Ligand dissociation from estrogen receptor is mediated by receptor dimerization: Evidence from molecular dynamics simulations

Estrogen Receptor (ER) is an important target for pharmaceutical design. Like other ligand-dependent transcription factors, hormone binding regulates ER transcriptional activity. Nevertheless, the mechanisms by which ligands enter and leave ERs and other nuclear receptors remain poorly understood. Here, we report results of locally enhanced sampling molecular dynamics simulations to identify dissociation pathways of two ER ligands [the natural hormone 17 beta-estradiol (E-2) and the selective ER modulator raloxifene (RAL)] from the human ER alpha ligand-binding domain in monomeric and dimeric forms. E-2 dissociation occurs via three different pathways in ER monomers. One resembles the mousetrap mechanism (Path I), involving repositioning of helix 12 (H12), others involve the separation of H8 and H11 (Path II), and a variant of this pathway at the bottom of the ligand-binding domain (Path II`). RAL leaves the receptor through Path I and a Path I variant in which the ligand leaves the receptor through the loop region between H11 and H12 (Path I`). Remarkably, ER dimerization strongly suppresses Paths II and II` for E-2 dissociation and modifies RAL escape routes. We propose that differences in ligand release pathways detected in the simulations for ER monomers and dimers provide an explanation for previously observed effects of ER quaternary state on ligand dissociation rates and suggest that dimerization may play an important, and hitherto unexpected, role in regulation of ligand dissociation rates throughout the nuclear receptor family.

Intentions and willingness to use complementary and alternative medicines : what potential patients believe about CAMs

This paper explores the intentions and willingness of a sample of Australian consumers (N = 356) to use Complementary and Alternative Medicine (CAM). Participants considered using CAMs at least once in the next two months and rated the likelihood of certain consequences of CAM use, whether important others would approve, and if barriers would prevent them from using CAMs. People intending to use CAMs (high intenders) were more likely than those low on intention (low intenders) to endorse positive outcomes of CAM use and believe that important others would support their CAM use. High intenders were less likely than low intenders to believe that barriers would prevent use. Low intenders (n = 200) were also asked to consider their response to a free CAM trial. Those willing to accept a trial were more likely than those unwilling to believe that CAMs could improve health and less likely to believe that laziness would prevent use. These results identify important beliefs which may influence people’s decisions to use CAMs.

Ghrelin gene-related peptides : multifunctional endocrine/autocrine modulators in health and disease

Ghrelin is a multi-functional peptide hormone which affects various processes including growth hormone and insulin release, appetite regulation, gut motility, metabolism and cancer cell proliferation. Ghrelin is produced in the stomach and in other normal and pathological cell types. It may act as an endocrine or autocrine/paracrine factor. The ghrelin gene encodes a precursor protein, preproghrelin, from which ghrelin and other potentially active peptides are derived by alternative mRNA splicing and/or proteolytic processing. The metabolic role of the peptide obestatin, derived from the preproghrelin C-terminal region, is controversial. However, it has direct effects on cancer cell proliferation. The regulation of ghrelin expression and the mechanisms through which the peptide products arise are unclear. We have recently re-examined the organisation of the ghrelin gene and identified several novel exons and transcripts. One transcript, which lacks the ghrelin-coding region of preproghrelin, contains the coding sequence of obestatin. Furthermore, we have identified an overlapping gene on the antisense strand of ghrelin, GHRLOS, which generates transcripts that may function as non-coding regulatory RNAs or code for novel, short bioactive peptides. The identification of these novel ghrelin-gene related transcripts and peptides raises critical questions regarding their physiological function and their role in obesity, diabetes and cancer.

