Effect of ivabradine on cardiac arrhythmias: Antiarrhythmic or proarrhythmic?

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Solubility and pKa determination of six structurally related phenothiazines

Solubilities of six structurally related phenothiazines, namely chlorpromazine hydrochloride, fluphenazine dihydrochloride, promazine hydrochloride, thioridazine hydrochloride, trifluoperazine dihydrochloride, and triflupromazine hydrochloride at constant pH were measured in the temperature range from 290 K to 350 K in three important drugs solvents: water, ethanol and 1-octanol using the dynamic method and UV-vis method. Dissociation constants and corresponding pK(a) values of drugs were obtained with Bates-Schwarzenbach method at temperature 298.15K in the buffer solutions. Our experimental pK(a) values for chlorpromazine hydrochloride, fluphenazine dihydrochloride, promazine hydrochloride, thioridazine hydrochloride, trifluoperazine dihydrochloride, and triflupromazine hydrochloride are 9.15, 10.01, 9.37, 8.89, 8.97, and 9.03, respectively. The basic thermal properties of pure drugs i.e. melting and solid-solid phase transition as well as glass-transition temperatures, the enthalpy of melting and phase transitions and the molar heat capacity at glass transition (at constant pressure) were measured with differential scanning microcalorimetry (DSC) technique. Molar volumes were calculated with Barton group contribution method. The experimental solubility data were correlated by means of three commonly known G(E) equations: the Wilson, NRTL and UNIQUAC with the assumption that the systems studied here have revealed simple eutectic mixtures. The root-mean-square deviations of temperature were used for the precision of the correlation. The activity coefficients of drugs at saturated solutions in each correlated binary mixture were calculated from the experimental data. These new data will help in all prediction-methods and their precision.     

Characterization of genes associated with internalization of enteroaggregative Escherichia coli

On animal models enteroaggregative Escherichia coli (EAEC) can cause mild, but significant mucosal damage, suggesting the invasive capability of these strains. In the study we investigated the ability of typical, aggR-positive and atypical, aggR-negative EAEC isolates to enter intestinal epithelial Int407 cells in relation to the distribution of genes encoding the putative invasins described among pathogenic E. coli categories. The results demonstrated that regardless of origin and affiliation to typical and atypical EAEC, most isolates examined were internalized by the epithelial cells to different extent. Although as many as 50 (84.3%) EAEC demonstrated a variety of combinations of the aggB, afaD, ipaH and tia genes determined, there was no correlation between the invasion efficiency of these strains and the presence of any particular gene involved in invasion. Most of EAEC examined belonged to phylogenetic group B2 and D.     

Pretreatment serum levels of hematopoietic cytokines in patients with colorectal adenomas and cancer

Background and aim Hematopoietic cytokines (HCs) regulate the proliferation and differentiation of hematopoietic progenitor cells, and it was proved that HCs can promote cancer growth. The aim of this study is to determine whether HCs might be useful in the diagnosis of colorectal cancer.Materials and methods We compared the serum levels of stem cell factor (SCF), interleukin 3 (IL-3), granulocyte–macrophage colony-stimulating factor (GM-CSF), and macrophage colony-stimulating factor (M-CSF) in 97 colorectal cancer patients with those in 35 patients with colorectal adenomas and 65 healthy subjects (control group). Additionally, we investigated commonly accepted tumor markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9). HCs were determined using enzyme linked immunosorbent assay (ELISA). CEA and CA 19-9 were measured by microparticle enzyme immunoassay.Results Serum levels of GM-CSF, M-CSF, and tumor markers were significantly higher in cancer patients as compared to the control group and adenomas patients. Of these, hematopoietic cytokines were found elevated in the higher proportion of patients than CEA and CA 19-9. The sensitivity of SCF was higher than the sensitivity of other cytokines, but diagnostic specificity and predictive value were highest for M-CSF. Moreover, the M-CSF area under the receiver operating characteristic curve was larger than the areas of other cytokines. The highest values of diagnostic parameters were observed for the combined use of M-CSF with CEA.Conclusion The obtained data support the M-CSF usefulness as a tumor marker for colorectal cancer, especially in combination with CEA.     

