Blocking the maturation of OncomiRNAs using pri-miRNA-17∼92 aptamer in retinoblastoma

The miR-17∼92. or oncomiR-1, cluster encodes oncogenic microRNAs (miRNAs), and it also promotes retinoblastoma (RB) tumor formation. Antagomir and miRNA mimics based approaches are widely tried against oncogenic and tumor suppressive miRNAs. Other methods for targeting cancer related miRNAs are still under development. In the current study, we focused on the pri-miRNA-17∼92 aptamer (pri-apt), which can potentially replace the mix of five antagomirs by one aptamer that function to abrogate the maturation of miR-17, miR-18a, and miR-19b (P<0.05) for targeting RB. We used RB cell lines WERI-Rb1 and Y79 as an in vitro model. Cellular changes upon transfecting the pri-apt led to S-phase arrest in WERI-Rb1 cells and onset of apoptosis in both Y79 and WERI-Rb1 cell lines. There was increased cytotoxicity as measured by lactate dehydrogenase activity in pri-apt treated Y79 cells (P<0.05), and significant inhibition of cell proliferation was observed in both of the cell lines. Thus we showed the antiproliferative property of pri-apt in RB cell lines, which can be readily modified by developing appropriate vectors for the delivery of the aptamer specifically to cancer cells.

Nurse-led titration of angiotensin converting enzyme inhibitors, beta-adrenergic blocking agents, and angiotensin receptor blockers for people with heart failure with reduced ejection fraction

BACKGROUND: Heart failure is associated with high mortality and hospital readmissions. Beta-adrenergic blocking agents, angiotensin converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) can improve survival and reduce hospital readmissions and are recommended as first-line therapy in the treatment of heart failure. Evidence has also shown that there is a dose-dependent relationship of these medications with patient outcomes. Despite this evidence, primary care physicians are reluctant to up-titrate these medications. New strategies aimed at facilitating this up-titration are warranted. Nurse-led titration (NLT) is one such strategy. OBJECTIVES: To assess the effects of NLT of beta-adrenergic blocking agents, ACEIs, and ARBs in patients with heart failure with reduced ejection fraction (HFrEF) in terms of safety and patient outcomes. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials in the Cochrane Library (CENTRAL Issue 11 of 12, 19/12/2014), MEDLINE OVID (1946 to November week 3 2014), and EMBASE Classic and EMBASE OVID (1947 to 2014 week 50). We also searched reference lists of relevant primary studies, systematic reviews, clinical trial registries, and unpublished theses sources. We used no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing NLT of beta-adrenergic blocking agents, ACEIs, and/or ARBs comparing the optimisation of these medications by a nurse to optimisation by another health professional in patients with HFrEF. DATA COLLECTION AND ANALYSIS: Two review authors (AD & JC) independently assessed studies for eligibility and risk of bias. We contacted primary authors if we required additional information. We examined quality of evidence using the GRADE rating tool for RCTs. We analysed extracted data by risk ratio (RR) with 95% confidence interval (CI) for dichotomous data to measure effect sizes of intervention group compared with usual-care group. Meta-analyses used the fixed-effect Mantel-Haenszel method. We assessed heterogeneity between studies by Chi(2) and I(2). MAIN RESULTS: We included seven studies (1684 participants) in the review. One study enrolled participants from a residential care facility, and the other six studies from primary care and outpatient clinics. All-cause hospital admission data was available in four studies (556 participants). Participants in the NLT group experienced a lower rate of all-cause hospital admissions (RR 0.80, 95% CI 0.72 to 0.88, high-quality evidence) and fewer hospital admissions related to heart failure (RR 0.51, 95% CI 0.36 to 0.72, moderate-quality evidence) compared to the usual-care group. Six studies (902 participants) examined all-cause mortality. All-cause mortality was also lower in the NLT group (RR 0.66, 95% CI 0.48 to 0.92, moderate-quality evidence) compared to usual care. Approximately 27 deaths could be avoided for every 1000 people receiving NLT of beta-adrenergic blocking agents, ACEIs, and ARBs. Only three studies (370 participants) reported outcomes on all-cause and heart failure-related event-free survival. Participants in the NLT group were more likely to remain event free compared to participants in the usual-care group (RR 0.60, 95% CI 0.46 to 0.77, moderate-quality evidence). Five studies (966 participants) reported on the number of participants reaching target dose of beta-adrenergic blocking agents. This was also higher in the NLT group compared to usual care (RR 1.99, 95% CI 1.61 to 2.47, low-quality evidence). However, there was a substantial degree of heterogeneity in this pooled analysis. We rated the risk of bias in these studies as high mainly due to a lack of clarity regarding incomplete outcome data, lack of reporting on adverse events associated with the intervention, and the inability to blind participants and personnel. Participants in the NLT group reached maximal dose of beta-adrenergic blocking agents in half the time compared with participants in usual care. Two studies reported on adverse events; one of these studies stated there were no adverse events, and the other study found one adverse event but did not specify the type or severity of the adverse event. AUTHORS' CONCLUSIONS: Participants in the NLT group experienced fewer hospital admissions for any cause and an increase in survival and number of participants reaching target dose within a shorter time period. However, the quality of evidence regarding the proportion of participants reaching target dose was low and should be interpreted with caution. We found high-quality evidence supporting NLT as one strategy that may improve the optimisation of beta-adrenergic blocking agents resulting in a reduction in hospital admissions. Despite evidence of a dose-dependent relationship of beta-adrenergic blocking agents, ACEIs, and ARBs with improving outcomes in patients with HFrEF, the translation of this evidence into clinical practice is poor. NLT is one strategy that facilitates the implementation of this evidence into practice.

