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C H Enterprises, Roofing - Contractors, listed under "Roofing - Contractors" category, is located at 2350 W Moffat Pl Denver CO, 80221 and can be reached by 3034800523 phone number. C H Enterprises has currently 0 reviews.This business profile is not yet claimed, and if you are the owner, claim your business profile for free. If you are not the owner you can invite this business to join by email or by phone.Browse all Roofing - Contractors in Denver CO. Discover census data for Denver, CO.
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We are specialized in masonry work with more than 25 years experience.
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Concrete Work, Masonry, Stucco
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Objective: The role of phosphodiesterase III inhibition and calcium sensitization in the cardiac actions of levosimendan, (R)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propane dinitrile, was studied. Methods: Various heart preparations were used to investigate positive inotropy, chronotropy, coronary flow and calcium sensitivity of contractile proteins. The cAMP- and cGMP-dependent protein kinases (PKA and PKG) were inhibited by KT5720 and KT5823, respectively. Furthermore, the synthesis of cAMP was stimulated by forskolin and increased phosphorylation of troponin I was induced by isoprenaline. Results: In Langendorff guinea-pig heart, levosimendan (0.01–1 μM) and milrinone (0.1–10 μM) increased the left ventricular systolic peak pressure almost to the same extent. In the presence of KT5720 (1 μM) milrinone was devoid of positive inotropic activity. In contrast, KT5720 did not antagonize the inotropic effect of levosimendan at ≤0.03 μM (= up to the EC50 of levosimendan). The effects of levosimendan and milrinone on heart rate and coronary flow were not affected by KT5720. The PKG inhibitor, KT5823 (1 μM), on the other hand, potentiated the levosimendan-induced increase in coronary flow while it had no effect on the increase induced by milrinone. The mechanical parameters were not affected by KT5823. In the papillary muscle, the positive inotropic effect of milrinone but not that of levosimendan was potentiated by forskolin (0.1 μM). In contrast to milrinone, the positive inotropy by levosimendan was decreased by isoprenaline pretreatment (0.1 μM; 3 min). In line with this, the calcium-sensitizing effect of levosimendan was decreased in skinned fibers prepared from isoprenaline-treated hearts. Conclusions: Our results indicate that the cardiac effects of levosimendan at its therapeutically relevant concentrations were not mediated through PKA or PKG and its positive inotropy is therefore most probably due to the previously reported troponin-C-mediated calcium sensitization of contractile proteins.
Time for primary review 26 days.
1 Introduction
Calcium sensitization of contractile proteins has become a new promising approach to increase contractile force in the failing heart. An advantage of this mechanism is that it does not increase intracellular calcium whereby arrhythmias due to spontaneous release of calcium from overloaded intracellular calcium stores may be avoided. Furthermore, since the amount of calcium required for the contraction force is lower during calcium sensitization, the energy needed for calcium handling is reduced. An important disadvantage of calcium sensitization may, however, be related to prolonged relaxation [1, 2]. In order to compensate the impaired relaxation, attempts to accelerate intracellular calcium handling by another mechanism have been included as a pharmacological property for some calcium sensitizers. For example, the calcium sensitizer, pimobendan, which increases the affinity of troponin C (cTnC) for calcium, accelerates calcium handling through phosphodiesterase III (PDE III) inhibition [3]. Pimobendan, however, is a very weak calcium-sensitizing agent [4, 5] and therefore in clinical use does not reach concentrations high enough to cause calcium sensitization. This makes it impossible to judge how successful the balance between the increased calcium affinity of cTnC and accelerated calcium handling would be in practice. In pimobendan therapy, the formation of the potent metabolite, UDCG 212Cl, further complicates the evaluation [5–7]. The calcium sensitizer, EMD 53998, acts beyond troponin in the contraction cascade [8, 9]. Thus, the target protein of EMD 53998 is not directly affected by calcium and therefore the compound prolongs relaxation despite its potent PDE III inhibitory property [2, 10].
The novel potent calcium sensitizer levosimendan, (R)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl]hydrazono]propane dinitrile, does not increase the affinity of cTnC for calcium [11, 12] but stabilises the calcium-induced conformation of this protein [13]. In other words, the binding of levosimendan itself to cTnC occurs in a calcium-dependent manner and therefore the calcium sensitization does not prolong relaxation [11, 14]. The presence of PDE III inhibition with subsequent accelerated calcium handling is therefore not necessary. However, in purified enzyme preparations levosimendan is a potent PDE III inhibitor and this makes it important to evaluate the role of PDE III inhibition in its cardiac actions.
The above examples of different types of calcium sensitizers show that the proportions of calcium sensitization and PDE III inhibition cannot be accurately evaluated just by analysing the relaxation of cardiac muscle and therefore the use of pharmacological tools is needed. The muscarinic receptor agonists, carbachol and adenosine, are the pharmacological tools most frequently used in the evaluation of PDE inhibition [5, 15, 16]. However, these agents may not only counteract the contribution of PDE inhibition to the positive inotropic effect of calcium sensitizers, but they may also eliminate the calcium-sensitizing mechanism as well by altering the phosphorylation state of contractile proteins. In order to avoid this kind of problem, we used the new specific inhibitors, KT5720 and KT5823, for the cAMP- and cGMP-dependent protein kinases (PKA and PKG), respectively [17, 18]. As far as we know, these protein kinase inhibitors have not previously been studied in isolated heart. In addition to these investigations, we carried out experiments with isolated papillary muscles and skinned fibers to further elucidate the ratio between calcium sensitization and PDE III inhibition in the positive inotropic effect of levosimendan.
2 Methods
2.1 Selection of the pharmacological tools
Our preliminary experiments in guinea-pig papillary muscles demonstrated that, depending on the concentration, carbachol may induce negative or positive inotropy, which supports the concept that it has several mechanisms of action [19–22]. At a seemingly ineffective concentration (≈10 μM) carbachol probably has balanced effects at least on two second-messenger systems which indirectly and fully counteract each other by properly changing the phosphorylation state of proteins. As evidence for the carbachol-induced alterations at the level of contractile proteins the compound has been found to increase the calcium sensitivity of myofibrils in intact muscle [15]. Furthermore, we found that carbachol abolished the stimulus strength sensitivity of twitch tension in electrically paced papillary muscles, which may be due to the increase in intracellular sodium concentration mediated through muscarinic receptor stimulation [23]. Since the positive inotropy by levosimendan was markedly dependent on the stimulus strength, we considered that the use of carbachol is questionable when characterising the role of PDE inhibition in levosimendan inotropy. The use of receptor agonists like carbachol and adenosine become even more questionable when we take into account that they may alter the concentration of cAMP in other compartments than those containing PDE III. This is probable since the PDE III isoenzyme may occur only in a particular form close to the sarcoplasmic reticulum [24]. Subsequently, the interaction of a calcium sensitizer with carbachol or adenosine reveals only how the different receptor-mediated second-messenger systems indirectly modify the response to the calcium sensitizer.
We have demonstrated in the present study that for levosimendan the above aspects were very important and they should not be overlooked. Therefore, the specific protein kinase inhibitors, KT5720 and KT5823, were used as pharmacological tools when the function of PKA or PKG needed to be antagonised in the isolated heart. Our aim was to achieve as complete inhibition of PKA or PKG as possible but still maintaining selectivity of inhibition. This requirement led us to choose 1 μM concentration for both KT5720 and KT5823. This concentration clearly exceeds the IC50 (0.06 μM) of KT5720 for PKA and the IC50 (0.234 μM) of KT5823 for PKG [17, 18]. KT5720 and KT5823 had no effects of their own in the present study and therefore we could not select the inhibitor concentrations by constructing concentration–response curves for them. For stimulation of the PKA-mediated biochemical reactions in papillary muscles we used a submaximal concentration (0.1 μM) of forskolin which increased cAMP synthesis by activating adenylate cyclase. Furthermore, isoprenaline (0.1 μM) and atenolol (1 μM) were used for stimulation and blockade of β-adrenoceptors, respectively. The PDE III inhibitor, milrinone, was a reference compound for levosimendan.
