Morphine-induced receptor endocytosis in a novel knockin mouse reduces tolerance and dependence

Abstract Opioid drugs, such as morphine, are among the most effective analgesics available. However, their utility for the treatment of chronic pain is limited by side effects including tolerance and dependence. Morphine acts primarily through the mu-opioid receptor (MOP-R) , which is also a target of endogenous opioids. However, unlike endogenous ligands, morphine fails to promote substantial receptor endocytosis both in vitro, and in vivo. Receptor endocytosis serves at least two important functions in signal transduction. First, desensitization and endocytosis act as an "off" switch by uncoupling receptors from G protein. Second, endocytosis functions as an "on" switch, resensitizing receptors by recycling them to the plasma membrane. Thus, both the off and on function of the MOP-R are altered in response to morphine compared to endogenous ligands. To examine whether the low degree of endocytosis induced by morphine contributes to tolerance and dependence, we generated a knockin mouse that expresses a mutant MOP-R that undergoes morphine-induced endocytosis. Morphine remains an excellent antinociceptive agent in these mice. Importantly, these mice display substantially reduced antinociceptive tolerance and physical dependence. These data suggest that opioid drugs with a pharmacological profile similar to morphine but the ability to promote endocytosis could provide analgesia while having a reduced liability for promoting tolerance and dependence

Face authentication test on the BANCA database

This work details the results of a face authentication test (FAT2004) (http://www.ee.surrey.ac.uk/banca/icpr2004) held in conjunction with the 17th International Conference on Pattern Recognition. The contest was held on the publicly available BANCA database (http://www.ee.surrey.ac.uk/banca) according to a defined protocol (E. Bailly-Bailliere et al., June 2003). The competition also had a sequestered part in which institutions had to submit their algorithms for independent testing. 13 different verification algorithms from 10 institutions submitted results. Also, a standard set of face recognition software packages from the Internet (http://www.cs.colostate.edu/evalfacerec) were used to provide a baseline performance measure.

Destination positioning opportunities using personal values : elicited through the Repertory Test with Laddering Analysis

While in many travel situations there is an almost limitless range of available destinations, travellers will usually only actively consider two to six in their decision set. One of the greatest challenges facing destination marketers is positioning their destination, against the myriad of competing places that offer similar features, into consumer decision sets. Since positioning requires a narrow focus, marketing communications must present a succinct and meaningful proposition, the selection of which is often problematic for destination marketing organisations (DMO), which deal with a diverse and often eclectic range of attributes in addition to self-interested and demanding stakeholders who have interests in different market segments. This paper reports the application of two qualitative techniques used to explore the range of cognitive attributes, consequences and personal values that represent potential positioning opportunities in the context of short break holidays. The Repertory Test is an effective technique for understanding the salient attributes used by a traveller to differentiate destinations, and Laddering Analysis enables the researcher to explore the smaller set of consequences and personal values guiding such decision making. A key finding of the research was that while individuals might vary in their repertoire of salient attributes, there was a commonality of shared consequences and values. This has important implications for DMOs, since a brand positioning theme that is based on a value will subsume multiple and diverse attributes. It is posited that such a theme will appeal to a broader range of travellers, as well as appease a greater number of destination stakeholders, than would an attribute based theme.

Mechanical behaviours of pumpkin peel under compression test

Mechanical damages such as bruising, collision and impact during food processing stages diminish quality and quantity of productions as well as efficiency of operations. Studying mechanical characteristics of food materials will help to enhance current industrial practices. Mechanical properties of fruits and vegetables describe how these materials behave under loading in real industrial operations. Optimizing and designing more efficient equipments require accurate and precise information of tissue behaviours. FE modelling of food industrial processes is an effective method of studying interrelation of variables during mechanical operation. In this study, empirical investigation has been done on mechanical properties of pumpkin peel. The test was a part of FE modelling and simulation of mechanical peeling stage of tough skinned vegetables. The compression test has been conducted on Jap variety of pumpkin. Additionally, stress strain curve, bio-yield and toughness of pumpkin skin have been calculated. The required energy for reaching bio-yield point was 493.75, 507.71 and 451.71 N.mm for 1.25, 10 and 20 mm/min loading speed respectively. Average value of force in bio-yield point for pumpkin peel was 310 N.

