Acetaminophen, via its reactive metabolite N-acetyl-p-benzo-quinoneimine and transient receptor potential ankyrin-1 stimulation, causes neurogenic inflammation in the airways and other tissues in rodents

Acetaminophen [N-acetyl-p-aminophenol (APAP)] is the most common antipyretic/analgesic medicine worldwide. If APAP is overdosed, its metabolite, N-acetyl-p-benzo-quinoneimine (NAPQI), causes liver damage. However, epidemiological evidence has associated previous use of therapeutic APAP doses with the risk of chronic obstructive pulmonary disease (COPD) and asthma. The transient receptor potential ankyrin-1 (TRPA1) channel is expressed by peptidergic primary sensory neurons. Because NAPQI, like other TRPA1 activators, is an electrophilic molecule, we hypothesized that APAP, via NAPQI, stimulates TRPA1, thus causing airway neurogenic inflammation. NAPQI selectively excites human recombinant and native (neuroblastoma cells) TRPA1. TRPA1 activation by NAPQI releases proinflammatory neuropeptides (substance P and calcitonin gene-related peptide) from sensory nerve terminals in rodent airways, thereby causing neurogenic edema and neutrophilia. Single or repeated administration of therapeutic (15-60 mg/kg) APAP doses to mice produces detectable levels of NAPQI in the lung, and increases neutrophil numbers, myeloperoxidase activity, and cytokine and chemokine levels in the airways or skin. Inflammatory responses evoked by NAPQI and APAP are abated by TRPA1 antagonism or are absent in TRPA1-deficient mice. This novel pathway, distinguished from the tissue-damaging effect of NAPQI, may contribute to the risk of COPD and asthma associated with therapeutic APAP use.-Nassini, R., Materazzi, S., Andre, E., Sartiani, L., Aldini, G., Trevisani, M., Carnini, C., Massi, D., Pedretti, P., Carini, M., Cerbai, E., Preti, D., Villetti, G., Civelli, M., Trevisan, G., Azzari, C., Stokesberry, S., Sadofsky, L., McGarvey, L., Patacchini, R., Geppetti, P. Acetaminophen, via its reactive metabolite N-acetyl-p-benzo-quinoneimine and transient receptor potential ankyrin-1 stimulation causes neurogenic inflammation in the airways and other tissues in rodents. FASEB J. 24, 4904-4916 (2010). www.fasebj.org

GYY4137, a novel hydrogen sulfide-releasing molecule, protects against endotoxic shock in the rat

GYY4137 (morpholin-4-ium-4-methoxyphenyl(morpholino) phosphinodithioate) is a slow-releasing hydrogen sulfide (H2S) donor. Administration of GYY4137 (50 mg/kg, iv) to anesthetized rats 10 min after lipopolysaccharide (LPS; 4 mg/kg, iv) decreased the slowly developing hypotension. GYY4137 inhibited LPS-induced TNF-alpha production in rat blood and reduced the LPS-evoked rise in NF-kappa B;B activation, inducible nitric oxide synthase/cyclooxygenase-2 expression, and generation of PGE(2) and nitrate/nitrite in RAW 264.7 macrophages. GYY4137 (50 mg/kg, ip) administered to conscious rats 1 or 2 h after (but not 1 h before) LPS decreased the subsequent (4 h) rise in plasma proinflammatory cytokines (TNF-alpha, IL-1 beta, IL-6), nitrite/nitrate, C-reactive protein, and L-selectin. GYY4137 administration also decreased the LPS-evoked increase in lung myeloperoxidase activity, increased plasma concentration of the anti-inflammatory cytokine IL-10, and decreased tissue damage as determined histologically and by measurement of plasma creatinine and alanine aminotransferase activity. Tune-expired GYY4137 (50 mg/kg, ip) did not affect the LPS-induced rise in plasma TNF-alpha or lung myeloperoxidase activity. GYY4137 also decreased the LPS-mediated upregulation of liver transcription factors (NF-kappa B and STAT-3). These results suggest ail anti-inflammatory effect of GYY4137. The possibility that GYY4137 and other slow-releasing H2S donors exert anti-inflammatory activity in other models of inflammation and in humans warrants further study. (C) 2009 Elsevier Inc. All rights reserved.

