Impact of an integrated community-based model of care for older people with complex conditions on hospital emergency presentations and admissions: a step-wedged cluster randomized trial.

BACKGROUND: Health systems must reorient towards preventative and co-ordinated care to reduce hospital demand and achieve positive and fiscally responsible outcomes for older persons with complex needs. Integrated care models can improve outcomes by aligning primary practice with the specialist health and social services required to manage complex needs. This paper describes the impact of a community-facing program that integrates care at the primary-secondary interface on the rate of Emergency Department (ED) presentation and hospital admissions among older people with complex needs. METHODS: The Older Persons Enablement and Rehabilitation for Complex Health Conditions (OPEN ARCH) study is a multicentre randomised controlled trial with a stepped wedge cluster design. General practitioners (GPs; n = 14) in primary practice within the Cairns region are considered 'clusters' each comprising a mixed number of participants. 80 community-dwelling persons over 70 years of age if non-Indigenous and over 50 years of age if Indigenous were included at baseline with no new participants added during the study. Clusters were randomly assigned to one of three steps that represent the time at which they would commence the OPEN ARCH intervention, and the subsequent intervention duration (3, 6, or 9 months). Each participant was its own control. GPs and participants were not blinded. The primary outcomes were ED presentations and hospital admissions. Data were collected from Queensland Health Casemix data and analysed with multilevel mixed-effects Poisson regression modelling to estimate the effectiveness of the OPEN ARCH intervention. Data were analysed at the cluster and participant levels. RESULTS: Five clusters were randomised to steps 1 and 2, and 4 clusters randomised to step 3. All clusters (n = 14) completed the trial accounting for 80 participants. An effect size of 9% in service use (95% CI) was expected. The OPEN ARCH intervention was found to not make a statistically significant difference to ED presentations or admissions. However, a stabilising of ED presentations and a trend toward lower hospitalisation rates over time was observed. CONCLUSIONS: While this study detected no statistically significant change in ED presentations or hospital admissions, a plateauing of ED presentation and admission rates is a clinically significant finding for older persons with complex needs. Multi-sectoral integrated programs of care require an adequate preparation period and sufficient duration of intervention for effectiveness to be measured. TRIAL REGISTRATION: The OPEN ARCH study received ethical approval from the Far North Queensland Human Research Ethics Committee, HREC/17/QCH/104-1174 and is registered on the Australian and New Zealand Trials Registry, ACTRN12617000198325p .

Development of a risk prediction model for Barrett's esophagus in an Australian population.

Esophageal adenocarcinoma has poor 5-year survival rates. Increased survival might be achieved with earlier treatment, but requires earlier identification of the precursor, Barrett's esophagus. Population screening is not cost effective, this may be improved by targeted screening directed at individuals more likely to have Barrett's esophagus. To develop a risk prediction tool for Barrett's esophagus, this study compared individuals with Barrett's esophagus against population controls. Participants completed a questionnaire comprising 35 questions addressing medical history, symptom history, lifestyle factors, anthropomorphic measures, and demographic details. Statistical analysis addressed differences between cases and controls, and entailed initial variable selection, checking of model assumptions, and establishing calibration and discrimination. The area under the curve (AUC) was used to assess overall accuracy. One hundred and twenty individuals with Barrett's esophagus and 235 population controls completed the questionnaire. Significant differences were identified for age, gender, reflux history, family reflux history, history of hypertension, alcoholic drinks per week, and body mass index. These were used to develop a risk prediction model. The AUC was 0.82 (95% CI 0.78-0.87). Good calibration between predicted and observed risk was noted (Hosmer-Lemeshow test P = 0.67). At the point minimizing false positives and false negatives, the model achieved a sensitivity of 84.96% and a specificity of 66%. A well-calibrated risk prediction model with good discrimination has been developed to identify patients with Barrett's esophagus. The model needs to be externally validated before consideration for clinical practice.

Management of Indigenous patients presenting with non ST-segment elevation acute coronary syndrome in South Australia: a retrospective cohort study.

