Epidermal growth factor-mediated activation of the map kinase cascade results in altered expression and function of ABCG2 (BCRP).

Epidermal growth factor (EGF) is a multifunctional growth factor known to play a major role in proliferation and differentiation processes. EGF-induced differentiation is a prerequisite for function of various cell types, among them cytotrophoblasts, a functionally important cellular fraction in human placenta. Stimulation of cytotrophoblasts with EGF results in formation of a multinuclear syncytium representing the feto-maternal interface, which protects the fetus against exogenous substances. It is well established that part of this protection system is based on ATP-binding cassette (ABC) transporters such as ABCG2 (breast cancer resistance protein, BCRP). However, little is known about regulation of transport proteins in the framework of EGF-mediated cellular differentiation. In the present work we show a significant increase of ABCG2 expression by EGF in cytotrophoblasts, BeWo, and MCF-7 cells on both mRNA and protein levels. This increase resulted in decreased sensitivity to the ABCG2 substrates mitoxantrone and topotecan. In each cell type, EGF increases expression of ABCG2 by activation of mitogen-activated protein kinase cascade via phosphorylation of extracellular regulated kinase (ERK)1/2 and c-jun NH-terminal kinase/stress-activated protein kinase (JNK/SAPK). Consequently, the increase of ABCG2 by EGF was abolished by pretreatment of cells with the tyrosine kinase inhibitor 4-(3-chloroanillino)-6,7-dimethoxyquinazoline (AG1478) or the mitogen-activated protein kinase kinase inhibitor 2'-amino-3'methoxyflavone (PD 98059), thereby reestablishing sensitivity toward mitoxantrone. Moreover, analysis of ABCG2 expression during placental development revealed a significant increase in preterm versus term placenta. Taken together, our data show regulation of ABCG2 expression by EGF. In view of EGF signal transduction as a target for drugs (e.g., gefitinib), which are in turn substrates and/or inhibitors of ABCG2, this regulation has therapeutic consequences.     

Determinants for myocardial hypertrophy in mild essential hypertension. The effect of sodium chloride on left-ventricular hypertrophy

The impact of clinical parameters on the pathogenesis of myocardial hypertrophy was examined in 75 male patients with mild essential hypertension. Clinical parameters were age, body weight, sodium excretion (as an estimate for dietary salt intake), systolic and diastolic blood pressure at work, casual blood pressure, resting and stress blood pressure during mental stress test and physical exercise. Left ventricular mass as a parameter for the degree of left ventricular hypertrophy was assessed by 2-D guided M-mode echocardiography. Left ventricular mass correlated with body weight (r = 0.47, p less than 0.002), with body mass index (r = 0.48, p less than 0.001), with systolic blood pressure at the worksite (r = 0.28, p less than or equal to 0.05), and systolic blood pressure at rest (r = 0.35, p less than or equal to 0.01), whereas no correlation was found between casual or stress blood pressure readings during physical exercise and mental stress with the degree of left ventricular hypertrophy. Sodium excretion was related to the end-diastolic diameter of the left ventricle (r = 0.33, p less than or equal to 0.01) and to left ventricular mass (r = 0.35, p less than or equal to 0.01). Multiple regression analysis revealed that sodium excretion over 24 hours, systolic blood pressure at the worksite and body mass index were independent determinants of left ventricular mass. Thus, dietary salt intake was found to modulate the degree of left ventricular hypertrophy independently of the pressure load imposed on the myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relation of hemodynamic reaction during stress to left ventricular hypertrophy in essential hypertension

To elucidate the impact of increased afterload during physical and mental stress on myocardial hypertrophy, a homogeneous population of 73 patients with untreated mild-to-moderate essential hypertension were enrolled in the current study. Left ventricular mass and cross-sectional area, both determined by 2-D guided M-mode echocardiography, were related to blood pressure measured at rest as well as during various stress situations. Left ventricular mass and cross-sectional area correlated with systolic pressure at work site (r = 0.28 and r = 0.23 respectively, P less than .05) and systolic pressure at complete rest (r = 0.35 and r = 0.33, P less than .01). Neither the response in blood pressure to mental arithmetic or a bicycle exercise test performed in the laboratory, nor blood pressure during both stress tests were significantly related to the degree of left ventricular hypertrophy. In addition, patients with a hyperreactive response to mental arithmetic or to the physical stress test did not disclose a greater left ventricular mass than normoreactors. Examining the hemodynamic response pattern during mental arithmetic, we found that patients with vasoconstriction during mental stress had a greater left ventricular mass than individuals with vasodilation during mental stress (244 +/- 73 v 204 +/- 53 g, P less than .05), but this was due to the impact of obesity on left ventricular mass (analysis of covariance: F = 2.1, P = NS). Thus, blood pressure at work site and at rest, but not blood pressure during mental or physical stress, nor the response of blood pressure to both stress tests, was linked to the degree of left ventricular hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of tadalafil on blood flow,pain, and function in chronic cold Complex Regional Pain Syndrome: a randomized controlled trial

Background  

This double-blind, randomized, controlled trial investigated the effect of the phosphodiesterase-5 inhibitor tadalafil on the microcirculation in patients with cold Complex Regional Pain Syndrome (CRPS) in one lower extremity.     