Tongue-tied?: An Active Analysis of Brian Friel's Translations

This article has arisen from a research-led production of Translations by Brian Friel for Queen’s University’s Tyrone Guthrie Society in February 2010. Drawing partly on a review of the existing critical literature and also from questions left unresolved by a previous experience of directing the play, the production sought to address through ‘active analysis’ (Merlin 2001) a number of research questions relating to the embodied nature of the rehearsal process and the historicity of Friel’s play. The analysis invokes Bergson (1910), Lefebvre (1991) and Worthern (2006) in establishing a performative correlative for insightful but more literary studies by Connolly (1993), Lojek (1994) and McGrath (1989 & 1999). A detailed account of the rehearsal process helps reveal the extent to which the idea of failure of communication is embedded in the text and embodied in performance, while an experiment with the partial use of the Irish language casts further light on Friel’s extraordinary device of rendering two languages through the medium of one. The use of music to counterpoint, rather than underscore the action, together with an achronological sequence of projected historical images inspired by Andrews (1983) provided me as director a means to challenge the audience’s presuppositions about the play. The sense of palimpsest, of the layered histories, that this evoked also served to highlight Friel’s use of the wider stylistic palette of Anglo-Irish drama, revealing Translations as a forerunner for Stewart Parker’s more explicit formal experiments in Northern Star. In rehearsal and performance Friel’s place in the continuum of the Irish theatrical canon became clear, as stylistic allusions to O’Casey, Shaw, Wilde and Beckett were embodied by the actors on the rehearsal room floor.

Active immunisation of lambs with a monoclonal antibody against clenbuterol

An experiment was undertaken with 50 Texel x Suffolk-Cheviot lambs (54+/-8.8 days of age) to investigate the effects of active immunisation with a murine monoclonal antibody against clenburerol on growth and carcass characteristics. Animals on treatments 1 and 2 each received 0.1 mg of clenbuterol antibody while animals on treatments 3 and 4 received 0.1 mg of antibody encapsulated within a synthetic polymer. Diethylaminoethyl (DEAE)-dextran was used as the adjuvant in treatments 1 and 3 and saponin in treatments 2 and 4. Control animals were immunised with saponin only. Four immunisations were given at 4-week intervals. Animals were slaughtered 3 weeks after the final immunisation. Each vaccine evoked a similar level of antibody response while the control group showed no titres. Lamb growth rate did not vary significantly between the vaccinated and control groups. Dressing proportion was higher (P

Instituting order: the limitations of Nasser’s post-colonial planning visions for Cairo in the case of the indigenous quarter of Bulaq (1952–1970)

This paper investigates the limitations of postcolonial planning practices that aimed to modernise Cairo’s urban spaces during Gamal Abdel Nasser rule (1952–70). Following the Free Officers revolution of 1952, ambition to display urban order through forceful change in the city’s built environment was in action. Nasser’s visions of modernity were explicit in a series of attempts to reshape several prime locations in central Cairo, which included the old traditional waterfront quarter, in Bulaq Abul Ela. An analysis of the Bulaq planning scheme drafted in 1966 reveals insights into how notions of order were spatialised to integrate with Cairo’s complex urban fabric. The official plans to regularise Bulaq also strongly demonstrates how this was a top-down, centralised process in terms of governance, with full utilisation of state resources, namely the military and the media. From a wider perspective, planning practices under Nasser demonstrated an evident break with the past to eliminate memories of colonisation and disorder. Drawing on original resources, archival material, meeting minutes and maps of this historical but dilapidated quarter of Cairo, this paper gives an insight into how Nasser’s government attempted to convey a sense of order in a revolutionary country without, however, having an understanding of order as a coherent, multilayered and sequential process of change.

Re-imaging the Periphery: The Reproduction of Space in Cairo

This chapter examines Cairo’s path towards reassembling a modern spatial order in one of its oldest quarters, Bulaq Abul Ela, and the implications of this on the spatial experience of its inhabitants. The ambitions of space reproduction in Cairo are revealed during the attempt to engender a debate as to how this vision affected Bulaq’s riverfront zone as its periphery; how it was spatialised and to what extent the planners’ conception of urban space actually responded to the people’s needs when creating a new spatial reality. It uncovers the peripheral/central position that residents assume with regards to their living spaces to reveal new meanings, images, stories and places to replace the increasingly undesirable authentic fabric of Bulaq.