AIM: Using Australian guidelines for management of acute coronary syndromes, we assessed the probability of an Indigenous patient receiving interventional and therapeutic care after presenting in two metropolitan hospitals. METHODS: A retrospective case note review of patients admitted through two Adelaide public tertiary hospital emergency departments from December 2007 to December 2009. The study cohort was 488 patients with high-risk clinical features without ST-segment elevation. RESULTS: Indigenous patients were significantly younger, present later in the disease process and have a higher burden of cardiovascular risk factors when compared with non-Indigenous patients. Indigenous patients were 54% more likely to receive angiography (Risk ratios (RR) = 1.54; 95% CI 1.31; 1.81) than non-Indigenous patients, however, this difference disappeared after adjustment for age, sex and propensity score. Indigenous patients were 20% more likely to receive the recommended medications (RR = 1.19, 95% CI 1.01; 1.40) compared with non-Indigenous patients. Patients over 65 years were 53% less likely to receive an angiogram (RR = 0.47, 95% CI 0.38; 0.56) and were 35% less likely to receive the recommended medications (RR = 0.65, 95% CI 0.54; 0.78) than a patient at the ages of 18-49. Women were almost 20% less likely to receive an angiogram (RR = 0.81, 95% CI 0.66; 0.99) and 20% less likely to receive the recommended medications (RR = 0.80, 95% CI 0.71; 0.91) when compared with men. The likelihood of receiving medications on discharge was significantly influenced by age, gender, ethnicity, comorbid burden and revascularisation. CONCLUSIONS: The younger age and significantly higher-risk profile of Indigenous adults presenting to SA hospitals with acute coronary syndromes appears to lead to different management decisions, which may well be led by patient factors. Many of these risk conditions can be better managed in the primary care setting.

Effect of a general practitioner management plan on health outcomes and hospitalisations in older patients with diabetes.

BACKGROUND: Little is known about the impact of a general practitioner management plan (GPMP) on health outcomes of patients with diabetes. AIM: To examine the impact of a GPMP on the risk of hospitalisation for diabetes. METHODS: A retrospective study using administrative data from the Australian Government Department of Veterans' Affairs was conducted (1 July 2006 to 30 June 2014) of diabetes patients either exposed or unexposed to a GPMP. The primary end-point was the risk of first hospitalisation for a diabetes-related complication and was assessed using Cox proportional hazard regression models with death as a competing risk. Secondary end-points included rates of receiving guideline care for diabetes, with differences assessed using Poisson regression analyses. RESULTS: A total of 16 214 patients with diabetes were included; 8091 had a GPMP, and 8123 did not. After 1 year, 545 (6.7%) patients with a GPMP and 634 (7.8%) of patients without a GPMP were hospitalised for a diabetes complication. There was a 22% reduction in the risk of being hospitalised for a diabetes complication (adjusted hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.69-0.87, P < 0.0001) for those who received a GPMP by comparison to those who did not. Increased rates of diabetes guideline care, HbA1c claims (adjusted HR 1.29, 95% CI 1.25-1.33) and microalbuminura claims (adjusted HR 1.65, 95% CI 1.58-1.72) were observed after a GPMP. CONCLUSION: Provision of a GPMP in older patients with diabetes resulted in improved health outcomes, delaying the risk of hospitalisation at 12 months for diabetes complications. GPMP should be included as part of routine primary care for older patients with diabetes.

Efficacy of a basal bolus insulin protocol to treat prednisolone-induced hyperglycaemia in hospitalised patients.

BACKGROUND/AIM: Few studies have specifically investigated treatment of prednisolone-induced hyperglycaemia. AIM: To determine if a basal bolus insulin (BBI) protocol for inpatient hyperglycaemia is effective in patients prescribed acute prednisolone for an inflammatory disease. METHODS: In a cross-sectional study, 66 patients with type 2 diabetes admitted to a general medical ward and treated with BBI for up to 5 days were studied. Twenty-four patients were taking prednisolone ≥10 mg/day to treat an acute inflammatory disease. The remaining 42 patients were a control group. The primary outcome was mean daily blood glucose level. RESULTS: There were no significant differences in glycosylated haemoglobin (8.1 ± 1.0 vs 8.1 ± 1.6%, P = 0.88), age (77 ± 11 vs 75 ± 14 years, P = 0.57), male sex (63 vs 60%, P = 0.81) or body mass index (30.0 ± 5.3 vs 30.2 ± 11.5 kg/m(2) , P = 0.90) between patients taking prednisolone and controls. Mean daily glucose concentration was higher in patients taking prednisolone than in controls (12.2 ± 0.3 vs 10.0 ± 0.1 mmol/L, P < 0.001). Blood glucose level was higher in patients on prednisolone at 1700 h (14.6 ± 0.6 vs 10.3 ± 0.3 mmol/L, P < 0.001) and 2100 h (14.5 ± 0.6 vs 10.5 ± 0.3 mmol/L, P < 0.001), with no significant differences at 0700 h and 1200 h. These findings occurred despite patients taking prednisolone receiving a higher daily insulin dose than controls (0.67-0.70 vs 0.61-0.65 U/kg, P = 0.001) because of higher doses of ultra-rapid-acting insulin at 1200 h and 1700 h. CONCLUSIONS: Hospitalised patients taking prednisolone had substantial afternoon and evening hyperglycaemia despite receiving BBI via a protocol for inpatient hyperglycaemia. Specific insulin regimens for prednisolone-induced hyperglycaemia are needed that recommend more insulin during this time period.

