MicroRNAs targeting mutant K-ras by electrotransfer inhibit human colorectal adenocarcinoma cell growth in vitro and in vivo

Mutations of K-ras have been found in 30-60% of colorectal carcinomas and are believed to be associated with tumor initiation, tumor progression and metastasis formation. Therefore, silencing of mutant K-ras expression has become an attractive therapeutic strategy for colorectal cancer treatment. The aim of our study was to investigate the effect of microRNA (miRNA) molecules directed against K-ras (miRNA-K-ras) on K-ras expression level and the growth of colorectal carcinoma cell line LoVo in vitro and in vivo. In addition, we evaluated electroporation as a gene delivery method for transfection of LoVo cells and tumors with plasmid DNA encoding miRNA-K-ras (pmiRNA-K-ras). Results of our study indicated that miRNAs targeting K-ras efficiently reduced K-ras expression and cell survival after in vitro electrotransfection of LoVo cells with pmiRNA-K-ras. In vivo, electroporation has proven to be a simple and efficient delivery method for local administration of pmiRNA-K-ras molecules into LoVo tumors. This therapy shows pronounced antitumor effectiveness and has no side effects. The obtained results demonstrate that electrogene therapy with miRNA-K-ras molecules can be potential therapeutic strategy for treatment of colorectal cancers harboring K-ras mutations. © 2010 Nature Publishing Group All rights reserved.

Pharmacist prescribing of venous thromboembolism prophylaxis in a surgical pre-admission clinic

Venous thromboembolism (VTE) is the term used to describe the disease process which presents as either deep vein thrombosis or pulmonary embolism. It is a major cause of death and disability worldwide and places a large financial burden on healthcare systems. Multiple risk factors have been identified for the development of VTE, including hospitalisation for acute medical illness and surgery. Documentation of VTE risk assessment is a critical part of any patient admission, driven by evidence that a risk assessment is a trigger for VTE prophylaxis to be considered. In the United Kingdom, healthcare services have set targets for VTE risk assessment documentation and financial incentives are linked to targets being met...

BIM for sustainable whole-of-life transport infrastructure asset management

The US National Institute of Standards and Technology (NIST) showed that, in 2004, owners and operations managers bore two thirds of the total industry cost burden from inadequate interoperability in construction projects from inception to operation, amounting to USD10.6 billion. Building Information Modelling (BIM) and similar tools were identified by Engineers Australia in 2005 as potential instruments to significantly reduce this sum, which in Australia could amount to total industry-wide cost burden of AUD12 billion. Public sector road authorities in Australia have a key responsibility in driving initiatives to reduce greenhouse gas emissions from the construction and operations of transport infrastructure. However, as previous research has shown the Environmental Impact Assessment process, typically used for project approvals and permitting based on project designs available at the consent stage, lacks Key Performance Indicators (KPIs) that include long-term impact factors and transfer of information throughout the project life cycle. In the building construction industry, BIM is widely used to model sustainability KPIs such as energy consumption, and integrated with facility management systems. This paper proposes that a similar use of BIM in early design phases of transport infrastructure could provide: (i) productivity gains through improved interoperability and documentation; (ii) the opportunity to carry out detailed cost-benefit analyses leading to significant operational cost savings; (iii) coordinated planning of street and highway lighting with other energy and environmental considerations; iv) measurable KPIs that include long-term impact factors which are transferable throughout the project life cycle; and (v) the opportunity for integrating design documentation with sustainability whole-of-life targets.

The 1989 Comprehensive Plan of Action (CPA) and refugee policy in Southeast Asia : twenty years forward what has changed?

In 2012, the only South East Asian countries that have ratified the 1951 Convention relating to the Status of Refugees and the 1967 Protocol Relating to the Status of Refugees (hereafter referred to as the 1951 Convention and 1967 Protocol) is Philippines (signed 1954), Cambodia (signed 1995) and Timor Leste (signed 2001). Countries such as Indonesia, Malaysia and Thailand have annual asylum seeking populations from Myanmar, South Asia and Middle East, that are estimated to be at 15 000-20 000 per country (UNHCR 2012). The lack of a permanent and formal asylum processing process in these countries means that that asylum-seeking populations in the region are reliant on the local offices of the United Nations High Commission for Refugees based in the region to process their claims. These offices rely upon the good will of these governments to have a presence near detection camps and in capital cities to process claims of those who manage to reach the UNHCR representative office. The only burden sharing mechanism within the region primarily exists under the Bali Process on People Smuggling, Trafficking in Persons and Related Transnational Crime (the Bali Process), introduced in 2002. The Bali Process refers to an informal cooperative agreement amongst the states from the Asia-Pacific region, with Australia and Indonesia as the co-chairs, which discusses its namesake: primarily anti-people smuggling activities and migration protocols. There is no provision within this process to discuss the development of national asylum seeking legislation, processes for domestic processing of asylum claims or burden sharing in contrast to other regions such as Africa and South America (i.e. 2009 African Union Convention for the Protection and Assistance of the Internally Displaced, 1969 African Union Convention Governing the Specific Aspects of Refugee Problems in Africa and 1984 Cartagena Declaration on Refugees [Americas]) (PEF 2010: 19).

