Diclofenac Prolongs Repolarization in Ventricular Muscle with Impaired Repolarization Reserve

Background: The aim of the present work was to characterize the electrophysiological effects of the non-steroidal anti- inflammatory drug diclofenac and to study the possible proarrhythmic potency of the drug in ventricular muscle. Methods: Ion currents were recorded using voltage clamp technique in canine single ventricular cells and action potentials were obtained from canine ventricular preparations using microelectrodes. The proarrhythmic potency of the drug was investigated in an anaesthetized rabbit proarrhythmia model. Results: Action potentials were slightly lengthened in ventricular muscle but were shortened in Purkinje fibers by diclofenac (20 mM). The maximum upstroke velocity was decreased in both preparations. Larger repolarization prolongation was observed when repolarization reserve was impaired by previous BaCl 2 application. Diclofenac (3 mg/kg) did not prolong while dofetilide (25 mg/kg) significantly lengthened the QT c interval in anaesthetized rabbits. The addition of diclofenac following reduction of repolarization reserve by dofetilide further prolonged QT c . Diclofenac alone did not induce Torsades de Pointes ventricular tachycardia (TdP) while TdP incidence following dofetilide was 20%. However, the combination of diclofenac and dofetilide significantly increased TdP incidence (62%). In single ventricular cells diclofenac (30 mM) decreased the amplitude of rapid (I Kr ) and slow (I Ks ) delayed rectifier currents thereby attenuating repolarization reserve. L-type calcium current (I Ca ) was slightly diminished, but the transient outward (I to ) and inward rectifier (I K1 ) potassium currents were not influenced. Conclusions: Diclofenac at therapeutic concentrations and even at high dose does not prolong repolarization markedly and does not increase the risk of arrhythmia in normal heart. However, high dose diclofenac treatment may lengthen repolarization and enhance proarrhythmic risk in hearts with reduced repolarization reserve

Fragment reattachment, reproductive status, and health indicators of the invasive colonial tunicate Didemnum vexillum with implications for dispersal

This manuscript is not subject to U.S. copyright. The definitive version was published in Biological Invasions 14 (2012): 2133-2140, doi:10.1007/s10530-012-0219-8.The invasive colonial tunicate Didemnum vexillum is now widespread in coastal and offshore waters of New England, USA. D. vexillum can inflict ecological and economic damage through biofouling and habitat modification. Natural and anthropogenic processes that fragment colonies of D. vexillum may be accelerating the spread of this invader. Reattachment success and fragment viability were confirmed in the laboratory after four weeks of suspension in experimental aquaria. The shape of suspended D. vexillum fragments progressed from flattened to globular spheres and then flattened again after reattachment to the substrate. Reproductive activity, confirmed by the presence of eggs and larvae, was observed for fragments suspended up to three weeks suggesting that D. vexillum is capable of reproducing while in a fragmented, suspended state. An index of colony health was used to monitor change in D. vexillum health while in suspension. Overall, colony health declined with time in suspension although colonies that appeared dead (black and gray in overall color) still contained a substantial number of healthy live zooids. These results suggest that activities that cause fragmentation can significantly facilitate the spread of D. vexillum. Coastal managers should consider reducing or eliminating, when practical, activities that return fragmented colonies of D. vexillum to the water. In-water cleaning of biofouling and dredging are likely expediting the spread of this invasive species unless biofouling can be contained and removed from the water.This research was funded by the NOAA Aquatic Invasive Species Program

Multi-cancer computational analysis reveals invasion-associated variant of desmoplastic reaction involving INHBA, THBS2 and COL11A1

<p>Abstract</p> <p>Background</p> <p>Despite extensive research, the details of the biological mechanisms by which cancer cells acquire motility and invasiveness are largely unknown. This study identifies an invasion associated gene signature shedding light on these mechanisms.</p> <p>Methods</p> <p>We analyze data from multiple cancers using a novel computational method identifying sets of genes whose coordinated overexpression indicates the presence of a particular phenotype, in this case high-stage cancer.</p> <p>Results</p> <p>We conclude that there is one shared "core" metastasis-associated gene expression signature corresponding to a specific variant of stromal desmoplastic reaction, present in a large subset of samples that have exceeded a threshold of invasive transition specific to each cancer, indicating that the corresponding biological mechanism is triggered at that point. For example this threshold is reached at stage IIIc in ovarian cancer and at stage II in colorectal cancer. Therefore, its presence indicates that the corresponding stage has been reached. It has several features, such as coordinated overexpression of particular collagens, mainly <it>COL11A1 </it>and other genes, mainly <it>THBS2 </it>and <it>INHBA</it>. The composition of the overexpressed genes indicates invasion-facilitating altered proteolysis in the extracellular matrix. The prominent presence in the signature of INHBA in all cancers strongly suggests a biological mechanism centered on activin A induced TGF-β signaling, because activin A is a member of the TGF-β superfamily consisting of an INHBA homodimer. Furthermore, we establish that the signature is predictive of neoadjuvant therapy response in at least one breast cancer data set.</p> <p>Conclusions</p> <p>Therefore, these results can be used for developing high specificity biomarkers sensing cancer invasion and predicting response to neoadjuvant therapy, as well as potential multi-cancer metastasis inhibiting therapeutics targeting the corresponding biological mechanism.</p

Sociological and Communication-Theoretical Perspectives on the Commercialization of the Sciences

