Thromboxane A2 inhibition of SKCa after NO synthase block in rat middle cerebral artery

NO/prostanoid independent, EDHF-mediated hyperpolarization and dilation in rat middle cerebral arteries is mediated solely by endothelial cell IK(Ca). However, when the NO-pathway is also active, both SK(Ca) and IK(Ca) contribute to EDHF responses. As the SK(Ca) component can be inhibited by stimulation of thromboxane A(2) (TxA(2)) TP receptors and NO has the potential ability to inhibit thromboxane synthesis, we investigated whether TxA(2) might explain loss of functional input from SK(Ca) during NOS inhibition in cerebral arteries. EXPERIMENTAL APPROACH: Rat middle cerebral arteries were mounted in a wire myograph. Endothelium-dependent responses to the PAR2 agonist, SLIGRL were assessed as simultaneous changes in smooth muscle membrane potential and tension. KEY RESULTS: Responses were obtained in the presence of L-NAME as appropriate. Inhibition of TP receptors with either ICI 192,605 or SQ 29,548, did not affect EDHF mediated hyperpolarization and relaxation, but in their presence neither TRAM-34 nor apamin (to block IK(Ca) and SK(Ca) respectively) individually affected the EDHF response. However, in combination they virtually abolished it. Similar effects were obtained in the presence of the thromboxane synthase inhibitor, furegrelate, which additionally revealed an iberiotoxin-sensitive residual EDHF hyperpolarization and relaxation in the combined presence of TRAM-34 and apamin. CONCLUSIONS AND IMPLICATIONS: In the rat middle cerebral artery, inhibition of NOS leads to a loss of the SK(Ca) component of EDHF responses. Either antagonism of TP receptors or block of thromboxane synthase restores an input through SK(Ca). These data indicate that NO normally enables SK(Ca) activity in rat middle cerebral arteries.

Evidence for involvement of both IKCa and SKCa channels in hyperpolarizing responses of the rat middle cerebral artery

Endothelium-derived hyperpolarizing factor responses in the rat middle cerebral artery are blocked by inhibiting IKCa channels alone, contrasting with peripheral vessels where block of both IKCa and SKCa is required. As the contribution of IKCa and SKCa to endothelium-dependent hyperpolarization differs in peripheral arteries, depending on the level of arterial constriction, we investigated the possibility that SKCa might contribute to equivalent hyperpolarization in cerebral arteries under certain conditions. METHODS: Rat middle cerebral arteries (approximately 175 microm) were mounted in a wire myograph. The effect of KCa channel blockers on endothelium-dependent responses to the protease-activated receptor 2 agonist, SLIGRL (20 micromol/L), were then assessed as simultaneous changes in tension and membrane potential. These data were correlated with the distribution of arterial KCa channels revealed with immunohistochemistry. RESULTS: SLIGRL hyperpolarized and relaxed cerebral arteries undergoing variable levels of stretch-induced tone. The relaxation was unaffected by specific inhibitors of IKCa (TRAM-34, 1 micromol/L) or SKCa (apamin, 50 nmol/L) alone or in combination. In contrast, the associated smooth-muscle hyperpolarization was inhibited, but only with these blockers in combination. Blocking nitric oxide synthase (NOS) or guanylyl cyclase evoked smooth-muscle depolarization and constriction, with both hyperpolarization and relaxation to SLIGRL being abolished by TRAM-34 alone, whereas apamin had no effect. Immunolabeling showed SKCa and IKCa within the endothelium. CONCLUSIONS: In the absence of NO, IKCa underpins endothelium-dependent hyperpolarization and relaxation in cerebral arteries. However, when NOS is active SKCa contributes to hyperpolarization, whatever the extent of background contraction. These changes may have relevance in vascular disease states where NO release is compromised and when the levels of SKCa expression may be altered.

The cost of choice: how corporate real estate managers evaluate business space options

Firms are faced with a wider set of choices when they identify a need for new office space. They can build or purchase accommodation, lease space for long or short periods with or without the inclusion of services, or they can use “instant office” solutions provided by serviced office operators. But how do they evaluate these alternatives and are they able to make rational choices? The research found that the shortening of business horizons lead to the desire for more office space on short-term contracts often with the inclusion of at least some facilities management and business support services. The need for greater flexibility, particularly in financial terms, was highlighted as an important criteria when selecting new office accommodation. The current office portfolios held were perceived not to meet these requirements. However, there was often a lack of good quality data available within occupiers which could be used to help them analyse the range of choices in the market. Additionally, there were other organisational constraints to making decisions about inclusive real estate products. These included fragmentation of decisions-making, internal politics and the lack of assessment of business risk alongside real estate risk. Overall therefore, corporate occupiers themselves act as an interial force to the development of new and innovative real estate products.

