Pharmacological consequence of the A118G μ opioid receptor polymorphism on morphine-and fentanyl-mediated modulation of Ca2+ channels in humanized mouse sensory neurons

Background: The most common functional single nucleotide polymorphism of the human OPRM1 gene, A118G, has been shown to be associated with interindividual differences in opioid analgesic requirements, particularly with morphine, in patients with acute postoperative pain. The purpose of this study was to examine whether this polymorphism would modulate the morphine and fentanyl pharmacological profile of sensory neurons isolated from a humanized mouse model homozygous for either the 118A or 118G allele. Methods: The coupling of wild-type and mutant μ opioid receptors to voltage-gated Ca channels after exposure to either ligand was examined by employing the whole cell variant of the patch-clamp technique in acutely dissociated trigeminal ganglion neurons. Morphine-mediated antinociception was measured in mice carrying either the 118AA or 118GG allele. RESULTS:: The biophysical parameters (cell size, current density, and peak current amplitude potential) measured from both groups of sensory neurons were not significantly different. In 118GG neurons, morphine was approximately fivefold less potent and 26% less efficacious than that observed in 118AA neurons. On the other hand, the potency and efficacy of fentanyl were similar for both groups of neurons. Morphine-mediated analgesia in 118GG mice was significantly reduced compared with the 118AA mice. Conclusions: This study provides evidence to suggest that the diminished clinical effect observed with morphine in 118G carriers results from an alteration of the receptor's pharmacology in sensory neurons. In addition, the impaired analgesic response with morphine may explain why carriers of this receptor variant have an increased susceptibility to become addicted to opioids. © 2011 the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology.

Epistatic effects of potassium channel variation on cardiac repolarization and atrial fibrillation risk

Objectives The aim of this study was to evaluate the role of cardiac K+ channel gene variants in families with atrial fibrillation (AF). Background The K+ channels play a major role in atrial repolarization but single mutations in cardiac K+ channel genes are infrequently present in AF families. The collective effect of background K+ channel variants of varying prevalence and effect size on the atrial substrate for AF is largely unexplored. Methods Genes encoding the major cardiac K+ channels were resequenced in 80 AF probands. Nonsynonymous coding sequence variants identified in AF probands were evaluated in 240 control subjects. Novel variants were characterized using patch-clamp techniques and in silico modeling was performed using the Courtemanche atrial cell model. Results Nineteen nonsynonymous variants in 9 genes were found, including 11 rare variants. Rare variants were more frequent in AF probands (18.8% vs. 4.2%, p < 0.001), and the mean number of variants was greater (0.21 vs. 0.04, p < 0.001). The majority of K+ channel variants individually had modest functional effects. Modeling simulations to evaluate combinations of K+ channel variants of varying population frequency indicated that simultaneous small perturbations of multiple current densities had nonlinear interactions and could result in substantial (>30 ms) shortening or lengthening of action potential duration as well as increased dispersion of repolarization. Conclusions Families with AF show an excess of rare functional K+ channel gene variants of varying phenotypic effect size that may contribute to an atrial arrhythmogenic substrate. Atrial cell modeling is a useful tool to assess epistatic interactions between multiple variants.

Nedd4-2(NEDD4L) controls intracellular Na(+)-mediated activity of voltage-gated sodium channels in primary cortical neurons.

Nedd4-2, a HECT (homologous with E6-associated protein C-terminus)-type ubiquitin protein ligase, has been implicated in regulating several ion channels, including Navs (voltage-gated sodium channels). In Xenopus oocytes Nedd4-2 strongly inhibits the activity of multiple Navs. However, the conditions under which Nedd4-2 mediates native Nav regulation remain uncharacterized. Using Nedd4-2-deficient mice, we demonstrate in the present study that in foetal cortical neurons Nedd4-2 regulates Navs specifically in response to elevated intracellular Na(+), but does not affect steady-state Nav activity. In dorsal root ganglia neurons from the same mice, however, Nedd4-2 does not control Nav activities. The results of the present study provide the first physiological evidence for an essential function of Nedd4-2 in regulating Navs in the central nervous system.