Genetically attenuated Plasmodium berghei liver stages induce sterile protracted protection that is mediated by major histocompatibility complex Class I-dependent interferon-gamma-producing CD8+ T cells

At present, radiation-attenuated plasmodia sporozoites ( gamma -spz) is the only vaccine that induces sterile and lasting protection in malaria-naive humans and laboratory rodents. However, gamma -spz are not without risks. For example, the heterogeneity of the gamma -spz could explain occasional breakthrough infections. To avoid this possibility, we constructed a double-knockout P. berghei parasite by removing 2 genes, UIS3 and UIS4, that are up-regulated in infective spz. We evaluated the double-knockout Pbuis3(-)/4(-) parasites for protective efficacy and the contribution of CD8(+) T cells to protection. Pbuis3(-)/4(-) spz induced sterile and protracted protection in C57BL/6 mice. Protection was linked to CD8(+) T cells, given that mice deficient in beta (2)m were not protected. Pbuis3(-)/4(-) spz-immune CD8(+) T cells consisted of effector/memory phenotypes and produced interferon- gamma . On the basis of these observations, we propose that the development of genetically attenuated P. falciparum parasites is warranted for tests in clinical trials as a pre-erythrocytic stage vaccine candidate.     

Myocardial asynchrony in patients with postinfarction intraventricular conduction defects

BACKGROUND: Postinfarction intraventricular conduction defects lead to asynchronous activation of the myocardium.Hypothesis: The aim of the current study is to evaluate contraction asynchrony in postinfarction patients with intraventricular conduction defects. METHODS: A total of 158 patients 6 months postmyocardial infarction and 15 healthy subjects underwent echocardiography to evaluate atrioventricular, interventricular, intraventricular asynchrony, and myocardial performance index (MPI). A subgroup of 126 patients had intraventricular conduction defects in ECG, whereas 32 with normal QRS complex served as controls. RESULTS: All patients postmyocardial infarction showed intraventricular asynchrony and markedly higher MPI. Comparing groups with and without intraventricular conduction defects postmyocardial infarction, those with left bundle branch block (BBB) had significantly higher parameters of all asynchrony types; those with right BBB and left posterior hemiblock (LPH) had significantly higher interventricular asynchrony parameters; those with left anterior hemiblock did not show significant differences in asynchrony parameters as compared with subjects without postinfarction conduction defects. CONCLUSIONS: (1) Patients 6 months postmyocardial infarction show intraventricular asynchrony and markedly higher MPI. (2) Postinfarction patients with LBBB have the highest parameters of atrioventricular, interventricular and intraventricular asynchrony as compared with postinfarction patients with other and without conduction defects. (3) In postinfarction patients with RBBB or LPH parameters of interventricular asynchrony are significantly higher as compared with postinfarction patients without intraventricular conduction defects.     

507 A Novel Mechanism of Fas Signaling Suppression by PMLRARα in Acute Promyelocytic Leukemia

Presence of potential inhibitors of Fas could block Fas signaling and explain cancer cells resistance to apoptosis. In this study, we found that PMLRARα binds to Fas and blocks Fas-mediated apoptosis through recruiting c-FLIP in APL. Targeting tissue-specific inhibitors of Fas such as PMLRARα would improve cancer therapy.

Full Abstract

Fas plays a critical role in cell proliferation and in the selective killing of autoreactive lymphocytes and abnormal cells, including infected cells. To explain the common expression of Fas and the resistance to the Fas-induced apoptosis observed in some normal and cancer cells, we have screened cells for potential regulators of the Fas death receptor. By using mass spectrometry analysis of Fas-associated proteins, we identified peptides derived from promyelocytic leukemia (PML).PML enhances

     

A seed coat bedding assay shows that RGL2-dependent release of abscisic acid by the endosperm controls embryo growth in Arabidopsis dormant seeds

Seed dormancy is an ecologically important adaptive trait in plants whereby germination is repressed even under favorable germination conditions such as imbibition with water. In Arabidopsis and most plant species, dormancy absolutely requires an unidentified seed coat germination-repressive activity and constitutively higher abscisic acid (ABA) levels upon seed imbibition. The mechanisms underlying these processes and their possible relationship are incompletely understood. We developed a "seed coat bedding" assay monitoring the growth of dissected embryos cultured on a layer of seed coats, allowing combinatorial experiments using dormant, nondormant, and various genetically modified seed coat and embryonic materials. This assay, combined with direct ABA measurements, revealed that, upon imbibition, dormant coats, unlike nondormant coats, actively produce and release ABA to repress embryo germination, whatever the embryo origin, i.e., from dormant, nondormant, or never dormant aba seeds, unable to synthesize ABA. The persistent high ABA levels in imbibed dormant seeds requires the permanent expression of the DELLA gene RGL2, where it remains insensitive to gibberellins (GA) unlike in nondormant seeds. These findings present the seed coat as an organ actively controlling germination upon seed imbibition and provide a framework to investigate how environmental factors break seed dormancy.