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Background An accurate measure of the impact of COVID-19 is the infection fatality ratio, or the proportion of deaths among those infected, which is independent of variable testing rates between nations. The risk of mortality from COVID-19 depends strongly on age and current single estimates of the infection fatality ratio do not account for differences in national age profiles. In addition, it is unclear whether age influences cumulative death trajectories, or if differences between regions are because of the effect and timing of public health interventions. Our objective is to determine whether (1) infection fatality ratios and (2) death trajectories are clustered into more than one group due to differences in national age profiles. Methods National age standardised infection fatality ratios were derived from age stratified estimates from China and population estimates from the World Health Organisation. The infection fatality ratios were clustered into groups using Gaussian mixture models. Trajectory analysis clustered cumulative death rates at two time points, 50 and 150 days after the first reported death. Findings Infection fatality ratios from 201 nations were clustered into three groups: young, middle and older, with corresponding means (SD) of 0.20% (0.03%), 0.38% (0.11%) and 0.93% (0.21%). At 50 and 150 days, there were two and three clusters, respectively, of cumulative death trajectories from 122 nations with at least 25 deaths reported at 100 days. The first cluster had steadily increasing or stable cumulative death rates, while the second and third clusters had moderate and fast increases in rates, respectively. Fifty-eight nations changed cluster group membership between time points. There was an association between the infection fatality ratio clusters and the change in trajectory clusters between 50 and 150 days (p=0.014). Conclusion Differences in national age profiles created three clusters in the COVID-19 infection fatality ratio, with the impact on younger nations less than the current estimate 0.5-1.0%. National cumulative death rates were clustered into steady, moderate or fast trajectories. Changes in death rate trajectories between 50 and 150 days were associated with the infection fatality ratio clusters, however evidence for the influence of age on death trajectories is mixed.

Invasive meningococcal disease (IMD) is an uncommon but life-threatening infection caused by Neisseria meningitidis. Serogroups B, C, W and Y cause most IMD cases in Australia. The highest incidence occurs in children under 5 years of age. A second peak occurs in adolescents and young adults, which is also the age of highest carriage prevalence of N. meningitidis. Meningococcal serogroup B (MenB) disease predominated nationally before 2016 and has remained the predominant cause of IMD in South Australia with 82% of cases, compared with 35% in New South Wales, 35% in Queensland, 9% in Victoria, 29% in Western Australia and 36% nationally in 2016. MenB vaccination is recommended by the Australian Technical Advisory Group on Immunisation for infants up to 2 years of age and adolescents aged 15-19 years (age 15-24 years for at-risk groups, such as people living in close quarters or smokers), laboratory workers with exposure to N. meningitidis, and Aboriginal and Torres Strait Islander children from age 2 months to 19 years. Due to the epidemiology and disease burden from MenB, a meningococcal B vaccine program has been implemented in South Australia for individuals with age-specific incidence rates higher than the mean rate of 2.8/100 000 population in South Australia in the period 2000-2017, including infants, young children (< 4 years) and adolescents (15-20 years). Program evaluation of vaccine effectiveness against IMD is important. As observational evidence also suggests 4CMenB may have an impact on Neisseria gonorrhoeae with genetic homology between bacterial species, the vaccine impact on gonorrhoea will also be assessed.

We used a pragmatic randomised controlled trial to evaluate a behavioural change strategy targeting carers of chronically hypoxaemic patients using long-term home oxygen therapy. Intervention group carers participated in personalised educational sessions focusing on motivating carers to take actions to assist patients. All patients received usual care. Effectiveness was measured through a composite event of patient survival to hospitalisation, residential care admission or death to 12 months. Secondary outcomes at baseline, 3, 6 and 12 months included carer and patient emotional and physical well-being. No difference between intervention ( n = 100) and control ( n = 97) patients was found for the composite outcome (hazard ratio (HR) 1.22, 95% confidence interval (CI) = 0.89, 1.68; p = 0.22). Improved fatigue, mastery, vitality and general health occurred in intervention group patients (all p values < 0.05). No benefits were seen in carer outcomes. Mortality was significantly higher in intervention patients (HR = 2.01, 95% CI = 1.00, 4.14; p = 0.05; adjusted for Australia-modified Karnofsky Performance Status), with a significant diagnosis–intervention interaction ( p = 0.028) showing higher mortality in patients with COPD (HR 4.26; 95% CI = 1.60, 11.35) but not those with interstitial lung disease (HR 0.83; 95% CI = 0.28, 2.46). No difference was detected in the primary outcome, but patient mortality was higher when carers had received the intervention, especially in the most disabled patients. Trials examining behavioural change interventions in severe disease should stratify for functionality, and both risks and benefits should be independently monitored. Trial registration: Australian New Zealand Clinical Trials Registry (ACTRN12607000177459).

Objective: Gestational Diabetes Mellitus (GDM) increases the risk of type 2 diabetes. A register can be used to follow-up high risk women for early intervention to prevent progression to type 2 diabetes. We evaluate the performance of the world’s first national gestational diabetes register. Research design and methods: Observational study that used data linkage to merge: (1) pathology data from the Australian states of Victoria (VIC) and South Australia (SA); (2) birth records from the Consultative Council on Obstetric and Paediatric Mortality and Morbidity (CCOPMM, VIC) and the South Australian Perinatal Statistics Collection (SAPSC, SA); (3) GDM and type 2 diabetes register data from the National Gestational Diabetes Register (NGDR). All pregnancies registered on CCOPMM and SAPSC for 2012 and 2013 were included–other data back to 2008 were used to support the analyses. Rates of screening for GDM, rates of registration on the NGDR, and rates of follow-up laboratory screening for type 2 diabetes are reported. Results: Estimated GDM screening rates were 86% in SA and 97% in VIC. Rates of registration on the NGDR ranged from 73% in SA (2013) to 91% in VIC (2013). During the study period rates of screening at six weeks postpartum ranged from 43% in SA (2012) to 58% in VIC (2013). There was little evidence of recall letters resulting in screening 12 months follow-up. Conclusions: GDM Screening and NGDR registration was effective in Australia. Recall by mail-out to young mothers and their GP’s for type 2 diabetes follow-up testing proved ineffective. Published version