2.2 Preparations
2.2.1 Isolated heart
The guinea-pig (4 weeks old; weight 300–350 g) was sacrificed and the heart was rapidly excised and rinsed in ice-cold oxygenated perfusion buffer. A cannula was inserted into the aorta and retrograde perfusion of the heart began as soon as the heart was placed in a thermostatically controlled moist chamber of a Langendorff apparatus (Hugo Sachs Elektronik, KG, Germany). Modified Tyrode solution (37°C), gassed with 95% O2 and 5% CO2 in a thermostatically controlled bulb oxygenator, was used as a perfusion buffer. The composition of the Tyrode solution was (in mM) NaCl 135; MgCl2·6H2O 1; KCl 5; CaCl2·H2O 2; NaHCO3 15; Na2HPO4·H2O 1; glucose 10; pH 7.3–7.4.
The experiments were carried out under constant pressure conditions (50 mmHg). After a short pre-stabilization period (10 min) a latex balloon (size 4) was placed in the left ventricle. The balloon was attached to a stainless-steel cannula coupled to a pressure transducer. The latex balloon, the cannula and the chamber of the pressure transducer were filled with an ethylene glycol/water (1:1) mixture. The isovolumetric left ventricular pressure was recorded with a pressure transducer. The pressure signal was amplified by using a two-channel bridge amplifier (Type 301, Hugo Sachs Elektronik, KG, Germany) connected to a Macintosh IIci computer. At the beginning of the experiment, the volume of the balloon was adjusted to obtain a diastolic pressure of approximately 5 mmHg. Coronary flow (ml/min) was continuously recorded by an electromagnetic flow meter (Narcomatic RT-500, Hugo Sachs Elektronik, KG, Germany) with a flow probe inserted above the aortic cannula. The flow meter was also connected to the computer. Samples recorded for 3 s from the pressure and flow signals were digitised and collected into the computer at every 20 s. The beating rate (HR) and the left ventricular systolic pressure (LVSP) of the heart were obtained from the digitised (1 kHz frequency) pressure signals. The left ventricular pressure signals were used to calculate the maximum positive and negative pressure derivatives (+dP/dtmax and −dP/dtmax, respectively). The coronary flow was obtained from the digitised flow meter signal.
The hearts were allowed to stabilise approximately for 30 min to reach a steady state in the measured parameters. Thereafter, dimethyl sulfoxide (DMSO, 0.1% final concentration), the vehicle for the protein kinase inhibitors, KT5720 (1 μM) and KT5823 (1 μM), was added to the perfusion buffer. The heart was exposed to DMSO alone for 15 min before addition of the protein kinase inhibitor in order to check that DMSO was ineffective. The DMSO concentration was kept constant throughout the experiment. Levosimendan or milrinone was added to the buffer 60 min after the start of exposure of the heart to either of the protein kinase inhibitors or to DMSO. The concentration–response curves for 0.01–1 μM levosimendan and 0.1–10 μM milrinone were obtained in the absence and presence of the protein kinase inhibitors by increasing the concentrations at 15 min intervals.
2.2.2 Papillary muscle
The right ventricular papillary muscle of the guinea-pig heart was mounted for measurement of isometric tension as previously described by Haikala et al. [25]. For pacing of the papillary muscle the electrical pulses were conducted through platinum wire electrodes inserted on both sides of the muscle (1 mm apart from the muscle surface). The field stimulation occurred at 20% above threshold or at twofold threshold voltage. A force-displacement transducer was connected to a driver amplifier and a programmable scanner. The amplified signal was digitised at 1 kHz frequency by a programmable digitizer. Subsequently, twitch tension of the papillary muscle was analysed by a Macintosh IIci computer.
After a stabilising period of about 40 min various concentrations of levosimendan or milrinone (final concentrations 0.03, 0.1, 0.3, 1, 3, 10 and 30 μM) were successively added to the superfusion buffer at 10 min intervals. The same concentration range was used when levosimendan and milrinone were investigated during the accelerated synthesis of cAMP induced by forskolin (0.1 μM). Similarly, levosimendan was studied also in the presence of 1 μM atenolol. In another group of studies 1 μM levosimendan and 10 μM milrinone were tested before and after a short period (3 min) of exposure of the papillary muscle to 0.1 μM isoprenaline. In all studies data from 5–6 papillary muscles in each group were used to calculate the mean changes in twitch tension.
2.2.3 Skinned fibers
The calcium-sensitizing effect of levosimendan was investigated in two types of skinned fibers obtained either from unpretreated or isoprenaline-pretreated (0.1 μM for 10 min) isolated, spontaneously beating guinea-pig hearts. Fast and complete perforation of the cell membranes was achieved by retrogradely conducting saponin solution (250 μg/ml) through the aorta into the coronary arteries of the heart [14, 26, 27]. The fibers dissected from the papillary muscles were further mildly sonicated and treated with saponin for 30 min. The details of this procedure have been earlier described by Haikala et al. [14]. The slightly acidic pH of 6.7 was chosen in order to mimic the pH in the ischemic myocardium in which the calcium sensitivity is decreased and in which the benefits of levosimendan should be most prominent. The fibers were induced to contract in the desired free pCa (−log[Ca2+]) which was calculated by using a program developed by Fabiato and Fabiato [28]. The absolute stability constants used were as reported by Fabiato [29]. At the beginning of the experiment the fiber was stretched in 'relaxing' (calcium free) solution (22°C) until the resting tension amounted to approximately 2% of the maximum force produced by the fiber. Then, the 'relaxing' solution was replaced with the 'activating' (pCa 5.8) solution which roughly corresponds to the intracellular cytoplasmic calcium during the muscle contraction. When the tension produced by the fiber had reached a steady state, various concentrations of levosimendan (final concentrations 0.3, 1, 3, and 10 μM) were successively added to the solution at 6 min intervals. The maximum tension which was produced by the fiber at pCa 4.8 was determined after washing out the test compound.
2.3 Data analysis
In order to verify that the selected concentration range for levosimendan and milrinone produced positive inotropy to the same extent in the isolated heart the levosimendan group was compared with the milrinone group by using ANCOVA (repeated measures). The same statistical test was used when the hearts treated with the protein kinase inhibitors were compared with those exposed to levosimendan or milrinone alone. One-factor ANOVA (repeated measures) followed by Dunnett's t-test was used, when the measured parameters were compared to the initial values recorded just before the first concentration of levosimendan or milrinone was added to the test medium.
2.4 Drugs and reagents
Levosimendan and milrinone synthesised at Orion Pharma, as well as isoprenaline, KT5720 and KT5823 (Sigma Chemical Co., St Louis, USA) and forskolin (Calbiochem-Novobiochem, La Jolla, USA) were dissolved in DMSO. The amount of DMSO did not exceed 0.4% in any of the experiments and in isolated heart it was kept at 0.1%. All other chemicals were purchased from E. Merck (Darmstadt, Germany).
3 Results
3.1 Isolated heart
In Fig. 1, the differences of initials levels of HR, CF, LVSP and −dP/dtmax between various groups were not due to the effects of the protein kinase inhibitors, KT5720 and KT5823, since these differences were already present before the inhibitors were added to the perfusion buffer. Therefore, KT5720 and KT5823 at 1 μM were considered to be devoid of own effects.
