KCNQ Currents and Their Contribution to Resting Membrane Potential and the Excitability of Interstitial Cells of Cajal From the Guinea Pig Bladder

PURPOSE: The presence of novel KCNQ currents was investigated in guinea pig bladder interstitial cells of Cajal and their contribution to the maintenance of the resting membrane potential was assessed. MATERIALS AND METHODS: Enzymatically dispersed interstitial cells of Cajal were patch clamped with K(+) filled pipettes in voltage clamp and current clamp modes. Pharmacological modulators of KCNQ channels were tested on membrane currents and the resting membrane potential. RESULTS: Cells were stepped from -60 to 40 mV to evoke voltage dependent currents using a modified K(+) pipette solution containing ethylene glycol tetraacetic acid (5 mM) and adenosine triphosphate (3 mM) to eliminate large conductance Ca activated K channel and K(adenosine triphosphate) currents. Application of the KCNQ blockers XE991, linopirdine (Tocris Bioscience, Ellisville, Missouri) and chromanol 293B (Sigma) decreased the outward current in concentration dependent fashion. The current-voltage relationship of XE991 sensitive current revealed a voltage dependent, outwardly rectifying current that activated positive to -60 mV and showed little inactivation. The KCNQ openers flupirtine and meclofenamic acid (Sigma) increased outward currents across the voltage range. In current clamp mode XE991 or chromanol 293B decreased interstitial cell of Cajal resting membrane potential and elicited the firing of spontaneous transient depolarizations in otherwise quiescent cells. Flupirtine or meclofenamic acid hyperpolarized interstitial cells of Cajal and inhibited any spontaneous electrical activity. CONCLUSIONS: This study provides electrophysiological evidence that bladder interstitial cells of Cajal have KCNQ currents with a role in the regulation of interstitial cell of Cajal resting membrane potential and excitability. These novel findings provide key information on the ion channels present in bladder interstitial cells of Cajal and they may indicate relevant targets for the development of new therapies for bladder instability.

Restraing Regulatory Capture? Anglo America, Crisis Politics and Trajectories of Change in Global Financial Governance

A growing number of respected commentators now argue that regulatory capture of public agencies and public policy by leading banks was one of the main causal factors behind the financial crisis of 2007–2009, resulting in a permissive regulatory environment. This regulatory environment placed a faith in banks own internal risk models, contributed to pro-cyclical behaviour and turned a blind eye to excessive risk taking. The article argues that a form of ‘multi-level regulatory capture’ characterized the global financial architecture prior to the crisis. Simultaneously, regulatory capture fed off, but also nourished the financial boom, in a fashion that mirrored the life cycle of the boom itself. Minimizing future financial booms and crises will require continuous, conscious and explicit efforts to restrain financial regulatory capture now and into the future. The article assesses the extent to which this has been achieved in current global financial governance reform efforts and highlights some of the persistent difficulties that will continue to hamper efforts to restrain regulatory capture. The evidence concerning the extent to which regulatory capture is being effectively restrained is somewhat mixed, and where it is happening it is largely unintentional and accidental. Recent reforms have overlooked the political causes of the crisis and have failed to focus explicitly or systematically on regulatory capture.

Filming and Performing Renaissance History

Over the last one hundred years, many of the events and personalities of the sixteenth and seventeenth centuries have been brought before home, cinema, exhibition, festival and theatrical audiences via a variety of visual media. This collection, for the first time, examines these representations, looking at recent television series, documentaries, feature films, pageantry, theatre and popular culture in a range of cultural and linguistic guises. Filming and Performing Renaissance History opens up wider avenues of interpretive opportunity and substitutes a more generous, nuanced acknowledgement of the ways in which the 'Renaissance' is made to signify across disciplines and in relation to a whole series of events and personalities. Accessing the Renaissance in this fashion generates a genuine sense of the modalities of historical representation, of what the Renaissance 'means' and of how its meanings have been negotiated in modernity.

Steady state pharmacokinetic profile of indomethacin in elderly patients and young volunteers

The steady-state pharmacokinetic profile of indomethacin was examined in twelve healthy volunteers (4 m, 8 f; 20-34 y) and in 12 elderly subjects (7 m, 5 f; 70-88 y). Two formulations of indomethacin were examined, providing duplicate data for each subject group. The subjects received each formulation of indomethacin (25 mg tid) for 6 days in a single blind crossover fashion. On day 7, after an overnight fast, a final 25 mg dose of indomethacin was given and plasma concentrations measured over the following 12 h. Kinetic parameters Cpmin, Tmax and AUC (0-12 h) were determined. There were no differences in the pharmacokinetic parameters between young and elderly subjects or between data for the two formulations of indomethacin. AUC values (micrograms.ml-1.h), for example, for the two formulations in the young subjects were 5.85 and 6.85 while the values for the elderly subjects were 6.55 and 6.50 respectively. When each treatment period was considered independently there was a significant difference between young and elderly subjects with regard to compliance. The rates of non compliance (over and under compliance) using a capsule count technique were, however, low with a mean maximum value of 5.8% being recorded for the elderly subjects.