Background Currently, there is a lack of guidelines for the use of short-acting bronchodilators (SABD) in people admitted to hospital for acute exacerbation of chronic obstructive pulmonary disease (AECOPD), despite routine use in practice and risk of cardiac adverse events. Aim To review the evidence that underpins use and optimal dose, in terms of risk versus benefit, of SABD for inpatient management of AECOPD and collate the results for future guidelines. Methods Medline, Embase, the Cochrane Central Register of Controlled Trials, clinicaltrials.gov and International Clinical Trials Registry Platform were searched (inception to November 2017) for published and ongoing studies. Included studies were randomised controlled trials or controlled clinical trials investigating the effect of SABD (β2-agonist and/or ipratropium) on inpatients with a diagnosis of AECOPD. This review was undertaken in accordance with PRISMA guidelines and a pre-defined protocol. Due to heterogeneous methodologies, meta-analysis was not possible so the results were synthesised qualitatively. Results Of 1378 studies identified, 10 met inclusion criteria. Narrative synthesis of 10 studies revealed no significant differences in most outcomes of interest relative to dose, delivery via inhaler or nebuliser, and type of β2-agonist used. However, some evidence demonstrated significantly increased cardiac side effects with increased dosage of β2-agonist (45% versus 24%), P

Objective The extent to which existing and future research can impact on reducing health disparities relates not only to the evidence available, but the ability to find that evidence. Our objective is to quantify experts' literature searching effectiveness with respect to Aboriginal and Torres Strait Islander people's health. Methods Nine journals were dual reviewed, and a ‘gold standard’ set of relevant articles was identified. Health librarians (n = 25) completed a standardised searching task using OVID MEDLINE, and results were compared with the gold standard. Sensitivity, specificity and precision rates were calculated. Results The gold standard comprised 136 of 1469 (9.3%) records from nine journals. Searches achieved a mean sensitivity of 53.2% (median = 64.7%, range 0.0–93.4%), specificity of 97.4% (median = 99.4%, range 52.6–100%) and precision of 83.3% (median = 91.0%, range 16.7–100%). Self-estimates of search sensitivity (post hoc) were significantly higher than observed (M = 78.9%, t = 4.812, P

Background: Delirium has a significant impact on nursing practice from diagnosis and management, with under-detection and variable management of delirium being international problems. This study aimed to explore nurses’ assessment and management of delirium when caring for people with cancer, the elderly or older people requiring psychiatric care in the inpatient setting. Methods: Participants in this qualitative study were nurses working in Australian public hospital inpatient dedicated units in palliative care, aged care (geriatrics), aged care (geriatric) psychiatry and oncology. Semi-structured interviews were used to explore nurses’ views about specific areas of delirium assessment and management. Purposive sampling was used and interviews conducted until thematic saturation reached. A thematic content analysis was performed from a grounded theory perspective. Results: A total of 40 participants were included in the study. The analysis revealed four broad analytical themes: (1) superficial recognition and understanding of the operational definition of delirium or recognition of delirium as a syndrome; (2) nursing assessment: investigative versus a problem solving approach; (3) management: maintaining dignity and minimizing chaos; and (4) distress and the effect on others. Discussion: Nurses have limited knowledge of the features of delirium regardless of their specialty discipline. Delirium was uniformly identified as a highly distressing experience for patients, families and staff alike. The majority of nurses had a superficial understanding of delirium management, and adopted a task-orientated approach aimed at addressing the more noticeable problems. These findings have implications for both education and knowledge translation. Innovative approaches are needed to align health professional behaviours with best evidence delirium care.

Link to Open Access version only under publisher copyright policy., Objective: To determine the prevalence of completion of advance directives (ADs) and wills by South Australians aged 15 years and over. Design, setting and participants: Statewide population-based survey of a single member (aged 15 years and over) of 3055 South Australian households between 4 September and 12 December 2012. Main outcome measures: Prevalence and sociodemographic determinants of completion of the four recognised legal ADs in South Australia (enduring power of attorney [EPA] for finance, enduring power of guardianship [EPG] for health care/lifestyle, medical power of attorney [MPA] for medical treatment and anticipatory direction for end-of-life care) and wills. Results: Nearly half the 3055 survey participants had not completed any AD document or will. Financial documents were more likely to be completed than health care documents. In multivariate analysis, the odds of not having completed any AD was higher among those aged 15–24 years compared with those aged over 65 years (odds ratio [OR], 55.3; 95% CI, 31.3–97.7) and 25–44 years (OR, 24.9; 95% CI, 17.3–36.1). Similarly, the odds were higher for those born in another country (OR, 2.0; 95% CI, 1.6–2.4); those never married (OR, 3.1; 95% CI, 2.3–4.2) or in de facto relationships (OR, 2.8; 95% CI, 2.1–3.8) or separated/divorced (OR, 1.8; 85% CI, 1.3–2.4) compared with those married; those who left school in Year 12 or before (OR, 1.5; 95% CI, 1.1–1.9) or with a bachelor degree (OR, 1.5; 95% CI, 1.1–2.0) compared with those who had completed a trade/apprenticeship, certificate/diploma; and those in blue collar occupations (OR 1.6; 95% CI, 1.3–2.2) or not employed (OR, 2.2; 95% CI, 1.4–3.6) versus professionals. The odds of not having completed any AD were lower for those living in rural or regional areas (OR, 0.8, 95% CI, 0.6–1.0) compared with the metropolitan area, and for those in the highest income bracket earning more than $80 000 (OR, 0.6; 95% CI, 0.5–0.8) compared with those in the middle bracket earning $40 000–$80 000. Conclusion: Completion rates of ADs among South Australians remain low, with financial instruments more likely to be completed than health care and lifestyle instruments. The odds of not completing ADs were associated with age and socioeconomic characteristics. General practitioners are in a good position to target advance care planning towards relevant patient groups, which would likely improve rates of decision making in future health care.

Cognitive-Experiential Self Theory assumes that reasoning conforms to a parallel dual processing model (comprising rational and experiential systems), through which we make sense of the world. The Rational Experiential Inventory was developed to measure an individual’s preference for rational (need for cognition) and experiential (faith in intuition) thinking, with individual differences proposed to influence the respective dominance of each. While small but consistent gender effects have been found previously, age effects have rarely been reported or investigated across the lifespan. We examine both age and gender differences in Rational Experiential Inventory scores, using combined data from five studies involving adult participants ( n = 520, 61.9% male) with a mean age of 41.45 years ( SD = 11.73, range 20–74 years). Results suggest a convergence of the rational and experiential systems in adulthood, although the timing may be different for women and men. In later adulthood, the relationship appears to diverge again.

