The highs (B1H) and lows (B1L) of human heart B1-adrenoceptors (AR)

The 1AR has two binding sites which can be activated to cause cardiostimulation. The first, termed, 1HAR (high affinity site of 1AR) is activated by noradrenaline and adrenaline and is blocked by relatively low concentrations of β-blockers including carvedilol (Kaumann and Molenaar, 2008). The other, termed, 1LAR (low affinity site of 1AR) has lower affinity for noradrenaline and adrenaline and is activated by some β-blockers including CGP12177 and pindolol, at higher concentrations than those required to block the receptor (Kaumann and Molenaar, 2008). (-)-CGP12177 is a non-conventional partial agonist that causes modest and transient increases of contractile force in human atrial trabeculae (Kaumann and Molenaar, 2008). These effects are markedly increased and maintained by inhibition of phosphodiesterase PDE3. The stimulant effects of (-)-CGP12177 at human β1ARs was verified with recombinant receptors (Kaumann and Molenaar, 2008). However, in a recent report it was proposed that the positive inotropic effects of CGP12177 are mediated through 3ARs in human right atrium (Skeberdis et al 2008). This proposal was not consistent with the lack of blockade of (-)-CGP12177 inotropic effects or increases in L-type Ca2+ current (ICa-L ) by the β3AR blocker 1 μM LY748,337 (Christ et al, 2010). On the otherhand, (-)-CGP12177 increases in inotropic effects and ICa-L were blocked by (-)-bupranolol 1-10 μM (Christ et al, 2010). Chronic infusion of (-)-CGP 12177 (10 mg/Kg/24 hours) for four weeks in an aortic constriction mouse model of heart failure caused an increase in left ventricular wall thickness, fibrosis and inflammation-related left ventricular gene expression levels. Christ T et al (2010) Br J Pharmacol, In press Kaumann A and Molenaar P (2008) Pharmacol Ther 118, 303-336 Skeberdis VA et al (2008) J Clin Invest, 118, 3219-3227

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.

Caveat Anicula! Beware of the Quiet Little Old Ladies : Demographics, Pharmacotherapy, Survival and Readmissions in a 10 Year Cohort of Heart Failure Patients with Preserved Systolic Function

Objective--To determine whether heart failure with preserved systolic function (HFPSF) has different natural history from left ventricular systolic dysfunction (LVSD). Design and setting--A retrospective analysis of 10 years of data (for patients admitted between 1 July 1994 and 30 June 2004, and with a study census date of 30 June 2005) routinely collected as part of clinical practice in a large tertiary referral hospital.Main outcome measures-- Sociodemographic characteristics, diagnostic features, comorbid conditions, pharmacotherapies, readmission rates and survival.Results--Of the 2961 patients admitted with chronic heart failure, 753 had echocardiograms available for this analysis. Of these, 189 (25%) had normal left ventricular size and systolic function. In comparison to patients with LVSD, those with HFPSF were more often female (62.4% v 38.5%; P = 0.001), had less social support, and were more likely to live in nursing homes (17.9% v 7.6%; P < 0.001), and had a greater prevalence of renal impairment (86.7% v 6.2%; P = 0.004), anaemia (34.3% v 6.3%; P = 0.013) and atrial fibrillation (51.3% v 47.1%; P = 0.008), but significantly less ischaemic heart disease (53.4% v 81.2%; P = 0.001). Patients with HFPSF were less likely to be prescribed an angiotensin-converting enzyme inhibitor (61.9% v 72.5%; P = 0.008); carvedilol was used more frequently in LVSD (1.5% v 8.8%; P < 0.001). Readmission rates were higher in the HFPSF group (median, 2 v 1.5 admissions; P = 0.032), particularly for malignancy (4.2% v 1.8%; P < 0.001) and anaemia (3.9% v 2.3%; P < 0.001). Both groups had the same poor survival rate (P = 0.912). Conclusions--Patients with HFPSF were predominantly older women with less social support and higher readmission rates for associated comorbid illnesses. We therefore propose that reduced survival in HFPSF may relate more to comorbid conditions than suboptimal cardiac management.

Human atrial beta1L-adrenoceptor but not beta3-adrenoceptor activation increases force and Ca2+ current at physiological temperature

BACKGROUND AND PURPOSE It has been proposed that BRL37344, SR58611 and CGP12177 activate b3-adrenoceptors in human atrium to increase contractility and L-type Ca2+ current (ICa-L). b3-adrenoceptor agonists are potentially beneficial for the treatment of a variety of diseases but concomitant cardiostimulation would be potentially harmful. It has also been proposed that (-)-CGP12177 activates the low affinity binding site of the b1-adrenoceptor in human atrium. We therefore used BRL37344, SR58611 and (-)-CGP12177 with selective b-adrenoceptor subtype antagonists to clarify cardiostimulant b-adrenoceptor subtypes in human atrium. EXPERIMENTAL APPROACH Human right atrium was obtained from patients without heart failure undergoing coronary artery bypass or valve surgery. Cardiomyocytes were prepared to test BRL37344, SR58611 and CGP12177 effects on ICa-L. Contractile effects were determined on right atrial trabeculae. KEY RESULTS BRL37344 increased force which was antagonized by blockade of b1- and b2-adrenoceptors but not by blockade of b3-adrenoceptors with b3-adrenoceptor-selective L-748,337 (1 mM). The b3-adrenoceptor agonist SR58611 (1 nM–10 mM) did not affect atrial force. BRL37344 and SR58611 did not increase ICa-L at 37°C, but did at 24°C which was prevented by L-748,337. (-)-CGP12177 increased force and ICa-L at both 24°C and 37°C which was prevented by (-)-bupranolol (1–10 mM), but not L-748,337. CONCLUSIONS AND IMPLICATIONS We conclude that the inotropic responses to BRL37344 are mediated through b1- and b2-adrenoceptors. The inotropic and ICa-L responses to (-)-CGP12177 are mediated through the low affinity site b1L-adrenoceptor of the b1-adrenoceptor. b3-adrenoceptor-mediated increases in ICa-L are restricted to low temperatures. Human atrial b3-adrenoceptors do not change contractility and ICa-L at physiological temperature.

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.