Ovarian suppression in a marsupial following single treatment with a gonadotrophin-releasing hormone agonist in microspheres.

The effect of treatment with Lucrin Depot (1 month), a microsphere gonadotrophin-releasing hormone agonist preparation, was investigated in the fat-tailed dunnart (Sminthopsis crassicaudata) as a potential strategy to synchronise cycling. The status of the ovaries (ovarian size, number and size of Graafian follicles and corpora lutea) and reproductive tract (weight, vascularity and muscularity) in twelve untreated females were assessed to establish the activity parameters for randomly selected cycling animals. Thirty-six females were treated with 1mgkg-1 (n=12), 10mgkg-1 (n=12) or 20mgkg-1 (n=12) Lucrin Depot. At 4, 6 and 8 weeks the reproductive tracts were assessed using the criteria developed in the untreated females. All of the females treated with 10mgkg-1 showed suppression at 4 weeks and 25% showed return of reproductive activity at 8 weeks. A dose of 1mgkg-1 did not appear to suppress reproductive activity and 20mgkg-1 gave equivocal results, with evidence of both suppression and activity. The results indicate that Lucrin Depot appears to be a promising agent to regulate and potentially synchronise breeding activity in the fat-tailed dunnart.

PerCEN trial participant perspectives on the implementation and outcomes of person-centered dementia care and environments.

BACKGROUND: Well-being and various forms of agitation in people with dementia can be improved in a person-centered long-term care setting. Data obtained during the Person-Centered Dementia Care and Environment (PerCEN) randomized controlled trial shed light on the factors that influenced the adoption and outcomes of person-centered interventions in long-term care from the perspective of study participants. METHODS: Data were obtained from PerCEN participants: individual semi-structured interviews with care managers (29), nurses and care staff (70); telephone surveys with family members (73); staff reports of care approaches; and 131 field note entries recorded by the person-centered care and environment facilitators. Data were interpreted inductively using content analysis, code building, theme development, and synthesis of findings. RESULTS: All data sources confirmed that, when adopted, the person-centered model increased the number and variety of opportunities for resident interaction, improved flexibility in care regimens, enhanced staff's attention to resident needs, reduced resident agitation, and improved their well-being. Barriers and enablers for the person-centered model related to leadership, manager, staff and family appreciation of the model, staff's capacity, effective communication and team work among direct care staff, care service flexibility, and staff education on how to focus care on the person's well-being. CONCLUSIONS: Successful knowledge translation of the person-centered model starts with managerial leadership and support; it is sustained when staff are educated and assisted to apply the model, and, along with families, come to appreciate the benefits of flexible care services and teamwork in achieving resident well-being. The Australian New Zealand Clinical Trials Registry number is ACTRN 12608000095369.

PerCEN: a cluster randomized controlled trial of person-centered residential care and environment for people with dementia.

BACKGROUND: There is good evidence of the positive effects of person-centered care (PCC) on agitation in dementia. We hypothesized that a person-centered environment (PCE) would achieve similar outcomes by focusing on positive environmental stimuli, and that there would be enhanced outcomes by combining PCC and PCE. METHODS: 38 Australian residential aged care homes with scope for improvement in both PCC and PCE were stratified, then randomized to one of four intervention groups: (1) PCC; (2) PCE; (3) PCC +PCE; (4) no intervention. People with dementia, over 60 years of age and consented were eligible. Co-outcomes assessed pre and four months post-intervention and at 8 months follow-up were resident agitation, emotional responses in care, quality of life and depression, and care interaction quality. RESULTS: From 38 homes randomized, 601 people with dementia were recruited. At follow-up the mean change for quality of life and agitation was significantly different for PCE (p = 0.02, p = 0.05, respectively) and PCC (p = 0.0003, p = 0.002 respectively), compared with the non-intervention group (p = 0.48, p = 0.93 respectively). Quality of life improved non-significantly for PCC+PCE (p = 0.08), but not for agitation (p = 0.37). Improvements in care interaction quality (p = 0.006) and in emotional responses to care (p = 0.01) in PCC+PCE were not observed in the other groups. Depression scores did not change in any of the groups. Intervention compliance for PCC was 59%, for PCE 54% and for PCC+PCE 66%. CONCLUSION: The hypothesis that PCC+PCE would improve quality of life and agitation even further was not supported, even though there were improvements in the quality of care interactions and resident emotional responses to care for some of this group. The Australian New Zealand Clinical Trials Registry Number is ACTRN 12608000095369.