Church of St George and St Thomas

Abstract: A vibrant inner city parish needed space for meetings, language classes, children’s play and other support accommodation as well as a clearer link between the interior of the listed church and the space outside.

The project builds itself about the entrance to the church. The form is manipulated such that the intervention recedes from those entering the church, drawing them into the plan before becoming readable as an addition. The resultant poché between this entrance sequence and the fabric of the church is hollowed out to provide the required accommodation. These rooms are insulated and lined in cork to allow for their use separate to the main body of the church. With budget at a premium the construction methodology was developed from an analysis of traditional Irish boat building techniques, which allowed the use of the solid timber to act as the primary structure with no additional material support.

Constructed in solid walnut the intervention reads with the existing brick interior and yet is clearly identifiable as a contemporary addition.

Aims / Objectives Questions

1 To accommodate new space inside an existing protected structure.
2 To form a new threshold between interior and exterior.
3 To develop an affordable means of construction that would be durable and rapid to erect.
4 To make a contemporary addition in sympathy with the qualities of the existing protect structure, in line with best conservation practice and research.
5 Traditional forms of construction as a model for contemporary technologies.

INTRAVASCULAR ANTI-IGE CHALLENGE IN PERFUSED LUNGS - MEDIATOR RELEASE AND VASCULAR PRESSOR-RESPONSE

Intravascular application of goat anti-rabbit immunoglobulin E (IgE) was used to stimulate parenchymal mast cells in situ in perfused rabbit lungs. Sustained pulmonary arterial pressure rise was evoked in the absence of lung vascular permeability increase and lung edema formation. Early prostaglandin (PG) D2 and histamine release into the perfusate was documented, accompanied by more sustained liberation of cysteinyl leukotrienes (LT), LTB4, and PGI2. The quantities of these inflammatory mediators displayed the following order: histamine > cysteinyl-LT > PGI2 > LTB4 > PGD2. Pressor response and inflammatory mediator release revealed corresponding bell-shaped dose dependencies. Cyclooxygenase inhibition (acetylsalicylic acid) suppressed prostanoid generation, increased LT release, and did not substantially affect pressor response and histamine liberation. BW755 C, a cyclo- and lipoxygenase inhibitor, blocked the release of cysteinyl-LT and markedly reduced the liberation of the other inflammatory mediators as well as the pressor response. The H-1-antagonist clemastine caused a moderate reduction of the anti-IgE-provoked pressure rise. We conclude that intravascular anti-IgE challenge in intact lungs provokes the release of an inflammatory mediator profile compatible with in situ lung parenchymal mast cell activation. Pulmonary hypertension represents the predominant vascular response, presumably mediated by cysteinyl-LT and, to a minor extent, histamine liberation.

Risk and resilience: The moderating role of social coping for maternal mental health in a setting of political conflict:The moderating role of social coping for maternal mental health in a setting of political conflict

Violence can threaten individual wellbeing and tear at the social fabric of communities. At the same time, suffering can mobilize social coping and mutual support. Thus, the backdrop of political violence increases risk factors and stimulates resilience. The current study examined the moderating role of social coping as reflective of risk and resiliency in Northern Ireland, a setting of protracted conflict. Specifically, structural equation modeling was used to investigate whether social coping protects from or exacerbates the negative impact of sectarian crime and nonsectarian crime on maternal mental health (N?=?631). Nonsectarian crime predicted greater psychological distress for mothers in Belfast. Mixed support was found for the buffering and depletion moderation hypotheses; social coping functioned differently for nonsectarian crime and sectarian crime. Greater social coping buffered mothers' psychological distress from the negative effects of nonsectarian crime, but exacerbated maternal mental health problems when facing sectarian crime. Results suggest that social coping is a complex phenomenon, particularly in settings of protracted political violence. Implications for interventions aimed at alleviating psychological distress by enhancing mothers' social coping in contexts of intergroup conflict are discussed. We would like to thank the many families in Northern Ireland who have participated in the project. We would also like to express our appreciation for the project staff, graduate students, and undergraduate students at the University of Notre Dame and the University of Ulster. A special thanks to Cindy Bergeman and Dan Lapsley for feedback on earlier drafts of this manuscript. This research was supported by NICHD grant 046933-05 to the E. Mark Cummings.