Inter-hemispheric mesospheric coupling in a comprehensive middle atmosphere model

Observations of noctilucent clouds have revealed a surprising coupling between the winter stratosphere and the summer polar mesopause region. In spite of the great distance involved, this inter-hemispheric link has been suggested to be the principal reason for both the year-to-year variability and the hemispheric differences in the frequency of occurrence of these high-altitude clouds. In this study, we investigate the dynamical influence of the winter stratosphere on the summer mesosphere using simulations from the vertically extended version of the Canadian Middle Atmosphere Model (CMAM). We find that for both Northern and Southern Hemispheres, variability in the summer polar mesopause region from one year to another can be traced back to the planetary-wave flux entering the winter stratosphere. The teleconnection pattern is the same for both positive and negative wave-flux anomalies. Using a composite analysis to isolate the events, it is argued that the mechanism for interhemispheric coupling is a feedback between summer mesosphere gravity-wave drag (GWD) and zonal wind, which is induced by an anomaly in mesospheric cross-equatorial flow, the latter arising from the anomaly in winter hemisphere GWD induced by the anomaly in stratospheric conditions.

Vertical propagation of information in a middle atmosphere data assimilation system by gravity-wave drag feedbacks

The mesospheric response to the 2002 Antarctic Stratospheric Sudden Warming (SSW) is analysed using the Canadian Middle Atmosphere Model Data Assimilation System (CMAM-DAS), where it represents a vertical propagation of information from the observations into the data-free mesosphere. The CMAM-DAS simulates a cooling in the lowest part of the mesosphere which is accomplished by resolved motions, but which is extended to the mid- to upper mesosphere by the response of the model's non-orographic gravity-wave drag parameterization to the change in zonal winds. The basic mechanism is that elucidated by Holton consisting of a net eastward wave-drag anomaly in the mesosphere during the SSW, although in this case there is a net upwelling in the polar mesosphere. Since the zonal-mean mesospheric response is shown to be predictable, this demonstrates that variations in the mesospheric state can be slaved to the lower atmosphere through gravity-wave drag.

Transnational urbanism in Port of Spain: returning middle-class urban elites

Port of Spain, Trinidad offers an ideal context in which to analyze pre-retirement return migration to a Global South urban realm, expanding transnational urban research beyond the conventional focus on Global North metropolitan destinations. In this article, we draw on the transnational narratives of a selected sample of relatively youthful Trinidadians, who have spent many years abroad acquiring education and professional experience, but who have then decided to return in mid-career to the capital region of the island nation of their birth, or of their parent(s). Theoretically, we position these returning professionals as members of a "middling" transnational urban class whose return is at least partly motivated by a desire to "make a difference." Our results contribute to a growing literature that documents the role of transnational middle-class urban elites returning elsewhere in the Carribbean: "middling" transnational urbanism is reshaping key facets of urbanization in the Global South.

Possible role for K+ in endothelium-derived hyperpolarizing factor–linked dilatation in rat middle cerebral artery

Background and Purpose— Endothelium-derived hyperpolarizing factor (EDHF) and K+ are vasodilators in the cerebral circulation. Recently, K+ has been suggested to contribute to EDHF-mediated responses in peripheral vessels. The EDHF response to the protease-activated receptor 2 ligand SLIGRL was characterized in cerebral arteries and used to assess whether K+ contributes as an EDHF. Methods— Rat middle cerebral arteries were mounted in either a wire or pressure myograph. Concentration-response curves to SLIGRL and K+ were constructed in the presence and absence of a variety of blocking agents. In some experiments, changes in tension and smooth muscle cell membrane potential were recorded simultaneously. Results— SLIGRL (0.02 to 20 μmol/L) stimulated concentration and endothelium-dependent relaxation. In the presence of NG-nitro-L-arginine methyl ester, relaxation to SLIGRL was associated with hyperpolarization and sensitivity to a specific inhibitor of IKCa, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (1μmol/L), reflecting activation of EDHF. Combined inhibition of KIR with Ba2+ (30μmol/L) and Na+/K+-ATPase with ouabain (1 μmol/L) markedly attenuated the relaxation to EDHF. Raising extracellular [K+] to 15 mmol/L also stimulated smooth muscle relaxation and hyperpolarization, which was also attenuated by combined application of Ba2+ and ouabain. Conclusions— SLIGRL evokes EDHF-mediated relaxation in the rat middle cerebral artery, underpinned by hyperpolarization of the smooth muscle. The profile of blockade of EDHF-mediated hyperpolarization and relaxation supports a pivotal role for IKCa channels. Furthermore, similar inhibition of responses to EDHF and exogenous K+ with Ba2+ and ouabain suggests that K+ may contribute as an EDHF in the middle cerebral artery.