Objectives: We previously reported a high incidence of alcohol-related acute pancreatitis (AP) in Goa, India, where country-made alcoholic products are consumed in addition to the commercially available alcoholic products. We aimed to analyze the composition of these country-made alcoholic products consumed by a population with a high incidence of alcohol-related AP. Methods: Three locally distilled alcoholic products (ethanol content, >20%) regularly consumed by patients developing AP, as determined by responses in a patient questionnaire, were selected. Three commercially available products with comparable ethanol content (rum, whiskey, and brandy) were used for comparison. Representative samples were analyzed using gas chromatography/mass spectrometry. Compound assignments used mass spectral searches of the NIST library (2008). Results: Commercially available rum, whiskey, and brandy used for comparison contained the 2 major constituents, ethanol and water. In addition, the country-made alcoholic products contained a higher level of by-products including long-chain alcohols (eg, butanol, propanol), aldehydes (eg, acetaldehyde), acids (eg, acetic acid), and even traces of methanol. Conclusions: Country-made alcoholic products contain many compounds in addition to ethanol. Given the high incidence of alcohol-related AP in the population where these products are consumed, further evaluation of their constituents in relation to the induction of pancreatic damage is warranted.

Summary Background: Despite a strong evidence-base for several therapies recommended in the management of acute coronary syndromes (ACS), many patients do not receive these therapies. The barriers preventing translation of evidence into practice are incompletely understood. The aim of this study was to survey clinicians regarding barriers to implementing recommendations of recently published national clinical guidelines and to determine the extent to which these impact clinical practice. Methods: A survey of clinicians at hospitals included in Australian Collaborative Acute Coronary Syndromes Prospective Audit (ACACIA, n = 3402, PML0051) was conducted, measuring self-stated knowledge, beliefs and guideline-concordant behaviours in relation to their care of ACS patients. Correlations between individual respondents’ self-estimated rates and clinician’s institutional rates of guideline-concordant behaviours were performed. Results: Most respondents (n = 50/86, 58%) were aware of current guidelines and their scope, achieving 7/10 (Interquartile Range (IQR) = 2) median score on knowledge questions. Belief in benefits and agreement with guideline-recommended therapy was high. However, none of these factors correlated with increased use of guideline therapies. Apart from clopidogrel (rs = 0.28, p

Fluid and electrolyte homeostasis depend on a balance between the intake and output of water. Aging is characterized by reduced homeostatic capacity. Changes in the control of both water intake and excretion accompany aging and may predispose the elderly to disturbances in sodium and water balance. Reduced thirst and water intake in response to water deprivation and thermal dehydration have been observed in healthy elderly persons. This reduction, combined with reduced renal water-conservation capacity, may predispose the elderly to dangerous dehydration when illness increases water losses or physical incapacity prevents access to water. The reasons for the thirst deficit are not clear. The elderly have a reduced capacity to excrete a water load, which means they are predisposed to water overload and hyponatremia. Furthermore, various neuroendocrine changes in the elderly affect fluid and electrolyte homeostasis. More studies are needed to understand the etiology of the disturbances of fluid intake and output so that they can be better prevented and treated.

Background The World Health Organization has identified cognitive determinants of hand hygiene as an outstanding research question. This study investigated whether doctors' preferences for a rational thinking style or an experiential thinking style are associated with hand hygiene compliance. Methods This was an observational study of hand hygiene practices of 32 doctors in 2 teaching hospitals in South Australia. Compliance rates were correlated with self-reported thinking styles. The doctors were observed by a trained observer during a ward round or outpatient clinic and were unaware that hand hygiene was under observation. The main outcome measures were hand hygiene compliance (hand hygiene compliance tool) and thinking style (Rational-Experiential Inventory). Results An overall mean compliance rate of 7.6% (standard deviation ± 7.2%) was found. Compliance was significantly positively correlated with experiential/automatic thinking ( r = .46; P = .004) and the observational setting of ward rounds (vs clinics) ( r = -.47; P = .003). No significant relationship was found between compliance and a rational/deliberate thinking style ( r = -.01; P = .472). Conclusions Hand hygiene is more experiential than rational. Findings suggest that certain promotional strategies appealing to the experiential thinking mode may improve compliance, and that traditional approaches based on logic and reasoning alone probably will not work.

Cardiovascular disease imposes a heavy burden of morbidity and mortality on the Australian community. This situation is likely to exacerbate as the number of elderly Australians increase. Management of acute coronary syndromes (ACS) is underpinned by a robust evidence base, which is outlined in clinical practice guidelines. Yet, despite wide diffusion of guidelines, many Australians who experience acute coronary syndromes do not receive optimal care. This article reviews what we have learnt from previous quality improvement initiatives and discusses what we need to know to improve acute coronary syndromes management in Australia.

Objective: To produce safer and more integrated hospital discharge planning practices for older people living in rural and remote settings. Design: Plan–Do–Study–Act framework using case-note audit and focus groups. Setting: Central Yorke Peninsula Hospital in South Australia. Subjects: All patients aged 65 years or older admitted between October 2001 and June 2002. Interventions: Range of communication strategies designed to improve discharge planning practices. Main outcome measures: Percentage of patients with documented discharge plan, Percentage of patients risk screened, Percentage of community health service provider referrals, Percentage of patients followed up within 10 days of discharge. Results: There was a significant increase in the proportion of patients with a documented discharge plan for both non-Aboriginal (23%) and Aboriginal patients (52%). There was also a significant increase in the proportion of patients who received timely and informative risk screening (41% for non-Aboriginal and 58% for Aboriginal patients). Referrals to community health service providers also increased significantly from baseline to the intervention period (14% for non-Aboriginal and 33% for Aboriginal patients). The project also resulted in improved communication processes between hospital staff and community health service providers. Conclusions: This National Demonstration Hospitals Program project has impacted on both hospital discharge planning and the hospital–community interface. Flow-on effects to other initiatives within the region are likely.