Levosimendan concentration-dependently increased the HR to the same extent in the absence and presence of the PKA inhibitor, KT5720 (1 μM), or the PKG inhibitor, KT5823 (1 μM) (Fig. 1A). In all groups the maximum increase of 27–30% was seen at 1 μM levosimendan. The magnitude of the positive chronotropic effect of milrinone (0.1–10 μM) was comparable to that of levosimendan (0.01–1 μM), but unlike with levosimendan the maximum effect was not reached at the concentrations used. Furthermore, the PKA and PKG inhibitors did not change the effect of milrinone on the spontaneous HR (Fig. 1A).
Levosimendan alone increased the coronary flow concentration-dependently and maximally by 64% at 1 μM (Fig. 1B). The increase in coronary flow by milrinone alone did not differ from that induced by levosimendan except that the maximum effect was not reached at the milrinone concentrations used. The response to levosimendan or milrinone was slightly and to the same extent decreased in the presence of KT5720 (1 μM). In contrast, the levosimendan-induced increase in coronary flow was almost twofold in the presence of KT5823 (1 μM) (Fig. 1B). The PKG inhibitor, KT5823, did not alter the milrinone-induced increase in coronary flow (Fig. 1B).
The increasing effects of levosimendan alone (0.01–1 μM) and milrinone alone (0.1–10 μM) on the LVSP did not differ statistically significantly (P=0.356) from each other (Fig. 1C). The EC50 concentration for levosimendan was about 0.03 μM and that for milrinone was about 0.6 μM (Fig. 1C). Levosimendan increased LVSP maximally by 17 mmHg (+19%) at 0.3 μM and milrinone maximally by 14 mmHg (+15%) at 3 μM. In the presence of the PKA inhibitor, KT5720 (1 μM), the effect of levosimendan was not altered at concentrations up to its EC50 concentration, but it was reduced by 30% at 0.3 μM. In contrast, milrinone did not increase statistically significantly LVSP at any of the tested concentrations when it was combined with KT5720 (Fig. 1C). In the presence of the PKG inhibitor, KT5823, the increasing effect of levosimendan or milrinone on LVSP was similar to that when the compounds were tested alone (Fig. 1C).
The increasing effects of levosimendan and milrinone on +dP/dtmax were qualitatively similar to those on LVSP and therefore the data are not presented. Levosimendan and milrinone alone increased −dP/dtmax maximally by 37 and 33%, respectively (Fig. 1D). KT5720 was unable to decrease statistically significantly the effect of levosimendan on −dP/dtmax at the levosimendan concentrations giving up to 70% of the maximum effect. Only at the two highest concentrations was 19–31% antagonism seen (Fig. 1D). In contrast, the corresponding effect of milrinone was markedly antagonised by KT5720 at all effective concentrations of milrinone. The magnitude of the antagonism was 40 and 50% at 1 and 10 μM milrinone, respectively (Fig. 1D). The PKG inhibitor, KT5823, did not affect statistically significantly the increasing effect of levosimendan or milrinone on −dP/dtmax (Fig. 1D).
3.2 Papillary muscle
The concentration–response curve of levosimendan on twitch tension displayed a bell-shaped form. Furthermore, the levosimendan-induced increase in twitch tension markedly depended on the stimulus strength used in the pacing of the papillary muscle. A similar phenomenon was not seen with milrinone (Fig. 2). The EC50 concentrations for levosimendan were 0.1 and 0.3 μM when the papillary muscles were paced at twofold or at 20% above threshold voltage, respectively. The maximum increases of 330 mg (+127%) and 90 mg (+45%) in twitch tension were reached at 1 and 3 μM, respectively. The EC50 for milrinone was about 2 μM independently of the stimulus strength used. The maximum increase of 240 mg in twitch tension induced by milrinone was also not affected by the stimulus strength (Fig. 2).
In papillary muscles paced at twofold threshold voltage forskolin (0.1 μM) increased twitch tension by 27 and 23% when it was used to accelerate the cAMP synthesis in the levosimendan and milrinone studies, respectively (Fig. 3A,B). The levosimendan-induced increase in twitch tension was not markedly changed in the presence of forskolin (Fig. 3A). In contrast, the positive inotropic effect of milrinone was almost twofold when it was combined with forskolin (Fig. 3B).
The initial twitch tension changed less than 10% by treatment of the β1-adrenoceptor antagonist, atenolol (1 μM). However, atenolol abolished the stimulus sensitivity of the twitch tension and thereby eliminated the stimulus strength dependency of the inotropic response to levosimendan (Fig. 4).
The single 1 μM concentration of levosimendan increased twitch tension by 400 mg (Fig. 5A, first exposure; stimulus strength twofold threshold) whereas under similar experimental conditions the stepwise increase in levosimendan concentration from 0.03 up to 1 μM increased it by 330 mg (Fig. 2A, stimulus strength twofold threshold). The single 10 μM concentration of milrinone and its stepwise concentration increase from 0.03 up to 10 μM increased twitch tension by 379 and 208 mg, respectively (Fig. 2B and 5A).
After the single exposure of papillary muscles to either 1 μM levosimendan or 10 μM milrinone and the subsequent 30 min wash-out period the twitch tension in the milrinone group but not in the levosimendan group decreased below the initial twitch tension (Fig. 5A, W versus C1, P<0.01). A similar phenomenon was seen also in the levosimendan group after subsequent exposure of the same papillary muscles to 0.1 μM isoprenaline for 3 min followed by 10 min wash-out (Fig. 5A, C2 versus W). Levosimendan at 1 μM and milrinone at 10 μM increased twitch to the same extent (from +180 to +190%) when these concentrations were tested before isoprenaline. After isoprenaline (and its wash-out period) milrinone was percentually as efficient as before isoprenaline, but the levosimendan-induced increase in twitch tension was only 78% (Fig. 5B).
3.3 Skinned fibers
In skinned fibers obtained from naive guinea-pig hearts levosimendan (0.3–10 μM) concentration-dependently increased the calcium-induced tension at pCa 5.8 from 7 to 26% of the maximum tension produced by the fibers at pCa 4.8 (Fig. 6). When the fibers were dissected from isoprenaline-pretreated (0.1 μM, for 10 min) hearts the levosimendan-induced increase in tension was only from 6 to 16% of the maximum tension.
4 Discussion
The novel calcium sensitizer, levosimendan ([1, 14], was found to be 10–20 times more potent as a positive inotropic compound than the PDE III inhibitor, milrinone. In the presence of the PKA inhibitor, KT5720 [18], milrinone was devoid of the positive inotropic effect, which verifies the concept that PDE III inhibition is its major mechanism of action [30]. In contrast, KT5720 did not antagonise the increase in LVSP produced by levosimendan at concentrations up to its EC50 (0.03 μM). In heart failure patients 95–98% of levosimendan is bound to plasma proteins and therefore its active free plasma concentration is less than 0.02 μM in therapy [31]. In the light of the present results the positive inotropy by levosimendan at its therapeutically relevant concentrations is not due to PDE III inhibition or to the activation of PKA. This perfectly agrees with the previously found lack of effect of 0.03 μM levosimendan on cAMP and phosphorylation of cTnI [11]. These parameters, however, increase at higher levosimendan concentrations [11]. In agreement, we found that at higher concentrations the levosimendan inotropy was partially antagonised by KT5720. In addition, the concentration–response curve of levosimendan on LVSP was bending downwards at high concentration range. This may be due to the levosimendan-induced opening of ATP-sensitive K+ channels which shortens the action potential, leading to reduced calcium influx and contraction force [32]. It seems that this mechanism of action of levosimendan became potentiated during PKA inhibition.
