Intravenous injection of leconotide, an omega conotoxin : synergistic antihyperalgesic effects with morphine in a rat model of bone cancer pain

Objective.  Leconotide (CVID, AM336, CNSB004) is an omega conopeptide similar to ziconotide, which blocks voltage sensitive calcium channels. However, unlike ziconotide, which must be administered intrathecally, leconotide can be given intravenously because it is less toxic. This study investigated the antihyperalgesic potency of leconotide given intravenously alone and in combinations with morphine-administered intraperitoneally, in a rat model of bone cancer pain. Design.  Syngeneic rat prostate cancer cells AT3B-1 were injected into one tibia of male Wistar rats. The tumor expanded within the bone causing hyperalgesia to heat applied to the ipsilateral hind paw. Measurements were made of the maximum dose (MD) of morphine and leconotide given alone and in combinations that caused no effect in an open-field activity monitor, rotarod, and blood pressure and heart rate measurements. Paw withdrawal thresholds from noxious heat were measured. Dose response curves for morphine (0.312–5.0 mg/kg intraperitoneal) and leconotide (0.002–200 µg/kg intravenous) given alone were plotted and responses compared with those caused by morphine and leconotide in combinations. Results.  Leconotide caused minimal antihyperalgesic effects when administered alone. Morphine given alone intraperitoneally caused dose-related antihyperalgesic effects (ED50 = 2.40 ± 1.24 mg/kg), which were increased by coadministration of leconotide 20 µg/kg (morphine ED50 = 0.16 ± 1.30 mg/kg); 0.2 µg/kg (morphine ED50 = 0.39 ± 1.27 mg/kg); and 0.02 µg/kg (morphine ED50 = 1.24 ± 1.30 mg/kg). Conclusions.  Leconotide caused a significant increase in reversal by morphine of the bone cancer-induced hyperalgesia without increasing the side effect profile of either drug. Clinical Implication.  Translation into clinical practice of the method of analgesia described here will improve the quantity and quality of analgesia in patients with bone metastases. The use of an ordinary parenteral route for administration of the calcium channel blocker (leconotide) at low dose opens up the technique to large numbers of patients who could not have an intrathecal catheter for drug administration. Furthermore, the potentiating synergistic effect with morphine on hyperalgesia without increased side effects will lead to greater analgesia with improved quality of life.

Implications of differences in technical efficiency of fishing boats for capacity measurement and reduction

Capacity measurement and reduction is a major international issue to emerge in the new millennium. However, there has been limited assessment of the success of capacity reduction schemes (CRS). In this paper, the success of a CRS is assessed for a European fishery characterised by differences in efficiency levels of individual boats. In such a fishery, given it is assumed that the least efficient producers are the first to exit through a CRS, the reduction in harvesting capacity is less than the nominal reduction in physical fleet capacity. Further, there is potential for harvesting capacity to increase if remaining vessels improve their efficiency.

Identification of salivary N-glycoproteins and measurement of glycosylation site occupancy by boronate glycoprotein enrichment and liquid chromatography/electrospray ionization tandem mass spectrometry

RATIONALE Diseases including cancer and congenital disorders of glycosylation have been associated with changes in the site-specific extent of protein glycosylation. Saliva can be non-invasively sampled and is rich in glycoproteins, giving it the potential to be a useful biofluid for the discovery and detection of disease biomarkers associated with changes in glycosylation. METHODS Saliva was collected from healthy individuals and glycoproteins were enriched using phenylboronic acid based glycoprotein enrichment resin. Proteins were deglycosylated with peptide-N-glycosidase F and digested with AspN or trypsin. Desalted peptides and deglycosylated peptides were separated by reversed-phase liquid chromatography and detected with on-line electrospray ionization quadrupole-time-of-flight mass spectrometry using a 5600 TripleTof instrument. Site-specific glycosylation occupancy was semi-quantitatively determined from the abundance of deglycosylated and nonglycosylated versions of each given peptide. RESULTS Glycoprotein enrichment identified 67 independent glycosylation sites from 24 unique proteins, a 3.9-fold increase in the number of glycosylation sites identified. Enrichment of glycoproteins rather than glycopeptides allowed detection of both deglycosylated and nonglycosylated versions of each peptide, and thereby robust measurement of site-specific occupancy at 21 asparagines. Healthy individuals showed limited biological variability in occupancy, with partially modified sites having characteristics consistent with inefficient glycosylation by oligosaccharyltransferase. Inclusion of negative controls without enzymatic deglycosylation controlled for spontaneous chemical deamidation, and identified asparagines previously incorrectly annotated as glycosylated. CONCLUSIONS We developed a sample preparation and mass spectrometry detection strategy for rapid and efficient measurement of site-specific glycosylation occupancy on diverse salivary glycoproteins suitable for biomarker discovery and detection of changes in glycosylation occupancy in human disease.