Background: Poorly executed transfers of older patients from hospitals to long-term care facilities carry the risk of fragmentation of care, poor clinical outcomes, inappropriate use of emergency department services, and hospital readmission. Objective: This study was conducted to assess the impact of adding a pharmacist transition coordinator on evidence-based medication management and health outcomes in older adults undergoing first-time transfer from a hospital to a long-term care facility. Methods: This randomized, single-blind, controlled trial enrolled hospitalized older adults awaiting transfer to a long-term residential care facility for the first time. Patients were randomized either to receive the services of the pharmacist transition coordinator (intervention group) or to undergo the usual hospital discharge process (control group). The intervention included medication-management transfer summaries from hospitals, timely coordinated medication reviews by accredited community pharmacists, and case conferences with physicians and pharmacists. The primary outcome was the quality of prescribing, measured using the Medication Appropriateness Index (MAI). Secondary outcomes were emergency department visits, hospital readmissions, adverse drug events, falls, worsening mobility, worsening behaviors, increased confusion, and worsening pain. Results: One hundred ten older adults (67 women, 43 men; mean [SD] age, 82.7 [6.4] years) were recruited from 3 metropolitan hospitals and assigned to 85 metropolitan long-term care facilities. Fifty-six patients were randomized to the intervention group and 54 to the control group; 44 patients in each group were evaluable at 8-week follow-up. There were no significant differences in baseline characteristics between treatment groups, with the exception of the number of medications discontinued during hospitalization: a mean of 1.1 more drugs was discontinued in the control group compared with the intervention group (P = 0.011). The majority of patients (35 [62.5%] in the intervention group, 41 [76.0%] in the control group) changed physicians as part of the transition to a long-term care facility. At 8-week follow-up, there was no change in MAI from baseline in the intervention group, whereas it had worsened in the control group (mean [95% CI], 2.5 [1.4–3.7] vs 6.5 [3.9–9.1], respectively; P = 0.007). Patients who received the intervention and were alive at follow-up exhibited a significant protective effect of the intervention against worsening pain (relative risk ratio [95% CI], 0.55 [0.32–0.94]; P = 0.023) and hospital usage (ie, the combination of emergency department visits and hospital readmissions) (0.38 [0.15–0.99]; P = 0.035), but did not differ from control patients in terms of adverse drug events (1.05 [0.66–1.68]), falls (1.19 [0.71–1.99]), worsening mobility (0.39 [0.13–1.15]), worsening behaviors (0.52 [0.25–1.10]), or increased confusion (0.59 [0.28–1.22]). When data for patients who had died were included, the intervention had no effect on hospital usage in all patients (0.58 [0.28–1.21]). Conclusions: Older people transferring from hospital to a long-term care facility are vulnerable to fragmentation of care and adverse events. In this study, use of a pharmacist transition coordinator improved aspects of inappropriate use of medicines across health sectors.

Objectives: A clinical informationist could provide the best available published evidence in response to clinicians’ questions identified during the process of care. This study sought to assess the feasibility of an informationist service and to propose a model for its delivery in an Australian teaching hospital. Whilst similar services are increasing in the UK, with a long history in the USA, this is the first Australian study in an acute public hospital. Methods: The views of 40/49 (82%) medical staff at the Daw Park Repatriation General Hospital, South Australia were canvassed using a questionnaire designed to address key issues relating to a proposed service. Results: Doctors were receptive to its potential benefits, perceived it as relevant and likely to be used, and were interested in a pilot. They typically indicated a required response time of 24 h. They expressed limited concerns other than a likely high workload for such a service, and reported currently searching infrequently for evidence in response to clinical questions, citing time issues and unavailability of computers as current key barriers to pursuing clinical questions. Conclusions: An informationist service is feasible. Results suggest that a pilot could be run in an area of acute medicine where questions about therapy and diagnosis are likely to proliferate, and the informationist should attend consultant ward rounds and clinical meetings, aiming to provide a response within 24 h.

Evidence-based practice (EBP) first evolved within medicine in the early 1990s, and has since influenced nearly every clinical discipline. Despite differing definitions, its central tenet remains the appropriate integration of relevant best practice (usually based on published research findings when available) into clinical practice. EBP has also attracted criticisms; but, notwithstanding these, there are many reasons why healthcare professionals need to have an understanding of EBP as it now stands, ranging from its potential to contribute to improved clinical outcomes, through to participation in the further development and refinement of EBP. Minimally, clinicians should be aware of, understand, and be able to find EBP resources that provide access to research already appraised for both its quality and relevance. More extensive EBP skills remain highly desirable, and might be viewed as essential skills for life-long learning regardless of EBP.

Audit is an important step in the process of health care evaluation and quality improvement. Some of the barriers to audit include the lack of support in initiating an audit, difficulty with data collection and lack of time. Auditmaker is a computer package that guides the clinician through the initial process of designing an audit, choosing factors and outcomes to analyse, then provides customizable data entry forms, and finally simple reports summarizing the data. It has user-friendly features, such as help buttons, drop-down lists and built in comorbidities and outcomes of common interest. It provides a generic tool for performing an audit as well as providing an opportunity for different clinicians in different institutions or practice settings to perform similar audits using the same data collection tool, which can provide the basis of benchmarking. Auditmaker is available for downloading from the ACEPBCP website: http://www.acebcp.org.au.

Summary 1. Angiotensin (Ang) II causes cardiac hypertrophy in vitro and in vivo. It also stimulates the release of endothelin (ET)-1. Endothelin-1 induces hypertrophy of cardiomyocytes in vitro. 2. In the present study, we examined whether the cardiac hypertrophic action of AngII in vivo was mediated by ET-1 via ETA receptors. We also determined whether arginine vasopressin (AVP), another ET-1 stimulator, could cause cardiac hypertrophy in vivo through an ET-1-dependent pathway. 3. In Sprague-Dawley rats (n = 8 per group), we determined whether the orally administered ETA receptor antagonist BMS 193884 could attenuate the cardiac hypertrophic effect of: (i) i.v. AngII infusion at either 100 or 200 ng/kg per min, i.v., for 1 week; (ii) AngII infusion at 100 ng/kg per min, i.v., for 2 weeks; and (iii) AVP infusion at either 2 or 10 ng/kg per min, i.v., for 1 week. Mean arterial pressure and heart rate were also measured. 4. Infusion with AngII for both 1 and 2 weeks increased left ventricular weight. Only AngII infusion at 200 ng/kg per min for 1 week increased blood pressure. Endothelin ETA receptor blockade did not attenuate the left ventricular hypertrophy, even though it reduced the hypertensive effect of AngII. Arginine vasopressin increased blood pressure, but did not cause cardiac hypertrophy. 5. We showed that AngII can cause cardiac hypertrophy through a direct, blood pressure-independent effect on the heart. Endothelin-1 did not mediate the cardiac hypertrophic effect of AngII through ETA receptors. This may indicate the involvement of ETB receptors in this model of cardiac hypertrophy. Arginine vasopressin did not cause cardiac hypertrophy in vivo.

Background: Gestational diabetes mellitus (GDM) is defined as glucose intolerance with its onset or first recognition during pregnancy. Post-GDM women have a life-time risk exceeding 70% of developing type 2 diabetes mellitus (T2DM). Lifestyle modifications reduce the incidence of T2DM by up to 58% for high-risk individuals. Methods/Design: The Mothers After Gestational Diabetes in Australia Diabetes Prevention Program (MAGDA-DPP) is a randomized controlled trial aiming to assess the effectiveness of a structured diabetes prevention intervention for post-GDM women. This trial has an intervention group participating in a diabetes prevention program (DPP), and a control group receiving usual care from their general practitioners during the same time period. The 12month intervention comprises an individual session followed by five group sessions at two-week intervals, and two follow-up telephone calls. A total of 574 women will be recruited, with 287 in each arm. The women will undergo blood tests, anthropometric measurements, and self-reported health status, diet, physical activity, quality of life, depression, risk perception and healthcare service usage, at baseline and 12 months. At completion, primary outcome (changes in diabetes risk) and secondary outcome (changes in psychosocial and quality of life measurements and in cardiovascular disease risk factors) will be assessed in both groups. Discussion: This study aims to show whether MAGDA-DPP leads to a reduction in diabetes risk for post-GDM women. The characteristics that predict intervention completion and improvement in clinical and behavioral measures will be useful for further development of DPPs for this population.

