Spinal cord vascular degeneration impairs duloxetine penetration

IntroductionChronic pain is a prevalent physically debilitating health-related morbidity. Frontline analgesics are inadequate, providing only partial pain relief in only a proportion of the patient cohort. Here, we explore whether alterations in spinal cord vascular perfusion are a factor in reducing the analgesic capability of the noradrenaline reuptake inhibitor, duloxetine.MethodAn established rodent model of spinal cord vascular degeneration was used. Endothelial-specific vascular endothelial growth factor receptor 2 knockout mouse was induced via hydroxytamoxifen administered via intrathecal injection. Duloxetine was administered via intraperitoneal injection, and nociceptive behavioural testing was performed in both WT and VEGFR2KO mice. LC-MS/MS was performed to explore the accumulation of duloxetine in the spinal cord in WT and VEGFR2KO mice.ResultsSpinal cord vascular degeneration leads to heat hypersensitivity and a decline in capillary perfusion. The integrity of noradrenergic projections (dopa - hydroxylase labelled) in the dorsal horn remained unaltered in WT and VEGFR2KO mice. There was an association between dorsal horn blood flow with the abundance of accumulated duloxetine in the spinal cord and analgesic capacity. In VEGFR2KO mice, the abundance of duloxetine in the lumbar spinal cord was reduced and was correlated with reduced anti-nociceptive capability of duloxetine.DiscussionHere, we show that an impaired vascular network in the spinal cord impairs the anti-nociceptive action of duloxetine. This highlights that the spinal cord vascular network is crucial to maintaining the efficacy of analgesics to provide pain relief

A new P-wave tomographic model (cap22) for North America: implications for the subduction and cratonic metasomatic modification history of western Canada and Alaska

Our understanding of the present-day state and evolution of the Canadian and Alaskan mantle is hindered by a lack of absolute P-wavespeed constraints that provide complementary sensitivity to composition in conjunction with existing S-wavespeed models. Consequently, cratonic modification, orogenic history of western North America and complexities within the Alaskan Proto-Pacific subduction system remain enigmatic. One challenge concerns the difficulties in extracting absolute arrival-time measurements from often-noisy data recorded by temporary seismograph networks required to fill gaps in continental and global databases. Using the Absolute Arrival-time Recovery Method (AARM), we extract >180,000 new absolute arrival-time residuals from seismograph stations across Canada and Alaska and combine these data with USArray and global arrival-time data from the contiguous US and Alaska. We develop a new absolute P-wavespeed tomographic model, CAP22, spanning North America that significantly improves resolution in Canada and Alaska over previous models. Slow wavespeeds below the Canadian Cordillera sharply abut fast wavespeeds of the continental interior at the Rocky Mountain Trench in southwest Canada. Slow wavespeeds below the Mackenzie Mountains continue farther inland in northwest Canada, indicating Proterozoic-Archean metasomatism of the Slave craton. Inherited tectonic lineaments colocated with this north-south wavespeed boundary suggest that both the crust and mantle may control Cordilleran orogenic processes. In Alaska, fast upper mantle wavespeeds below the Wrangell Volcanic Field favor a conventional subduction related mechanism for volcanism. Finally, seismic evidence for the subducted Kula and Yukon slabs indicate tectonic reconstructions of western North America may require revision

Dynamics of trimming the content of face representations for categorization in the brain

To understand visual cognition, it is imperative to determine when, how and with what information the human brain categorizes the visual input. Visual categorization consistently involves at least an early and a late stage: the occipito-temporal N170 event related potential related to stimulus encoding and the parietal P300 involved in perceptual decisions. Here we sought to understand how the brain globally transforms its representations of face categories from their early encoding to the later decision stage over the 400 ms time window encompassing the N170 and P300 brain events. We applied classification image techniques to the behavioral and electroencephalographic data of three observers who categorized seven facial expressions of emotion and report two main findings: (1) Over the 400 ms time course, processing of facial features initially spreads bilaterally across the left and right occipito-temporal regions to dynamically converge onto the centro-parietal region; (2) Concurrently, information processing gradually shifts from encoding common face features across all spatial scales (e.g. the eyes) to representing only the finer scales of the diagnostic features that are richer in useful information for behavior (e.g. the wide opened eyes in 'fear'; the detailed mouth in 'happy'). Our findings suggest that the brain refines its diagnostic representations of visual categories over the first 400 ms of processing by trimming a thorough encoding of features over the N170, to leave only the detailed information important for perceptual decisions over the P300