Some calcium-sensitizing compounds acting beyond troponin in the cascade of the contraction trigger seriously impair the relaxation of the cardiac muscle [1, 2]. In contrast, levosimendan which binds calcium-dependently to cTnC [13] is devoid of this disadvantage [14]. The present results show that even in the presence of a PKA inhibitor levosimendan does not impair relaxation but increases the negative dP/dtmax. The milrinone-induced increase in the negative dP/dtmax was markedly antagonised by KT5720. However, the effect was not completely abolished probably because of the increase in HR.
HR is known to affect the contraction force of the heart. In the present study, however, the levosimendan- and milrinone-induced increases in the spontaneous HR were similar in the presence and absence of KT5720. Therefore, the evaluation of the role of PKA in the inotropic effects of these test compounds was valid. The lack of effect of KT5720 on the positive chronotropy induced by the test compounds cannot be explained by the poor penetration of KT5720 into cardiac cells, since the positive inotropy by milrinone was completely abolished by KT5720. Therefore, it is probable that the positive chronotropy induced by levosimendan or milrinone is mediated through their direct or G-protein-mediated effects on ion channels producing an inward current in the atrial pacemaker cells.
KT5720 only tended to decrease the levosimendan- or milrinone-induced increase in coronary flow. Therefore, the differences seen in the positive inotropic effects of levosimendan and milrinone were not affected by changes in the coronary flow. These findings also suggest that the major mechanism of the coronary dilatation by milrinone is not mediated by the same PKA subtype as that involved in its positive inotropic effect.
The PKG inhibitor, KT5823 [17], did not antagonise the positive inotropic effect of levosimendan or milrinone. Also no interaction between KT5823 and the test compounds could be shown on the positive chronotropic effects. However, KT5823 potentiated the levosimendan- but not the milrinone-induced increase in coronary flow. Thus, the coronary dilatory mechanism of action of levosimendan differs from that of milrinone and it does not seem to be mediated through the activation of PKG. The K+ current through the delayed rectifier K+ channels should be limited during PKG inhibition since these channels are normally activated by PKG [33]. In this situation, the efflux of K+ ions may occur more through the ATP-sensitive K+ channels, which may potentiate the vasodilatory effect mediated through these channels. Recently, patch clamp studies in rat mesenteric arterial cells have revealed that the vasodilation caused by levosimendan may be based on opening of the ATP-sensitive K+ channels [34]. Thus, the interaction of levosimendan and KT5823 on coronary flow could be due to this mechanism of action of levosimendan.
The positive inotropy by levosimendan was found to depend on the strength of electrical stimuli. The phenomenon was not seen with milrinone, indicating that it was not due to PDE III inhibition and cAMP. Furthermore, the β1-adrenoceptor antagonist, atenolol, decreased the sensitivity of twitch tension to the stimulus strength. Thus, the high stimulus strength may have enhanced the release of noradrenaline from adrenergic nerve terminals, which leads to the activation of β1-adrenoceptors and to the direct Gs-protein-mediated opening of calcium channels [35–37]. The high stimulus strength then finally increases intracellular calcium transient, which in turn increases the number of activated cTnC molecules. Since the binding of levosimendan to cTnC is calcium-dependent, it had an increased number of binding sites when more cTnC molecules became activated. Therefore, the calcium sensitization and subsequently the positive inotropy caused by levosimendan was potentiated when a high stimulus strength was used.
Forskolin increases cAMP and the intracellular calcium transient [38]. The increased calcium activates more cTnC molecules and may then potentiate calcium sensitization by levosimendan. In order to minimise this potential artefact in the evaluation of the role of PDE III inhibition and to keep the calcium transient above the critical level, we paced the papillary muscles with the stimulus strength at twofold threshold. The results showed that the positive inotropic effect of milrinone but not that of levosimendan was markedly potentiated by forskolin. Therefore, the role of PDE III inhibition in levosimendan inotropy seems to be negligible. In contrast, PDE III inhibition was an important mechanism for milrinone as suggested in several previous reports [30, 39].
Isoprenaline induces PKA-mediated phosphorylation of cTnI which leads to the altered conformation of cTnC [40, 41]. This may inhibit the binding of levosimendan to cTnC and thereby antagonize its positive inotropy. Our studies with isoprenaline showed that the positive inotropy by levosimendan at the concentration giving a maximum effect was decreased by 60–70% in isoprenaline-pretreated muscles. In contrast, the inotropic response to milrinone was not altered by similar isoprenaline pretreatment. Thus, cTnC seems to be the target protein for levosimendan also in the intact muscle and most of its positive inotropy may then be due to calcium sensitization. Furthermore, when levosimendan was added to the buffer, the positive inotropy by isoprenaline had completely ceased due to its wash-out. Therefore the effect of levosimendan was affected only by the altered phosphorylation of contractile proteins and no longer by the increased intracellular calcium transient. In another study, forskolin and levosimendan were investigated simultaneously, which means that also the increased calcium transient induced by forskolin affected the response to levosimendan. These experimental differences explain why the action of levosimendan was altered differently in the forskolin and isoprenaline studies.
The stepwise increase in levosimendan or milrinone concentrations decreased the positive inotropy by 17 and 45%, respectively, as compared to the effect after a single high concentration. Thus, it seems that the tachyphylaxis developed to milrinone was more marked than that to levosimendan. Furthermore, after washing out of milrinone or isoprenaline the twitch tension decreased below the basal level. This phenomenon of 'pharmacological stunning' probably due to the prolonged phosphorylation of cTnI was not observed after washing out of levosimendan.
The calcium sensitization caused by levosimendan occurs at 10 times lower concentrations at 37°C than at 22°C [11]. Therefore, the present skinned fiber experiments carried out at 22°C should not be directly compared with the other studies performed at 37°C. In contrast, our skinned fiber results show how the calcium sensitization by levosimendan was regulated through protein phosphorylation. As indicated by the results, the calcium-sensitizing effect of levosimendan was markedly decreased in the skinned fibers dissected from the isoprenaline-treated heart. Therefore, it is probable that the cAMP-mediated phosphorylation of cTnI [11, 42] antagonises the action of levosimendan on cTnC. This agrees also with the reduced positive inotropy seen at the high PDE III inhibitory concentrations of levosimendan. This phenomenon, however, may in part be due to the opening of ATP-sensitive K+ channels [32]. In contrast, the isoprenaline pretreatment did not antagonize the milrinone inotropy probably because milrinone and isoprenaline change the protein phosphorylation in a similar manner and because milrinone does not act as a calcium-sensitizing agent.
In patients with congestive heart failure (CHF) the sympathetic tone is increased. Despite this, the cAMP-generating pathways and subsequently the phosphorylation of contractile proteins in the failing heart are down-regulated [43]. Therefore, our finding that levosimendan-induced calcium sensitization was antagonised by isoprenaline pretreatment does not mean a lack of effect of levosimendan in CHF. Vice versa, the decreased activity of the cAMP system in the failing heart should favour the calcium-sensitizing effect of levosimendan on contractile proteins.
In conclusion, the positive inotropic effect of levosimendan up to its EC50 concentration was not antagonised by PKA or PKG inhibitors and may therefore be due to the calcium sensitization of contractile proteins. At higher concentrations, the contribution of PDE III inhibition was present and was probably mediated through the increased intracellular calcium transient which potentiates the effect of levosimendan on cTnC. The ratio for calcium sensitization versus PDE III inhibition was roughly 70 versus 30% at the maximum inotropic concentration of levosimendan (0.3 μM). The increased phosphorylation of contractile proteins by PKA antagonised both the calcium-sensitizing and the positive inotropic effect of levosimendan. This supports the hypothesis that calcium sensitization by levosimendan is mediated through cTnC also in intact cardiac muscle. Furthermore, the positive chronotropic effects of levosimendan and milrinone may not be mediated by PKA or PKG. Finally, the mechanism of the coronary-flow-increasing action of levosimendan differs from that of milrinone and is probably not mediated through activation of PKA or PKG. The potentiated effect of levosimendan on coronary flow during PKG inhibition suggests that levosimendan may induce coronary dilatation through the opening of K+ channels.