1. Drinking behaviour after water deprivation is one of the standard tests used to study thirst in humans and animals. Diurnal cycle and food availability are known to influence water intake, but have not been considered in previous studies of thirst after water deprivation. In the present study, we examined the effects of diurnal variation and food availability on water intake after 24 h water deprivation in rats. 2. All rats cycled through four treatments in varying order. These treatments were: (i) 24 h water deprivation with free access to food from 1900 h one day to 1900 h the next day, followed by free access to both food and water (Night-with-Food); (ii) 24 h water deprivation with free access to food from from 1900 h one day to 1900 h the next day, followed by free access to water but not food (Night-without-Food); (iii) 24 h water deprivation with free access to food from 0700 h one day to 0700 h the next day, followed by free access to both food and water (Day-with-Food); or (iv) 24 h water deprivation with free access to food from 0700 h one day to 0700 h the next day, followed by free access to water but not food (Day-without-Food). The amount of water consumed during the first 6 h, post-24 h water deprivation, was examined under each condition. 3. There was a significant diurnal effect (P < 0.001) and a significant food availability effect (P = 0.007) on the water consumed in the 6 h period after water deprivation. Most water was consumed by the Night-with-Food group and the least amount of water was consumed by the Day-without-Food group. These effects persisted after correction for water intake during 6 h periods from 0700 and 1900 h with and without food but without previous water deprivation. The diurnal and food availability effects on water consumption were independent (P = 0.5). 4. The coefficient of variability for each group suggests that the most sensitive measurements of water intake are obtained during the day in the absence of food. 5. We conclude that both the time of day and access to food independently alter water intake in rats subjected to a previous 24 h water deprivation. Our study also supports the validity of performing water intake measurements in thirst studies in rats during the day.

The objective of this study was to determine whether there are differences in the prevalence, clinical and laboratory manifestations, and morbidity and mortality of systemic lupus erythematosus (SLE) between Aborigines and Caucasians in Central Australia. The medical records of all patients diagnosed with SLE upto December 1999 were reviewed retrospectively. Prevalence of SLE was 1:1360 for Aborigines and 1:5170 for Caucasians. The prevalences of malar rash, discoid rash, photosensitivity, oral ulcers, pleuritis, anticardiolipin antibodies and lupus anticoagulant were higher in Caucasians than in Aborigines. The prevalences of anti-Sm antibody and anti-RNP antibody were higher in Aborigines than in Caucasians. These differences did not attain statistical significance. There was a low prevalence of renal disease in Aborigines and Caucasians. Mortality was low in Aborigines and nil in Caucasians. Although there is a high prevalence of SLE in Aborigines in Central Australia, renal involvement and mortality are low.

Objective The syndrome of inappropriate secretion of antidiuretic hormone is a rare disorder in dogs characterised by hypo-osmolality and persistent arginine vasopressin production in the absence of hypovolaemia and/or hypotension. The study describes the efficacy and safety of the nonpeptide selective arginine vasopressin V-2 receptor antagonist OPC-31260 in a dog with the naturally occurring syndrome. Design The detailed case history of a dog with spontaneous syndrome of inappropriate secretion of antidiuretic hormone that received long-term therapy with oral OPC-31260 is presented. Effects of the first dose of OPC-31260 and of a dose administered after a continuous dosing period of 12 days are reported. Procedure Packed cell volume, plasma sodium, total protein, arginine vasopressin, renin activity, atrial natriuretic peptide, urine specific gravity, urine output, heart rate and body weight were monitored for 2 h before, and for 4 h after, the first dose of OPC-31260. The same parameters plus plasma osmolality and urine osmolality were monitored when an identical dose was administered after 12 days of therapy. Results Oral administration of OPC-31260 at 3 mg/kg body weight resulted in marked aquaresis with increased urine output and decline in urine specific gravity within 1 h. Corresponding increases in concentrations of plasma sodium, plasma osmolality and plasma renin activity were recorded over a 4 h period. Arginine vasopressin concentration remained inappropriately elevated throughout the study. Results were similar when the trial procedure was repeated after a stabilisation period of 12 days. Long-term therapy with OPC-31260 at a dose of 3 mg/kg body weight orally every 12 h resulted in good control of clinical signs with no deleterious effects detected during a 3-year follow-up period. Despite sustained clinical benefits observed in this case, plasma sodium did not normalise with continued administration of the drug. Conclusions Treatment of a dog with naturally occurring syndrome of inappropriate secretion of antidiuretic hormone with OPC-31260 at 3 mg/kg body weight orally every 12 h resulted in marked aquaresis and significant palliation of clinical signs with no discernible side-effects detected over a 3-year period. Thus, OPC-31260 appears to offer a feasible medical alternative to water restriction for treatment of dogs with syndrome of inappropriate secretion of antidiuretic hormone. Higher doses of OPC-31260 may be required to achieve and maintain normal plasma sodium in dogs with this syndrome.

Evidence-based medicine is a process by which clinicians translate clinical information needs into answerable questions, track down answers to those needs as efficiently and effectively as possible using the best evidence available, apply the information to patients and evaluate their performance. Implementing evidence-based medicine is fragmented and variable. The National Health and Medical Research Council of Australia has implemented a research program to determine successful strategies for implementation and sustaining of evidence-based clinical practice. In addition this research program will help to answer whether evidence-based practice improves patient outcomes. This paper describes this program and other strategies that improve the application of evidence-based practice in clinical settings.

