Usefulness of transesophageal echocardiography before cardioversion in atrial arrhythmias

Background: Although many thromboembolism risk factors are well defined, formation of thrombus ordense spontaneous contrast (sludge) in the left atrium remains enigmatic and confounding. Exclusionof the thrombus is extremely important with respect to planned reversal of sinus rhythm. Data regardingthe routine transesophagal echocardiography (TEE) before cardioversion are inconclusive. The authorsfocused on analyzing the usefulness of TEE before cardioversion by assessment of factors influencing therisk of thrombus and/or dense spontaneous echo contrast with the intention of extending indications forTEE in the group with a high risk of thrombus or to forgo TEE in the low risk group. Methods: Two hundred sixty-nine consecutive patients with persistent (> 48 h) atrial fibrillationor atrial flutter, in whom a direct current cardioversion was planned, were undergoing TEE for thedetection of the left atrial thrombus or dense spontaneous echo contrast. Additional clinical and echocardiographic data were collected. The relationship between both thrombus and dense spontaneous echo contrast and covariates was analyzed with the use of binary logistic regression. Results: Left atrium (LA) appendage (LAA) thrombus and/or sludge were detected in 79 (29%)patients. Signs of dementia in mini-mental state examination (hazard ratio [HR]: 1.16; p = 0.005),low velocities in LAA (HR: 3.38; p = 0.032); presence of spontaneous echo contrast in LA (HR: 3.38;p = 0,003) consecutive episode of AF (HR: 2.27; p = 0,046); longer duration of atrial fibrillation (HR:1.009; p = 0.022); were significant predictors of thrombus and/or dense spontaneous echo contrast.None of the patients with a CHA2DS2VASc score ≤ 1 had thrombus or sludge in the LAA. Among patientswith a CHA2DS2VASc score > 1, the prevalence of thrombus or sludge in LAA was independentof the CHA2DS2VASc score value.Conclusions: Amongst many factors, including an established as risk for thromboembolism onlya few of them increased the risk for the presence of thrombus in LAA: low velocities in LAA, presenceof spontaneous echo contrast, longer duration of arrhythmia, consecutive (not first) arrhythmia episodeand signs of dementia from a mini-mental state examination questionnaire. It was believed that therecould be a need for an extension of indications of TEE in vast majority of the patients with atrial arrhythmias, due most often to an unpredictable occurrence of thrombus and potentially disastrousthromboembolism. The only exception could have been the group of the patients with a CHA2DS2VAScscore ≤ 1

Podwyższenie progu stymulacji u chorego z implantowanym układem stymulującym AAI w przebiegu ogólnoustrojowego zakażenia

W niniejszej pracy przedstawiono przypadek 72-letniego mężczyzny z wszczepionym rozrusznikiem typu AAI oraz znacznym zwiekszeniem wartości progu stymulacji ponad 4 lata po zabiegu implantacji. Obserwowano zalezność między narastaniem progu stymulacji i ogólnoustrojowym zakażeniem. W miarę pogarszania się stanu ogólnego pacjenta w przebiegu urosepsy odnotowano stopniowe narastanie, a następnie niemierzalne wartości progu stymulacji w kanale przedsionkowym. Po zastosowaniu skutecznej terapii wartości progu stymulacji obniżyły się. (Folia Cardiol. 2004; 11: 619–623

Podwyższenie progu stymulacji u chorego z implantowanym układem stymulującym AAI w przebiegu ogólnoustrojowego zakażenia

W niniejszej pracy przedstawiono przypadek 72-letniego mężczyzny z wszczepionym rozrusznikiem typu AAI oraz znacznym zwiekszeniem wartości progu stymulacji ponad 4 lata po zabiegu implantacji. Obserwowano zalezność między narastaniem progu stymulacji i ogólnoustrojowym zakażeniem. W miarę pogarszania się stanu ogólnego pacjenta w przebiegu urosepsy odnotowano stopniowe narastanie, a następnie niemierzalne wartości progu stymulacji w kanale przedsionkowym. Po zastosowaniu skutecznej terapii wartości progu stymulacji obniżyły się. (Folia Cardiol. 2004; 11: 619–623

Constitutive activation of MET signaling impairs myogenic differentiation of rhabdomyosarcoma and promotes its development and progression