Can company-fund manager meetings convey informational benefits? Exploring the rationalisation of equity investment decision making by UK fund managers

Conventional economic theory, applied to information released by listed companies, equates ‘useful’ with ‘price-sensitive’. Stock exchange rules accordingly prohibit the selec- tive, private communication of price-sensitive information. Yet, even in the absence of such communication, UK equity fund managers routinely meet privately with the senior execu- tives of the companies in which they invest. Moreover, they consider these brief, formal and formulaic meetings to be their most important sources of investment information. In this paper we ask how that can be. Drawing on interview and observation data with fund managers and CFOs, we find evidence for three, non-mutually exclusive explanations: that the characterisation of information in conventional economic theory is too restricted, that fund managers fail to act with the rationality that conventional economic theory assumes, and/or that the primary value of the meetings for fund managers is not related to their investment decision making but to the claims of superior knowledge made to clients in marketing their active fund management expertise. Our findings suggest a disconnect between economic theory and economic policy based on that theory, as well as a corre- sponding limitation in research studies that test information-usefulness by assuming it to be synonymous with price-sensitivity. We draw implications for further research into the role of tacit knowledge in equity investment decision-making, and also into the effects of the principal–agent relationship between fund managers and their clients.

The use of risk registers by project managers

The construction industry is widely recognised as being inherent with risk and uncertainty. This necessitates the need for effective project risk management to achieve the project objectives of time, cost and quality. A popular tool employed in projects to aid in the management of risk is a risk register. This tool documents the project risks and is often employed by the Project Manager (PM) to manage the associated risks on a project. This research aims to ascertain how widely risk registers are used by Project Managers as part of their risk management practices. To achieve this aim entailed interviewing ten PMs, to discuss their use of the risk register as a risk management tool. The results from these interviews indicated the prevalent use of this document and recognised its effectiveness in the management of project risks. The findings identified the front end and feasibility phases of a project as crucial stages for using risk registers, noting it as a vital ingredient in the risk response planning of the decision making process. Moreover, the composition of the risk register was also understood, with an insight into how PMs produce and develop this tool also ascertained. In conclusion, this research signifies the extensive use of the risk register by PMs. A majority of PMs were of the view that risk registers constitute an essential component of their project risk management practices. This suggests a need for further research on the extent to which risk registers actually help PMs to control the risks in a construction project, particularly residual risks, and how this can be improved to minimize deviations from expected outcomes.

Middle and Late Cenomanian anoxia in shallow and deeper shelf environments of western Morocco

The response of shallow-water sequences to oceanic anoxic event 2 and mid-Cenomanian events 1a and 1b was investigated along the west African margin of Morocco north of Agadir (Azazoul) and correlated with the deep-water sequence of the Tarfaya Basin (Mohammed Beach) based on biostratigraphy, mineralogy, phosphorus and stable isotopes. In the deeper Mohammed Beach section results show double peaks in δ13Corg for mid-Cenomanian events 1a and 1b (Rotalipora reicheli biozone, lower CC10a biozone), the characteristic oceanic anoxic event 2 δ13C excursion (Rotalipora cushmani extinction, top of CC10a biozone) and laminated (anoxic) black shale. In the shallow environment north of Agadir, a fluctuating sea-level associated with dysoxic, brackish and mesotrophic conditions prevailed during the middle to late Cenomanian, as indicated by oyster biostromes, nannofossils, planktonic and benthonic foraminiferal assemblages. Anoxic conditions characteristic of oceanic anoxic event 2 (for example, laminated black shales) did not reach into shallow-water environments until the maximum transgression of the early Turonian. Climate conditions decoupled along the western margin of Morocco between mid-Cenomanian event 1b and the Cenomanian–Turonian boundary, as also observed in eastern Tethys. North of Agadir alternating humid and dry seasonal conditions prevailed, whereas in the Tarfaya Basin the climate was dry and seasonal. This climatic decoupling can be attributed to variations in the Intertropical Convergence Zone and in the intensity of the north-east trade winds in tropical areas.