The hormone arginine vasopressin (AVP) contributes to water retention and vasoconstriction in congestive heart failure (CHF) through effects at the V2 and V1a receptors, respectively. The effect of long-term V2 receptor (V2R) blockade using OPC-31260 was assessed in a rat model of postinfarction-induced CHF. Rats underwent coronary artery ligation or sham operation and were treated for 6 mo with oral OPC-31260 (10 mg ⋅ kg−1 ⋅ day−1) or vehicle. CHF was characterized by left ventricular remodeling and impaired systolic function, increased cardiac and lung weight, and elevated plasma atrial natriuretic peptide; plasma AVP and plasma renin activity were not increased. Chronic V2R blockade increased urine volume ( P < 0.01) and decreased urine osmolality ( P < 0.01) but had no natriuretic effects. V2R blockade did not activate the renin-angiotensin system but increased plasma AVP in CHF ( P < 0.01). V2R blockade did not influence cardiac remodeling, cardiac function, or survival. These results suggest that AVP plays a major role in water retention through the renal V2R in a rat model of CHF. V2R blockade using OPC-31260 may represent an alternative to standard diuretic therapy in the management of water retention that characterizes heart failure.

Abstract Cyclosporine-induced hypertension is a major problem in transplant therapy. The pathophysiology of this disease is unclear. Cyclosporine increases endothelin synthesis and release, which may contribute to this hypertension. We examined the effects of chronic endothelin receptor blockade with the novel nonpeptide endothelin receptor antagonist bosentan in two animal models of cyclosporine-induced hypertension. Cyclosporine was administered daily to female Wistar rats (10 mg/kg per day SC for 30 days) and marmosets (30 mg/kg per day PO for 20 days). Control rats received vehicle. Tail-cuff systolic pressure was significantly elevated in the cyclosporine-treated animals before the last week of treatment. Bosentan (100 mg/kg) in arabic gum or arabic gum alone was given daily to the rats by gavage during the last 5 days of cyclosporine treatment and to the marmosets for the last 7 days of cyclosporine treatment. Tail-cuff systolic pressure was measured daily during bosentan treatment. Bosentan but not gum alone significantly lowered blood pressure in the cyclosporine-hypertensive rats from 134±1 to 122±3 mm Hg ( P P

Abstract Abnormalities of the vasopressin system are found in genetic hypertension. This study compares the delayed effects of a brief period of vasopressin V1A receptor blockade and angiotensin-converting enzyme inhibition in young female and male spontaneously hypertensive rats (SHR) on the development of hypertension in adult life. In a separate study, the role of vasopressin in the maintenance of blood pressure in adult SHR was assessed. Young SHR received either the nonpeptide vasopressin V1A receptor antagonist OPC-21268, the angiotensin-converting enzyme inhibitor ramipril, or vehicle from 6 to 10 weeks of age. During the treatment period, OPC-21268 and ramipril reduced systolic blood pressure compared with control SHR ( P P

The gene for the sheep arginine vasopressin type 1a (V1a) receptor subtype was cloned from a genomic library. The deduced amino acid sequence shows characteristics of a G-protein coupled receptor and high sequence identity to human and rat V1a receptor sequences (81% and 73%, respectively). Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed a tissue distribution consistent with a type V1a receptor. The genomic DNA (7.1 kb) contains a 1586 bp intron between the putative 6th and 7th transmembrane domains.

1. To investigate the mechanism of hepatic V1a vasopressin receptor down-regulation in streptozotocin-induced diabetes mellitus in the rat, we measured hepatic V1a receptor mRNA by in situ hybridization histochemistry using oligonucleotide probes to the V1a receptor and Northern blotting. 2. Diabetes mellitus caused hyperglycaemia, hyperosmolality and increased plasma vasopressin concentrations (P < 0.01). Hepatoycte V1a receptor mRNA was reduced by 76% in diabetic rats (P < 0.01) and by 53% in insulin-treated diabetic rats (P < 0.01) versus control rats, in parallel with reduced V1a radioligand binding and vasopressin-stimulated inositol phosphates production. There was a similar decrease in hepatic V1a/18S mRNA density ratio in the diabetic and diabetic + insulin groups (both P < 0.05 versus control). 3. These findings suggest that altered V1a mRNA transcription is responsible for the reduced hepatic V1a receptor density in diabetes mellitus.

Context: Evidence-based approaches are needed to improve the delivery of specialized palliative care. Conclusion: A single case conference added to current specialized community-based palliative care reduced hospitalizations and better maintained performance status. Comparatively, patient/caregiver education was less effective; GP education was not effective. Methods: This 2 × 2 × 2 factorial cluster randomized controlled trial was conducted at an Australian community-based palliative care service, allowing three simultaneous comparative effectiveness studies. Participating patients were newly referred adults, experiencing pain, and who were expected to live >48 hours. Patients enrolled with their general practitioners (GPs) and were randomized three times: 1) individualized interdisciplinary case conference including their GP vs. control, 2) educational outreach visiting for GPs about pain management vs. control, and 3) structured educational visiting for patients/caregivers about pain management vs. control. The control condition was current palliative care. Outcomes included Australia-modified Karnofsky Performance Status (AKPS) and pain from 60 days after randomization and hospitalizations. Objectives: The aim of this trial was to improve on current models of service provision. Results: There were 461 participants: mean age 71 years, 50% male, 91% with cancer, median survival 179 days, and median baseline AKPS 60. Only 47% of individuals randomized to the case conferencing intervention received it; based on a priori-defined analyses, 32% of participants were included in final analyses. Case conferencing reduced hospitalizations by 26% (least squares means hospitalizations per patient: case conference 1.26 [SE 0.10] vs. control 1.70 [SE 0.13], P = 0.0069) and better maintained performance status (AKPS case conferences 57.3 [SE 1.5] vs. control 51.7 [SE 2.3], P = 0.0368). Among patients with declining function (AKPS

Arginine vasopressin binding site characterisation was performed on purified nuclei and plasma membranes from livers of Sprague-Dawley rats. [125I][d(CH2)5,Sarc7,Arg8]vasopressin, a selective V1 vasopressin receptor antagonist radioligand, bound to the nuclei in a protein concentration and time dependent manner. Scatchard analysis of nuclear binding sites revealed a single binding site with maximal binding site density (Bmax) of 115 +/- 13 fmol/mg protein and affinity (KD) of 5.2 +/- 0.7 nM. Plasma membrane binding demonstrated a Bmax of 529 +/- 25 fmol/mg protein and KD of 1.9 +/- 0.1 nM. The displacement profile for nuclear binding sites using vasopressin analogues was similar to that for plasma membrane binding sites and was typical of a V1 vasopressin receptor type. There was no evidence of V2-like vasopressin receptor binding using [3H]des-Gly-NH9(2)[d(CH2)5,D-Ile2,Ile4,Arg8]vasopressi n, a selective V2 vasopressin receptor radioligand, in the nuclear or membrane fractions. These results suggest the existence of nuclear V1-like vasopressin binding sites.