Freedom of Expression and Hate Speech

This is a study of free speech and hate speech with reference to the international standards and to the United States jurisprudence. The study, in a comparative and critical fashion, depicts the historical evolution and the application of the concept of ‘free speech,’ within the context of ‘hate speech.’ The main question of this article is how free speech can be discerned from hate speech, and whether the latter should be restricted. To this end, it examines the regulation of free speech under the First Amendment to the United States Constitution, and in light of the international standards, particularly under the International Convention on the Elimination of All Forms of Racial Discrimination, International Covenant on Civil and Political Rights, and the European Convention on Human Rights and Fundamental Freedoms. The study not only illustrates how elusive the endeavour of striking a balance between free speech and other vital interests could be, but also discusses whether and how hate speech should be eliminated within the ‘marketplace of ideas.’

Re-imagining DDR Ex-combatants, leadership and moral agency in conflict transformation

Drawing upon criminological studies in the field of prisoner rehabilitation, this essay explores the relevance of the Demobilisation, Disarmament and Reintegration (DDR) framework to the process of conflict transformation in Northern Ireland. In a similar fashion to the critique of 'passivity' offered by, for example, the 'strengths based' or 'good lives' approach to prisoner resettlement and reintegration more generally, the authors contend that the Northern Ireland peace process offers conspicuous examples of former prisoners and combatants as agents and indeed leaders in the process of conflict transformation. They draw out three broad styles of leadership which have emerged amongst ex-combatants over the course of the Northern Ireland transition from conflict-political, military and communal. They suggest that cumulatively such leadership speaks to the potential of ex-prisoners and ex-combatants as moral agents in conflict transformation around which peacemaking can be constructed rather than as obstacles which must be 'managed' out of existence.

SYNTHESIS AND PROPERTIES OF DITHYMIDINE PHOSPHATE ANALOGS CONTAINING 3'-THIOTHYMIDINE

Dithymidine-3'-S-phosphorothioate (d(TspT)) has been prepared from a 5'-O-monomethoxytritylthymidine-3'-S- phosphorothioamidite (7) by activation with 5-(p- nitrophenyl)tetrazole in the presence of 3'-O- acetylthymidine. The resulting dinucleoside phosphorothioite is readily oxidised to the corresponding 3'-S-phosphorothioate using either tetrabutylammonium (TBA) perlodate or TBA oxone and has been deprotected under standard conditions to yield d(TspT). This dithymidine phosphate analogue is comparatively resistant to hydrolysis by nuclease P1, but the P-S bond is readily cleaved by aqueous solutions of either iodine or silver nitrate. Dithymidine-3'-S-phosphorodithioate (d[Tsp(s)T] was prepared in an analogous fashion using sulphur to oxidise the intermediate dinucleoside phosphoro thiolte. Absolute stereochemistry has been assigned to the diastereoisomers of d by comparing their physical and chemical properties to those of the dinucleoside phosphorothioates.

Comparison of passive millimeter-wave and IR imagery in a nautical environment

Results are presented from a trial in which a real-time passive millimetre-wave camera was mounted on a landing craft. The vessel was operated on rivers in the UK, and imagery of surrounding terrain, structures, obstacles and other vessels was obtained. An IR camera was also used, and the differences in signatures of various features are discussed. Opportunities for image fusion are highlighted.

Structure of the Plasmodium falciparum M17 aminopeptidase and significance for the design of drugs targeting the neutral exopeptidases

Current therapeutics and prophylactics for malaria are under severe challenge as a result of the rapid emergence of drug-resistant parasites. The human malaria parasite Plasmodium falciparum expresses two neutral aminopeptidases, PfA-M1 and PfA-M17, which function in regulating the intracellular pool of amino acids required for growth and development inside the red blood cell. These enzymes are essential for parasite viability and are validated therapeutic targets. We previously reported the x-ray crystal structure of the monomeric PfA-M1 and proposed a mechanism for substrate entry and free amino acid release from the active site. Here, we present the x-ray crystal structure of the hexameric leucine aminopeptidase, PfA-M17, alone and in complex with two inhibitors with antimalarial activity. The six active sites of the PfA-M17 hexamer are arranged in a disc-like fashion so that they are orientated inwards to form a central catalytic cavity; flexible loops that sit at each of the six entrances to the catalytic cavern function to regulate substrate access. In stark contrast to PfA-M1, PfA-M17 has a narrow and hydrophobic primary specificity pocket which accounts for its highly restricted substrate specificity. We also explicate the essential roles for the metal-binding centers in these enzymes (two in PfA-M17 and one in PfA-M1) in both substrate and drug binding. Our detailed understanding of the PfA-M1 and PfA- M17 active sites now permits a rational approach in the development of a unique class of two-target and/or combination antimalarial therapy.