We appreciate the skilful technical contributions of Ritva Huuhilo and Heikki Olkkonen in performing the experiments in the present study.
Haikala H, Ovaska M, Pollesello P, et al. Modification of contraction trigger through troponin C. Bas Res Cardiol 1997:in press.
Endoh M. Characteristics of regulation of intracellular calcium mobilization and sensitivity by β-adrenoceptor and muscarinic agonists, and a novel inotropic agent, MCI-154 in canine ventricular myocardium. In: Yamada K, Shibata S, Katz AM, Fabiato F, editors. Recent advances in Ca channels and Ca-antagonists. New York: Pergamon Press, 1990:51–59.
Kase H. New inhibitors of protein kinases from microbial source. In: Biology of actinomycetes. Proceedings, 7th international symposium on biology of actinomycetes, 1988:159–164.
Endo M, Kitazawa T. E-C coupling studies on skinned cardiac fibers. In: Morad M, editor. Biophysical aspects of cardiac muscle. New York: Academic Press, 1978:307–327.
Yokoshiki H, Katsube Y, Sperelakis N. The novel calcium sensitizer levosimendan activates the ATP-sensitive K+ channel in rat ventricular cells. J. Pharmacol. Exp. Ther. 1997:in press.
Sperelakis N, Tohse N, Ohya Y, Masuda H. Cyclic GMP regulation of calcium slow channels in cardiac muscle and vascular smooth muscle cells. In: Murad F, editor. Advances in pharmacology, vol. 26. San Diego: Academic Press, 1994:234.
Yokoshiki H, Katsube Y, Sperelakis N. The novel calcium sensitizer levosimendan hyperpolarizes and activates the glibenclamide-sensitive K+ channel in rat mesenteric arterial cell. Eur. J. Pharmacol. 1997:in press.


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|Photos (See all 37 | slideshow)
|Videos (see all 2)
|Edward Woodward
|David Callan (43 episodes, 1967-1972)
|Russell Hunter
|Lonely (41 episodes, 1967-1972)
|Lisa Langdon
|Liz March - Hunter's Secretary / ... (31 episodes, 1967-1972)
|Anthony Valentine
|Toby Meres (30 episodes, 1967-1972)
|William Squire
|Hunter (19 episodes, 1970-1972)
Series Directed by
|Peter Duguid
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|Jim Goddard
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|Mike Vardy
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|Reginald Collin
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|Bill Bain
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|Piers Haggard
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|Robert Tronson
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Series Writing credits
|James Mitchell
|(30 episodes, 1967-1972)
|Ray Jenkins
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|Bill Craig
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|Robert Banks Stewart
|(3 episodes, 1967-1969)
|Trevor Preston
|(3 episodes, 1969-1972)
|John Kershaw
|(2 episodes, 1969-1972)
|William Emms
|(2 episodes, 1969-1970)
|Michael Winder
|(2 episodes, 1969-1970)
Series Produced by
|Reginald Collin
|producer (35 episodes, 1969-1972)
|John Kershaw
|associate producer (14 episodes, 1969)
|Lloyd Shirley
|executive producer (8 episodes, 1967-1969)
|Terence Feely
|associate producer (7 episodes, 1967-1969)
Series Original Music by
|Jack Trombey
|(unknown episodes, 1970-1972)
Series Cinematography by
|Michael Elphick
|(1 episode, 1969)
Series Production Design by
|David Marshall
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|Peter Le Page
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|Neville Green
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|Stan Woodward
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Series Art Department
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Series Other crew
|George Markstein
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|Christopher Toyne
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I think I managed to see the entire series bar a couple of episodes and
the story lines were always excellent. Great casting throughout. Alas,
I realize how old I have become now when I see how Anthony Valentine
has aged - have just watched a 2005 episode of the BBCs "New Tricks"
this evening, in which he featured. Sadly don't seem to have seen
Edward Woodward in many productions during the years since "Callan".
I only ever saw the "Callan" episodes in black and white - colour TV didn't reach New Zealand until several years after it was available in the USA and Europe, and we couldn't afford a colour set until 1982 - but I wonder whether viewing it in black and white added more gritty realism to the plots, and perhaps if I watched it now remastered in colour, would I find it slightly disappointing? I haven't noticed it around on DVD but if I do, don't think I'll be tempted to buy, as I prefer to remember it still with great enjoyment.
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Sewer Department funding comes primarily from user rates and a portion of the property tax revenue that is collected by Placer County.
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Sewer and Water Department Permit Application.
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Dr Martin StevenLecturer
Research Overview
My research interests lie in the area of political parties and elections - especially European politics, British politics and multi-level governance. I focus comparatively on the relationship between parties and public policy, and have published in journals such as 'Representation', 'The Political Quarterly', and the 'Australian Journal of Political Science', as well as in a monograph for Routledge.
I am presently researching the policies of political parties that prefer to be identified as 'Euro-realist' as opposed to 'Euro-sceptic', especially those affiliated to the European Conservatives and Reformists (ECR) - and have the following article forthcoming in the journal, Representation:
'Euro-realism in the 2014 European Parliament elections: the European Conservatives and Reformists (ECR) and the democratic deficit'
I am also working on a project with my Lancaster colleague, Mark Garnett, analysing the way left of centre parties use political communication - to be published in an edited volume in 2017 by Palgrave Macmillan.
Current Teaching
PPR.224 European Union Politics
PPR.339 Elections, Voters and Political Parties
PPR.427 Public Policy
Career Details
I graduated with a first class honours degree and doctorate (university anniversary scholarship) from the Department of Politics, University of Glasgow, also acting as a graduate teaching assistant in the School of Social and Political Science at the University of Edinburgh, as well as spending a period as a visiting researcher in the Department of Political Science, McGill University, Montreal. I have worked for an NGO with Edinburgh and London offices, and in 2008, won the Political Studies Association prize for the best article published in the journal, politics.
PhD in Public Policy (University Anniversary Scholar), Department of Politics, University of Glasgow
Professional Role
Convener of Postgraduate Studies in Politics
PhD Supervision Interests
Comparative European politics (especially British); Political parties and elections; Public policy and political economy
'Euro-realism' in the 2014 European Parliament elections: the European Conservatives and Reformists (ECR) and the democratic deficit
Steven, M.H.M. 2/11/2016 In: Representation. 52, 1, p. 1-12.
Journal article
Consulting and compromising: the (non-)religious policy preferences of British MEPs
Steven, M. 18/05/2015 In: Religion at the European Parliament and in European multi-level governance . London : Routledge
Chapter (peer-reviewed)
Consulting and compromising: the (non-)religious policy preferences of British MEPs
Steven, M. 06/2014 In: Religion, State and Society. 42, 2-3, p. 180-195. 16 p.
Journal article
Religion in European multi-level parliamentary politics: the policy preferences of British and Irish MEPs
Steven, M. 14/06/2013 Lancaster University
Working paper
Framing electoral reform in the 2011 UK Alternative Vote referendum campaign
Lundberg, T., Steven, M. 2013 In: Australian Journal of Political Science. 48, 1, p. 15-27. 13 p.