Choice impulsivity: Definitions, measurement issues, and clinical implications

Background Impulsivity critically relates to many psychiatric disorders. Given the multifaceted construct that impulsivity represents, defining core aspects of impulsivity is vital for the assessment and understanding of clinical conditions. Choice impulsivity (CI), involving the preferential selection of smaller sooner rewards over larger later rewards, represents one important type of impulsivity. Method The International Society for Research on Impulsivity (InSRI) convened to discuss the definition and assessment of CI and provide recommendations regarding measurement across species. Results Commonly used preclinical and clinical CI behavioral tasks are described, and considerations for each task are provided to guide CI task selection. Differences in assessment of CI (self-report, behavioral) and calculating CI indices (e.g., area-under-the-curve, indifference point, steepness of discounting curve) are discussed along with properties of specific behavioral tasks used in preclinical and clinical settings. Conclusions The InSRI group recommends inclusion of measures of CI in human studies examining impulsivity. Animal studies examining impulsivity should also include assessments of CI and these measures should be harmonized in accordance with human studies of the disorders being modeled in the preclinical investigations. The choice of specific CI measures to be included should be based on the goals of the study and existing preclinical and clinical literature using established CI measures.

Are bone-anchored prostheses about to revolutionise the world of prosthetics?

Individuals with limb amputation fitted with conventional socket-suspended prostheses often experience socket related discomfort leading to a significant decrease in quality of life. Most of these concerns can be overcome by surgical techniques enabling bone-anchored prostheses. In this case, the prosthesis is attached directly to the residual skeleton through a percutaneous implant. The primary aim of this study is to present the current advances in these surgical techniques worldwide with a strong focus on the developments in Australia. The secondary aim is to provide an overview of the possible critical changes that may occurred in the world of prosthetic following these developments in bone-anchored prostheses.

Supine to standing Cobb angle change in idiopathic scoliosis : the effect of endplate pre-selection

Background Supine imaging modalities provide valuable 3D information on scoliotic anatomy, but the altered spine geometry between the supine and standing positions affects the Cobb angle measurement. Previous studies report a mean 7°-10° Cobb angle increase from supine to standing, but none have reported the effect of endplate pre-selection or whether other parameters affect this Cobb angle difference. Methods Cobb angles from existing coronal radiographs were compared to those on existing low-dose CT scans taken within three months of the reference radiograph for a group of females with adolescent idiopathic scoliosis. Reformatted coronal CT images were used to measure supine Cobb angles with and without endplate pre-selection (end-plates selected from the radiographs) by two observers on three separate occasions. Inter and intra-observer measurement variability were assessed. Multi-linear regression was used to investigate whether there was a relationship between supine to standing Cobb angle change and eight variables: patient age, mass, standing Cobb angle, Risser sign, ligament laxity, Lenke type, fulcrum flexibility and time delay between radiograph and CT scan. Results Fifty-two patients with right thoracic Lenke Type 1 curves and mean age 14.6 years (SD 1.8) were included. The mean Cobb angle on standing radiographs was 51.9° (SD 6.7). The mean Cobb angle on supine CT images without pre-selection of endplates was 41.1° (SD 6.4). The mean Cobb angle on supine CT images with endplate pre-selection was 40.5° (SD 6.6). Pre-selecting vertebral endplates increased the mean Cobb change by 0.6° (SD 2.3, range −9° to 6°). When free to do so, observers chose different levels for the end vertebrae in 39% of cases. Multi-linear regression revealed a statistically significant relationship between supine to standing Cobb change and fulcrum flexibility (p = 0.001), age (p = 0.027) and standing Cobb angle (p < 0.001). The 95% confidence intervals for intra-observer and inter-observer measurement variability were 3.1° and 3.6°, respectively. Conclusions Pre-selecting vertebral endplates causes minor changes to the mean supine to standing Cobb change. There is a statistically significant relationship between supine to standing Cobb change and fulcrum flexibility such that this difference can be considered a potential alternative measure of spinal flexibility.