Osteosarcoma: use of MR imaging and MR spectroscopy in clinical decision making

Magnetic resonance (MR) imaging was performed on 14 patients with histologically proved osteosarcoma (mean age, 14.4 years). There was excellent correlation of intramedullary tumor extent as determined with MR imaging and pathologic examination (r = 99%). This was facilitated by the presence of a chemical shift artifact at the tumor-marrow interface on the T1-weighted images. The correlation between CT and pathologic findings was not as good (r = 84%). In a single patient, however, a 10-cm length of sclerotic bone was incorrectly interpreted as being tumor. If this case is excluded, the correlation between CT and pathologic findings improves significantly (r = 96%). T2-weighted images were optimal in demonstrating soft-tissue bulk and breach of the epiphysis or cortex. Vascular involvement was also readily defined. The T2 value of the tumor soft-tissue component decreased in patients who were deemed to have responded well to therapy. Two patients with very high T2 values after chemotherapy developed wide-spread metastatic disease and died. Phosphorus-31 MR spectroscopy of five patients with osteosarcoma showed elevated levels of phosphomonoesters (PMEs), inorganic phosphate (Pi), and phosphodiesters (PDEs). PME and PDE peak areas decreased in three patients after chemotherapy, while Pi peak areas increased.     

A rare pacemaker complication of a perforation by a ventricular screw electrode causing hemothorax

The myocardial perforation of a pacemaker electrode is an extremely rare complication associated with the danger of cardiac tamponade. We report on a perforation of a ventricular screw-in electrode with migration through the pericardium and bleeding in the left thoracic cavity. Two-dimensional echocardiography in combination with clinical, electrocardiographic and X-ray examination permits a reliable non-invasive diagnosis.     

Embolieprotektion bei der interventionellen Behandlung aortokoronarer Bypassstenosen

Summary No-reflow is an unpredictable complication after percutaneous intervention in saphenous vein grafts. Plaque embolism, vasoconstriction and thrombosis are mechanisms that lead to poor distal run-off. Treatments with alternative techniques like DCA, TEC and ELCA as well as phamacological attempts like GP IIb/IIIA inhibitors, vasodilators and calcium-channel blockers do not improve outcome. This is the rationale for the developement of mechanical devices to prevent distal embolization. Two concepts of distal protection devices are currently realized: occlusive balloon and filtering devices. The largest experience comes from the PercuSurge GuardWire^TM, an occlusive balloon device. The recently presented data from the SAFER trial showed a significant prevention of distal embolization and improvement in clinical outcome. The second generation of filter devices is under investigation; the advantages of these systems are the preservation of blood flow and precise angiography-guided stent positioning. Another issue of investigation is a broader use of protection devices in carotid stenting, and in interventions in acute MI and acute coronary syndroms. Zusammenfassung Das “no-reflow Phänomen' stellt eine nicht vorhersehbare Komplikation der percutanen Intervention an aorto-koronaren venösen Bypassstenosen dar. Die Embolisation von Plaquematerial, Vasokonstriktion und periphere Thrombose sind Mechanismen die zu einem verzögerten distalen Blutabstrom führen. Weder der Einsatz von alternativen Techniken wie der DCA, TEC oder ELCA noch pharmakologische Ansätze mit GP IIb/IIIa-Inhibitoren, Vasodilatantien oder Kalziumantagonisten verbessern das klinische Ergebnis. Vor diesem Hintergrund stellen die neuen Systeme zur mechanischen Vermeidung der peripheren Embolisation eine logische Weiterentwicklung dar. Zwei Konzepte der distalen Protektion werden z.Zt. verfolgt: Systeme mit distaler Ballonokklusion und Filtersysteme. Die größte klinische Erfahrung liegt für ein ballon-okklusives System, den PercuSurge Guard Wire^TM, vor. Die kürzlich präsentierten Ergebnisse der SAFER-Studie zeigten eine signifikante Prävention der distalen Embolisation und eine Verbesserung des klinischen Ergebnisses. Die zweite Generation der Filtersysteme befindet sich zur Zeit im Stadium der klinischen Prüfung. Die Aufrechterhaltung des Blutfusses und die Möglichkeit der präzisen, angiografisch kontrollierten Stentplatzierung sind die Vorteile dieser Systeme. In klinischer Prüfung ist ebenfalls der erweiterte Einsatz der distalen Embolieprotektion bei der Karotisangioplastie und bei Interventionen im akuten Myokardinfarkt und der instabilen Angina pectoris.     

Cyanotic patient with right ventricular dilatation and ventricular arrhythmias

Uhl's disease is a very rare congenital anomaly of the heart. Extreme dilatation of the right ventricle is accompanied by virtual absence of the right ventricular myocardium. We report on a 30-year-old woman with ventricular arrhythmias and atrial-septal defect where the diagnosis was made by echocardiography and confirmed by angiocardiography. Diagnostic and therapeutic possibilities are discussed.