Love, faith and hope - a secondary analysis of prostate cancer survivors and their partners.

BACKGROUND: Men's experience of recovery from treatment for prostate cancer has been extensively researched with reports highlighting the physical side effects of treatments such as erectile dysfunction and incontinence. The psychological, emotional and spiritual burden of prostate cancer on men and their partners has received far less attention. DESIGN: In this study, a secondary thematic analysis of data from a series of separate but related qualitative studies with prostate cancer survivors and their partners was conducted to further explore themes of love, hope and faith within this population. RESULTS: This study identified unresolved needs related to the emotive concepts of love, hope and faith. The findings from this study can be employed to refine psychosocial assessments of men with prostate cancer, and provide a more comprehensive understanding of prostate cancer survivors supportive care needs.

General practitioner management plans delaying time to next potentially preventable hospitalisation for patients with heart failure.

BACKGROUND: Several studies have shown that the Australian Medicare-funded chronic disease management programme can lead to improvements in care processes. No study has examined the impact on long-term health outcomes. AIMS: This retrospective cohort study assessed the association between provision of a general practitioner management plan and time to next potentially preventable hospitalisation for older patients with heart failure. METHODS: We used the Australian Government Department of Veterans' Affairs (DVA) claims database and compared patients exposed to a general practitioner management plan with those who did not receive the service. Kaplan-Meier analysis and Cox proportional hazards models were used to compare time until next potentially preventable hospitalisation for heart failure between the exposed and unexposed groups. RESULTS: There were 1993 patients exposed to a general practitioner management plan and 3986 unexposed patients. Adjusted results showed a 23% reduction in the rate of potentially preventable hospitalisation for heart failure at any time (adjusted hazard ratio, 0.77; 95% confidence interval, 0.64 to 0.92; P = 0.0051) among those with a general practitioner management plan compared with the unexposed patients. Within one year, 8.6% of the exposed group compared with 10.7% of the unexposed group had a potentially preventable hospitalisation for heart failure. CONCLUSIONS: A general practitioner management plan is associated with delayed time to next potentially preventable hospitalisation for heart failure.

Nocturnal non-invasive nasal ventilation in stable hypercapnic COPD: a randomised controlled trial.

BACKGROUND: Sleep hypoventilation has been proposed as a cause of progressive hypercapnic respiratory failure and death in patients with severe chronic obstructive pulmonary disease (COPD). A study was undertaken to determine the effects of nocturnal non-invasive bi-level pressure support ventilation (NIV) on survival, lung function and quality of life in patients with severe hypercapnic COPD. METHOD: A multicentre, open-label, randomised controlled trial of NIV plus long-term oxygen therapy (LTOT) versus LTOT alone was performed in four Australian University Hospital sleep/respiratory medicine departments in patients with severe stable smoking-related COPD (forced expiratory volume in 1 s (FEV1.0) <1.5 litres or <50% predicted and ratio of FEV1.0 to forced vital capacity (FVC) <60% with awake arterial carbon dioxide tension (PaCO2) >46 mm Hg and on LTOT for at least 3 months) and age <80 years. Patients with sleep apnoea (apnoea-hypopnoea index >20/h) or morbid obesity (body mass index >40) were excluded. Outcome measures were survival, spirometry, arterial blood gases, polysomnography, general and disease-specific quality of life and mood. RESULTS: 144 patients were randomised (72 to NIV + LTOT and 72 to LTOT alone). NIV improved sleep quality and sleep-related hypercapnia acutely, and patients complied well with therapy (mean (SD) nightly use 4.5 (3.2) h). Compared with LTOT alone, NIV (mean follow-up 2.21 years, range 0.01-5.59) showed an improvement in survival with the adjusted but not the unadjusted Cox model (adjusted hazard ratio (HR) 0.63, 95% CI 0.40 to 0.99, p = 0.045; unadjusted HR 0.82, 95% CI 0.53 to 1.25, p = NS). FEV1.0 and PaCO2 measured at 6 and 12 months were not different between groups. Patients assigned to NIV + LTOT had reduced general and mental health and vigour. CONCLUSIONS: Nocturnal NIV in stable oxygen-dependent patients with hypercapnic COPD may improve survival, but this appears to be at the cost of worsening quality of life. TRIAL REGISTRATION NUMBER: ACTRN12605000205639.

