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More than four decades passed since sigma receptors were first mentioned. Since then, existence of at least two receptor subtypes and their tissue distributions have been proposed. Nowadays, it is clear, that sigma receptors are unique ubiquitous proteins with pluripotent function, which can interact with so many different classes of proteins. As the endoplasmic resident proteins, they work as molecular chaperones - accompany various proteins during their folding, ensure trafficking of the maturated proteins between cellular organelles and regulate their functions. In the heart, sigma receptor type 1 is more dominant. Cardiac sigma 1 receptors regulate response to endoplasmic reticulum stress, modulates calcium signaling in cardiomyocyte and can affect function of voltage-gated ion channels. They contributed in pathophysiology of cardiac hypertrophy, heart failure and many other cardiovascular disorders. Therefore, sigma receptors are potential novel targets for specific treatment of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Tyrosine kinases inhibitors (TKi) represent a relatively novel class of anticancer drugs that target cellular pathways overexpressed in certain types of malignancies, such as chronic myeloid leukaemia (CML). Nilotinib, ponatinib and imatinib exhibit cardiotoxic and vascular effects. In this study, we focused on possible cardiotoxicity of nilotinib using H9c2 cells as a suitable cell model. We studied role of endoplasmic reticulum (ER) stress and apoptosis in nilotinib toxicity using a complex approach. Nilotinib impaired mitochondrial function and induced formation of ROS under clinically relevant concentrations. In addition, ability of nilotinib to induce ER stress has been shown. These events result in apoptotic cell death. All these mechanisms contribute to cytotoxic effect of the drug. In addition, involvement of ER stress in nilotinib toxicity may be important in co-treatment with pharmaceuticals affecting ER and ER stress, e.g. beta-blockers or sartans, and should be further investigated. [ABSTRACT FROM AUTHOR]

Administration of anaesthesia during the daytime is important and may influence specific aspects ofin vivoanimal experiments. The aim of the present study was to refer to the suitability of the use of ketamine/xylazine anaesthesia in chronobiological studies. Study was performed in ketamine-/xylazine-anaesthetized female Wistar rats (100 mg/kg/15 mg/kg, i.m) after adaptation to a light–dark (LD) cycle (12 h:12 h). Heart rate (HR), rectal temperature, ECG parameters, autonomic nervous system activity, acid-base balance and Na+, K+, Ca2+and Cl−plasma concentrations were evaluated in dependence on LD cycle. LD differences were found in the HR, rectal temperature, RR, PQ and QTc intervals, QRS complex,Pwave amplitude, in power HF, LF and VLF components, in paO2and HCO3−, and in Na+, Cl−and Ca2+ions. Ketamine/xylazine anaesthesia may be applicable in chronobiological studies. It does not disturb LD differences, but it can modify them probably without loss of rhythmicity. [ABSTRACT FROM AUTHOR]

Aim: The Na+/Ca2+ exchanger (NCX) is a major Ca2+ extrusion system in the plasma membrane of cardiomyocytes and an important component participating on the excitation–contraction coupling process in muscle cells. NCX1 isoform is the most abundant in the heart and is known to be changed after development of ischaemia or myocardial infarction. Objective of this study was to investigate the effect of stress factors (immobilization, cold and short-term hypoxia) on the expression of NCX1, in vivo, in the heart of rat and mouse. Methods: We compared gene expression and protein levels of control and stressed animals. The activity of NCX was measured by the whole cell configuration using the patch clamp. We also measured physiological parameters of the heart in physiological conditions and under ischaemia-reperfusion to compare response of control and stressed hearts. Results: We have found that only strong stress stimulus (hypoxia, immobilization) applied repeatedly for several days elevated the NCX1 mRNA level. Cold, which is a weaker stressor that activates mainly sympathoneural, and only marginally adrenomedullary system did not affect the gene expression of NCX1. Thus, from these results it appears that hormones produced by the adrenal medulla (mainly adrenaline) might be involved in this process. To study possible mechanism of the NCX1 regulation by stress, we focused on the possible role of the hypothalamo–pituitary–adrenocortical pathway in the activation of catecholamine synthesis in the adrenal medulla. We have already published that cortisol affects activity, but not the gene expression of NCX1. In this work, we used corticotropin-releasing hormone (CRH) knockout mice, where secretion of corticosterone and subsequently adrenaline is significantly suppressed. As no increase in NCX1 mRNA was observed in CRH knockout mice due to immobilization stress, we proposed that adrenaline (probably regulated via corticosterone) is involved in the regulation of NCX1 gene expression during stress. Conclusions: The gene expression and protein levels of the NCX1 are increased by the strong stress stimuli, e.g. hypoxia, or immobilization stress. The activity of NCX1 is decreased. Based on these results, we assume that the gene expression of NCX is increased as a consequence of suppressed activity of this transport system. [ABSTRACT FROM AUTHOR]

Phenylethanolamine N-methyltransferase (PNMT) is the final enzyme in the catecholamine synthesizing cascade that converts noradrenaline (NA) to adrenaline (Adr). Both of these catecholamines are physiologically important hormones and neurotransmitters in mammals with profound influence on the activity of the cardiovascular system. Although PNMT activity and gene expression have been reported in the neonatal and also adult rat heart, little is known about the identity of the cells expressing PNMT mRNA. In this study, we have shown that besides PNMT in neuronal and intrinsic cardiac cells, this enzyme is expressed also in rat cardiomyocytes, as shown by immunofluorescence in isolated cardiomyocytes.To determine which cells in the heart more sensitively show stress-induced changes in PNMT mRNA expression, we performed chemical sympathectomy by administration of 6-hydroxydopamine (6-OHDA), which destroys catecholaminergic terminals. We determined PNMT mRNA levels in the left atria and ventricles of control and stressed rats. In the rats treated with 6-OHDA, PNMT mRNA levels were not changed under normal, physiological conditions compared to vehicle treated rats. Similar results were observed on isolated cardiomyocytes from control and 6-OHDA treated rats. However, 6-OHDA treatment prevented immobilization-induced increase in PNMT mRNA expression. The results allow us to propose that in the heart, the immobilization-induced increase in PNMT gene expression is probably not in cardiomyocytes, but in neuronal cells. [ABSTRACT FROM AUTHOR]

Main principles of Cochem model, a coordinated interdisciplinary cooperation that is step-by-step being established at some Czech courts, in order to solve custody disputes in more effective and more children-friendly way. How does the traditional role of a psychologist (be it expert witness or a therapeutist) change within this cooperation of experts? Learn more about advantages and challenges, this change of attitude brings along. Contribute to discussion about the absence of systematic support service for children in divorce. (Fulltext in Czech)

Liver function and the presence of HBsAg and anti-HBsAg were studied in 90 hypertransfused thalassaemic children. Increased serum transaminases were found in 62 patients, and persisted from more than 6 months in 45 cases. Liver biopsy in this latter group led to a diagnosis of 14 cases of chronic persistent hepatitis, 9 cases of aggressive hepatitis, and 3 cases of hepatic fibrosis. In Italy thalassaemic children undergoing hypertransfusion therapy frequently encounter SH virus infection, with a consequent hepatitis that is generally anicteric and unrecognized unless systematically sought. In a liver already stressed by the concomitant iron overload, hepatitis infection might thus play a key role in the evolution of cirrhosis which frequently affects thalassaemics. [ABSTRACT FROM AUTHOR]