Thrust allocation with linear constrained quadratic cost function

In this paper, a method of thrust allocation based on a linearly constrained quadratic cost function capable of handling rotating azimuths is presented. The problem formulation accounts for magnitude and rate constraints on both thruster forces and azimuth angles. The advantage of this formulation is that the solution can be found with a finite number of iterations for each time step. Experiments with a model ship are used to validate the thrust allocation system.

CORR Insights® : loss of cement-bone interlock in retrieved tibial components from total knee arthroplasties

Most surgeons cement the tibial component in total knee replacement surgery. Mid-term registry data from a number of countries, including those from the United Kingdom and Australia, support the excellent survivorship of cemented tibial components. In spite of this success, results can always be improved, and cementing technique can play a role. Cementing technique on the tibia is not standardized, and surgeons still differ about the best ways to deliver cement into the cancellous bone of the upper tibia. Questions remain regarding whether to use a gun or a syringe to inject the cement into the cancellous bone of the tibial plateau . The ideal cement penetration into the tibial plateau is debated, though most reports suggest that 4 mm to 10 mm is ideal. Thicker mantles are thought to be dangerous due to the risk of bone necrosis, but there is little in the literature to support this contention...

The association between the measurement of adherence to anti-diabetes medicine and the HbA1c

BACKGROUND: Adherence to medicines is important in subjects with diabetes, as nonadherence is associated with an increased risk of morbidity and mortality. However, it is not clear whether there is an association between adherence to medicines and glycaemic control, as not all studies have shown this. One of the reasons for this discrepancy may be that, although there is a standard measure of glycaemic control i.e. HbA1c, there is no standard measure of adherence to medicines. Adherence to medicines can be measured either qualitatively by Morisky or non-Morisky methods or quantitatively using the medicines possession ratio (MPR). AIMS OF THE REVIEW: The aims of this literature review are (1) to determine whether there is an association between adherence to anti-diabetes medicines and glycaemic control, and (2) whether any such association is dependent on how adherence is measured. Methods A literature search of Medline, CINAHL and the Internet (Google) was undertaken with search terms; 'diabetes' with 'adherence' (or compliance, concordance, persistence, continuation) with 'HbA1c' (or glycaemic control). RESULTS: Twenty-three studies were included; 10 qualitative and 12 quantitative studies, and one study using both methods. For the qualitative methods measurements of adherence to anti-diabetes medicines (non-Morisky and Morisky), eight out of ten studies show an association with HbA1c. Nine of ten studies using the quantitative MPR, and two studies using MPR for insulin only, have also shown an association between adherence to anti-diabetes medicines and HbA1c. However, the one study that used both Morisky and MPR did not show an association. Three of the four studies that did not show a relationship, did not use a range of HbA1c values in their regression analysis. The other study that did not show a relationship was specifically in a low income population. CONCLUSIONS: Most studies show an association between adherence to anti-diabetes medicines and HbA1c levels, and this seems to be independent of method used to measure adherence. However, to show an association it is necessary to have a range of HbA1c values. Also, the association is not always apparent in low income populations.

kmth price sealed-bid auctions with general independent values and equilibrium linear mark-ups

A generalised bidding model is developed to calculate a bidder’s expected profit and auctioners expected revenue/payment for both a General Independent Value and Independent Private Value (IPV) kmth price sealed-bid auction (where the mth bidder wins at the kth bid payment) using a linear (affine) mark-up function. The Common Value (CV) assumption, and highbid and lowbid symmetric and asymmetric First Price Auctions and Second Price Auctions are included as special cases. The optimal n bidder symmetric analytical results are then provided for the uniform IPV and CV models in equilibrium. Final comments concern implications, the assumptions involved and prospects for further research.