Photographing Vladimir Putin: Masculinity, Nationalism and Visuality in Russian Political Culture

This article introduces the study of photographs of politicians as an object of geopolitical analysis. It does this through exploring the holiday photographs of Vladimir Putin released by the Kremlin in 2007, 2009, and 2010. Putin's biography provides a backdrop to a detailed analysis of the geopolitical representations contained in the photographs of him. In the same fashion as other images, the photographs seek to provide a contemporary view of events and, at the same time, serve as a medium through which particular political scripts are narrated. The photographs also help to reproduce (and question) hegemonic discourses about public forms of masculinity in Russia. This article is intended to contribute to the debate on how visual images can help make sense of the geopolitical world

Hydrodynamics and mixer-induced bubble formation in micro bubble columns with single and multiple-channels

A hydrodynamic characterization of an industrially used gas-liquid contacting microchannel. device is discussed, viz. the micro bubble column of IMM. Furthermore, similar characterization of a gas-liquid flow microchip of TU/e, with two tailored mixer designs, is used to solve fundamental issues on hydrodynamics, and therefore, to achieve further design and operating optimization of that chip and the IMM device. Flow pattern maps are presented in a dimensionless fashion for further predictions on new fluidic systems for optimum single-channel multiphase operation. Bubble formation was investigated in the two types of mixers and pinch-off and hydrodynamic decay mechanisms are observed. The impact of these mechanisms on bubble size, bubble size distributions, and on the corresponding flow patterns, i.e., the type of mixer design, can be decisive for the flow pattern map and thus, may be used to alter flow pattern maps. The bubble sizes and their distribution were improved for the tailored designs, i.e., smaller and more regular bubbles were generated. Finally, the impact of multi-channel distribution for gas and liquid flow is demonstrated. Intermediate flow patterns such as slug-annular flow, also found for single-phase operation, and the simultaneous coexistence of flow regimes are presented, with the latter providing evidence of flow maldistribution.

SUBLINGUAL CAPTOPRIL - A PHARMACOKINETIC AND PHARMACODYNAMIC EVALUATION

In this study we compared the pharmacokinetics and pharmacodynamics of captopril after sublingual and peroral administration. Single 25 mg doses of captopril were administered sublingually and perorally on two different occasions in a randomised cross-over fashion to eight healthy volunteers aged 22-35 years. The kinetics of unchanged captopril, plasma renin activity (PRA), BP and heart rate were studied over three hours after both peroral and sublingual administration of captopril.

Physicochemical and drug diffusion analysis of rifampicin containing polyethylene glycol-poly(epsilon-caprolactone) networks designed for medical device applications

This study reports the physicochemical and drug diffusion properties of rifampicin containing poly(epsilon-caprolactone) (PCL)/polyethylene glycol (PEG) networks, designed as bioactive biomaterials. Uniquely, the effects of the states of both rifampicin and PEG and the interplay between these components on these properties are described. PCL matrices containing rifampicin (1-5%, w/w) and PEG 200 (0-15%, w/w) were prepared by casting from an organic solvent (dichloromethane). The films were subsequently characterized in terms of their thermal/thermorheological, surface and tensile properties, biodegradation and drug diffusion/release properties. Incorporation of PEG and/or rifampicin significantly affected the tensile and surface properties of PCL, lowering the ultimate tensile strength, % elongation at break, Young modulus and storage and loss moduli. Both in the absence and presence of PEG, solubilisation of rifampicin within the crystalline domains of PCL was observed. PEG was present as a dispersed liquid phase. The release of rifampicin (3% loading) was unaffected by the presence of PEG. Similarly the release of rifampicin (5%) was unaffected by low concentrations of PEG (5-10%) however, at higher loadings, the release rate of rifampicin was enhanced by the presence of PEG. Rifampicin release (10% loading) was enhanced by the presence of PEG in a concentration dependent fashion. These observations were accredited to enhanced porosity of the matrix. In all cases, diffusion-controlled release of rifampicin occurred which was unaffected by polymer degradation. This study has uniquely illustrated the effect of hydrophilic pore formers on the physicochemical properties of PCL. Interestingly, enhanced diffusion controlled release was only observed from biomaterials containing high loadings of PEG and rifampicin (5, 10%), concentrations that were shown to affect the mechanical properties of the biomaterials. Care should therefore be shown when adopting this strategy to enhance release of bioactive agents from biomaterials. (C) 2011 Elsevier B.V. All rights reserved.

Production and Productive Reason

This article explores two rival understandings of production and what it means to be a rational productive subject. Against ‘technicist’ models of productive reason, it defends a ‘phronetic’ model on both normative and pragmatic grounds. The discussion begins with a description of the general principles underpinning technicist theories of workplace organisation, principles which continue to inform work design approaches to this day. The technicist model is thereafter criticised on three counts: that it represents a specific managerial agenda which privileges sectional interests; that it is suspect morally for a number of reasons; and that despite its aspiration of arriving at ‘one best method’, it represents but one way of organising work processes. The phronetic model is then set out using the notion of ‘practices’ as a guide. This notion is important in providing a view of production in which technical reason is subsumed under a broader practical reason incorporating individual experience and judgement. Against the charge that this view is merely an instance of nostalgic craft romanticism having little relevance to present industrial realities, there are recognisable contemporary instances of phronetic production, one of the most interesting being Volvo’s innovations in automotive assembly systems.