Journal article
The Conservative Party and Devolved National Identities: Scotland and Wales Compared
Steven, M., Llyr ap Gareth, O., Baston, L. 03/2012 In: National Identities. 14, 1, p. 71-81. 11 p.
Journal article
Mixed messages (for some) parties - the Scottish council elections of 2012
Steven, M., Denver, D., Bochel, H. 2012 In: Scottish Affairs. 80, Summer
Journal article
Scottish Council Elections 2012: Results and Statistics
Steven, M., Denver, D., Bochel, H. 2012 University of Plymouth.
Commissioned report
Scottish Devolution and National Identity
Soule, D., Leith, M., Steven, M. 2012 In: National Identities. 14, 1, 10 p.
Christianity and British Politics: A Neglected Dimension
Steven, M. 2011 In: Politics and Religion in Western Europe. London : Routledge
Chapter (peer-reviewed)
Christianity and Party Politics: Keeping the Faith
Steven, M. 2011 London : Routledge. ISBN: 9780415556606.
The 2011 Scottish Parliament Election
Curtice, J., Steven, M. 2011 Electoral Reform Society. 40 p.
Commissioned report
Party over Policy? Scottish Nationalism and the Politics of Independence
Leith, M., Steven, M. 04/2010 In: The Political Quarterly. 81, 2, p. 263-269. 7 p.
Journal article
Working with the Single Transferable Vote
Steven, M. 2010 Electoral Reform Society. 26 p.
Commissioned report
Religious Lobbies in the European Union: From Dominant Church to Faith-Based Organisation
Steven, M. 03/2009 In: Religion, State and Society. 37, 1-2, p. 181-191. 11 p.
Journal article
Religious Lobbies in the European Union: From Dominant Church to Faith-Based Organisation
Steven, M. 2009 In: Religion, Politics and Law in the European Union. London : Routledge
Chapter (peer-reviewed)
Secessionist Politics and Religious Conservatism: The Scottish National Party and Faith-Based Interests
Steven, M. 10/2008 In: Politics. 28, 3, p. 188-196. 9 p.
Journal article
Electoral Reform and Democratic Engagement
Steven, M. 2008 In: Representation. 44, 4, 8 p.
The 2007 Scottish Parliament Election
Steven, M. 2007 Electoral Reform Society. 44 p.
Commissioned report
The Place of Religion in Devolved Scottish Politics: An Interest Group Analysis of the Scottish Churches
Steven, M. 2007 In: Scottish Affairs.
Journal article


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Grammar issue
I don't understand what would be the best way to replace this sentence.
See example:
We were told frequently to presentable.
asked Sep 09 '13 at 06:44 Tzu- Wei Tang New member
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Hero of the day
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TrapX Study Points to Invasive Attacks Against Hospitals
TrapX describes Medical Device Hijack 2 as a focused, customized exploit and attack by organized crime against hospitals' network-connected medical devices.Hackers are increasingly going after hospitals and are honing their techniques, according to a new report, titled "Anatomy of an Attack—Medical Device Hijack 2" (MEDJACK 2), from TrapX security. The MEDJACK 2 report is a follow-up to a 2015 study from TrapX that details how hackers are exploiting medical devices and facilities to steal information. Multiple studies in 2016 so far have identified a growing trend of ransomware attacks on hospitals. While some forms of ransomware are delivered by generic exploit kits, the MEDJACK attacks are not exploit kits in the same category as the Angler exploit kit, for example. "MEDJACK 2 represents a laser-focused, customized exploit and attack by organized crime against hospitals' network-connected medical devices," Moshe Ben-Simon, co-founder and vice president of services and Trapx Labs at TrapX, told eWEEK. "While MEDJACK.2 can support ransomware attacks, the primary goal is the far more lucrative theft of patient data."
In contrast, Angler is much more of a standard exploit toolkit designed for Microsoft Windows operating systems, where the user has failed to install updates or falls prey to a browser-based vulnerability, Ben-Simon said. Angler is more of a toolkit or software as a service for unsophisticated attackers to build exploits for almost any purpose.
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Bluetip Cover Songs
Songs covered by Bluetip
The The B-52s song "52 Girls" was covered by Bluetip on the album " Post Mortem Anthem"
Bluetip songs that have been covered
None yet. Why not add a new one .
We don't have an image for Bluetip yet. Why not upload one?


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Talk:Amiga Corporation
|WikiProject Computing / Amiga
|(Rated Start-class, High-importance)
Amiga, Inc.[edit]
I just created this article called "Amiga Corporation". It deals with the history of the company that created the Lorraine, later to be called the Amiga, computer. To put together the article, I got information first from the Jay Miner article then from Commodore International. There is no information about Amiga, Inc. in the Atari article. But the information that I did find is somewhat contradictory. I meshed it as best as I can, but I suggest that the contradictions be decided in this article and then be distributed back to the other two articles. Val42 00:46, 19 November 2005 (UTC)
- Just to add some confusion, Amiga Inc is a company which still exists today [1], but at the moment, Amiga, Inc. redirects here, ie, Amiga Corporation. I don't know whether they should be mentioned in the same article or should be separate articles, but it's misleading to have Amiga, Inc. redirecting to a page talking about a company which is now defunct. Mdwh 16:53, 26 November 2005 (UTC)
- I originally created the article as "Amiga, Inc.". I found out later that the original company was called "Amiga Corporation" and that the other name is the current company; they weren't both the same name, though close. I agree that there should be an article about the current Amiga company, "Amiga, Inc.", but right now, I could only create a stub for it. Val42 17:00, 26 November 2005 (UTC)
- Amiga, Inc. and Amiga (disambiguation) articles have now been created. Other pages have been updated appropriately. Val42 17:43, 26 November 2005 (UTC)
Just thinking[edit]
Please dont think this much.
"From this point on the former Amiga Corporation was a division of Commodore. Over the next few years Commodore's management proved to be as annoying as Atari's, and most of the team members left or were fired."
"proved to be as annoying..." strikes me as lazy, if not in contradiction of the NPOV policy of Wikipedia. Most observers aren't entirely happy with Commodore's managing of the Amiga, but "annoying" doesn't really explain what those concerns with, it's just a subjective insult.
Dave Haynie quote about Amiga/Atari loan[edit]
This Usenet post by Dave Haynie seems to contradict the claim made elsewhere about the loan. I slapped a {{dubious}} on the original claim, but removed it as the reference given had some good evidence. Haynie's version of events is still worth reading, however. Fourohfour 15:34, 9 November 2006 (UTC)
The problem with that post though is that it incorrectly states Tramiel loaned the money, when it was Warner Atari that did the loan. Secondly, Haynie (by his own admission in that post) wasn't around at the time these dealings were happening, and much of what people (including later Amiga people) go on has been the missinformation by RJ Mical. The document provided as reference is one of several that Curt (the site owner and historian) has. Likewise, Joe Decuir (who was at both companies during the time of these happenings) has confirmed it. --Marty Goldberg 16:19, 9 November 2006 (UTC)
Santa Clara?[edit]
This article says that Amiga was in Santa Clara. My understanding has always been that it was in Los Gatos. A few other Wikipedia articles (e.g., Amiga Ranger Chipset, Jay Miner) also refer to Los Gatos. Anyone have any reliable source either way? TJRC (talk) 02:28, 6 December 2012 (UTC)


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TAP - a Gastropub
Serves meat, vegan options available. Some items can be made Vegan (mostly side items) and still are clearly marked on the menu. Chips and salsa can be vegan without the cheese. No longer offers vegan desserts. Some ingredients on the menu are organic. Atmosphere is modern bar, casual dress code. Wi-fi, beer bar, live music Fridays, trivia Tuesdays. Note: Reported that fries are fried in same frier as fish, please confirm and inform HappyCow.
