Phosphodiesterase PDE3, but not PDE4, reduces β1- and β2-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients

Background and purpose Phosphodiesterases PDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3-selective inhibitor cilostamide (0.3-1μM) or PDE4 inhibitor rolipram (1-10μM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium. Experimental approach Right and left ventricular trabeculae from freshly explanted hearts of 5 non-β-blocker-treated and 15 metoprolol-treated patients with terminal heart failure were paced to contract at 1Hz. The effects of (-)-noradrenaline, mediated through β1-adrenoceptors (β2-adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through β2-adrenoceptors (β1-adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of PDE inhibitors. Catecholamine potencies were estimated from –logEC50s. Key results Cilostamide did not significantly potentiate the inotropic effects of the catecholamines in non-β-blocker-treated patients. Cilostamide caused greater potentiation (P=0.037) of the positive inotropic effects of (-)-adrenaline (0.78±0.12 log units) than (-)-noradrenaline (0.47±0.12 log units) in metoprolol-treated patients. Lusitropic effects of the catecholamines were also potentiated by cilostamide. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline on right and left ventricular trabeculae from metoprolol-treated patients. Conclusions and implications Metoprolol induces a control by PDE3 of ventricular effects mediated through both β1- and β2-adrenoceptors, thereby further reducing sympathetic cardiostimulation in patients with terminal heart failure. Concurrent therapy with a PDE3 blocker and metoprolol could conceivably facilitate cardiostimulation evoked by adrenaline through β2-adrenoceptors. PDE4 does not appear to reduce inotropic and lusitropic effects of catecholamines in failing human ventricle.

Role of low affinity beta1-adrenergic receptors in normal and diseased hearts

ROLE OF LOW AFFINITY β1-ADRENERGIC RECEPTOR IN NORMAL AND DISEASED HEARTS Background: The β1-adrenergic receptor (AR) has at least two binding sites, 1HAR and 1LAR (high and low affinity site of the 1AR respectively) which cause cardiostimulation. Some β-blockers, for example (-)-pindolol and (-)-CGP 12177 can activate β1LAR at higher concentrations than those required to block β1HAR. While β1HAR can be blocked by all clinically used β-blockers, β1LAR is relatively resistant to blockade. Thus, chronic β1LAR activation may occur in the setting of β-blocker therapy, thereby mediating persistent βAR signaling. Thus, it is important to determine the potential significance of β1LAR in vivo, particularly in disease settings. Method and result: C57Bl/6 male mice were used. Chronic (4 weeks) β1LAR activation was achieved by treatment with (-)-CGP12177 via osmotic minipump. Cardiac function was assessed by echocardiography and catheterization. (-)-CGP12177 treatment in healthy mice increased heart rate and left ventricular (LV) contractility without detectable LV remodelling or hypertrophy. In mice subjected to an 8-week period of aorta banding, (-)-CGP12177 treatment given during 4-8 weeks led to a positive inotropic effect. (-)-CGP12177 treatment exacerbated LV remodelling indicated by a worsening of LV hypertrophy by ??% (estimated by weight, wall thickness, cardiomyocyte size) and interstitial/perivascular fibrosis (by histology). Importantly, (-)-CGP12177 treatment to aorta banded mice exacerbated cardiac expression of hypertrophic, fibrogenic and inflammatory genes (all p<0.05 vs. non-treated control with aorta banding).. Conclusion: β1LAR activation provides functional support to the heart, in both normal and diseased (pressure overload) settings. Sustained β1LAR activation in the diseased heart exacerbates LV remodelling and therefore may promote disease progression from compensatory hypertrophy to heart failure. Word count: 270

The significance of endogeneity problems in crash models: An examination of left-turn lanes in intersection crash models

Crash prediction models are used for a variety of purposes including forecasting the expected future performance of various transportation system segments with similar traits. The influence of intersection features on safety have been examined extensively because intersections experience a relatively large proportion of motor vehicle conflicts and crashes compared to other segments in the transportation system. The effects of left-turn lanes at intersections in particular have seen mixed results in the literature. Some researchers have found that left-turn lanes are beneficial to safety while others have reported detrimental effects on safety. This inconsistency is not surprising given that the installation of left-turn lanes is often endogenous, that is, influenced by crash counts and/or traffic volumes. Endogeneity creates problems in econometric and statistical models and is likely to account for the inconsistencies reported in the literature. This paper reports on a limited-information maximum likelihood (LIML) estimation approach to compensate for endogeneity between left-turn lane presence and angle crashes. The effects of endogeneity are mitigated using the approach, revealing the unbiased effect of left-turn lanes on crash frequency for a dataset of Georgia intersections. The research shows that without accounting for endogeneity, left-turn lanes ‘appear’ to contribute to crashes; however, when endogeneity is accounted for in the model, left-turn lanes reduce angle crash frequencies as expected by engineering judgment. Other endogenous variables may lurk in crash models as well, suggesting that the method may be used to correct simultaneity problems with other variables and in other transportation modeling contexts.