SUMMARY 1. OPC-21268 and OPC-31260 are newly developed orally active non-peptide vasopressin (AVP) V1 and V2 receptor antagonists, respectively. The effects of the two compounds on human vessels have not been studied. 2. The effects of the two compounds on AVP-induced contraction of human internal mammary arteries (IMA) were investigated. Their effects were compared with the peptide V1 and V2 antagonists d(CH2)sSar7AVP (SAVP) and d(CH2)5D-Ileu211eu4AVP (Ileu2 Ileu4AVP), respectively. 3. The V1 antagonist OPC-21268 failed to antagonize AVP-induced contraction at low concentrations and potentiated the contraction at higher concentration (3 × 10−-7 mol/L, P

The pattern of regional brain activation in humans during thirst associated with dehydration, increased blood osmolality, and decreased blood volume is not known. Furthermore, there is little information available about associations between activation in osmoreceptive brain regions such as the organum vasculosum of the lamina terminalis and the brain regions implicated in thirst and its satiation in humans. With the objective of investigating the neuroanatomical correlates of dehydration and activation in the ventral lamina terminalis, this study involved exercise-induced sweating in 15 people and measures of regional cerebral blood flow (rCBF) using a functional magnetic resonance imaging technique called pulsed arterial spin labeling. Regional brain activations during dehydration, thirst, and postdrinking were consistent with the network previously identified during systemic hypertonic infusions, thus providing further evidence that the network is involved in monitoring body fluid and the experience of thirst. rCBF measurements in the ventral lamina terminalis were correlated with whole brain rCBF measures to identify regions that correlated with the osmoreceptive region. Regions implicated in the experience of thirst were identified including cingulate cortex, prefrontal cortex, striatum, parahippocampus, and cerebellum. Furthermore, the correlation of rCBF between the ventral lamina terminalis and the cingulate cortex and insula was different for the states of thirst and recent drinking, suggesting that functional connectivity of the ventral lamina terminalis is a dynamic process influenced by hydration status and ingestive behavior.

SUMMARY 1. A vasopressin binding protein purified from rat liver membranes was used to immunize Balb/c mice and, subsequently, for the screening of hybrids raised in two different cell fusions. 2. Three hybrids were obtained which secreted monoclonal antibodies (MoAb) that bound to the purified solubilized receptor as detected by an enzyme-linked immunosorbent assay technique. All three MoAb immunoprecipitated the purified receptor. 3. In addition, the MoAb bound in a concentration-dependent manner to crude liver, kidney and anterior pituitary membranes, tissues known to contain arginine vasopressin (AVP) receptors but not to cardiac ventricle membranes which lack AVP receptors. 4. However, the binding of [125I]-[d(CH2)5, Sar7]AVP (a specific radiolabelled V1 antagonist) to the membrane-bound receptor was not inhibited by these antibodies. 5. These results suggest that MoAb recognize epitopes which are common to rat liver, kidney and anterior pituitary membranes but are not at the ligand binding site.

1. A vasopressin (AVP) binding protein was purified from rat liver membranes by an improved method using [125I][d(CH2)5'Sarcosine7]AVP, a selective V1 AVP radioligand and a combination of CHAPS solubilization, gel filtration, lectin affinity and FPLC ion exchange chromatography. 2. The purified protein exhibited a maximum binding activity of 2480 pmol/mg protein with a KD of 4.5 nmol/L, which corresponds to a purification of approximately 26,700-fold. The molecular weight of this protein was 70,000 Da. 3. The binding of [125I][d(CH2)5'Sarcosine7]AVP to the solubilized membranes was dependent on the protein concentration, and was inhibited by the unlabelled peptides [d(CH2)5'Sarcosine7]AVP, AVP, and to a lesser degree by peptides with high V2 receptor affinity, such as 1-desamino-D-AVP and [d(CH2)5'D-Ileu2-Ileu4]AVP. 4. In addition, an AVP anti-idiotypic monoclonal antibody bound to both the partially purified and purified lectin affinity AVP binding protein in a concentration-dependent manner. These results indicate that the purified protein displays similar characteristics to the liver membrane-bound AVP V1 receptor.

A study of the preferred thinking styles among senior health professionals is reported. A total of 49 medical consultants, 50 senior nurses and 53 health managers from two public teaching hospitals in Adelaide, Australia, were invited via a personal letter to complete a questionnaire comprising measures of thinking style (the Rational Experiential Inventory) and cognitive style (two dimensions of the Myers–Briggs Type Indicator®). Managers reported a higher preference for ‘rational’ reasoning than nurses, whereas medical consultants reported a lower preference for ‘experiential’ reasoning than both managers and nurses. Cognitive style was largely homogenous. Although generalisation of the findings may be limited due to small sample sizes and the self-selection of participants, an understanding of the thinking styles of senior health professionals will likely inform the design and evaluation of future change strategies. What is known about the topic?Research outcomes cannot change population health unless they are adopted, but changing the practices of healthcare workers to reduce ‘know–do’ gaps is not simple. Although there is some evidence to support professionally-oriented strategies such as educational outreach, audit and feedback and reminders, success is sometimes limited, potentially reflecting the limited use of theory in informing the choice of implementation strategies. Non-theoretical approaches may obscure the behavioural determinants of, and mechanisms for, change, making it impossible to generalise lessons learned form one situation to other contexts. What does this paper add?This paper highlights the growing recognition of the need for theory in this important field, and examines a psychological theory for its potential use. Findings provide useful preliminary descriptive data about thinking dispositions within and between three key groups of healthcare decision-makers: senior consultants, senior nurses and managers. It adds to a modest but accumulating research base that explores the tenets of a specified theory among healthcare professionals, reporting reliable differences between individuals in terms of cognitive processing (i.e. how they prefer to think). What are the implications for practitioners?Those faced with implementing change should consider theoretically-driven approaches in their selection of strategies. Based on the theory explored herein, two versions of a message, each targeting a different cognitive processing mode, should be more successful than one version only. This should be true for all three professional groups, and represents a testable strategy for future research.

Objective: To evaluate the impact of an acute assessment unit (AAU) on length of hospital stay (LOS), emergency department (ED) waiting times, direct discharge rate, unplanned readmission rate and all-cause hospital mortality of general medical patients. Design and setting: Retrospective comparison of data for general medical patients admitted to a tertiary teaching hospital in Adelaide, South Australia, before and after the establishment of an AAU (reference years, 2003 [before] and 2006 [after]). Main outcome measures: Mean LOS, ED waiting times and all-cause hospital mortality during calendar years 2003 (pre-establishment) and 2006 (post-establishment). Results: Following the establishment of an AAU, the mean LOS shortened (from 6.8 days in 2003 to 5.7 days in 2006; P< 0.001) despite a 50.5% increase in the number of admissions (from 2652 to 3992). The number of admitted patients waiting in the ED more than 8 hours for a hospital bed decreased (from 28.7% to 17.9%; P< 0.001), as did the number waiting more than 12 hours (from 20.2% to 10.4%; P< 0.001). The rates of unplanned readmission within 7 and 28 days did not change. The all-cause hospital mortality for general medical admissions was 4.6% in 2003 v 3.7% in 2006 (P= 0.056). Conclusion: The establishment of an AAU within the general medical service coincided with decreases in both LOS and ED waiting times, despite a 50% increase in admissions. This structural reform in the process of acute medical care may have contributed to the improvement in these key health care performance indices without compromising the quality of patient care.