Reverse cope elimination of hydroxylamines and alkenes or alkynes: theoretical investigation of tether length and substituent effects.

Quantum mechanical calculations have been used to study the intramolecular additions of hydroxylamines to alkenes and alkynes ("reverse Cope eliminations"). In intermolecular reverse Cope eliminations, alkynes are more reactive than alkenes. However, competition experiments have shown that tethering the hydroxylamine to the alkene or alkyne can reverse the reactivity order from that normally observed. The exact outcome depends on the length of the tether. In agreement with experiment, a range of density functional theory methods and CBS-QB3 calculations predict that the activation energies for intramolecular reverse Cope eliminations follow the order 6-exo-dig < 5-exo-trig < 5-exo-dig ≈ 7-exo-dig. The order of the barriers for the 5-, 6-, and 7-exo-dig reactions of alkynes arises mainly from differences in tether strain in the transition states (TSs), but is also influenced by the TS interaction between the hydroxylamine and alkyne. Cyclization onto an alkene in the 5-exo-trig fashion incurs slightly less tether strain than a 6-exo-dig alkyne cyclization, but its activation energy is higher because the hydroxylamine fragment must distort more before the TS is reached. If the alkene terminus is substituted with two methyl groups, the barrier becomes so much higher that it is also disfavored compared to the 5- and 7-exo-dig cyclizations.

Study protocol of a randomised controlled group trial of client and care outcomes in the residential dementia care setting.

PURPOSE: Literature suggests that quality of life (QOL), quality of care (QOC) and Behavioural and Psychological Symptoms of Dementia (BPSD) can be improved by relatively simple and inexpensive person-centred approaches to nursing care practices (PCC) and modifications to physical environment (PCE). Most research on this topic is observational and few randomised controlled trials have included an economic evaluation of PCC and PCE together. The PerCEN study aims to confirm the value of evidence-based nursing by evaluating the efficacy and cost effectiveness of implementing PCC and PCE in residential dementia care services. This article describes the PerCEN study protocol (ANZCTR 12608000095369). DESIGN/METHODS: The 3-year study commenced in 2009 in 38 eligible government-accredited residential dementia care homes in New South Wales, Australia. Study participants include 605 consented residents over 60 years of age with dementia and 380 consenting permanent direct-care staff. The study employs a factorial, group-randomised, cohort design with stratification to evaluate the main effects of PCC and PCE and their joint effects (PCC + PCE), compared with Usual Care (UC) and Usual Environment (UE) on QOL, QOC and BPSD in dementia. RESULTS: The primary outcomes analysis will use a mixed-model analysis of covariance to determine the effects of PCC and PCE on resident QOL and BPSD, and QOC, adjusting for stratification and other potential confounders. The incremental cost of providing PCE and PCC over UC and UE will be calculated; costs and outcomes will be presented as a cost-consequence analysis and cost-effectiveness ratios will be estimated as a cost per unit change in resident QOL and BPSD. IMPLICATIONS: This cluster-randomised trial will rigorously test Kitwood's Social-Psychological Theory of Personhood in Dementia (Kitwood & Bredin 1992). The results will provide timely and solid evidence that can inform policy and nursing practice development in improving the person's QOL and QOC, and reducing BPSD.

2' biaryl amides as novel and subtype selective M1 agonists. Part II: Further optimization and profiling.

Further optimization of the biaryl amide series via extensively exploring structure-activity relationships resulted in potent and subtype selective M(1) agonists exemplified by compounds 9a and 9j with good rat PK properties including CNS penetration. Synthesis, structure-activity relationships, subtype selectivity for M(1) over M(2-5), and DMPK properties of these novel compounds are described.

2' biaryl amides as novel and subtype selective M1 agonists. Part I: Identification, synthesis, and initial SAR.

Biaryl amides were discovered as novel and subtype selective M(1) muscarinic acetylcholine receptor agonists. The identification, synthesis, and initial structure-activity relationships that led to compounds 3j and 4c, possessing good M(1) agonist potency and intrinsic activity, and subtype selectivity for M(1) over M(2-5), are described.

The discovery of a series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles as highly brain penetrant, selective muscarinic M1 agonists.

A series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles are reported which were found to be potent and selective muscarinic M1 agonists. By control of the physicochemical characteristics of the series, particularly the lipophilicity, compounds with good metabolic stability and excellent brain penetration were identified. An exemplar of the series was shown to be pro-cognitive in the novel object recognition rat model of temporal induced memory deficit.