An introduction to the Australian and New Zealand flux tower network - OzFlux

Published: 31 October 2016OzFlux is the regional Australian and New Zealand flux tower network that aims to provide a continental-scale national research facility to monitor and assess trends, and improve predictions, of Australia's terrestrial biosphere and climate. This paper describes the evolution, design, and current status of OzFlux as well as provides an overview of data processing. We analyse measurements from all sites within the Australian portion of the OzFlux network and two sites from New Zealand. The response of the Australian biomes to climate was largely consistent with global studies except that Australian systems had a lower ecosystem water-use efficiency. Australian semi-arid/arid ecosystems are important because of their huge extent (70 %) and they have evolved with common moisture limitations. We also found that Australian ecosystems had a similar radiation-use efficiency per unit leaf area compared to global values that indicates a convergence toward a similar biochemical efficiency. The two New Zealand sites represented extremes in productivity for a moist temperate climate zone, with the grazed dairy farm site having the highest GPP of any OzFlux site (2620 gC m⁻² yr⁻¹) and the natural raised peat bog site having a very low GPP (820 gC m⁻² yr⁻¹). The paper discusses the utility of the flux data and the synergies between flux, remote sensing, and modelling. Lastly, the paper looks ahead at the future direction of the network and concludes that there has been a substantial contribution by OzFlux, and considerable opportunities remain to further advance our understanding of ecosystem response to disturbances, including drought, fire, land-use and land-cover change, land management, and climate change, which are relevant both nationally and internationally. It is suggested that a synergistic approach is required to address all of the spatial, ecological, human, and cultural challenges of managing the delicately balanced ecosystems in Australasia.Jason Beringer ... Wayne Meyer ... et al

A Cultural Quest: A Study of Organizational Use of New Cultural Resources in Strategy Formation.

Our study was motivated by the growing influence in cultural sociology and organizational research of the view of culture as a “toolkit”, from which individuals draw resources flexibly to develop strategies of action that address different circumstances. To investigate if and how organizations can also use new and diverse cultural resources, we undertook a historical case study of the incorporation of new cultural resources in an organization’s cultural repertoire. In-depth analysis of four rounds of incorporation of new cultural resources led to the development of a robust theoretical model that identifies cultural repertoire enrichment and organizational identity redefinition as two core mechanisms that facilitate the use of new cultural resources for the development of unconventional strategies and strategic versatility. Our model contributes to organizational research novel theoretical understanding regarding the use of cultural resources in strategy formation and change

The Neuroscience of Sadness: A Multidisciplinary Synthesis and Collaborative Review for the Human Affectome Project

Sadness is typically characterized by raised inner eyebrows, lowered corners of the mouth, reduced walking speed, and slumped posture. Ancient subcortical circuitry provides a neuroanatomical foundation, extending from dorsal periaqueductal grey to subgenual anterior cingulate, the latter of which is now a treatment target in disorders of sadness. Electrophysiological studies further emphasize a role for reduced left relative to right frontal asymmetry in sadness, underpinning interest in the transcranial stimulation of left dorsolateral prefrontal cortex as an antidepressant target. Neuroimaging studies – including meta-analyses – indicate that sadness is associated with reduced cortical activation, which may contribute to reduced parasympathetic inhibitory control over medullary cardioacceleratory circuits. Reduced cardiac control may – in part – contribute to epidemiological reports of reduced life expectancy in affective disorders, effects equivalent to heavy smoking. We suggest that the field may be moving toward a theoretical consensus, in which different models relating to basic emotion theory and psychological constructionism may be considered as complementary, working at different levels of the phylogenetic hierarchy

Combining Logics to Transform Organizational Agency: Blending Industry and Art at Alessi