Altered nociceptive, endocrine, and dorsal horn neuron responses in rats following a neonatal immune challenge

Summary The neonatal period is characterized by significant plasticity where the immune, endocrine, and nociceptive systems undergo fine-tuning and maturation. Painful experiences during this period can result in long-term alterations in the neurocircuitry underlying nociception, including increased sensitivity to mechanical or thermal stimuli. Less is known about the impact of neonatal exposure to mild inflammatory stimuli, such as lipopolysaccharide (LPS), on subsequent inflammatory pain responses. Here we examine the impact of neonatal LPS exposure on inflammatory pain sensitivity and HPA axis activity during the first three postnatal weeks. Wistar rats were injected with LPS (0.05 mg/kg IP, Salmonella enteritidis) or saline on postnatal days (PNDs) 3 and 5 and later subjected to the formalin test at PNDs 7, 13, and 22. One hour after formalin injection, blood was collected to assess corticosterone responses. Transverse spinal cord slices were also prepared for whole-cell patch clamp recording from lumbar superficial dorsal horn neurons (SDH). Brains were obtained at PND 22 and the hypothalamus was isolated to measure glucocorticoid (GR) and mineralocorticoid receptor (MR) transcript expression using qRT-PCR. Behavioural analyses indicate that at PND 7, no significant differences were observed between saline- or LPS-challenged rats. At PND 13, LPS-challenged rats exhibited enhanced licking (p < .01), and at PND 22, increased flinching in response to formalin injection (p < .05). LPS-challenged rats also displayed increased plasma corticosterone at PND 7 and PND 22 (p < .001) but not at PND 13 following formalin administration. Furthermore, at PND 22 neonatal LPS exposure induced decreased levels of GR mRNA and increased levels of MR mRNA in the hypothalamus. The intrinsic properties of SDH neurons were similar at PND 7 and PND 13. However, at PND 22, ipsilateral SDH neurons in LPS-challenged rats had a lower input resistance compared to their saline-challenged counterparts (p < .05). These data suggest neonatal LPS exposure produces developmentally regulated changes in formalin-induced behavioural responses, corticosterone levels, and dorsal horn neuron properties following noxious stimulation later in life. These findings highlight the importance of immune activation during the neonatal period in shaping pain sensitivity later in life. This programming involves both spinal cord neurons and the HPA axis.

PIPP #1 - Pedestrian Interaction Patch Project

The Pedestrian Interaction Patch Project (PIPP) seeks to exert influence over and encourage abnormal pedestrian behavior. By placing an unadvertised (and non recording) interactive video manipulation system and projection source in a high traffic public area, the PIPP allows pedestrians to privately (and publically) re-engage with a previously inactive physical environment, like a commonly used walkway or corridor. This system, the results of which are projected in real time on the architectural surface, inadvertently provides pedestrians with questions around preconceived notions of self and space. In an attempt to re-activate our relationship with the physical surrounds we occupy each day the PIPP creates a new set of memories to be recalled as we re-enter known environments once PIPP has moved on and as such re-enlivens our relationship with the everyday architecture we stroll past everyday. The PIPP environment is controlled using the software program Isadora, devised by Mark Coniglio at Troika Ranch, and contains a series of video manipulation patches that are designed to not only grab the pedestrians attention but to also encourage a sense of play and interaction between the architecture, the digital environment, the initially unsuspecting participant(s) and the pedestrian audience. The PIPP was included as part of the planned walking tour for the “Playing in Urban Spaces” seminar day, and was an installation that ran for the length of the symposium in a reclaimed pedestrian space that was encountered by both the participants and general public during the course of the day long event. Ideally once discovered PIPP encouraged pedestrians to return through the course of the seminar day to see if the environmental patches had changed or altered, and changed their standard route to include the PIPP installation or to avoid it, either way, encouraging an active response to the pathways normally traveled or newly discovered each day.

PIPP #2 : Pedestrian Interaction Patch Project

Presented as part of the Sampled Festival at Sadlers Wells UK in January 2009, PIPP #2 continues the exploration of the first installation (PIPP #1 Leeds) and asks audiences to connect with an interactive work presented in the foyer of a major dance festival. Literally choreographing their own dances on the walls of the venue, pedestrians re-connect with the architectural surrounds generating unique memories of self.

Defending the patch : a labour geography analysis of unions’ construction of and responses to the problem of declining union membership amongst youth