The typicality and accessibility of consumer attitudes toward television advertising : implications for the measurement of attitudes toward advertising in general

Despite the wide array of contemporary advertising formats and media, television advertising remains the most dominant form to which typical consumers are exposed. Research on attitudes toward advertising in general (Att-AiG) implicitly assumes that the Att-AiG measure represents advertising as a whole. A major finding of the current research is that consumers tend to have a mental representation, or exemplar, of the most typical type of advertising—television advertising—when they report their Att-AiG. Therefore, in reality, Att-AiG primarily reflects attitudes toward television advertising. In addition, the results of our experiments indicate that television ad exemplars generate temporal changes in consumers’ reported Att-AiG and attitudes toward television advertising. Theoretical and practical implications are discussed.

Understanding Uncertainties in Non-Linear Population Trajectories: A Bayesian Semi-Parametric Hierarchical Approach to Large-Scale Surveys of Coral Cover

Recently, attempts to improve decision making in species management have focussed on uncertainties associated with modelling temporal fluctuations in populations. Reducing model uncertainty is challenging; while larger samples improve estimation of species trajectories and reduce statistical errors, they typically amplify variability in observed trajectories. In particular, traditional modelling approaches aimed at estimating population trajectories usually do not account well for nonlinearities and uncertainties associated with multi-scale observations characteristic of large spatio-temporal surveys. We present a Bayesian semi-parametric hierarchical model for simultaneously quantifying uncertainties associated with model structure and parameters, and scale-specific variability over time. We estimate uncertainty across a four-tiered spatial hierarchy of coral cover from the Great Barrier Reef. Coral variability is well described; however, our results show that, in the absence of additional model specifications, conclusions regarding coral trajectories become highly uncertain when considering multiple reefs, suggesting that management should focus more at the scale of individual reefs. The approach presented facilitates the description and estimation of population trajectories and associated uncertainties when variability cannot be attributed to specific causes and origins. We argue that our model can unlock value contained in large-scale datasets, provide guidance for understanding sources of uncertainty, and support better informed decision making

Mathematical modelling of intramembranous bone formation during fracture healing

During fracture healing, many complex and cryptic interactions occur between cells and bio-chemical molecules to bring about repair of damaged bone. In this thesis two mathematical models were developed, concerning the cellular differentiation of osteoblasts (bone forming cells) and the mineralisation of new bone tissue, allowing new insights into these processes. These models were mathematically analysed and simulated numerically, yielding results consistent with experimental data and highlighting the underlying pattern formation structure in these aspects of fracture healing.

Combining opinions for use in Bayesian networks: A measurement error approach

Bayesian networks (BNs) are graphical probabilistic models used for reasoning under uncertainty. These models are becoming increasing popular in a range of fields including ecology, computational biology, medical diagnosis, and forensics. In most of these cases, the BNs are quantified using information from experts, or from user opinions. An interest therefore lies in the way in which multiple opinions can be represented and used in a BN. This paper proposes the use of a measurement error model to combine opinions for use in the quantification of a BN. The multiple opinions are treated as a realisation of measurement error and the model uses the posterior probabilities ascribed to each node in the BN which are computed from the prior information given by each expert. The proposed model addresses the issues associated with current methods of combining opinions such as the absence of a coherent probability model, the lack of the conditional independence structure of the BN being maintained, and the provision of only a point estimate for the consensus. The proposed model is applied an existing Bayesian Network and performed well when compared to existing methods of combining opinions.