The typology of Irish hard rock aquifers based on an integrated hydrogeological and geophysical approach

Groundwater flow in hard-rock aquifers is strongly controlled by the characteristics and distribution of structural heterogeneity. A methodology for catchment-scale characterisation is presented, based on the integration of complementary, multi-scale hydrogeological, geophysical and geological approaches. This was applied to three contrasting catchments underlain by metamorphic rocks in the northern parts of Ireland (Republic of Ireland and Northern Ireland, UK). Cross-validated surface and borehole geophysical investigations confirm the discontinuous overburden, lithological compartmentalisation of the bedrock and important spatial variations of the weathered bedrock profiles at macro-scale. Fracture analysis suggests that the recent (Alpine) tectonic fabric exerts strong control on the internal aquifer structure at meso-scale, which is likely to impact on the anisotropy of aquifer properties. The combination of the interpretation of depth-specific hydraulic-test data with the structural information provided by geophysical tests allows characterisation of the hydrodynamic properties of the identified aquifer units. Regionally, the distribution of hydraulic conductivities can be described by inverse power laws specific to the aquifer litho-type. Observed groundwater flow directions reflect this multi-scale structure. The proposed integrated approach applies widely available investigative tools to identify key dominant structures controlling groundwater flow, characterising the aquifer type for each catchment and resolving the spatial distribution of relevant aquifer units and associated hydrodynamic parameters.

Free-space optoelectronic switching cores with MPLS for SANs over WDM ring networks

With increasing demands on storage devices in the modern communication environment, the storage area network (SAN) has evolved to provide a direct connection allowing these storage devices to be accessed efficiently. To optimize the performance of a SAN, a three-stage hybrid electronic/optical switching node architecture based on the concept of a MPLS label switching mechanism, aimed at serving as a multi-protocol label switching (MPLS) ingress label edge router (LER) for a SAN-enabled application, has been designed. New shutter-based free-space multi-channel optical switching cores are employed as the core switch fabric to solve the packet contention and switching path conflict problems. The system-level node architecture design constraints are evaluated through self-similar traffic sourced from real gigabit Ethernet network traces and storage systems. The extension performance of a SAN over a proposed WDM ring network, aimed at serving as an MPLS-enabled transport network, is also presented and demonstrated.

Vision Modulates Corticospinal Suppression in a Functionally Specific Manner during Movement of the Opposite Limb

The effect of vision on the excitability of corticospinal projections to the flexor carpi radialis (FCR) and extensor carpi radialis (ECR) muscles of right human forearm was investigated before and during discrete movement of the opposite limb. An external force opposed the initial phase of the movement (wrist flexion) and assisted the reverse phase, so that recruitment of the wrist extensors was minimized. Three conditions were used as follows: viewing the inactive right limb (Vision), viewing the mirror image of the moving left limb (Mirror), and with vision of the right limb occluded (No Vision). Transcranial magnetic stimulation was delivered to the left motor cortex: before, at the onset of, or during the left limb movement to obtain motor evoked potentials (MEPs) in the muscles of the right forearm. At and following movement onset, MEPs obtained in the right FCR were smaller in the Vision condition than in the Mirror and No Vision conditions. A distinct pattern of variation was obtained for the ECR. In all conditions, MEPs in this muscle were elevated upon or following movement of the opposite limb. An additional analysis of ipsilateral silent periods indicated that interhemispheric inhibition plays a role in mediating these effects. Activity-dependent changes in corticospinal output to a resting limb during discrete actions of the opposite limb are thus directly contingent upon where one looks. Furthermore, the extent to which vision exerts an influence upon projections to specific muscles varies in accordance with the functional contribution of their homologs to the intended action.