Impact of Interstitial Ni on the Thermoelectric Properties of the Half-Heusler TiNiSn.

TiNiSn is an intensively studied half-Heusler alloy that shows great potential for waste heat recovery. Here, we report on the structures and thermoelectric properties of a series of metal-rich TiNi1+ySn compositions prepared via solid-state reactions and hot pressing. A general relation between the amount of interstitial Ni and lattice parameter is determined from neutron powder diffraction. High-resolution synchrotron X-ray powder diffraction reveals the occurrence of strain broadening upon hot pressing, which is attributed to the metastable arrangement of interstitial Ni. Hall measurements confirm that interstitial Ni causes weak n-type doping and a reduction in carrier mobility, which limits the power factor to 2.5-3 mW m-1 K-2 for these samples. The thermal conductivity was modelled within the Callaway approximation and is quantitively linked to the amount of interstitial Ni, resulting in a predicted value of 12.7 W m-1 K-1 at 323 K for stoichiometric TiNiSn. Interstitial Ni leads to a reduction of the thermal band gap and moves the peak ZT = 0.4 to lower temperatures, thus offering the possibility to engineer a broad ZT plateau. This work adds further insight into the impact of small amounts of interstitial Ni on the thermal and electrical transport of TiNiSn.

Aripiprazole and its human metabolite are partial agonists at the human dopamine D2 receptor, but the rodent metabolite displays antagonist properties.

Aripiprazole is a novel antipsychotic drug, which displays partial agonist activity at the dopamine D(2) receptor. Aripiprazole has been extensively studied pre-clinically, both in vitro and in vivo, and these results have been correlated with clinical findings. However, aripiprazole is metabolised differently in rats and man and these metabolites may contribute to the profile of aripiprazole observed in vivo. We have therefore studied the interaction of aripiprazole and its principal rat and human metabolites in both in vitro models of dopamine hD(2) receptor function and affinity, and of in vivo models of dopamine rat D(2) receptor function. The human metabolite displayed similar levels of partial agonist activity to aripiprazole at the dopamine hD(2) receptor and displayed similar behavioural profile to aripiprazole in vivo, suggesting that in man the metabolite may maintain the effects of aripiprazole. In contrast, the rat metabolite displayed antagonist activity both in vitro and in vivo. Thus care must be taken in ascribing effects seen in vivo with aripiprazole in rats to dopamine D(2) receptor partial agonist activity in man, and that care must also be taken in extrapolating effects seen in rats to man, particularly from long-term studies.

CCR2: characterization of the antagonist binding site from a combined receptor modeling/mutagenesis approach.

We describe here a classical molecular modeling exercise that was carried out to provide a basis for the design of novel antagonist ligands of the CCR2 receptor. Using a theoretical model of the CCR2 receptor, docking studies were carried out to define plausible binding modes for the various known antagonist ligands, including our own series of indole piperidine compounds. On the basis of these results, a number of site-directed mutations (SDM) were designed that were intended to verify the proposed docking models. From these it was clear that further refinements would be necessary in the model. This was aided by the publication of a crystal structure of bovine rhodopsin, and a new receptor model was built by homology to this structure. This latest model enabled us to define ligand-docking hypotheses that were in complete agreement with the results of the SDM experiments.

SB-656104-A, a novel selective 5-HT7 receptor antagonist, modulates REM sleep in rats.