Left vs right in black and white : a review

LIKE much of the work that David Williamson is known for, Let the Sunshine concentrates on tensions between characters who operate mainly as mouthpieces for opposing ideologies. Left-wing documentary-maker Toby and his wife Ros have moved to Noosa to escape the rat race in Sydney and some bad press surrounding one of Toby's projects. Trying to make social connections in town, Ros has reconnected with high school classmate Natasha, now the cosmetically-enhanced wife of wealthy right-wing property developer Ron. The posturing and conflict between Toby and Ron come to a head when the women invite their grown children -- struggling songwriter Rick and stressed corporate lawyer Emma -- to dinner to celebrate Toby's birthday, and the results of this encounter drive the rest of the plot. The scenario of Let the Sunshine is contrived, the characters are stereotyped, and their conflicts are little more than an old clash of ideologies cast loosely across the mainstream news media's characterisation of the sides in debates about development, climate change and the economic crisis.

The Aboriginal voice and the left-leaning 'Australia' (Baz Luhrmann, 2008)

Arguing that Baz Luhrmann's "Australia" (2008) is a big-budget, non-independent film espousing a left-leaning political ideology in its non-racist representations of Aborigines on film, this paper suggests the addition of a 'fourth formation' to the 1984 Moore and Muecke model is warranted. According to their theorising, racist "first formation" films promote policies of assimilation whereas "second formation" films avoid overt political statements in favour of more acceptable multicultural liberalism. Moore and Muecke's seemingly ultimate "third formation films", however, blatantly foreground the director's leftist political dogma in a necessarily low budget, independent production. "Australia", on the other hand, is an advance on the third formation because its feminised Aboriginal voice is safely backed by a colossal production budget and indicates a transformation in public perceptions of Aboriginal issues. Furthermore, this paper argues that the use of low-cost post-production techniques such as voice-over narration by racially appropriate individuals and the use of diegetic song in Australia work to ensure the positive reception of the left-leaning message regarding the Stolen Generations. With these devices Luhrmann effectively counters the claims of right-wing denialists such as Andrew Bolt and Keith Windschuttle.

Taking a leap of faith : are investors left short changed?

This dissertation examines the compliance and performance of a large sample of faith based (religious) ethical funds - the Shari'ah-compliant equity funds (SEFs), which may be viewed as a form of ethical investing. SEFs screen their investment for compliance with Islamic law, where riba (conventional interest expense), maysir (gambling), gharar (excessive uncertainty), and non-halal (non-ethical) products are prohibited. Using a set of stringent Shari'ah screens similar to those of MSCI Islamic, we first examine the extent to which SEFs comply with the Shari'ah law. Results show that only about 27% of the equities held by SEFs are Shari'ah-compliant. While most of the fund holdings pass the business screens, only about 42% pass the total debt to total assets ratio screen. This finding suggests that, in order to overcome a significant reduction in the investment opportunity, Shari'ah principles are compromised, with SEFs adopting lax screening rules so as to achieve a financial performance. While younger funds and funds that charge higher fees and are domiciled in more Muslim countries are more Shari'ah-compliant, we find little evidence of a positive relationship between fund disclosure of the Shari'ah compliance framework and Shari'ah-compliance. Clearly, Shari'ah compliance remains a major challenge for fund managers and SEF investors should be aware of Shari'ah-compliance risk since the fund managers do not always fulfill their fiduciary obligation, as promised in their prospectus. Employing a matched firm approach for a survivorship free sample of 387 SEFs, we then examine an issue that has been heavily debated in the literature: Does ethical screening reduce investment performance? Results show that it does but only by an average of 0.04% per month if benchmarked against matched conventional funds - this is a relatively small price to pay for religious faith. Cross-sectional regressions show an inverse relationship between Shari'ah compliance and fund performance: every one percentage increase in total compliance decreases fund performance by 0.01% per month. However, compliance fails to explain differences in the performance between SEFs and matched funds. Although SEFs do not generally perform better during crisis periods, further analysis shows evidence of better performance relative to conventional funds only during the recent Global Financial Crisis; the latter is consistent with popular media claims.

Frank-starling control of a left ventricular assist device

A physiological control system was developed for a rotary left ventricular assist device (LVAD) in which the target pump flow rate (LVADQ) was set as a function of left atrial pressure (LAP), mimicking the Frank-Starling mechanism. The control strategy was implemented using linear PID control and was evaluated in a pulsatile mock circulation loop using a prototyped centrifugal pump by varying pulmonary vascular resistance to alter venous return. The control strategy automatically varied pump speed (2460 to 1740 to 2700 RPM) in response to a decrease and subsequent increase in venous return. In contrast, a fixed-speed pump caused a simulated ventricular suction event during low venous return and higher ventricular volumes during high venous return. The preload sensitivity was increased from 0.011 L/min/mmHg in fixed speed mode to 0.47L/min/mmHg, a value similar to that of the native healthy heart. The sensitivity varied automatically to maintain the LAP and LVADQ within a predefined zone. This control strategy requires the implantation of a pressure sensor in the left atrium and a flow sensor around the outflow cannula of the LVAD. However, appropriate pressure sensor technology is not yet commercially available and so an alternative measure of preload such as pulsatility of pump signals should be investigated.