Rhabdomyosarcoma (RMS) is a soft tissue sarcoma, which may originate from impaired differentiation of mesenchymal stem cells (MSC). Expression of MET receptor is elevated in alveolar RMS subtype (ARMS) which is associated with worse prognosis, compared to embryonal RMS (ERMS). Forced differentiation of ARMS cells diminishes MET level and, as shown previously, MET silencing induces differentiation of ARMS. In ERMS cells introduction of TPR-MET oncogene leads to an uncontrolled overstimulation of the MET receptor downstream signaling pathways. In vivo, tumors formed by those cells in NOD-SCID mice display inhibited differentiation, enhanced proliferation, diminished apoptosis and increased infiltration of neutrophils. Consequently, tumors grow significantly faster and they display enhanced ability to metastasize to lungs and to vascularize due to elevated VEGF, MMP9 and miR-378 expression. In vitro, TPR-MET ERMS cells display enhanced migration, chemotaxis and invasion toward HGF and SDF-1. Introduction of TPR-MET into MSC increases survival and may induce expression of early myogenic factors depending on the genetic background, and it blocks terminal differentiation of skeletal myoblasts. To conclude, our results suggest that activation of MET signaling may cause defects in myogenic differentiation leading to rhabdomyosarcoma development and progression

MET receptor is a potential therapeutic target in high grade cervical cancer

Cervical cancer is one of the leading causes of death among women suffering from tumors. Current treatment options are insufficient. Here, we investigated the MET receptor as a potential molecular target in advanced cervical cancer. Downregulation of MET receptor expression via RNA interference in different cervical carcinoma cell lines dramatically decreased tumor growth and forced tumor differentiation in vivo. MET receptor silencing also led to a dramatic decrease in cell size and a decrease in proliferation rate under normal and stress conditions. MET receptor downregulation also resulted in decreased cyclin D1 and c-myc levels but did not increase apoptosis. Subsequent experiments showed that downregulation of the MET receptor decreased the expression of a key regulator of the epithelial-to-mesenchymal transition, SLUG. and increased the expression of E-cadherin, a hallmark of the epithelial phenotype. Moreover, MET downregulation impairs expression and signaling of CXCR4 receptor, responsible for invasive phenotype. Taken together, our results strongly suggest that the MET receptor influences the oncogenic properties of cervical carcinoma cells in vitro and in vivo. These findings highlight a unique role of the MET receptor in cervical carcinoma cells and indicate the MET receptor as a potential therapeutic target for advanced cervical carcinoma

Multifunctional protein APPL2 contributes to survival of human glioma cells

Some endocytic proteins have recently been shown to play a role in tumorigenesis. In this study, we demonstrate that APPL2, an adapter protein with known endocytic functions, is upregulated in 40% cases of glioblastoma multiforme, the most common and aggressive cancer of the central nervous system. The silencing of APPL2 expression by small interfering RNAs (siRNAs) in glioma cells markedly reduces cell survival under conditions of low growth factor availability and enhances apoptosis (measured by executor caspase activity). Long‐term depletion of APPL2 by short hairpin RNAs (shRNAs), under regular growth factor availability, suppresses the cell transformation abilities, assessed by inhibited colony formation in soft agar and by reduced xenograft tumor growth in vivo. At the molecular level, the negative effect of APPL2 knockdown on cell survival is not due to the alterations in AKT or GSK3β activities which were reported to be modulated by APPL proteins. Instead, we attribute the reduced cell survival upon APPL2 depletion to the changes in gene expression, in particular to the upregulation of apoptosis‐related genes, such as UNC5B (a proapoptotic dependence receptor) and HRK (harakiri, an activator of apoptosis, which antagonizes anti‐apoptotic function of Bcl2). In support of this notion, the loss of glioma cell survival upon APPL2 knockdown can be rescued either by an excess of netrin‐1, the prosurvival ligand of UNC5B or by simultaneous silencing of HRK. Consistently, APPL2 overexpression reduces expression of HRK and caspase activation in cells treated with apoptosis inducers, resulting in the enhancement of cell viability. This prosurvival activity of APPL2 is independent of its endosomal localization. Cumulatively, our data indicate that a high level of APPL2 protein might enhance glioblastoma growth by maintaining low expression level of genes responsible for cell death induction