Flupirtine enhances the anti-hyperalgesic effects of morphine in a rat model of prostate bone metastasis

Objective Current treatments for cancer pain are often inadequate, particularly when metastasis to bone is involved. The addition to the treatment regimen of another drug that has a complementary analgesic effect may increase the overall analgesia without the necessity to increase doses, thus avoiding dose-related side effects. This project investigated the synergistic effect of the addition of the potassium channel (KCNQ2–3) modulator flupirtine to morphine treatment in a rat model of prostate cancer-induced bone pain. Design Syngeneic prostate cancer cells were injected into the right tibia of male Wistar rats under anesthesia. This led to expanding tumor within the bone in 2 weeks, together with the concurrent development of hyperalgesia to noxious heat. Paw withdrawal thresholds from noxious heat were measured before and after the maximum non-sedating doses of morphine and flupirtine given alone and in combinations. Dose-response curves for morphine (0.13–5.0 mg/kg ip) and flupirtine (1.25–10.0 mg/kg ip) given alone and in fixed-dose combinations were plotted and subjected to an isobolographic analysis. Results Both morphine (ED50 = 0.74 mg/kg) and flupirtine (ED50 = 3.32 mg/kg) caused dose-related anti-hyperalgesia at doses that did not cause sedation. Isobolographic analysis revealed that there was a synergistic interaction between flupirtine and morphine. Addition of flupirtine to morphine treatment improved morphine anti-hyperalgesia, and resulted in the reversal of cancer-induced heat hyperalgesia. Conclusions These results suggest that flupirtine in combination with morphine may be useful clinically to provide better analgesia at lower morphine doses in the management of pain caused by tumors growing in bone.

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.

MMP-14 is expressed in preeclamptic placentas and mediates release of soluble endoglin

Soluble endoglin is an anti-angiogenic protein that is released from the placenta and contributes to both maternal endothelial dysfunction and the clinical features of severe preeclampsia. The mechanism through which soluble endoglin is released from the placenta is currently unknown; however, recent work in colorectal cancer identified matrix metalloproteinase 14 (MMP-14) as the cleavage protease of endoglin. To determine whether this is also the mechanism responsible for soluble endoglin release in preeclampsia, we investigated the expression of MMP-14 within the placenta and the effects of its inhibition on soluble endoglin release. Placentas were obtained from severe, early onset preeclamptic pregnancies (n = 8) and gestationally matched preterm controls (n = 8). MMP-14 was predominately localized to the syncytiotrophoblast. Results from a proximity ligation assay showed protein interactions between endogenous MMP-14 and endoglin within the preeclamptic placenta. To demonstrate that this interaction produces soluble endoglin, we treated trophoblastic BeWo cells with either a broad-spectrum MMP inhibitor (GM6001) or MMP-14 siRNA. Both treatments produced a decrease in soluble endoglin (P ≤ 0.05). Treatment of mice bearing BeWo xenografts with GM6001 decreased circulating soluble endoglin levels in mouse serum (P ≤ 0.05). These findings indicate that MMP-14 is the likely cleavage protease of endoglin in the setting of preeclampsia. This approach provides a novel method for the development of potential therapeutics to reduce circulating soluble endoglin and ameliorate the clinical features of severe preeclampsia.

The adhesion molecule L1 regulates transendothelial migration and trafficking of dendritic cells

The adhesion molecule L1, which is extensively characterized in the nervous system, is also expressed in dendritic cells (DCs), but its function there has remained elusive. To address this issue, we ablated L1 expression in DCs of conditional knockout mice. L1-deficient DCs were impaired in adhesion to and transmigration through monolayers of either lymphatic or blood vessel endothelial cells, implicating L1 in transendothelial migration of DCs. In agreement with these findings, L1 was expressed in cutaneous DCs that migrated to draining lymph nodes, and its ablation reduced DC trafficking in vivo. Within the skin, L1 was found in Langerhans cells but not in dermal DCs, and L1 deficiency impaired Langerhans cell migration. Under inflammatory conditions, L1 also became expressed in vascular endothelium and enhanced transmigration of DCs, likely through L1 homophilic interactions. Our results implicate L1 in the regulation of DC trafficking and shed light on novel mechanisms underlying transendothelial migration of DCs. These observations might offer novel therapeutic perspectives for the treatment of certain immunological disorders.

Xenome--a tool for classifying reads from xenograft samples

Motivation Shotgun sequence read data derived from xenograft material contains a mixture of reads arising from the host and reads arising from the graft. Classifying the read mixture to separate the two allows for more precise analysis to be performed. Results We present a technique, with an associated tool Xenome, which performs fast, accurate and specific classification of xenograft-derived sequence read data. We have evaluated it on RNA-Seq data from human, mouse and human-in-mouse xenograft datasets.