If the trade union movement is to remain an influential force in the industrial, economic and socio/political arenas of industrialised nations it is vital that its recruitment of young members improve dramatically. Australian union membership levels have declined markedly over the last three decades and youth union membership levels have decreased more than any age group. Currently around 10% of young workers aged between 16-24 years are members of unions in Australia compared to 26% of workers aged 45-58 (Oliver, 2008). This decline has occurred throughout the union movement, in all states and in almost all industries and occupations. This research, which consists of interviews with union organisers and union officials, draws on perspectives from the labour geography literature to explore how union personnel located in various places, spaces and scales construct the issue of declining youth union membership. It explores the scale of connections within the labour movement and the extent to which these connections are leveraged to address the problem of youth union membership decline. To offer the reader a sense of context and perspective, the thesis firstly outlines the historical development of the union movement. It also reviews the literature on youth membership decline. Labour geography offers a rich and apposite analytical tool for investigation of this area. The notion of ‘scale’ as a dynamic, interactive, constructed and reconstructed entity (Ellem, 2006) is an appropriate lens for viewing youth-union membership issues. In this non-linear view, scale is a relational element which interplays with space, place and the environment (Howett, in Marston, 2000) rather than being ‘sequential’ and hierarchical. Importantly, the thesis investigates the notion of unions as ‘spaces of dependence’ (Cox, 1998a, p.2), organisations whose space is centred upon realising essential interests. It also considers the quality of unions’ interactions with others – their ‘spaces of engagement‘(Cox, 1998a, p.2), and the impact that this has upon their ability to recruit youth. The findings reveal that most respondents across the spectrum of the union movement attribute the decline in youth membership levels to factors external to the movement itself, such as changes to industrial relations legislation and the impact of globalisation on employment markets. However, participants also attribute responsibility for declining membership levels to the union movement itself, citing factors such as a lack of resourcing and a need to change unions’ perceived identity and methods of operation. The research further determined that networks of connections across the union movement are tenuous and, to date, are not being fully utilised to assist unions to overcome the youth recruitment dilemma. The study concludes that potential connections between unions are hampered by poor resourcing, workload issues and some deeply entrenched attitudes related to unions ‘defending (and maintaining) their patch’.

Interfacial debonding behavior of composite beam/plates with PZT patch

This paper studies interfacial debonding behavior of composite beams which include piezoelectric materials, adhesive and host beam. The focus is put on crack initiation and growth of the piezoelectric adhesive interface. Closed-form solutions of interface stresses and energy release rates are obtained for adhesive layer in the piezoelectric composite beams. Finite element analyses have been carried out to study the initiation and growth of interfaces crack for piezoelectric beams with interface element by ANSYS, in which the interface element of FE model is based on the cohesive zone models to characterize the fracture behavior of the interfacial debonding. The results have been compared with analystical solution, and the influence of different geometry and material parameters on the interfacial behavior of piezoelectric composite beams have been discussed.

Reduced-Size microstrip patch antenna for Bluetooth applications

A novel reduced-size microstrip rectangular patch antenna for Bluetooth operation is presented in this paper. The proposed antenna operates in the 2400 to 2484 MHz ISM Band. Although an air substrate is introduced, antenna occupies a small volume of 33.3×6.6×0.8 mm3. The gain and the impedance bandwidth of the antenna are predicted using a commercial Finite Element Method software package. The predicted results show good agreement with measured data.

Characteristics of a two-layer microstrip patch antenna for Bluetooth applications

A double-layer rectangular patch microstrip antenna suitable for Bluetooth applications is investigated. The patch is etched on a separate substrate which is suspended above the ground plane and supported by an MCX connector. The air gap between the patch and the ground plane increases the impedance bandwidth and can be used to tune the resonant frequency. This paper presents experimental results on the effects of various parameters on the antenna characteristics and provides guidelines for the design of such an antenna.

Anthropogenic landscape change promotes asymmetric dispersal and limits regional patch occupancy in a spatially structured bird population

1. Local extinctions in habitat patches and asymmetric dispersal between patches are key processes structuring animal populations in heterogeneous environments. Effective landscape conservation requires an understanding of how habitat loss and fragmentation influence demographic processes within populations and movement between populations. 2. We used patch occupancy surveys and molecular data for a rainforest bird, the logrunner (Orthonyx temminckii), to determine (i) the effects of landscape change and patch structure on local extinction; (ii) the asymmetry of emigration and immigration rates; (iii) the relative influence of local and between-population landscapes on asymmetric emigration and immigration; and (iv) the relative contributions of habitat loss and habitat fragmentation to asymmetric emigration and immigration. 3. Whether or not a patch was occupied by logrunners was primarily determined by the isolation of that patch. After controlling for patch isolation, patch occupancy declined in landscapes experiencing high levels of rainforest loss over the last 100 years. Habitat loss and fragmentation over the last century was more important than the current pattern of patch isolation alone, which suggested that immigration from neighbouring patches was unable to prevent local extinction in highly modified landscapes. 4. We discovered that dispersal between logrunner populations is highly asymmetric. Emigration rates were 39% lower when local landscapes were fragmented, but emigration was not limited by the structure of the between-population landscapes. In contrast, immigration was 37% greater when local landscapes were fragmented and was lower when the between-population landscapes were fragmented. Rainforest fragmentation influenced asymmetric dispersal to a greater extent than did rainforest loss, and a 60% reduction in mean patch area was capable of switching a population from being a net exporter to a net importer of dispersing logrunners. 5. The synergistic effects of landscape change on species occurrence and asymmetric dispersal have important implications for conservation. Conservation measures that maintain large patch sizes in the landscape may promote asymmetric dispersal from intact to fragmented landscapes and allow rainforest bird populations to persist in fragmented and degraded landscapes. These sink populations could form the kernel of source populations given sufficient habitat restoration. However, the success of this rescue effect will depend on the quality of the between-population landscapes.

