RalGPS2 is involved in tunneling nanotubes formation in 5637 bladder cancer cells.

RalGPS2 is a Ras-independent Guanine Nucleotide Exchange Factor (GEF) for RalA containing a PH domain and an SH3-binding region and it is involved in several cellular processes, such as cytokinesis, control of cell cycle progression, differentiation, cytoskeleton organization and rearrangement. Up to now, few data have been published regarding RalGPS2 role in cancer cells, and its involvement in bladder cancer is yet to be established. In this paper we demonstrated that RalGPS2 is expressed in urothelial carcinoma-derived 5637 cancer cells and is essential for cellular growth. These cells produces thin membrane protrusions that displayed the characteristics of actin rich tunneling nanotubes (TNTs) and here we show that RalGPS2 is involved in the formation of these cellular protrusions. In fact the overexpression of RalGPS2 or of its PH-domain increased markedly the number and the length of nanotubes, while the knock-down of RalGPS2 caused a strong reduction of these structures. Moreover, using a series of RalA mutants impaired in the interaction with different downstream components (Sec5, Exo84, RalBP1) we demonstrated that the interaction of RalA with Sec5 is required for TNTs formation. Furthermore, we found that RalGPS2 interacts with the transmembrane MHC class III protein leukocyte specific transcript 1 (LST1) and RalA, leading to the formation of a complex which promotes TNTs generation. These findings allow us to add novel elements to molecular models that have been previously proposed regarding TNTs formation.

Effects of transcatheter aortic valve implantation on left ventricular mass and global longitudinal strain: tissue Doppler and strain evaluation.

INTRODUCTION: Transcatheter aortic valve implantation is the option of choice for high surgical risk patients suffering from symptomatic aortic stenosis. We aimed to evaluate the influence of baseline global longitudinal strain on left ventricular mass regression after the procedure. METHODS: We enrolled 23 patients with pure symptomatic severe aortic stenosis who underwent CoreValve prosthesis (Medtronic, Minneapolis, MN) implantation. Everyone had echocardiography registration before the procedure and after six months in order to analyze two-, three-, and four-chamber peak longitudinal strain and global longitudinal strain. RESULTS: After the procedure New York Heart Association class, peak and mean aortic valve gradients (p<0.001 for all) improved. Interventricular septum and posterior wall thicknesses decreased (p<0.001 for both). Moreover, left ventricular mass index for body surface area changed from 190±44 to 143±30 g/m(2), (p<0.001). Finally, global longitudinal strain significantly increased (from 9.4±0.9 to 11.5±0.8%; p<0.001), as well as its components. Baseline global longitudinal strain correlated with left ventricular mass regression (r=0.560; p=0.005; 2-sided) and predicted it at linear regression analysis (B=23.707; p=0.005; adjusted R(2)=0.281). CONCLUSIONS: Global longitudinal strain and its components improved six months after the procedure. Moreover, baseline global longitudinal strain seemed to predict left ventricular mass regression in patients with pure aortic stenosis undergoing transcatheter aortic valve implantation. This finding could be related to the extent of myocardial fibrosis which is also responsible for lack of left ventricular mass regression and poorer prognosis.

The piezoresistive effect in graphene-based polymeric composites.

The strain-dependent electrical resistance of polyvinyl ester-based composites filled with different weight fractions of graphene nanoplatelets (GNPs) has been experimentally investigated. The GNP synthesis and nanocomposite fabrication process have been optimized in order to obtain highly homogeneous filler dispersion and outstanding electrical properties. The produced nanocomposites showed a low percolation threshold of 0.226 wt% and electrical conductivity of nearly 10 S m(-1) at only 4 wt% of GNPs. The piezoresistive response of thin nanocomposite laminae has been assessed by measuring the variation of the electrical resistance as a function of the flexural strain in three-point bending tests under both quasi-static monotonic and dynamic cyclic loading conditions. The obtained results showed higher strain sensitivity than traditional metal foil strain gauges or recently investigated carbon-based nanocomposite films.

Efficacy of ranolazine in a patient with idiopathic dilated cardiomyopathy and electrical storm.

A case of idiopathic dilated cardiomyopathy with an arrhythmic storm refractory to the usual antiarrhythmic therapy will be reported. The idiopathic structural heart disease of the patient is a vulnerable anatomic substrate in itself, for electrical instability and reentry mechanism, because of heterogeneous areas of scarred myocardium and low left ventricle ejection fraction. In this case, the ranolazine administration was safe and effective for the prevention of further electrical storms.

Short-term tolerability of morniflumate in patients with cutaneous hypersensitivity reactions to non-steroidal anti-inflammatory drugs.

Morniflumate is the morpholinoethyl ester of niflumic acid, a non-steroidal anti-inflammatory drug, derived from nicotinic acid. We studied 112 patients who had experienced cutaneous reactions after using non-steroidal anti-inflammatory drugs. Only two of all the patients who underwent an oral challenge with morniflumate had a positive result to the test. By demonstrating the low incidence of reactions to morniflumate through oral challenges, we suggest that patients with non-steroidal anti-inflammatory drug hypersensitivity may tolerate this drug which would therefore be a useful alternative.

A reporter system for replication-competent gammaretroviruses: the inGluc-MLV-DERSE assay.