Supporting residents’ expression of sexuality : the initial construction of a sexuality assessment tool for residential aged care facilities

Background: Sexuality is a key component of quality of life and well-being and a need to express one’s sexuality continues into old age. Staff and families in residential aged care facilities often find expressions of sexuality by residents, particularly those living with dementia, challenging and facilities often struggle to address individuals’ needs in this area. This paper describes the development of an assessment tool which enables residential aged care facilities to identify how supportive their organisation is of all residents’ expression of their sexuality, and thereby improve where required. Methods: Multi-phase design using qualitative methods and a Delphi technique. Tool items were derived from the literature and verified by qualitative interviews with aged care facility staff, residents and families. The final item pool was confirmed via a reactive Delphi process. Results: A final item pool of sixty-nine items grouped into seven key areas allows facilities to score their compliance with the areas identified as being supportive of older people’s expression of their sexuality in a residential aged care environment. Conclusions: The sexuality assessment tool (SexAT) guides practice to support the normalization of sexuality in aged care homes and assists facilities to identify where enhancements to the environment, policies, procedures and practices, information and education/training are required. The tool also enables facilities to monitor initiatives in these areas over time.

Good Practice Report : Postgraduate Research and Coursework Degrees

Over the past decade, enrolments in postgraduate courses in Australian universities have risen by 34% (or from 258,164 in 2004 to 347,363 in 2013) (uCube, 2014). This substantial growth can be attributed to increased demand for postgraduate coursework as continuing professional education, the expansion of Higher Degrees Research (HDR) intakes, and the development of postgraduate research and coursework degrees in new fields. At the same time, the establishment of the Australian Qualification Framework (AQF) and national Tertiary Education Quality and Standards Agency (TEQSA), as well as the internationalisation of postgraduate education, have brought challenges and opportunities to the sector. During the past five years, the Australian Government Office for Learning and Teaching (OLT) and its predecessor bodies have funded a number of projects and Fellowships on postgraduate coursework and research degrees. They span diverse topics–from entry pathways and research training to supporting international and Indigenous students, examination, scoping studies of new and emergent programs, and effective supervision. In 2014 the OLT commissioned this good practice report to review the grants and fellowships conducted between 2009 and 2014. Encompassing twenty-seven learning and teaching projects and fellowships, the aims of this report include providing universities and academics with an overview of the current state of postgraduate study in Australia and the major influences upon it; a coherent overview of funded projects’ findings and outcomes; and a central point to access good practices, resources and tools in summary form. The objectives of this good practice report are to provide: • A literature review, which contextualises the projects within the Australian and international Higher Education environment, emphasises factors that currently influence postgraduate programs, and highlights challenges and opportunities for the sector. It also explains variations in postgraduate course types and definitions within the Australian Qualification Framework (AQF), and identifies key learning and teaching issues as well as good practices identified in scholarly research and position papers. • A collated overview of the twenty-seven national learning and teaching projects and fellowships on postgraduate coursework and research, including a summary of each project’s aims and objectives, methodologies, outcomes and resources. • A summative index of project characteristics (topics, themes and approaches) and inventory of scholarly research outcomes of the completed projects (publications, reports) as well as resources produced (tools, methods, good practice case studies), and their location (URL Links, references, etc.). • A summary of good practices that have been identified from the literature and the findings of completed projects. • A set of recommendations to address remaining gaps in the field and areas in which further work or development are appropriate. Bringing this work together will help enable university course teams to improve the delivery and development of existing postgraduate courses and to develop new ones, and it will provide academics with an overview of good practices and resources for teaching, supervising and supporting postgraduate students.

The biology of an isolated population of American Flamingo Phoenicopterus ruber in the Galapagos Islands

A genetically and morphologically divergent population of c.500 American Flamingos, isolated from the parental Caribbean stock of Phoenicopterus ruber, occurs in the Galapagos archipelago. Based primarily on data from a 3-year study, we provide the first description of the feeding and breeding biology of this population. Galapagos provides a suitable habitat comprising lagoons on a number of islands, among which the flamingos travel in response to food and nest site availability. The occurrence and qualnity of some food species was associated with the chlorosity of lagoon water, as was the distribution of flamingos. They bred opportunistically at five lagoons on four islands, sometimes simultaneously on more than one island. Group display usually involved approx 20 birds and colonies contained as few as three nests. Laying occurred during nine months of the year... We review potential dangers to this unique population and suggest conservation measures.

The clinical utility of the Cornell Scale for Depression in Dementia as a routine assessment in nursing homes

Objective To examine the clinical utility of the Cornell Scale for Depression in Dementia (CSDD) in nursing homes. Setting 14 nursing homes in Sydney and Brisbane, Australia. Participants 92 residents with a mean age of 85 years. Measurements Consenting residents were assessed by care staff for depression using the CSDD as part of their routine assessment. Specialist clinicians conducted assessment of depression using the Semi-structured Clinical Diagnostic Interview for DSM-IV-TR Axis I Disorders for residents without dementia or the Provisional Diagnostic Criteria for Depression in Alzheimer Disease for residents with dementia to establish expert clinical diagnoses of depression. The diagnostic performance of the staff completed CSDD was analyzed against expert diagnosis using receiver operating characteristic (ROC) curves. Results The CSDD showed low diagnostic accuracy, with areas under the ROC curve being 0.69, 0.68 and 0.70 for the total sample, residents with dementia and residents without dementia, respectively. At the standard CSDD cutoff score, the sensitivity and specificity were 71% and 59% for the total sample, 69% and 57% for residents with dementia, and 75% and 61% for residents without dementia. The Youden index (for optimizing cut-points) suggested different depression cutoff scores for residents with and without dementia. Conclusion When administered by nursing home staff the clinical utility of the CSDD is highly questionable in identifying depression. The complexity of the scale, the time required for collecting relevant information, and staff skills and knowledge of assessing depression in older people must be considered when using the CSDD in nursing homes.