Both self-organization and organization are important for the further development of the sciences: the two dynamics condition and enable each other. Commercial and public considerations can interact and "interpenetrate" in historical organization; different codes of communication are then "recombined." However, self-organization in the symbolically generalized codes of communication can be expected to operate at the global level. The Triple Helix model allows for both a neo-institutional appreciation in terms of historical networks of university-industry-government relations and a neo-evolutionary interpretation in terms of three functions: (i) novelty production, (i) wealth generation, and (iii) political control. Using this model, one can appreciate both subdynamics. The mutual information in three dimensions enables us to measure the trade-off between organization and self-organization as a possible synergy. The question of optimization between commercial and public interests in the different sciences can thus be made empirical.Comment: Science & Education (forthcoming

Increased Short-Term Variability of the QT Interval in Professional Soccer Players: Possible Implications for Arrhythmia Prediction

BACKGROUND: Sudden cardiac death in competitive athletes is rare but it is significantly more frequent than in the normal population. The exact cause is seldom established and is mostly attributed to ventricular fibrillation. Myocardial hypertrophy and slow heart rate, both characteristic changes in top athletes in response to physical conditioning, could be associated with increased propensity for ventricular arrhythmias. We investigated conventional ECG parameters and temporal short-term beat-to-beat variability of repolarization (STV(QT)), a presumptive novel parameter for arrhythmia prediction, in professional soccer players. METHODS: Five-minute 12-lead electrocardiograms were recorded from professional soccer players (n = 76, all males, age 22.0±0.61 years) and age-matched healthy volunteers who do not participate in competitive sports (n = 76, all males, age 22.0±0.54 years). The ECGs were digitized and evaluated off-line. The temporal instability of beat-to-beat heart rate and repolarization were characterized by the calculation of short-term variability of the RR and QT intervals. RESULTS: Heart rate was significantly lower in professional soccer players at rest (61±1.2 vs. 72±1.5/min in controls). The QT interval was prolonged in players at rest (419±3.1 vs. 390±3.6 in controls, p<0.001). QTc was significantly longer in players compared to controls calculated with Fridericia and Hodges correction formulas. Importantly, STV(QT) was significantly higher in players both at rest and immediately after the game compared to controls (4.8±0.14 and 4.3±0.14 vs. 3.5±0.10 ms, both p<0.001, respectively). CONCLUSIONS: STV(QT) is significantly higher in professional soccer players compared to age-matched controls, however, further studies are needed to relate this finding to increased arrhythmia propensity in this population

Ascites induces modulation of α6β1 integrin and urokinase plasminogen activator receptor expression and associated functions in ovarian carcinoma

Interactions between cancer cells and the surrounding medium are not fully understood. In this study, we demonstrate that ascites induces selective changes in the expression of integrins and urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) in ovarian cancer cells. We hypothesise that this change of integrin and uPA/uPAR expression triggers signalling pathways responsible for modulating phenotype-dependent functional changes in ovarian cancer cells. Human ovarian surface epithelial (HOSE) cell lines and epithelial ovarian cancer cell lines were treated with ascites for 48 h. Ascites induced upregulation of α6 integrin, without any change in the expression of αv, β1 and β4 integrin subunits. Out of the four ovarian cancer cell lines studied, ascites induced enhancement in the expression of uPA/uPAR in the more invasive OVCA 433 and HEY cell lines without any change in the noninvasive OVHS1 and moderately invasive PEO.36 cell lines. On the other hand, no change in the expression of α6 integrin or uPAR, in response to ascites, was observed in HOSE cells. In response to ascites, enhancement in proliferation and in adhesion was observed in all four ovarian cancer cell lines studied. In contrast, no significant increase in proliferation or adhesion by ascites was observed in HOSE cells. Ascites-induced expression of uPA/uPAR correlated with the increased invasiveness of HEY and OVCA 433 cell lines but was not seen in OVHS1, PEO.36 and HOSE cell lines. Upregulation of α6 integrin and uPA/uPAR correlated with the activation of Ras and downstream Erk pathways. Ascites-induced activation of Ras and downstream Erk can be inhibited by using inhibitory antibodies against α6 and β1 integrin and uPAR, consistent with the inhibition of proliferation, adhesion and invasive functions of ovarian cancer cell lines. Based on these findings, we conclude that ascites can induce selective upregulation of integrin and uPA/uPAR in ovarian cancer cells and these changes may modulate the functions of ovarian carcinomas

How length of light exposure shapes the development of riverine algal biomass in temperate rivers?

The impact of cumulative daily solar radiation (CDSR) on the biomass of river phytoplankton (Chl-a) in the growing season was studied using a large dataset of rivers in the Carpathian Basin. The amount of solar radiation was cumulated over the range of 1–60 days. The CDSR–Chl-a relationship could be described by linear regression and appeared to be significant for almost all watercourses with the exception of rivers with short water residence time. To determine the most relevant time period of CDSR impacting phytoplankton biomass, the slopes of regressions were plotted against the accumulating number of days of light exposure (1–60). Two characteristic shapes were obtained: unimodal for rhithral rivers with hard substrate and steady increase for lowland potamal rivers with fine substrate. In both cases, there is an increasing tendency in the slope values with water residence time (WRT). It was demonstrated that CDSR has a pronounced impact on river phytoplankton biomass even in cases when WRT was shorter than the cumulated solar radiation period. These results indicate that development of phytoplankton within the river channel is a complex process in which meroplankton dynamics may have significant impacts. Our results have two implications: First, CDSR cannot be neglected in predictive modelling of riverine phytoplankton biomass. Second, climate models forecast increased drought with subsequently increased CDSR in several regions globally, which may trigger a rise in phytoplankton biomass in light-limited rivers with high nutrient concentrations