Although novel retroviral vectors for use in gene-therapy products are reducing the potential for formation of replication-competent retrovirus (RCR), it remains crucial to screen products for RCR for both research and clinical purposes. For clinical-grade gammaretrovirus-based vectors, RCR screening is achieved by an extended S(+)L(-) or marker-rescue assay, whereas standard methods for replication-competent lentivirus detection are still in development. In this report, we describe a rapid and sensitive method for replication-competent gammaretrovirus detection. We used this assay to detect three members of the gammaretrovirus family and compared the sensitivity of our assay with well-established methods for retrovirus detection, including the extended S(+)L(-) assay. Results presented here demonstrate that this assay should be useful for gene-therapy product testing.

Aortic valve stenosis and lipid-lowering therapy: the state of the art.

Aortic valve stenosis is the most common native valve disease and its most common cause in the United States and Europe is the calcification of a normal trileaflet. Recently, there is increasing evidence indicating that valve calcification has common underlying mechanisms with atherosclerosis. This connection raises interest in the potential efficacy of antiatherosclerosis medications in calcific valve stenosis (AS) therapy. Among them statins, are one of the most promising candidates, because of their pleiotropic effects. The aim of this review is to summarize and analyze the findings of contemporary studies and to discuss the rationale for statin usage in AS populations.

Stem cells and repair of the heart: cell-releasing epicardial scaffolds.

Cell transplantation represents the last frontier within the treatment of cardiac diseases. From the first paper published in 1992 that has documented the potentials of the transplantation of autologous skeletal muscle cells to treat the damage induced by acute myocardial infarction, innumerable techniques of implantation and types of cells used has been reported, greatly expanding this innovative and appealing field of search in cardiovascular medicine. Despite original promises and expectations, current evidences of stem cell transplantation are still weak and controversial. Therefore, alternative line of research are being explored, particularly in the field of techniques of cell implantation and engraftment. Besides direct implantation or myocardial colonization by bone marrow stimulation, epicardial application of cell-delivering systems (scaffold and patches) have gained popularity due to the possibility to apply selectively a cell-containing device which may gradually release the chosen cell type, alone or in combination with trophic substances. The scaffolds have proven to be successful in this respect and may represent a valid alternative to coronary, intra-myocardial, or venous injection of stem cells, or to stem cell stimulating factors. Finally these systems may be applied through minimally invasive procedures and act as external constraint to enhance ventricular reverse remodelling or limit further cardiac dilatation.

The importance of reducing heart rate in cardiovascular diseases: effects of Ivabradine.

Heart rate is a major determinant of cardiac output, myocardial oxygen consumption and coronary blood flow under physiological and pathological conditions. Experimental and clinical data have demonstrated that heart rate reduction is the main mechanism for reducing ischemia, improving left ventricular function, decreasing the risk of plaque rupture and post myocardial infarction mortality. Nowadays betablockers are the best class of drugs that can lower heart rate in patients with cardiovascular diseases, but sometimes their use is limited by some contraindications. Ivabradine is a new drug that reduces the firing rate of pacemaker cells in the sinoatrial node through a different mechanism with respect to betablockers. The purpose of this review is to investigate the main trials that support Ivabradine adoption in clinical practice.

Calcium sensing receptor and renal mineral ion transport.

Calcium sensing receptor (CaSR) is a component of the C family of the G protein-coupled receptors. It is ubiquitously expressed in human and mammal cells but is more expressed in parathyroid glands and kidney cells. It is located on the cell plasma membrane and senses the changes of extracellular calcium concentrations. Thus, it may modify cell functions according to serum calcium levels. CaSR has a key role in calcium homeostasis because it allows parathyroid glands and kidney to regulate PTH secretion and calcium reabsorption in order to keep serum calcium concentration within the normal range. CaSR appears as an important player in the regulation of renal calcium handling and body calcium metabolism. Thus, CaSR may protect human tissues against calcium excess. In kidneys, its protective effect includes the stimulation of diuresis and phosphate retention, along with the potential prevention of calcium precipitation and deposition in kidney tubules and interstitium.

Cyclosporin-A efficacy in chronic idiopathic urticaria.

Common drugs in the therapy of chronic idiopathic urticaria (CIU) include antihistamines alone or combined with corticosteroids, but severe unresponsive patients require alternative treatments. This retrospective study aims to evaluate clinical response and safety of low-dose and long-term oral Cyclosporin-A (CyA) in unresponsive patients. One hundred and ten CIU patients, unresponsive to a previous treatment (antihistamines plus prednisone 0.2 mg/kg/day), received additional oral CyA 1–3 mg/kg/day for 6 months. The patients were subdivided into three groups (A, B, C) according to the different CyA doses. Parameters of clinical efficacy including pruritus, and size and number of wheals were evaluated at baseline, after three and six months. All adverse events were recorded. The mean total symptom severity score decreased by 63% in Group A, 76% in Group B, and 85% in Group C after 6 months. Total disappearance of the symptoms was recorded in 43 patients (39.1%): 7 (28%) of Group A; 12 (37.5%) of Group B and 24 (45%) of Group C. After a mean of 2 months from CyA suspension, 14 patients (11%) had recurrence of symptoms. Minor side effects were noted in 8 patients (7%). Our study indicates that low-dose, long-term CyA therapy is efficacious and safe in severe unresponsive CIU.

Mitral valve prolapse and conduction disturbances: the forgotten association.

Various cardiac arrhythmias and conduction defects have been described in patients with mitral valve prolapse. We describe a case of a young woman affected by a mitral valve prolapse, involving the posterior mitral leaflet, with mild mitral regurgitation and an episode of syncope due to asystolia. It is hoped that this short communication will once again focus attention on the as yet unexplained association between mitral valve prolapse and various cardiac conduction disorders.