In response to water deprivation or heat stress, healthy elderly men experience reduced thirst compared with a young control group. Because water deprivation and heat stress produce hypertonicity as well as reduced extracellular fluid volume, the aim of this study was to determine whether the elderly also experience reduced thirst in response to hypertonicity without extracellular fluid volume depletion. To achieve this, after an overnight fast, healthy community-dwelling nonsmoking old (65-78 yr, n = 7) and young (20-32 yr, n = 7) men received 120-min hypertonic (0.855 M) and isotonic (0.154 M) saline infusions (0.06 ml.min-1.kg-1) in double-blind randomized order at least 2 wk apart. Both groups had increased thirst (P less than 0.001) and water intake (P less than 0.05) after the hypertonic saline infusion compared with the isotonic saline infusion. However, despite similar plasma sodium increases and less plasma volume expansion during the hypertonic saline infusion compared with the young group, the old group was less thirsty (P less than 0.01) and drank less room-temperature tap water (young 11.1 +/- 1.2 ml/kg, old 3.9 +/- 0.6 ml/kg, P less than 0.001). This reduced thirst in the old group seemed to be mainly due to a lower thirst sensitivity (P less than 0.05) to hypertonicity, although there was also a tendency toward an increased thirst threshold. Plasma arginine vasopressin increases were similar for the old and young groups with hypertonic saline, without significant changes during the isotonic saline infusion in either group.

SUMMARY 1. Balb/c mice were immunized against a vasopressin binding protein purified from rat liver. The hybrids produced from two cell fusions were screened against this receptor. Three hybrids were selected, cloned and expanded in serum-free media. The monoclonal antibodies (MoAb) secreted by these three hybrids were of the subclass IgM and were able to immunoprecipitate [125I]-labelled purified receptor. 2. All three MoAb bound to the purified solubilized receptor, crude liver and kidney membranes in a concentration-dependent manner. However, the binding of MoAb to the membranes did not inhibit the binding of [125I]-[d(CH2)5, Sar7]AVP, a selective V1 receptor radioligand, to the liver membrane-bound receptor. 3. These results suggest that the three MoAb recognize epitopes on the V1 receptor which are not denatured by solubilization, but are common to both rat liver and kidney membranes.

Background How humans think and make decisions is important in understanding behaviour. Hence an understanding of cognitive processes among physicians may inform our understanding of behaviour in relation to evidence implementation strategies. A personality theory, Cognitive-Experiential Self Theory (CEST) proposes a relationship between different ways of thinking and behaviour, and articulates pathways for behaviour change. However prior to the empirical testing of interventions based on CEST, it is first necessary to demonstrate its suitability among a sample of healthcare workers. Objectives To investigate the relationship between thinking styles and the knowledge and clinical practices of doctors directly involved in the management of acute coronary syndromes. Methods Self-reported doctors' thinking styles (N = 74) were correlated with results from a survey investigating knowledge, attitudes, and clinical practice, and evaluated against recently published acute coronary syndrome clinical guidelines. Results Guideline-discordant practice was associated with an experiential style of thinking. Conversely, guideline-concordant practice was associated with a higher preference for a rational style of reasoning. Conclusion Findings support that while guidelines might be necessary to communicate evidence, other strategies may be necessary to target discordant behaviours. Further research designed to examine the relationships found in the current study is required.

SUMMARY 1. Anaesthetized male Sprague-Dawley rats underwent unilateral nodose ganglionectomy or sham operation. 2. One week later hindbrain V1 vasopressin binding site density was assessed by in vitro autoradiography with the selective V1 antagonist radiolgand [125I] [d(CH2)5, Sar7]AVP. 3. Specific binding was observed in the nodose ganglion, nucleus tractus solitarius (NTS), area postrema, and inferior olive. Only binding in the medial subnucleus of the NTS was reduced by ipsilateral nodose ganglionectomy. 4. These findings are consistent with V1 vasopressin receptors occurring pre-synaptically on vagal primary viscerosensory afferent fibres. 5. Such receptors may be involved in the effect of AVP on blood pressure and/or the baroreflex.

Arginine vasopressin (AVP) acts on at least two receptor types, classified on the basis of their second messengers. The V1 receptor acts via mobilization of intracellular calcium through phosphatidylinositol hydrolysis and influences blood pressure and hepatic glycogenolysis. The V2 receptor acts via cAMP through activation of adenylate cyclase and causes antidiuresis. Previous studies of the different AVP receptors have been hampered by the use of nonselective radioligands, such as [3H]AVP (which binds to all types of V1 and V2 receptors, certain oxytocin receptors, and neurophysins) as well as the difficulty of measurement of second messengers. This paper describes the use of selective V1 and V2 radioligands with in vitro autoradiography to study V1 and V2 binding sites in rat tissues. [125I][1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 7-sarcosine] arginine vasopressin ([125I][d(CH2)5,Sarcosine7]AVP), a selective V1 antagonist radioligand, bound to regions of the brain, testis, superior cervical ganglion, liver, blood vessels, and renal medulla. Pharmacological characterization of [125I][d(CH2)5,Sarcosine7]AVP binding was consistent with that expected for binding to V1 receptors. There was no specific binding demonstrable to pituitary, renal glomeruli, gut, heart, spinal cord, ovary, adrenal medulla, or adrenal cortex. [3H]1-deamino [8-D-arginine] vasopressin [( 3H]DDAVP), a potent V2 receptor agonist radioligand, was used to study V2 receptors. Specific binding was only identified in the kidney consistent with the known distribution of antidiuretic V2 receptors on renal collecting tubules. No binding was demonstrated on endothelium or liver where DDAVP might influence clotting factor release, nor in the brain, spinal cord, sympathetic ganglia, heart or vascular smooth muscle, regions where DDAVP might cause vasodilatation. These studies demonstrate the use of these radioligands to study V1 and V2 receptors in a variety of tissues. Also, since these ligands are selective they are of particular use to study the different receptor subtypes in tissues where V1 and V2 receptors coexist, such as in the kidney.