: a comprehensive review

Behavioural and psychological symptoms of dementia (BPSD) are present in the course of the illness in up to 90% of patients with Alzheimer''s disease (AD). They are the main source of caregiver burden and one of the major factors contributing to early institutionalization. The involvement of a genetic component in BPSD aetiology seems beyond controversy, though the exact significance of particular polymorphisms is uncertain in the majority of cases. Multiple genes have been assessed for their putative influence on BPSD risk. In this paper we review the behavioural genetics of AD, particularly the importance, with respect to BPSD risk, of genes coding for apolipoprotein E and proteins involved in the process of neurotransmission: serotonin receptors, serotonin transporter, COMT, MAO-A, tryptophan hydroxylase and dopamine receptors. A general conclusion is the striking inconsistency of the findings, unsurprising in the field of psychiatric genetics. The potential reasons for such discrepancy are exhaustively discussed.