Category: Vegan-friendly, Lacto, Ovo, American, Beer/Wine, Take-out, Non-veg
Reviews (3)First Review by eesworthy
not very vegan - Edit
No real options, nice place just not for cegans
Changed menu, very few options - Edit
We ordered everything vegan on the menu and it was barely a dinner. They had some dips, olives, fries, boiled peanuts and a veggie plate with cucumber salad, pickled beets and very sweet Brussels sprouts.
The food was okay, salty and tangy to go with the beer, but not great on its own, and not a meal.
Decor is nice, very interesting, especially the bathrooms. Staff was great. Extensive, varied beer list. I wouldn't be surprised if this place had great non-veg food, but for a veg-friendly place, I think it's lacking.
Pros: Beer, Staff, Decor
Cons: Food
Good food but buyer beware! - Edit
My husband and I went to Tap last night for dinner. I have recently dropped the dairy from my lacto-ovo diet, and was excited to try the many vegan options after reading the review here and also looking at their menu on line. My husband, an omnivore, and I shared the Eggplant-Daiya app. It was delicious. I loved the flavor profile, the consistence and the balsamic dressed greens that accompanied the eggplant. I also ordered the portabella mushroom sandwich with no goat cheese or lemon ailoi, along with the white bean ragout (marked by an asterisk as vegan appropriate on the menu) as my entree.
The meal came out and smelled delicious. The mushroom, zucchini and onions on the sandwich were very good...well cooked without becoming a mushy mess. The ragout was good, but I noticed something that had an odd texture. I took it out of my mouth and it was a piece of crispy pork.
After speaking with the manager, I was informed that the dish *can* be made vegan, but that it is an option, not the standard way that the kitchen prepares it. It was sent back and a vegan version was brought out. The dish was quite good, but I left annoyed.
After ordering the vegan app and a veggie sandwich with no dairy, the server absolutely should have offered up the information that the dish needs to be specifically requested to be made vegan. She was unapologetic and basically left me feeling as if it was my fault for not specifying that the dish should be prepared vegan...EVEN THOUGH THE MENU INDICATED THAT IT IS A VEGAN OPTION!
The manager, Emma, came over while the vegan ragout was being prepared. She was apologetic and, as a vegetarian herself, indicated that the staff will be trained to clarify the menu. As the restaurant offers no vegan deserts, she offered my husband and I cappuccinos made with almond milk.
I would say that the food was good, that the management was good but that the serving staff clearly needs to be trained a little better...especially if the menu is going to be ambiguous.
Pros: Vegan options, Innovative dishes, Atmosphere
Cons: Uneducated staff, Misleading menu
Link to this page from your site.
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UCLA football: Sizing up quarterback competition
Unlike the past two seasons, UCLA doesn't have a quarterback competition for the No. 1 spot heading into fall camp. The job belongs to Kevin Prince. But there is a competition for No. 2.
"I know Richard Brehaut is chomping at the bit for a chance to prove that he's ready to go out," Coach Rick Neuheisel said. "When he got into the game, he never one time was nervous. He just didn't realize, and you fault him because you have to fault him, that's your job as a coach, but you can't fault him because he's young and he's brand new to this deal and being thrust into this environment, he just didn't realize how hard it is to remember everything. That goes into being a college quarterback.
"There was a time he forgot to bring a guy in motion. Well, that's why he doesn't get blocked. There was a time he forgets to line up on the line of scrimmage. All of a sudden Milton Knox gets down to the 1-yard line against Washington, but now it's a five-yard deal and it's third-and-15 and here comes the defensive ends with their ears pinned back and he's waiting for a guy to get open and he gets the ball stripped and we got a turnover rather than three points. It's right when Kevin (Prince) got hurt, a pivotal drive in the game. By themselves, you can kind of understand those mistakes. But in the context of a game, where you have to win — we're on a five-game losing streak — that can't happen. Absolutely can't happen.
"So, how does he respond to the adversity? Because there's going to be a change with (Kevin) Craft going into the game. Hopefully it was a wake-up call of how much more serious he has to take this, how much more commitment and dedication. I think he's taken that into light. It was a stark reality at the time it happened, but I still have high, high hopes for Richard Brehaut.
"Nick Crissman, we haven't had a chance to watch. He's been hurt for most of his time. I don't think you would have designed this offense for Nick. But when he was in there, he looked like he knew what he was doing in spring ball. Darius Bell, our new quarterback, brings a lot of weapons. He's been in this kind of offense at the City College of San Francisco. He's more of a runner, or at least a 50-50 guy, than the other guys in the program.
"We'll see how we incorporate him into this. I know he's got all the confidence of his brother, Kahlil (Bell). I think he's going to be a great asset. I know having been the fourth-team quarterback and having been the third-team quarterback, they think there's competition. As long as they think it and they get opportunities, then who knows what's going to happen."
- Part I: Neuheisel says Bruins are 'anxious to get back into a conference title race'
- Part II: Neuheisel on Kevin Prince, new tailbacks, 'finding the big play' on offense
- Part III: Sizing up the quarterback competition
- Part IV: Neuheisel on being picked eighth in Pac-10 -- 'We're better and we're going to prove that'
- Part V: Replacing Brian Price a team effort
- Part VI: QB play key to Pac-10 success
- Part VII: Neuheisel on why Pistol will work
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The Acerra family had sixteen children, including twelve ball-playing boys. It was the 1930s, and many families had lots of kids. But only one had enough to field a baseball team . . . with three on the bench! The Acerras were the longest-playing all-brother team in baseball history. They loved the game, but more important, they cared for and supported each other and stayed together as a team. Nothing life threw their way could stop them.
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Originally Posted by Jvan
Is there any IDE out there that is a complete solution for Javascript & HTML?
An editor with intelisense, line by line debugging? and a GUI layout tool?
Jvan, I know this is an older thread, but what did you ever find that met your above requirements? Are you still developing ExtJS or Sencha Touch? What are you using?
I recommend Safari. I'm using it on my iPad.
kombajny dla farmera. przydatne dmuchawy.
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RE/MAX Results Announces Fifth Annual Neighborhood Film Festival
RE/MAX Results presents its fifth annual Neighborhood Film Festival for 2014, themed "Find Your Place."
Minneapolis, MN, May 6, 2014 - (PressReleasePoint) - RE/MAX Results has announced the start of its fifth Neighborhood Film Festival. The annual event engages local videographers and cinema students around the Twin Cities area, inviting them to create a three-minute film sharing why they love their city or community. Themed "Find Your Place," the 2014 Neighborhood Film Festival offers larger prizes than ever and welcomes new sponsorship.
Joining RE/MAX Results is past sponsor Bell Mortgage of Bell State Bank & Trust as well as Dunn Bros Coffee, a new festival sponsor that will be offering its own individual award in addition to the main prizes. RE/MAX Results prizes range from a $1,000 cash award for the People's Choice to $6,000 for the first place winner. Total, the RE/MAX Results Neighborhood Film Festival will be awarding $15,000 in cash prizes.
The top films will be screened at the RE/MAX Results Neighborhood Film Festival Awards Ceremony at Riverview Theater on November 6th from 7:00-9:00 p.m. Community members and film enthusiasts, as well as friends and families of participants, are invited to attend. Tickets to the screening event will be $7.00 at the door.
RE/MAX Results will also be awarding five $2,000 scholarships to Minneapolis Community and Technical College (MCTC) students at the screening. Students who wish to participate in The Results Cinema Production Scholarship must submit a written essay by October 20, 2014. A film entry is not required, but students applying for the scholarship are still eligible to compete in the Neighborhood Film Festival as well.