1 (6-((R)-2-[2-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-ethyl]-pyrrolidine-1-sulphonyl)-1H-indole hydrochloride) (SB-656104-A), a novel 5-hydroxytryptamine (5-HT(7)) receptor antagonist, potently inhibited [(3)H]-SB-269970 binding to the human cloned 5-HT(7(a)) (pK(i) 8.7+/-0.1) and 5-HT(7(b)) (pK(i) 8.5+/-0.2) receptor variants and the rat native receptor (pK(i) 8.8+/-0.2). The compound displayed at least 30-fold selectivity for the human 5-HT(7(a)) receptor versus other human cloned 5-HT receptors apart from the 5-HT(1D) receptor ( approximately 10-fold selective). 2 SB-656104-A antagonised competitively the 5-carboxamidotryptamine (5-CT)-induced accumulation of cyclic AMP in h5-HT(7(a))/HEK293 cells with a pA(2) of 8.5. 3 Following a constant rate iv infusion to steady state in rats, SB-656104 had a blood clearance (CL(b)) of 58+/-6 ml min(-1) kg(-1) and was CNS penetrant with a steady-state brain : blood ratio of 0.9 : 1. Following i.p. administration to rats (10 mg kg(-1)), the compound displayed a t(1/2) of 1.4 h with mean brain and blood concentrations (at 1 h after dosing) of 0.80 and 1.0 micro M, respectively. 4 SB-656104-A produced a significant reversal of the 5-CT-induced hypothermic effect in guinea pigs, a pharmacodynamic model of 5-HT(7) receptor interaction in vivo (ED(50) 2 mg kg(-1)). 5 SB-656104-A, administered to rats at the beginning of the sleep period (CT 0), significantly increased the latency to onset of rapid eye movement (REM) sleep at 30 mg kg(-1) i.p. (+93%) and reduced the total amount of REM sleep at 10 and 30 mg kg(-1) i.p. with no significant effect on the latency to, or amount of, non-REM sleep. SB-269970-A produced qualitatively similar effects in the same study. 6 In summary, SB-656104-A is a novel 5-HT(7) receptor antagonist which has been utilised in the present study to provide further evidence for a role for 5-HT(7) receptors in the modulation of REM sleep.

The effects of increased market competition on hospital services in Shandong and Henan Provinces.

The Chinese government began a major reform of the hospital sector in the early 1980s. The main aim was to increase productivity by phasing out prospective global budgets from the government, and encouraging between-hospital competition for the business of user-pay and insured patients. This goal was to be achieved without unreasonable prejudice to the financial sustainability of hospitals or to the fairness of access and service provision. We explored the effects of these changes by analysing data for four levels of hospital in two of the most populous provinces between 1985 and 1999. We used data envelope analysis, and found that the majority of hospitals experienced a decline in productivity. Social efficiency (measured by the level of provision of unnecessary services) also declined, especially in the largest hospitals that could easily increase the use of expensive technologies. Most hospitals increased their economic sustainability, measured as the ratio between revenue and expenditures. However, the lowest-level hospitals experienced stable or reduced sustainability due to their inability to compete with marketing by higher-level hospitals. We conclude that, although there were many benefits, the overall impact of the introduction of market forces may have been negative. An important factor was that not all aspects (such as supplier-induced demand) were adequately controlled by government agencies. We suggest ways of alleviating the most problematic elements of current arrangements.

Testing the Birth Unit Design Spatial Evaluation Tool (BUDSET) in Australia: a pilot study.

OBJECTIVE: To pilot test the Birth Unit Design Spatial Evaluation Tool (BUDSET) in an Australian maternity care setting to determine whether such an instrument can measure the optimality of different birth settings. BACKGROUND: Optimally designed spaces to give birth are likely to influence a woman's ability to experience physiologically normal labor and birth. This is important in the current industrialized environment, where increased caesarean section rates are causing concerns. The measurement of an optimal birth space is currently impossible, because there are limited tools available. METHODS: A quantitative study was undertaken to pilot test the discriminant ability of the BUDSET in eight maternity units in New South Wales, Australia. Five auditors trained in the use of the BUDSET assessed the birth units using the BUDSET, which is based on 18 design principles and is divided into four domains (Fear Cascade, Facility, Aesthetics, and Support) with three to eight assessable items in each. Data were independently collected in eight birth units. Values for each of the domains were aggregated to provide an overall Optimality Score for each birth unit. RESULTS: A range of Optimality Scores was derived for each of the birth units (from 51 to 77 out of a possible 100 points). The BUDSET identified units with low-scoring domains. Essentially these were older units and conventional labor ward settings. CONCLUSION: The BUDSET provides a way to assess the optimality of birth units and determine which domain areas may need improvement. There is potential for improvements to existing birth spaces, and considerable improvement can be made with simple low-cost modifications. Further research is needed to validate the tool.

Developing the Birth Unit Design Spatial Evaluation Tool (BUDSET) in Australia: a qualitative study.