The validity and reliability of the Parent Fever Management Scale: A study from Palestine

Background Parental fever phobia and overuse of antipyretics to control fever is increasing. Little is known about childhood fever management among Arab parents. No scales to measure parents’ fever management practices in Palestine are available. Aims The aims of this study were to translate and examine the psychometric properties of the Arabic version of the Parent Fever Management Scale (PFMS). Methods A standard “forward–backward” procedure was used to translate PFMS into Arabic language. It was then validated on a convenience sample of 402 parents between July and October 2012. Descriptive statistics were used, and instrument reliability was assessed for internal consistency using Cronbach's alpha coefficient. Validity was confirmed using convergent and known group validation. Results Applying the recommended scoring method, the median (interquartile range) score of the PFMS was 26 (23-30). Acceptable internal consistency was found (Cronbach’s alpha = 0.733) and the test–retest reliability value was 0.92 (P < 0.001). The chi-squared (χ2) test showed a significant relationship between PFMS groups and frequent daily administration of antipyretic groups (χ2 = 52.86; P < 0.001). The PFMS sensitivity and specificity were 77.67% and 57.75%, respectively. The positive and negative predictive values were 67.89% and 32.11%, respectively. Conclusions The findings of this validation study indicate that the Arabic version of the PFMS is a reliable and valid measure which can be used as a useful tool for health professionals to identify parents’ fever management practices and thus provide targeted education to reduce the unnecessary burden of care they place on themselves when concerned for a febrile child.

Slaving and release in co-infection control

Background Animal and human infection with multiple parasite species is the norm rather than the exception, and empirical studies and animal models have provided evidence for a diverse range of interactions among parasites. We demonstrate how an optimal control strategy should be tailored to the pathogen community and tempered by species-level knowledge of drug sensitivity with use of a simple epidemiological model of gastro-intestinal nematodes. Methods We construct a fully mechanistic model of macroparasite co-infection and use it to explore a range of control scenarios involving chemotherapy as well as improvements to sanitation. Results Scenarios are presented whereby control not only releases a more resistant parasite from antagonistic interactions, but risks increasing co-infection rates, exacerbating the burden of disease. In contrast, synergisms between species result in their becoming epidemiologically slaved within hosts, presenting a novel opportunity for controlling drug resistant parasites by targeting co-circulating species. Conclusions Understanding the effects on control of multi-parasite species interactions, and vice versa, is of increasing urgency in the advent of integrated mass intervention programmes.

Demand for refilled reusable products

The conversion of one-way polyethylene terephthalate (PET) bottles into reusable bottles helps reduce environmental burden. Recently, the Ministry of the Environment in Japan began discussing the introduction of reusable bottles. One of the barriers to introducing the new type of bottle is consumer unwillingness to accept refilled reusable bottles. We administered the questionnaires to consumers in a pilot test on reusable PET bottles organized to analyze the demand for these products. To increase the demand for refilled reusable bottles, it is necessary to supply refilled reusable bottles that are acceptable to consumers who are concerned about container flaws and stains.

The technical efficiency of the Japanese banks : non-radial directional performance measurement with undesirable output

The paper analyses technical efficiency of the Japanese banks from 2000 to 2007. The estimation technique is based on the Russell directional distance function that takes into consideration not only desirable outputs but also an undesirable output that is represented by non-performing loans (NPLs). The results indicate that NPLs remain a significant burden as for banks' performance. We show that banks' inputs have to be utilised more efficiently, particularly labour and premises. We also argue that a further restructuring process is needed in the segment of Regional Banks. We conclude that the Japanese banking system is still far away from being fully consolidated and restructured.