The entry deadline for film submissions is October 23, 2014. Full guidelines and official rules, along with videos of previous years' entries, can be found online at ResultsFilmFestival.com. Learn more about participating in or sponsoring the RE/MAX Results Neighborhood Film Festival by inquiring online or calling the Festival Director, Ed Dillon, at 612.702.4200.
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Pacific Motor Inn puts you in a great location, within just a 10-minute walk of San Jose Convention Center and Tech Museum. Guests can visit the fitness center for a workout or splash around at the outdoor pool or seasonal outdoor pool. Rooms feature conveniences like refrigerators and microwaves.


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Call our experts: 888.808.FINE
Custom Stationery from luxury designers!NEW! Wedding Invitations Customize any Address Stamp to match your style!
Select a quantity and printing method. Changes are easily made later.
Add style to your envelopes with these fabulous address labels. These brown labels feature a sage green center that is topped with a subtle fleur de lys pattern. Add your initial to the center and your personalized text around the outside edge of the label to complete the look.


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Compared to the rest of the Louisville market, the Louisville submarket has smaller rates, so you should have no trouble finding a great deal in this depreciated submarket.
In the last 90 days, 55 listings have been posted online, so you'll want to check back regularly for new listings. About 2% of the listings in the Louisville are subleases, so you will probably need to sign a longer term lease with the landlord directly. There aren't many listings below 2,000 square feet on the market, so finding a space for a small business might be tough.
Even though the median size is 3,600 sqft, there are still 0 new listings below 2,000 sqft. Most buildings in this region are approximately 2 stories. Most buildings in this region were built in 1880 and are Class Class B.
Trends and status of the commercial real estate market in Louisville.
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Real time and historical data on commercial real estate listings in Louisville.


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Cosmetic Plastic Surgeons in Brookfield
You can choose a cosmetic plastic surgeon in Brookfield from this list with confidence, knowing that he or she possesses exceptional training, outstanding credentials and experience with all areas of the face and body.
This list features only plastic surgeons in the city of Brookfield. To widen your search, choose a nearby city from the list to the left, or click here to search by ZIP code.
|Surgeons highlighted below have purchased an Enhanced Practice Profile
|Personal Website
William G. Doubek, M.D.2400 Witzel Suite A Oshkosh, WI Tel: Click for phone number920-233-1540
|70.51 Miles
William G. Doubek, M.D.2400 Witzel Suite A Oshkosh, WI Tel: Click for phone number920.233.1540
|70.51 Miles
William G. Doubek, M.D.2400 Witzel Suite A Oshkosh, WI Tel: Click for phone number920-233-1540
|70.51 Miles
Landon S. Pryor, M.D.1639 North Alpine Rd. Suite 400 Rockford, IL Tel: Click for phone number815-977-4403
|70.51 Miles
M. Vincent Maklouf, M.D.9301 Golf Road Suite 110 Des Plaines, IL Tel: Click for phone number847-297-8001
|70.61 Miles
Peter E. Johnson, M.D.8901 W. Golf Road Suite 204 Des Plaines, IL Tel: Click for phone number847-296-5470
|70.61 Miles
William N. Georgis, M.D.6030 Garrett Lane Rockford, IL Tel: Click for phone number815-398-7600
|70.74 Miles
Gregory A. Turowski, M.D.9843 Gross Point Road Skokie, IL Tel: Click for phone number847-674-4646
|71.69 Miles
Sam Speron, M.D.950 N. Northwest Highway Suite 102 Park Ridge, IL Tel: Click for phone number847-696-9900
|72.76 Miles
Stefan M. Szczerba, M.D.10400 W Higgins Road Suite 100 Rosemont, IL Tel: Click for phone number847-853-9900
|74.16 Miles
The surgeons listed above are members of The American Society for Aesthetic Plastic Surgery, licensed by the state of Wisconsin and certified by The American Board of Plastic Surgery (ABPS).
Choose Your Plastic Surgeon Carefully
Remember, any licensed physician is legally allowed to advertise as a "cosmetic" surgeon, even if he or she has no formal surgical training. Your body is nothing to take chances with, so avoid the risk. Selecting a board-certified plastic surgeon from this list is your assurance that your doctor has the highest quality training and advanced surgical skills.
ABPS Certification and ASAPS Membership Matters
The ABPS is recognized by the American Board of Medical Specialties to certify doctors in the specialty of plastic surgery. Following medical school, ABPS-certified plastic surgeons must have completed a minimum of 5 years of surgical training, including an accredited plastic surgery residency program. Members of ASAPS must be in at least their third year of active practice following ABPS certification.


text: Home > Business Buying spree continues, SMC eyes media biz ABS-CBN News Posted at Jun 14 2012 04:49 PM | Updated as of Jun 15 2012 07:39 AM Share Save Facebook Twitter GPlus LinkedIn Pinterest MANILA, Philippines - Diversifying conglomerate San Miguel Corp. disclosed on Thursday that it plans to invest in the Philippine broadcasting industry. San Miguel President Ramon Ang said the company is seriously considering investing in media, which would pit it against PLDT's Manuel Pangilinan, which is also on a buying binge. Pangilinan's MediaQuest has been eyeing GMA Network, but the latter's owners have found his price offer too low. Pangilinan now owns the country's third largest network, TV5. Asked if San Miguel will try to bid for GMA Network, Ang did not comment. There are 2 government-sequestered networks for sale, Channels 9 and 13. Airline industry San Miguel will also continue to strengthen its foothold in the airline industry by expanding its business in the region. Ang did not disclose other details, but noted the company wants to synergize the operations of Philippine Airlines (PAL) with regional players so they can better tap the United States market and also Europe. He said it could be via a joint venture or acquisition. San Miguel made its first foray into the transportation sector back in April when it acquired an indirect stake in the flag carrier. The firm also confirmed reports it would sell P80 billion in perpetual preferred shares in August to refinance P72 billion worth of preferred shares issued to stockholders and the government back in 2009. – from a report by Ma. Eloisa Calderon, ANC Share Save Facebook Share on Twitter GPlus LinkedIn Pinterest Read More: Philippine Airlines San Miguel /news/02/27/17/de-lima-camp-questions-arrest-before-supreme-court/life/02/27/17/stars-shimmer-on-oscar-red-carpet-as-diamonds-and-gold-have-their-day/entertainment/02/27/17/jaya-admits-its-not-easy-to-judge-tawag-ng-tanghalan/business/02/27/17/sws-joblessness-rises-to-2-year-high-optimism-climbs/life/02/27/17/look-georgina-wilson-shares-full-photos-of-baby


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Our beautiful art deco venue, Pavilion Dance, can be hired for events, from conferences and away days to parties and celebrations.Read More
Company Chameleon
Thursday 9 March, 7.30pm
An evening of mesmerising and powerful dance theatre that turns the spotlight on mental health and the things we choose to hide
Dance can enrich communities, improve public health and increase social skills and life satisfaction.Read more
As a dance development organisation we strive to bring dance in as many ways as possible to as many people as possible across the South West region.Read more
Check out our vibrant programme of dance performances, live screenings and family shows!Read More
There are over 40 dance classes each week, for all ages and abilities - from Ballet to Ballroom, from Pilates to Parkour, and everything in between!Read more
An archive of relevant work for dance practitioners, students and everyone else interested in dance research.Read more
Our work is all about connecting as many people as possible with dance. Find out more about what we do, why it makes a difference and how you can help.
A brand new event for spring!
Kevin Edward Turner tells us a little more about himself, ahead of Witness...
Sadler's Wells is inviting applications from over 60's groups to perform in Elixir Extracts
Hannah Sampson tells us a little more about herself head of The Enormous Room...