Blocking HIV-1 transmission in the female reproductive tract: from microbicide development to exploring local antiviral responses

The majority of new HIV-1 infections are transmitted sexually by penetrating the mucosal barrier to infect target cells. The development of microbicides to restrain heterosexual HIV-1 transmission in the past two decades has proven to be a challenging endeavor. Therefore, better understanding of the tissue environment in the female reproductive tract may assist in the development of the next generation of microbicides to prevent HIV-1 transmission. In this review, we highlight the important factors involved in the heterosexual transmission of HIV-1, provide an update on microbicides' clinical trials, and discuss how different delivery platforms and local immunity may empower the development of next generation of microbicide to block HIV-1 transmission in the female reproductive tract.

National and international disability rights legislation: a qualitative account of its enactment in Australia

In this paper, a detailed analysis based on the lived experiences of the study participants and the researcher (each with vision impairment) in education, post school and in the pursuit for employment is developed. The policy discourses of disability legislation - both at national and international levels - are explored with particular reference to their enactment in Australia. The analysis focuses on the collective indifference to detached others, which is evident in the linguistic construction of people with disabilities in the United Nations [(2006). Convention of the Rights of Persons with Disabilities. New York: United Nations] and the Australian Standards for Education 2005 [Australian Department of Education, Science and Training. 2006. Disability Standards for Education 2005 Plus Guidance Notes. Accessed March 12, 2012. http://nla.gov.au/nla.arc-7692.]. Together, these elements reflect the neoliberal principles that cast a shadow over the discourses of the disability policies.

Australian security of payment legislation: impact of inconsistent case law

In Australia, a supreme court has a supervisory role over the statutory adjudication process that has been established within the security of payment legislation. In this role, the courts have quashed many adjudication determinations on the grounds of jurisdictional error in recent years. This is a problem as the courts’ involvement in statutory adjudication is contrary to the object of the legislation. When reviewing adjudication determinations, the courts have adopted different approaches with respect to determining the role of adjudicators and the essential jurisdictional facts that must exist in order for an adjudicator to have jurisdiction to hear a referred disputed matter. This diversification of judicial interpretation with respect to jurisdictional error is confusing, not only to construction professionals, but also to many lawyers. Via a desktop study– where the evidence is mainly garnered from case law, governmental reports and commentaries – this paper reviews the legal complexities involved in diagnosing jurisdictional errors. In doing so, the paper aims to answer the question as to why the adjudication process has become bogged down in the quagmire of judicial review. The paper concludes that the evolving inconsistency of case law in relation to statutory adjudication is a crucial factor contributing to the erosion of the object of the security of payment legislation in Australia. Moving forward, the paper argues that establishing a legislative review mechanism of jurisdictional challenges may be sufficient to address this problem.

Using steric bulk for selective recognition; blocking the binding site to differentiate guests

Selectivity is demonstrated in a supramolecular host:guest system using a receptor with a non-linear binding site. For the "open" receptor 1 strong binding for both flexible and rigid guests was observed. Receptor 2, with a "blocked" binding site, also bound flexible guests effectively but its affinity for rigid guests was 50 fold lower.

The state of legislation and policy protecting Australia's mangrove and salt marsh and their ecosystem services

Saline coastal wetlands, such as mangrove and coastal salt marsh, provide many ecosystem services. In Australia, large areas have been lost since European colonization, particularly as a result of drainage, infilling and flood-mitigation works, often starting in the mid-19th century and aimed primarily towards converting land to agricultural, urban or industrial uses. These threats remain ongoing, and will be exacerbated by rapid population growth and climate change in the 21st century. Establishing the effect of wetland loss on the delivery of ecosystem services is confounded by the absence of a nationally consistent approach to mapping wetlands and defining the boundaries of different types of coastal wetland. In addition, climate change and its projected effect on mangrove and salt marsh distribution and ecosystem services is poorly, if at all, acknowledged in existing legislation and policy. Intensifying climate change means that there is little time to be complacent; indeed, there is an urgent need for proper valuation of ecosystem services and explicit recognition of ecosystem services within policy and legislation. Seven actions are identified that could improve protection of coastal wetlands and the ecosystem services they provide, including benchmarking and improving coastal wetland extent and health, reducing complexity and inconsistency in governance arrangements, and facilitating wetland adaptation and ecosystem service delivery using a range of relevant mechanisms. Actions that build upon the momentum to mitigate climate change by sequestering carbon – ‘blue carbon’ – could achieve multiple desirable objectives, including climate-change mitigation and adaptation, floodplain rehabilitation and habitat protection.

Mental health legislation (civil) in Australia and China: a comparative study

This comparative review of statutory provisions of Australian and Chinese law focuses on accessibility of mental health care, diagnosis, admission and treatment orders for involuntary patients in civil cases as well as discharge procedures. The introduction contextualises the object of the comparative study, including key rights and principles that are used as the basis for analysis. Such factors as different political and legal systems, history, culture, and infrastructure resources of China and Australia form the background for the legal examination. Not surprisingly, these five factors, rather than statutory texts per se, are found to be the most important drivers of each country’s approach to the law of mental health. Two cases, XX v WW [2014] VSC 564 in Australia and Xu Lixin v Xu Canxing, Qingchun Psychiatric Rehabilitation Hospital of Shanghai [2015], known as the Right to Liberty Case, in China illustrate practical differences in legal approach to involuntary treatment. The comparative analysis concludes by identifying the most problematic aspects of the legislation in each country.