Napping, development and health from 0 to 5 years : a systematic review

Background Duration and quality of sleep affect child development and health. Encouragement of napping in preschool children has been suggested as a health-promoting strategy. Objectives The aim of this study is to assess evidence regarding the effects of napping on measures of child development and health. Design This study is a systematic review of published, original research articles of any design. Subjects Children aged 0–5 years. Method Electronic database search was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and assessment of research quality was carried out following a Grading of Recommendations, Assessment, Development and Evaluations (GRADE) protocol. Results Twenty-six articles met inclusion criteria. These were of heterogeneous quality; all had observational designs (GRADE-low). Development and health outcomes included salivary cortisol, night sleep, cognition, behaviour, obesity and accidents. The findings regarding cognition, behaviour and health impacts were inconsistent, probably because of variation in age and habitual napping status of the samples. The most consistent finding was an association between napping and later onset, shorter duration and poorer quality of night sleep, with evidence strongest beyond the age of 2 years. Limitations Studies were not randomised. Most did not obtain data on the children's habitual napping status or the context of napping. Many were reliant on parent report rather than direct observation or physiological measurement of sleep behaviour. Conclusions The evidence indicates that beyond the age of 2 years napping is associated with later night sleep onset and both reduced sleep quality and duration. The evidence regarding behaviour, health and cognition is less certain. There is a need for more systematic studies that use stronger designs. In preschool children presenting with sleep problems clinicians should investigate napping patterns.

Collaboration in Web N.0: Stigmergy and virtual pheromones

The aim of this project was to develop a general theory of stigmergy and a software design pattern to build collaborative websites. Stigmergy is a biological term used when describing some insect swarm-behaviour where 'food gathering' and 'nest building' activities demonstrate the emergence of self-organised societies achieved without an apparent management structure. The results of the project are an abstract model of stigmergy and a software design pattern for building Web 2.0 components exploiting this self-organizing phenomenon. A proof-of-concept implementation was also created demonstrating potential commercial viability for future website projects.

Enterprise business technology governance: A validation of three technology-governance competencies for boards of directors

The competent leadership and governance of digital transformation needs to involve the board of directors. The reported lack of such capability in boards is becoming a pressing issue. Underpinning leadership in such transformation are the competencies to effectively govern Enterprise Technology (ETG). In this paper we take the position that ETG competencies are essential in boards because competent enterprise business technology governance has been shown to contribute to increased revenue, profit, and returns. We report the industry validation processes of a set of three board-of-director competencies needed for effective ETG related to strategy and planning; investment and risk; and, innovation and value creation. We conclude that gaps in board ETG competence remain.

Using a theory of planned behaviour framework to explore hand hygiene beliefs at the ‘5 critical moments’ among Australian hospital-based nurses

Background Improving hand hygiene among health care workers (HCWs) is the single most effective intervention to reduce health care associated infections in hospitals. Understanding the cognitive determinants of hand hygiene decisions for HCWs with the greatest patient contact (nurses) is essential to improve compliance. The aim of this study was to explore hospital-based nurses’ beliefs associated with performing hand hygiene guided by the World Health Organization’s (WHO) 5 critical moments. Using the belief-base framework of the Theory of Planned Behaviour, we examined attitudinal, normative, and control beliefs underpinning nurses’ decisions to perform hand hygiene according to the recently implemented national guidelines. Methods Thematic content analysis of qualitative data from focus group discussions with hospital-based registered nurses from 5 wards across 3 hospitals in Queensland, Australia. Results Important advantages (protection of patient and self), disadvantages (time, hand damage), referents (supportive: patients, colleagues; unsupportive: some doctors), barriers (being too busy, emergency situations), and facilitators (accessibility of sinks/products, training, reminders) were identified. There was some equivocation regarding the relative importance of hand washing following contact with patient surroundings. Conclusions The belief base of the theory of planned behaviour provided a useful framework to explore systematically the underlying beliefs of nurses’ hand hygiene decisions according to the 5 critical moments, allowing comparisons with previous belief studies. A commitment to improve nurses’ hand hygiene practice across the 5 moments should focus on individual strategies to combat distraction from other duties, peer-based initiatives to foster a sense of shared responsibility, and management-driven solutions to tackle staffing and resource issues. Hand hygiene following touching a patient’s surroundings continues to be reported as the most neglected opportunity for compliance.