To understand how organizations combine conflicting institutional logics strategically to create and pursue new market opportunities, we conducted an in-depth longitudinal study of the multiple efforts of the Italian manufacturer of household goods Alessi to combine the logics of industrial manufacturing and cultural production. Over three decades, Alessi developed three different strategies to combine normative elements of the two logics, using each strategy to envision and pursue different market opportunities. By combining the logics of industrial manufacturing and cultural production, Alessi was able to envision new possibilities for value creation and to enact them through innovation in product design. The three strategies triggered a common set of mechanisms through which the purposeful combining of logics enabled the pursuit of opportunity, while each strategy structured the process differently. We develop a theoretical model linking the development of recombinant strategies to the dynamic restructuring of organizational agency and the related capacity to create and pursue new market opportunities. Our findings and theoretical insights advance understanding of the processes through which organizations challenge taken-for-granted beliefs and practices to create new market opportunities, use logics as resources to enable embedded agency, and design hybrid organizational arrangements

The association of cold weather and all-cause and cause-specific mortality in the island of Ireland between 1984 and 2007

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.This article has been made available through the Brunel Open Access Publishing Fund.Background This study aimed to assess the relationship between cold temperature and daily mortality in the Republic of Ireland (ROI) and Northern Ireland (NI), and to explore any differences in the population responses between the two jurisdictions. Methods A time-stratified case-crossover approach was used to examine this relationship in two adult national populations, between 1984 and 2007. Daily mortality risk was examined in association with exposure to daily maximum temperatures on the same day and up to 6 weeks preceding death, during the winter (December-February) and cold period (October-March), using distributed lag models. Model stratification by age and gender assessed for modification of the cold weather-mortality relationship. Results In the ROI, the impact of cold weather in winter persisted up to 35 days, with a cumulative mortality increase for all-causes of 6.4% (95%CI=4.8%-7.9%) in relation to every 1oC drop in daily maximum temperature, similar increases for cardiovascular disease (CVD) and stroke, and twice as much for respiratory causes. In NI, these associations were less pronounced for CVD causes, and overall extended up to 28 days. Effects of cold weather on mortality increased with age in both jurisdictions, and some suggestive gender differences were observed. Conclusions The study findings indicated strong cold weather-mortality associations in the island of Ireland; these effects were less persistent, and for CVD mortality, smaller in NI than in the ROI. Together with suggestive differences in associations by age and gender between the two Irish jurisdictions, the findings suggest potential contribution of underlying societal differences, and require further exploration. The evidence provided here will hope to contribute to the current efforts to modify fuel policy and reduce winter mortality in Ireland

Towards a European military culture?

Recent discussion of the Common Security and Foreign Policy has focussed on the international relations between European member states. Such a focus is entirely valid since the project is being driven forward by nation states. However, the success of the Common Security and Foreign Policy and especially the development of a specifically European military capability under the European Security and Defence Policy will depend not merely on the will of the participating nation-states. Above all, it will depend on the development of a common military culture at the level of weapons development and procurement and at the level of doctrine. The problem is that at neither level is the development of a European culture remotely in sight

Synthesis and crystal structures of 5'-phenylspiro[indoline-3, 2'-pyrrolidin]-2-one derivatives

<p>Abstract</p> <p>Background</p> <p>The spiro- indole-pyrrolidine ring system is a frequently encountered structural motif in many biologically important and pharmacologically relevant alkaloids. The derivatives of spirooxindole ring systems are used as antimicrobial, antitumour agents and as inhibitors of the human NKI receptor besides being found in a number of alkaloids like horsifiline, spirotryprostatin and (+) elacomine. The recently discovered small-molecule MDM2 inhibitor MI-219 and its analogues are in advanced preclinical development as cancer therapeutics.</p> <p>Results</p> <p>In the crystal structures of the two organic compounds, 4'-Nitro-3',5'-diphenylspiro[indoline-3,2'-pyrrolidin]-2-one and 3'-(4-Methoxyphenyl)- 4'-nitro -5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one, N-H···O hydrogen bonds make the R²₂(8) ring motif. Further, the structures are stabilized by intermolecular hydrogen bonds.</p> <p>Conclusion</p> <p>The crystal structures of 4'-Nitro-3',5'-diphenylspiro[indoline-3,2'-pyrrolidin]-2-one and 3'-(4-Methoxyphenyl)- 4'-nitro -5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one have been investigated in detail. In both the compounds, the R²₂(8) motif is present. Due to the substitution of methoxyphenyl instead of phenyl ring, the entire configuration is inverted with respect to the 2-oxyindole ring.</p