DEM test, visagraph eye movement recordings, and reading ability in children

Purpose. To determine how Developmental Eye Movement (DEM) test results relate to reading eye movement patterns recorded with the Visagraph in visually normal children, and whether DEM results and recorded eye movement patterns relate to standardized reading achievement scores. Methods. Fifty-nine school-age children (age = 9.7 ± 0.6 years) completed the DEM test and had eye movements recorded with the Visagraph III test while reading for comprehension. Monocular visual acuity in each eye and random dot stereoacuity were measured and standardized scores on independently administered reading comprehension tests [reading progress test (RPT)] were obtained. Results. Children with slower DEM horizontal and vertical adjusted times tended to have slower reading rates with the Visagraph (r = -0.547 and -0.414 respectively). Although a significant correlation was also found between the DEM ratio and Visagraph reading rate (r = -0.368), the strength of the relationship was less than that between DEM horizontal adjusted time and reading rate. DEM outcome scores were not significantly associated with RPT scores. When the relative contribution of reading ability (RPT) and DEM scores was accounted for in multivariate analysis, DEM outcomes were not significantly associated with Visagraph reading rate. RPT scores were associated with Visagraph outcomes of duration of fixations (r = -0.403) and calculated reading rate (r = 0.366) but not with DEM outcomes. Conclusions.DEM outcomes can identify children whose Visagraph recorded eye movement patterns show slow reading rates. However, when reading ability is accounted for, DEM outcomes are a poor predictor of reading rate. Visagraph outcomes of duration of fixation and reading rate relate to standardized reading achievement scores; however, DEM results do not. Copyright © 2011 American Academy of Optometry.

Body composition and appetite : fat-free mass (but not fat mass or BMI) is positively associated with self-determined meal size and daily energy intake in humans

The idea of body weight regulation implies that a biological mechanism exerts control over energy expenditure and food intake. This is a central tenet of energy homeostasis. However, the source and identity of the controlling mechanism have not been identified, although it is often presumed to be some long-acting signal related to body fat, such as leptin. Using a comprehensive experimental platform, we have investigated the relationship between biological and behavioural variables in two separate studies over a 12-week intervention period in obese adults (total n 92). All variables have been measured objectively and with a similar degree of scientific control and precision, including anthropometric factors, body composition, RMR and accumulative energy consumed at individual meals across the whole day. Results showed that meal size and daily energy intake (EI) were significantly correlated with fat-free mass (FFM, P values ,0·02–0·05) but not with fat mass (FM) or BMI (P values 0·11–0·45) (study 1, n 58). In study 2 (n 34), FFM (but not FM or BMI) predicted meal size and daily EI under two distinct dietary conditions (high-fat and low-fat). These data appear to indicate that, under these circumstances, some signal associated with lean mass (but not FM) exerts a determining effect over self-selected food consumption. This signal may be postulated to interact with a separate class of signals generated by FM. This finding may have implications for investigations of the molecular control of food intake and body weight and for the management of obesity.

The oral health of critically ill children : an observational cohort study

Aims and objectives: This study will describe the oral health status of critically ill children over time spent in the paediatric intensive care unit, examine influences on the development of poor oral health and explore the relationship between dysfunctional oral health and healthcare-associated infections. Background: The treatment modalities used to support children experiencing critical illness and the progression of critical illness may result in dysfunction in the oral cavity. In adults, oral health has been shown to worsen during critical illness as well as influence systemic health. Design: A prospective observational cohort design was used. Method: The study was undertaken at a single tertiary-referral Paediatric Intensive Care Unit. Oral health status was measured using the Oral Assessment Scale and culturing oropharyngeal flora. Information was also collected surrounding the use of supportive therapies, clinical characteristics of the children and the occurrence of healthcare-associated infections. Results: Of the 46 participants, 63% (n = 32) had oral dysfunction and 41% (n = 19) demonstrated pathogenic oropharyngeal colonisation during their critical illness. The potential systemic pathogens isolated from the oropharynx and included Candida sp., Staphylococcus aureus, Haemophilus influenzae, Enterococcus sp. and Pseudomonas aeruginosa. The severity of critical illness had a significant positive relationship (p < 0·05) with pathogenic and absent colonisation of the oropharynx. Sixty-three percent of healthcare-associated infections involved the preceding or simultaneous colonisation of the oropharynx by the causative pathogen. Conclusions: This study suggests paediatric oral health to be frequently dysfunctional and the oropharynx to repeatedly harbour potential systemic pathogens during childhood critical illness. Relevance to clinical practice: Given the frequency of poor oral health during childhood critical illness in this study and the subsequent potential systemic consequences, evidence based oral hygiene practices should be developed and validated to guide clinicians when nursing critically ill children.