OBJECTIVE: To develop a tool known as the Birth Unit Design Spatial Evaluation Tool (BUDSET), to assess the optimality of birth unit design. BACKGROUND: The space provided for childbirth influences the physiology of women in labor. Optimal birth spaces are likely to enable women to have physiologically normal labor and birth. The measurement of an optimal birth space is currently impossible, because limited tools are available. Research into optimal birth unit design is also limited. METHODS: The BUDSET was developed using a qualitative study. Data collection included an extensive literature review, interviews with key informants (architects, midwife clinicians, and researchers) and an expert panel. A Pattern Language format was used to synthesize the literature and data obtained from the key informants. RESULTS: The BUDSET is based on 18 design principles and is divided into four domains (Fear Cascade; Facility; Aesthetics; Support) with three to eight assessable items in each. CONCLUSION: Birth units must be designed so that they facilitate and support the physiology of normal childbirth. The BUDSET may provide a way to assess the optimality of birth units and determine which domain areas may need to be improved.

The relationship between birth unit design and safe, satisfying birth: developing a hypothetical model.

Recent advances in cross-disciplinary studies linking architecture and neuroscience have revealed that much of the built environment for health-care delivery may actually impair rather than improve health outcomes by disrupting effective communication and increasing patient and staff stress. This is also true for maternity care provision, where it is suggested that the design of the environment can also impact on the experiences and outcomes for birthing women. The aim of this paper is to describe the development of a conceptual model based on literature and understandings of design, communication, stress and model of care. The model explores potential relationships among a set of key variables that need to be considered by researchers wishing to determine the characteristics of optimal birth environments in relation to birth outcomes for women and infants. The conceptual model hypothesises that safe satisfying birth is reliant on the level of stress experienced by a woman and the staff around her, stress influences the quality of communication with women and between staff, and this process is mediated by the design of the birth unit and model of care. The conceptual model is offered as a starting point for researchers who have an appreciation of the complexity of birth and the ability to bring together colleagues from a range of disciplines to explore the pre-requisites for safe and effective maternity care in new ways.

Novel N-Substituted Benzimidazolones as Potent, Selective, CNS-Penetrant, and Orally Active M1 mAChR Agonists.

Virtual screening of the corporate compound collection yielded compound 1 as a subtype selective muscarinic M1 receptor agonist hit. Initial optimization of the N-capping group of the central piperidine ring resulted in compounds 2 and 3 with significantly improved potency and selectivity. Subsequent optimization of substituents on the phenyl ring of the benzimidazolone moiety led to the discovery of novel muscarinic M1 receptor agonists 4 and 5 with excellent potency, general and subtype selectivity, and pharmacokinetic (PK) properties including good central nervous system (CNS) penetration and oral bioavailability. Compound 5 showed robust in vivo activities in animal models of cognition enhancement. The combination of high potency, excellent selectivity, and good PK properties makes compounds 4 and 5 valuable tool compounds for investigating and validating potential therapeutic benefits resulting from selective M1 activation.

Studies towards the identification of a new generation of atypical antipsychotic agents.

A rational structure-activity relationship study around compound (1) is reported. The lead optimisation programme led to the identification of sulfonamide (25), a molecule combining dopamine D2/D3 receptor antagonism with serotonin 5-HT2A, 5-HT2C, 5-HT6 receptor antagonism for an effective treatment of schizophrenia. Compound (25) was shown to possess the required in vivo activity with no EPS liability.

States of uncertainty: governing the empire of biotechnology.

The biotechnological revolution presents states and governments with a set of challenges that they have difficulty meeting. Part of the problem is associated with common perceptions of the speed, volume and the radical uncertainty of the new developments. Globalisation is also implicated, especially in relation to the development of the knowledge economy and the role of multinational actors. This in turn contributes to the apparent decline in the confidence of the public that national governments will be effective in addressing mounting concern about the dangers inherent in new techniques and products. Under these circumstances, 'normal' governance begins to look more like 'failure' governance. This article asks whether the effects of the biotechnological revolution on governance can adequately be explained by the critique of imperialism proposed by Michael Hardt and Antonio Negri, and whether the state is in danger of becoming implicated in sponsorship of modernist schemes to improve the human condition of the kind analysed by James E Scott. Biotechnology does appear to have imperial qualities, while there are strong reasons for states to see biotechnology as a feasible and desirable set of developments. For some critics of biotechnology, like Francis Fukuyama, this is a lethal combination, and the powers of the state should be used to stop biotechnological development. Others, by contrast and more pragmatically, propose a check on what the state will support by the application of precautionary principles. The article concludes that the association between the biotechnology empire and the state, combined with the inescapable duty of the state to be the risk manager of last resort, alerts us to the complexities of uncertainty at the same time as it renders a merely restrictive precautionary approach impracticable.