Heat-related morbidity in Brisbane, Australia : spatial variation and area-level predictors

Background: Extreme heat is a leading weather-related cause of illness and death in many locations across the globe, including subtropical Australia. The possibility of increasingly frequent and severe heat waves warrants continued efforts to reduce this health burden, which could be accomplished by targeting intervention measures toward the most vulnerable communities. Objectives: We sought to quantify spatial variability in heat-related morbidity in Brisbane, Australia, to highlight regions of the city with the greatest risk. We also aimed to find area-level social and environmental determinants of high risk within Brisbane. Methods: We used a series of hierarchical Bayesian models to examine city-wide and intracity associations between temperature and morbidity using a 2007–2011 time series of geographically referenced hospital admissions data. The models accounted for long-term time trends, seasonality, and day of week and holiday effects. Results: On average, a 10°C increase in daily maximum temperature during the summer was associated with a 7.2% increase in hospital admissions (95% CI: 4.7, 9.8%) on the following day. Positive statistically significant relationships between admissions and temperature were found for 16 of the city’s 158 areas; negative relationships were found for 5 areas. High-risk areas were associated with a lack of high income earners and higher population density. Conclusions: Geographically targeted public health strategies for extreme heat may be effective in Brisbane, because morbidity risk was found to be spatially variable. Emergency responders, health officials, and city planners could focus on short- and long-term intervention measures that reach communities in the city with lower incomes and higher population densities, including reduction of urban heat island effects.

Proteomics in chronic wound research : potentials in healing and health

Chronic wounds, such as venous and diabetic leg ulcers, represent a significant health and financial burden to individuals and healthcare systems. In worst case scenarios this condition may require the amputation of an affected limb, with significant impact on patient quality of life and health. Presently there are no clinical biochemical analyses used in the diagnosis and management of this condition; moreover few biochemical therapies are accessible to patients. This presents a significant challenge in the efficient and efficacious treatment of chronic wounds by medical practitioners. A number of protein-centric investigations have analysed the wound environment and implicated a suite of molecular species predicted to be involved in the initiation or perpetuation of the condition. However, comprehensive proteomic investigation is yet to be engaged in the analysis of chronic wounds for the identification of molecular diagnostic/prognostic markers of healing or therapeutic targets. This review examines clinical chronic wound research and recommends a path towards proteomic investigation for the discovery of medically significant targets. Additionally, the supplementary documents associated with this review provide the first comprehensive summary of protein-centric, small molecule and elemental analyses in clinical chronic wound research.

Intravitreal drug delivery in retinal disease : are we out of our depth?

Introduction With the ever-increasing global burden of retinal disease, there is an urgent need to vastly improve formulation strategies that enhance posterior eye delivery of therapeutics. Despite intravitreal administration having demonstrated notable superiority over other routes in enhancing retinal drug availability, there still exist various significant physical/biochemical barriers preventing optimal drug delivery into the retina. A further complication lies with an inability to reliably translate laboratory-based retinal models into a clinical setting. Several formulation approaches have recently been evaluated to improve intravitreal therapeutic outcomes, and our aim in this review is to highlight strategies that hold the most promise. Areas covered We discuss the complex barriers faced by the intravitreal route and examine how formulation strategies including implants, nanoparticulate carriers, viral vectors and sonotherapy have been utilized to attain both sustained delivery and enhanced penetration through to the retina. We conclude by highlighting the advances and limitations of current in vitro, ex vivo and in vivo retinal models in use by researchers globally. Expert opinion Various nanoparticle compositions have demonstrated the ability to overcome the retinal barriers successfully; however, their utility is limited to the laboratory setting. Optimization of these formulations and the development of more robust experimental retinal models are necessary to translate success in the laboratory into clinically efficacious outcomes.

A FimH inhibitor prevents acute bladder infection and treats chronic cystitis caused by multidrug-resistant uropathogenic Escherichia coli ST131

Background. Escherichia coli O25b:H4-ST131 represents a predominant clone of multidrug-resistant uropathogens currently circulating worldwide in hospitals and the community. Urinary tract infections (UTIs) caused by E. coli ST131 are typically associated with limited treatment options and are often recurrent. Methods. Using established mouse models of acute and chronic UTI, we mapped the pathogenic trajectory of the reference E. coli ST131 UTI isolate, strain EC958. Results. We demonstrated that E. coli EC958 can invade bladder epithelial cells and form intracellular bacterial communities early during acute UTI. Moreover, E. coli EC958 persisted in the bladder and established chronic UTI. Prophylactic antibiotic administration failed to prevent E. coli EC958–mediated UTI. However, 1 oral dose of a small-molecular-weight compound that inhibits FimH, the type 1 fimbriae adhesin, significantly reduced bacterial colonization of the bladder and prevented acute UTI. Treatment of chronically infected mice with the same FimH inhibitor lowered their bladder bacterial burden by >1000-fold. Conclusions. In this study, we provide novel insight into the pathogenic mechanisms used by the globally disseminated E. coli ST131 clone during acute and chronic UTI and establish the potential of FimH inhibitors as an alternative treatment against multidrug-resistant E. coli.

