Synthesis and biological evaluation of 3-heterocyclyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines and analogues as subtype-selective inverse agonists for the GABA(A)alpha5 benzodiazepine binding site

The identification of a novel series of 7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines as GABA(A)alpha5 inverse agonists, which have both binding and functional (efficacy) selectivity for the benzodiazepine binding site of alpha5- over alpha1-, alpha2-, and alpha3-containing GABA(A) receptor subtypes, is described. Binding selectivity was determined to a large part by the degree of planarity of the fused ring system whereas functional selectivity was dependent on the nature of the heterocycle at the 3-position of the triazolopyridazine ring. 3-Furan and 5-methylisoxazole were shown to be optimal for GABA(A)alpha5 functional selectvity. 3-(5-Methylisoxazol-3-yl)-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine (43) was identified as a full inverse agonist at the GABA(A)alpha5 subtype with functional selectivity over the other GABA(A) receptor subtypes and good oral bioavailability.     

The Florida Department of Health and the Florida Association of County Health Department Business Administrators: a model of successful collaboration to sustain operational excellence.

The Florida Association of County Health Department Business Administrators, Inc., is an organization of public health business professionals working collaboratively with the state's department of health administrative offices in promoting best practices throughout local county health departments. This article discusses a number of joint initiatives, past and present, that are benefiting public health services in Florida. In addition, mentoring and training, contract management, cost allocation, and financial reporting, among others, are "hot button" topics of interest to all states in promoting improved administration of their public health programs.     

Discourses of the body in euthanasia: symptomatic, dependent, shameful and temporal

This theoretical paper is derived from a discourse analysis of the textual material from a study of the seven deaths associated with legalised euthanasia in the Northern Territory, Australia. The textual analysis utilises evidence from interviews, letters written by people seeking euthanasia, medical reports, coroner's records and media reports concerning the social experiment of legalised euthanasia in Australia. The paper does not discuss the euthanasia debate. It argues that the body is a neglected concern in the debates and offers a construction of the discourses of the body as symptomatic, dependent, shameful and temporal. Medical discourses frame the body as symptomatic but these people were also concerned with the loss of autonomy associated with dependence, with shame connected with loss of bodily functions and the embodied experience of determining a 'time to die'.     

Constructions of sexuality and intimacy after cancer: patient and health professional perspectives

With an increasing emphasis on the provision of psychosocial support for patients in cancer and palliative care, an emerging body of literature has highlighted the importance of providing the opportunity for patients to discuss issues of intimacy and sexuality with their health professionals. Very little is known about why health professionals struggle with this level of communication in clinical practice. The aim of this paper is to discuss constructions of intimacy and sexuality in cancer and palliative care from patient and health professional perspectives. A three stage reflexive inquiry was used to systematically and critically analyse data from semi-structured interviews (n=82), a textual analysis of 33 national and international clinical practice guidelines and participant feedback at 15 forums where preliminary research findings were presented to patients and health professionals in cancer and palliative care. The study was conducted across one public teaching hospital in Australia from 2002 to 2005. Data were further analysed drawing upon the work of Giddens on reflexivity, intimacy and sexuality, to reveal that the majority of health professionals embraced a less reflexive, more medicalised approach about patient issues of intimacy and sexuality after cancer. This was in stark contrast to the expectations of patients. Cancer had interrupted their sense of self, including how they experienced changes to intimate and sexual aspects of their lives, irrespective of their age, gender, culture, type of cancer or partnership status. Key findings from this project reveal incongruence between the way patients and health professionals constructed sexuality and intimacy. Structures which govern cancer and palliative care settings perpetrated the disparity and made it difficult for health professionals to regard patients as people with sexual and intimate needs or to express their own vulnerability when communicating about these issues in the clinical practice setting. A degree of reflexivity about personal and professional constructions of sexuality and intimacy was required for health professionals to confidently challenge these dominant forces and engage in the type of communication patients were seeking.     