Adjuvant use of nutritional and herbal medicines with antidepressants, mood stabilizers and benzodiazepines

Adjuvant use of nutritional and herbal medicines has potential to increase the efficacy of synthetic pharmaceuticals, and perhaps also decrease their side-effects by allowing lower doses to be prescribed. We evaluated current evidence for adjuvant use of nutritional and herbal medicines with antidepressants, mood stabilizers and benzodiazepines; and explored novel future areas of research. The paper also critiques current evidence for co-administration of St. John’s wort with synthetic antidepressants. We performed a systematic search of MEDLINE, CINAHL, PsycINFO, The Cochrane database, China National Knowledge Infrastructure and the Chinese Science Citation Database. Search results were supplemented by a review of reference lists and a forward search using the Web of Science. Where possible we calculated effect sizes. Encouraging evidence exists for the use of omega-3 fatty acids, SAMe, folic acid and l-tryptophan adjuvantly with antidepressants to enhance response and improve efficacy. Various nutrients also have emerging evidence as effective adjuncts with antipsychotics and mood stabilizers. While some evidence supports nutritional adjuvancy with various psychopharmacotherapies, adjuvant use of herbal therapies has not been sufficiently studied to warrant standard clinical application. This remains a promising area of research via robust, safety-conscious studies.

Adherence to medicines in the older-aged with chronic conditions : does an intervention concerning adherence by an allied health professional help?

Adherence to medicines is a major determinant of the effectiveness of medicines. However, estimates of non-adherence in the older-aged with chronic conditions vary from 40 to 75%. The problems caused by non-adherence in the older-aged include residential care and hospital admissions, progression of the disease, and increased costs to society. The reasons for non-adherence in the older-aged include items related to the medicine (e.g. cost, number of medicines, adverse effects) and those related to person (e.g. cognition, vision, depression). It is also known that there are many ways adherence can be increased (e.g. use of blister packs, cues). It is assumed that interventions by allied health professions, including a discussion of adherence, will improve adherence to medicines in the older aged but the evidence for this has not been reviewed. There is some evidence that telephone counselling about adherence by a nurse or pharmacist does improve adherence, short- and long-term. However, face-to-face intervention counselling at the pharmacy, or during a home visit by a pharmacist, has shown variable results with some studies showing improved adherence and some not. Education programs during hospital stays have not been shown to improve adherence on discharge, but education programs for subjects with hypertension have been shown to improve adherence. In combination with an education program, both counselling and a medicine review program have been shown to improve adherence short-term in the older-aged. Thus, there are many unanswered questions about the most effective interventions to promote adherence. More studies are needed to determine the most appropriate interventions by allied health professions, and these need to consider the disease state, demographics, and socio-economic status of the older-aged subject, and the intensity and duration of intervention needed.

Multifunctional magnetic mesoporous bioactive glass scaffolds with a hierarchical pore structure

Hyperthermia and local drug delivery have been proposed the potential therapeutic approaches for bone defects resulting from malignant bone tumors. Development of bioactive materials with magnetic and drug-delivery properties may potentially meet this target. The aim of this study is to develop a multifunctional mesoporous bioactive glass (MBG) scaffold system for both hyperthermia and local-drug delivery application potentially. For this aim, Iron (Fe) containing MBG (Fe-MBG) scaffolds with hierarchically large pores (300-500 µm) and fingerprint-like mesopores (4.5 nm) have been successfully prepared. The effect of Fe on the mesopore structure, physiochemical, magnetism, drug delivery and biological properties of MBG scaffolds has been systematically investigated. The results showed that the morphology of the mesopore varied from straight channels to curved fingerprint-like channels after incorporated parts of Fe into MBG scaffolds. The magnetism magnitude of MBG scaffolds can be tailored by controlling Fe contents. Furthermore, the incorporating of Fe into mesoporous MBG glass scaffolds enhanced the mitochondrial activity and bone-relative gene (ALP and OCN) expression of human bone marrow mesenchymal stem cells (BMSCs) on the scaffolds. The obtained Fe-MBG scaffolds also possessed high specific surface areas and sustained drug delivery. Therefore, Fe-MBG scaffolds are magnetic, degradable and bioactive. The multifunction of Fe-MBG scaffolds indicates that there is a great potential for Fe-MBG scaffolds to be used for the therapy and regeneration of large-bone defects caused by malignant bone tumors through the combination of hyperthermia, local drug delivery and their osteoconductivity.