Negotiating futility, managing emotions : nursing the transition to palliative care

Nurses play a pivotal role in caring for patients during the transition from life-prolonging care to palliative care. This is an area of nursing prone to emotional difficulty, interpersonal complexity, and interprofessional conflict. It is situated within complex social dynamics, including those related to establishing and accepting futility and reconciling the desire to maintain hope. Here, drawing on interviews with 20 Australian nurses, we unpack their accounts of nursing the transition to palliative care, focusing on the purpose of nursing at the point of transition; accounts of communication and strategies for representing palliative care; emotional engagement and burden; and key interprofessional challenges. We argue that in caring for patients approaching the end of life, nurses occupy precarious interpersonal and interprofessional spaces that involve a negotiated order around sentimental work, providing them with both capital (privileged access) and burden (emotional suffering) within their day-to-day work.

Human amnion epithelial cell transplantation abrogates lung fibrosis and augments repair

Rationale: Chronic lung disease characterized by loss of lung tissue,inflammation, and fibrosis represents a major global health burden. Cellular therapies that could restore pneumocytes and reduce inflammation and fibrosis would be a major advance in management. Objectives: To determine whether human amnion epithelial cells (hAECs), isolated from term placenta and having stem cell–like and antiinflammatory properties, could adopt an alveolar epithelial phenotype and repair a murine model of bleomycin-induced lung injury. Methods: Primary hAECs were cultured in small airway growth medium to determine whether the cells could adopt an alveolar epithelial phenotype. Undifferentiated primary hAECs were also injected parenterally into SCID mice after bleomycin-induced lung injury and analyzed for production of surfactant protein (SP)-A, SP-B, SP-C, and SP-D. Mouse lungs were also analyzed for inflammation and collagen deposition. Measurements and Main Results: hAECs grown in small airway growth medium developed an alveolar epithelial phenotype with lamellar body formation, production of SPs A–D, and SP-D secretion. Although hAECs injected into mice lacked SPs, hAECs recovered from mouse lungs 2 weeks posttransplantation produced SPs. hAECs remained engrafted over the 4-week test period. hAEC administration reduced inflammation in association with decreased monocyte chemoattractant protein-1, tumor necrosis factor-a, IL-1 and -6, and profibrotic transforming growth factor-b in mouse lungs. In addition,lung collagen content was significantly reduced by hAEC treatment as a possible consequence of increased degradation by matrix metalloproteinase-2 and down-regulation of the tissue inhibitors f matrix metalloproteinase-1 and 2. Conclusions: hAECs offer promise as a cellular therapy for alveolar restitution and to reduce lung inflammation and fibrosis.

The ADAMTS1 protease gene is required for mammary tumor growth and metastasis

A disintegrin and metalloprotease with thrombospondin motifs protein 1 (ADAMTS1) is a protease commonly up-regulated in metastatic carcinoma. Its overexpression in cancer cells promotes experimental metastasis, but whether ADAMTS1 is essential for metastatic progression is unknown. To address this question, we investigated mammary cancer progression and spontaneous metastasis in the MMTV-PyMT mouse mammary tumor model in Adamts1 knockout mice. Adamts1−/−/PyMT mice displayed significantly reduced mammary tumor and lung metastatic tumor burden and increased survival, compared with their wild-type and heterozygous littermates. Histological examination revealed an increased proportion of tumors with ductal carcinoma in situ and a lower proportion of high-grade invasive tumors in Adamts1−/−/PyMT mice, compared with Adamts1+/+/PyMT mice. Increased apoptosis with unaltered proliferation and vascular density in the Adamts1−/−/PyMT tumors suggested that reduced cell survival accounts for the lower tumor burden in ADAMTS1-deficient mice. Furthermore, Adamts1−/− tumor stroma had significantly lesser amounts of proteolytically cleaved versican and increased numbers of CD45+ leukocytes. Characterization of immune cell gene expression indicated that cytotoxic cell activation was increased in Adamts1−/− tumors, compared with Adamts1+/+ tumors. This finding is supported by significantly elevated IL-12+ cell numbers in Adamts1−/− tumors. Thus, in vivo ADAMTS1 may promote mammary tumor growth and progression to metastasis in the PyMT model and is a potential therapeutic target to prevent metastatic breast cancer.