Child disability case studies: an interprofessional learning opportunity for medical students and paediatric nursing students

CONTEXT: We describe an interprofessional learning (IPL) opportunity for pre-qualification medical and paediatric nursing students using community-based case studies of disabled children and their families. METHODS: A total of 160 students were randomly allocated into interprofessional and uniprofessional pairs. Each pair visited a disabled child at home and school and presented their experience to the rest of the group. Quantitative and qualitative evaluation methods were used to explore the learning experience. Data collection tools included a scale measuring attitudes towards IPL, which was completed by all students before and after their visits and focus groups. RESULTS: The value of the community setting and independent working of the case study was appreciated by the students. The intimacy involved in working in IP pairs demonstrated both positive and negative features. Nursing students showed more open and positive attitudes towards IPL than medical students. Nursing students in IP pairs appear to have benefited most from the exercise, notably in terms of confidence and self-esteem. Professional differences in communication skills and approach were identified as particular learning points for all students. CONCLUSIONS: The added value of combining quantitative and qualitative research methods is well demonstrated by this study. Learning opportunities from the case study were greater as a result of working interprofessionally. Student attitudes towards IPL and professional stereotyping changed as a result of this IPL exercise. The importance of the social context of learning and the contact hypothesis are supported by our findings.     

Do targets matter? A comparison of English and Welsh National Health priorities

National priorities and performance management regimes in the National Health Services of England and Wales diverged following devolution, most notably with respect to the use of waiting time targets, which have been progressively strengthened in England but were abandoned in Wales in the immediate post-devolution period. We analyse routine data collected over a six-year period from three English and one Welsh hospital trust close to the English-Welsh border to ascertain whether: (a) there is evidence of differential performance over time that relates to the country where the hospital is located; (b) within each hospital, there is evidence that English and Welsh patients faced different waiting times. Over the period the English hospitals recorded increased levels of activity, undertook proportionately more day case activity, and mortality rates fell. Activity levels remained constant in Wales, the proportion of day case activity fell, proportionately more non-elective patients were admitted, and mortality rates rose. There is partial evidence that English patients faced lower waiting times than their Welsh counterparts and were more likely to be admitted within a target waiting period. The stronger performance management regime operating in England appears to have contributed to higher levels of performance in the English hospitals over the period.     

The role of the palliative care nurse consultant in promoting continuity of end-of-life care

The provision of end-of-life care through a multidisciplinary integrated palliative-care approach is dependent on effective communication between professional groups and services. We did a qualitative study, using semi-structured individual and focus group interviews, in Melbourne, Australia. The research aim was to explore the experiences and strategies used by palliative care nurses to communicate with general practitioners. We found that palliative care nurse consultants in acute hospitals not only provided inpatient consultation, but also played an important part in facilitating continuity of care across healthcare services by improving existing communication strategies and establishing further communication networks. However, there were several issues that had the potential to disrupt communication, and this article reports on the role of the palliative care nurse consultant in addressing these issues.     

Stereoselective secretion of atenolol from PC12 cells

Stereoselective storage and release of the cardioselective beta adrenergic receptor antagonist atenolol was studied using cultured PC12 cells as a neural model. [3H]Atenolol efflux from preloaded PC12 cells was increased 4-fold in response to membrane depolarization by elevated extracellular potassium (50 mM). [3H]Norepinephrine release was enhanced 4.5-fold under the same conditions. Potassium-induced release of both [3H] atenolol and [3H]norepinephrine was inhibited completely in the absence of extracellular calcium. [3H]Atenolol release from PC12 cells was also reduced by the calcium channel antagonist nifedipine (IC50 = 1.6 +/- 0.5 nM). In addition, the calcium channel agonist BAY K8644 (1 microM) significantly enhanced potassium-induced [3H]atenolol efflux. After loading overnight, accumulation and storage of the (-)-enantiomer of atenolol by PC12 cells was found to be approximately 3-fold greater than that of the (+)-enantiomer. The (-)-enantiomer of atenolol was also preferentially released by 50 mM potassium with a (-)/(+)-enantiomer ratio of 3.6 to 1. The results support the existence within neurosecretory cells of storage and calcium-dependent release mechanisms which result in stereoselective secretion of the (-)-or active enantiomer of atenolol in response to membrane depolarization.