Training-induced modifications of corticospinal reactivity in severely affected stroke survivors

When permitted access to the appropriate forms of rehabilitation, many severely affected stroke survivors demonstrate a capacity for upper limb functional recovery well in excess of that formerly considered possible. Yet, the mechanisms through which improvements in arm function occur in such profoundly impaired individuals remain poorly understood. An exploratory study was undertaken to investigate the capacity for brain plasticity and functional adaptation, in response to 12-h training of reaching using the SMART Arm device, in a group of severely affected stroke survivors with chronic upper limb paresis. Twenty-eight stroke survivors were enroled. Eleven healthy adults provided normative data. To assess the integrity of ipsilateral and contralateral corticospinal pathways, transcranial magnetic stimulation was applied to evoke responses in triceps brachii during an elbow extension task. When present, contralateral motor-evoked potentials (MEPs) were delayed and reduced in amplitude compared to those obtained in healthy adults. Following training, contralateral responses were more prevalent and their average onset latency was reduced. There were no reliable changes in ipsilateral MEPs. Stroke survivors who exhibited contralateral MEPs prior to training achieved higher levels of arm function and exhibited greater improvements in performance than those who did not initially exhibit contralateral responses. Furthermore, decreases in the onset latency of contralateral MEPs were positively related to improvements in arm function. Our findings demonstrate that when severely impaired stroke survivors are provided with an appropriate rehabilitation modality, modifications of corticospinal reactivity occur in association with sustained improvements in upper limb function.

Diabetes downregulates large-conductance Ca2+-activated potassium beta 1 channel subunit in retinal arteriolar smooth muscle

Retinal vasoconstriction and reduced retinal blood flow precede the onset of diabetic retinopathy. The pathophysiological mechanisms that underlie increased retinal arteriolar tone during diabetes remain unclear. Normally, local Ca(2+) release events (Ca(2+)-sparks), trigger the activation of large-conductance Ca(2+)-activated K(+)(BK)-channels which hyperpolarize and relax vascular smooth muscle cells, thereby causing vasodilatation. In the present study, we examined BK channel function in retinal vascular smooth muscle cells from streptozotocin-induced diabetic rats. The BK channel inhibitor, Penitrem A, constricted nondiabetic retinal arterioles (pressurized to 70mmHg) by 28%. The BK current evoked by caffeine was dramatically reduced in retinal arterioles from diabetic animals even though caffeine-evoked [Ca(2+)](i) release was unaffected. Spontaneous BK currents were smaller in diabetic cells, but the amplitude of Ca(2+)-sparks was larger. The amplitudes of BK currents elicited by depolarizing voltage steps were similar in control and diabetic arterioles and mRNA expression of the pore-forming BKalpha subunit was unchanged. The Ca(2+)-sensitivity of single BK channels from diabetic retinal vascular smooth muscle cells was markedly reduced. The BKbeta1 subunit confers Ca(2+)-sensitivity to BK channel complexes and both transcript and protein levels for BKbeta1 were appreciably lower in diabetic retinal arterioles. The mean open times and the sensitivity of BK channels to tamoxifen were decreased in diabetic cells, consistent with a downregulation of BKbeta1 subunits. The potency of blockade by Pen A was lower for BK channels from diabetic animals. Thus, changes in the molecular composition of BK channels could account for retinal hypoperfusion in early diabetes, an idea having wider implications for the pathogenesis of diabetic hypertension.

Monitoring the moisture transport in building stones using fibre optic relative humidity sensors

Weathering of stone is one of the major reasons for the damage of stone masonry structures and it takes place due to interlinked chemical, physical and biological processes in stones. The key parameters involved in the deterioration processes are temperature, moisture and salt. It is now known that the sudden variations in temperature and moisture greatly accelerate the weathering process of the building stone fabric. Therefore, in order to monitor these sudden variations an effective and continuous monitoring system is needed. Furthermore, it must consist of robust sensors which are accurate and can survive in the harsh environments experienced in and around masonry structures. Although salt penetration is important for the rate of deterioration of stone masonry structures, the processes involved are much slower than the damage associated with temperature and moisture variations. Therefore, in this paper a novel fibre optic temperature cum relative humidity sensor is described and its applicability in monitoring building stones demonstrated. The performance of the sensor is assessed in an experiment comprising wetting and drying of limestone blocks. The results indicate that the novel fibre optic relative humidity sensor which is tailor made for applications in masonry structures performed well in wetting and drying tests, whilst commercial capacitance based sensors failed to recover during the drying regime for a long period after a wetting regime. That is, the fibre optic sensor has the capability to measure both sorption and de-sorption characteristics of stone blocks. This sensor is used in a test wall in Oxford and the data thus obtained strengthened the laboratory observations.