Building intercultural competence one “Patch” at a time

This paper describes a program called Patches that was implemented to assist a group of Australian and Malaysian pre-service teachers to enhance their intercultural competence through their involvement in a series of reciprocal learning activities. Each learning experience was considered a “patch” that eventually created a “quilt of intercultural learning.” The purpose of this study was to enhance the intercultural competence of domestic and international students through organized intercultural activities, through a series of reflective writing sessions, and mutual engagement on a common project. The effectiveness of the Patches program was analysed in accordance with Deardorff’s elements of intercultural competence. The qualitative findings indicate that both cohorts of preservice teachers showed elements of intercultural competence through participation in the program, with both groups reporting a deeper appreciation and understanding of how to communicate more effectively in intercultural contexts.

Optimal allocation of conservation effort among subpopulations of a threatened species: How important is patch quality?

Money is often a limiting factor in conservation, and attempting to conserve endangered species can be costly. Consequently, a framework for optimizing fiscally constrained conservation decisions for a single species is needed. In this paper we find the optimal budget allocation among isolated subpopulations of a threatened species to minimize local extinction probability. We solve the problem using stochastic dynamic programming, derive a useful and simple alternative guideline for allocating funds, and test its performance using forward simulation. The model considers subpopulations that persist in habitat patches of differing quality, which in our model is reflected in different relationships between money invested and extinction risk. We discover that, in most cases, subpopulations that are less efficient to manage should receive more money than those that are more efficient to manage, due to higher investment needed to reduce extinction risk. Our simple investment guideline performs almost as well as the exact optimal strategy. We illustrate our approach with a case study of the management of the Sumatran tiger, Panthera tigris sumatrae, in Kerinci Seblat National Park (KSNP), Indonesia. We find that different budgets should be allocated to the separate tiger subpopulations in KSNP. The subpopulation that is not at risk of extinction does not require any management investment. Based on the combination of risks of extinction and habitat quality, the optimal allocation for these particular tiger subpopulations is an unusual case: subpopulations that occur in higher-quality habitat (more efficient to manage) should receive more funds than the remaining subpopulation that is in lower-quality habitat. Because the yearly budget allocated to the KSNP for tiger conservation is small, to guarantee the persistence of all the subpopulations that are currently under threat we need to prioritize those that are easier to save. When allocating resources among subpopulations of a threatened species, the combined effects of differences in habitat quality, cost of action, and current subpopulation probability of extinction need to be integrated. We provide a useful guideline for allocating resources among isolated subpopulations of any threatened species. © 2010 by the Ecological Society of America.

Amblyopia treatment : an evidence-based approach to maximising treatment outcome

The basis of treatment for amblyopia (poor vision due to abnormal visual experience early in life) for 250 years has been patching of the unaffected eye for extended times to ensure a period of use of the affected eye. Over the last decade randomised controlled treatment trials have provided some evidence on how to tailor amblyopia therapy more precisely to achieve the best visual outcome with the least negative impact on the patient and the family. This review highlights the expansion of knowledge regarding treatment for amblyopia and aims to provide optometrists with a summary of research evidence to enable them to better treat amblyopia. Treatment for amblyopia is effective, as it reduces overall prevalence and severity of visual loss in this population. Correction of refractive error alone significantly improves visual acuity, sometimes to the point where further amblyopia treatment is not required. Atropine penalisation and patch occlusion are effective in treating amblyopia. Lesser amounts of occlusion or penalisation have been found to be just as effective as greater amounts. Recent evidence has highlighted that occlusion or penalisation in amblyopia treatment can create negative changes in behaviour in children and impact on family life. These complications should be considere when prescribing treatment because they can negatively affect compliance. Studies investigating the maximum age at which treatment of amblyopia can still be effective and the importance of near activities during occlusion are ongoing.