Copper-containing mesoporous bioactive glass scaffolds with multifunctional properties of angiogenesis capacity, osteostimulation and antibacterial activity

It is of great importance to develop multifunctional bioactive scaffolds, which combine angiogenesis capacity, osteostimulation, and antibacterial properties for regenerating lost bone tissues. In order to achieve this aim, we prepared copper (Cu)-containing mesoporous bioactive glass (Cu-MBG) scaffolds with interconnective large pores (several hundred micrometer) and well-ordered mesopore channels (around 5 nm). Both Cu-MBG scaffolds and their ionic extracts could stimulate hypoxia-inducible factor (HIF)-1a and vascular endothelial growth factor(VEGF) expression in human bone marrow stromal cells(hBMSCs). In addition, both Cu-MBG scaffolds and their ionic extracts significantly promoted the osteogenic differentiation of hBMSCs by improving their bone-related gene expression (alkaline phosphatase (ALP), osteopontin(OPN) and osteocalcin (OCN)). Furthermore, Cu-MBG scaffolds could maintain a sustained release of ibuprofen and significantly inhibited the viability of bacteria. This study indicates that the incorporation of Cu2þ ions into MBG scaffolds significantly enhances hypoxia-like tissue reaction leading to the coupling of angiogenesis and osteogenesis. Cu2þ ions play an important role to offer the multifunctional properties of MBG scaffold system. This study has demonstrated that it is possible to develop multifunctional scaffolds by combining enhanced angiogenesis potential, osteostimulation, and antibacterial properties for the treatment of large bone defects.

Multifunctional porous graphene for nanoelectronics and hydrogen storage : new properties revealed by first principle calculations

The lack of an obvious “band gap” is a formidable hurdle for making a nanotransistor from graphene. Here, we use density functional calculations to demonstrate for the first time that porosity such as evidenced in recently synthesized porous graphene (http://www.sciencedaily.com/releases/2009/11/091120084337.htm) opens a band gap. The size of the band gap (3.2 eV) is comparable to most popular photocatalytic titania and graphitic C3N4 materials. In addition, the adsorption of hydrogen on Li-decorated porous graphene is much stronger than that in regular Li-doped graphene due to the natural separation of Li cations, leading to a potential hydrogen storage gravimetric capacity of 12 wt %. In light of the most recent experimental progress on controlled synthesis, these results uncover new potential for the practical application of porous graphene in nanoelectronics and clean energy.

Inadequate management of medicines by the older-aged living in a retirement village

BACKGROUND: A comparison of the management of medicines by the older-aged living in freehold (fully owned) and rental homes in retirement villages has suggested that the older-aged living in rental, but not freehold, retirement villages may require help to manage their medicines. OBJECTIVE: The objective of this study was to investigate the management of medicines by the older-aged living independently in a leasehold (partly owned) home in retirement village to determine whether they also need help in managing their medicines. METHOD: Semi-structured interviews were conducted with 22 older-aged residents living in a leasehold retirement village. MAIN OUTCOME MEASURE: The main outcome measure was the perception of present and ongoing adherence. RESULTS: Amongst participants in the leasehold retirement village, with an average age of 82.9 years, the perceptions of present and ongoing adherence indicated that only 55 % of older-aged participants were adherent at the time of the study, and not likely to have problems with adherence within the next 6-12 months. Participants from the leasehold retirement village had a good understanding of 58 % of their illnesses. A mean of 9.8 medicines per person were prescribed. Cardiovascular medicines were the most commonly prescribed at 86 %. CONCLUSION: The older-aged living in leasehold retirement villages may require extra assistance/resources to manage their medicines.

Multifunctional agriculture in policy and practice? A comparative analysis of Norway and Australia

Ideals of productivist agriculture in the Western world have faded as the unintended consequences of intensive agriculture and pastoralism have contributed to rural decline and environmental problems. In Norway and Australia, there has been an increasing acceptance of the equal importance of social and environmental sustainability as well as economic sustainability. Alongside this shift is a belief that primary production needs to move away from an intensive, productivist-based agriculture to one that may be defined as post-productivist. In this paper, we argue that the dualism of productivism and post-productivism as concepts on agricultural policy regimes are too simplistic and discuss whether multifunctional agriculture is a better concept for a comparison of rural primary production at two extreme points of the scale, the market-oriented, liberalistic Australian agriculture and the market-protected small-scale Norwegian agriculture. We argue that multifunctionality in Australia rates relatively weakly as an ideology or policy and even less as a discourse or practice and hence is situated toward a ‘weak’ end of a continuum of a level of multifunctional agriculture. In Norwegian agriculture, multifunctional agriculture has thrived within a protectionist setting with the support of the public, the state and agricultural actors. In this sense it is very clearly a policy, practice and discourse that aims to preserve and conserve rural spaces, the cultural landscape, the farming way of life and food safety. Norway is as such situated toward a ‘strong’ end of a continuum of a level of multifunctional agriculture.

The importance of agency in facilitating the transition to a multifunctional countryside

We appreciate Holmes' body of work relating to transitions within the Australian landscape, and welcome the opportunity to engage in a discussion on this topic. The paper to which Holmes refers (Bjørkhaug and Richards, 2008) examined the application of agricultural (rather than landscape) multifunctionality in both Norway and Australia. Of specific focus was how non-tradeable concerns, such as environmental sustainability, faired under these divergent systems. We argued that Norway's multifunctionality was strong, due to it being embraced at both the policy and actor level, whereas Australia's could be described as weak. This ‘weak multifunctionality’ that we observed in Australia was due to an emerging bi-lateral (state and federal) policy framework that advocated the importance of environmental values which was rarely embraced by landholders who found themselves trapped on the ‘agricultural treadmill’. The nature of the treadmill is that alternative forms of land use are unthinkable when on-farm investments have been made that support the status quo – to get bigger and/or more efficient. For many of the Australian landholders interviewed in relation to this study, efficiency in production was at odds with the values necessary to effect a transition toward multifunctionality. For instance, graziers in Central Queensland were unconvinced of the value of conserving native flora and fauna when economic viability can be better assured through clear felling native forests to increase the productive capacity of the land.

Teaching and assessment of prescribing medicines : a multidisciplinary review

Background Prescribing is a complex task, requiring specific knowledge and skills, and the execution of effective, context-specific clinical reasoning. Prescribing errors can result in significant morbidity and mortality. For all professions with prescribing rights, a clear need exists to ensure students graduate with a well-defined set of prescribing skills, which will contribute to competent prescribing.

Burden of non-communicable diseases (NCDs) in Nepal and the availability and affordability of NCD medicines

Background: Traditionally communicable diseases were the main causes of burden in developing countries like Nepal. In recent years non-communicable diseases (NCDs), mainly cardiovascular diseases (CVDs), cancer, chronic respiratory diseases and diabetes mellitus, impose a larger disease burden compared to communicable diseases. Most elements of health and medicine policies in Nepal are still focused on communicable diseases. There is limited evidence about NCDs and NCD medicines in Nepal. Aim: To explore the gap between the burden of NCDs and the availability and affordability of NCD medicines in Nepal. Methods: Biomedical databases like Medline, Scopus, Web of Science and other online sources (including Global Burden of Diseases data) were searched for data on the burden of NCDs in term of Disability Adjusted Life Years (DALYs). The Essential Medicines List (EML) of Nepal was compared with World Health Organisation (EML) for inclusion of NCD medicines. Results: In Nepal, NCDs caused nearly 45% of the total 10.5 million DALYs in 2010. CVDs (15.2%), were the leading cause of NCDs burden followed by chronic respiratory diseases (14.7%), cancer (7.3%) and diabetes mellitus (3.2%). One hospital based national survey found that 37% of hospitalised patients had NCDs. Among them, 38% had heart disease followed by COPD (33%) , and diabetes (10%). Most (23 out of 28) non-cancer NCD medicines recommended in WHO-EML were present in Nepal's EML, theoretically indicating good availability. However, it is difficult to say whether they are accessible and affordable due to the lack of adequate data on access and pricing. Conclusion: This study gives some insight into the burden of NCDs. Although NCD medicines are available in Nepal, further research is required to determine whether they are accessible and affordable to the general population.