Providing reviews of evidence to COPD patients: controlled prospective 12-month trial.

The aim of this study was to evaluate a novel patient-held manual designed to reduce the evidence-practice gap in chronic obstructive pulmonary disease (COPD). The intervention manual contained summaries of research evidence. It was developed using current best practice for patient information materials and designed to cause discussion of evidence between patient and doctor. A controlled before-and-after study was employed in two similar but geographically separate regions of metropolitan Adelaide, South Australia. Participants had moderate to severe COPD, with 249 included at baseline and 201 completing the study. Evidence-based COPD management was measured using an indicator with three components: rates of influenza vaccination, bone density testing, and pulmonary rehabilitation. A survey of behavioral steps leading to practice change was conducted with the trial. Analysis, by median split of socioeconomic disadvantage, showed significant difference between study arms for only one component of the indicator of evidence-based practice, enrollment in pulmonary rehabilitation and only for the most socioeconomically disadvantaged stratum. For both socioeconomic strata, more intervention participants than control participants reported remembering being given the information material, reading part or all, and finding it very or quite helpful. Other significant differences were restricted to the stratum of greatest socioeconomic disadvantage: reading all of the material, learning from it, referring back, and talking to a doctor about a topic from the material. Above 90% of all participants who received the manual reported reading from it, 42% reported discussing topics with a doctor, but only 10% reported treatment change attributable to the manual. We have found that people with COPD will read an evidence manual developed using current best practice. However, the study demonstrated improvement for only one of the three components of an indicator of evidence-based disease management for only the most socioeconomically disadvantaged stratum of participants. Future interventions should be designed to better translate reading uptake into evidence-based disease management.

Influence of rheumatoid arthritis on work participation in Australia.

BACKGROUND: The aim of the study was to determine the prevalence of work disability in a cohort of Australians with rheumatoid arthritis. METHODS: A cross-sectional study of a sample of 497 individuals aged 18-65 years with rheumatoid arthritis in Adelaide, South Australia, was carried out. RESULTS: Of those employed, 130 (51%) were in full-time employment (> or= 35 h per week) work and 124 (49%) were in part-time employment (average 20 h per week). Overall, the observed/expected numbers working were 254/316 (relative risk 0.8 (0.69-0.91)). Using a comparator adjusted by removing those on the disability support pension, the relative risk of the working was 0.74. The observed/expected numbers working part time in the study group were 124/89 (relative risk 1.4 (1.25-1.65)). Those who continued to work had lower Health Assessment Questionnaire scores, less morning stiffness, superior scores for patient assessed level of function, lower pain scores, lower joint counts, a lower C-reactive protein, better measures of 'patient global assessment' and higher levels of education compared with the group who had ceased work. Overall, of those working at the time of diagnosis, 20% had ceased work within 5 years and approximately 40% had ceased work by 20 years. Of those who ceased work, the mean duration from time of diagnosis to work cessation was 7 years with half the subjects who ceased work doing so within 4 years of diagnosis. CONCLUSION: Work disability associated with rheumatoid arthritis in Australia is very significant and costly. Work disability occurs relatively early in the disease and is associated with several identifiable variables, many of which may be amenable to intervention strategies.

The effect of rheumatoid arthritis on personal income in Australia.

BACKGROUND: The aim of this study was to estimate the effect of rheumatoid arthritis (RA) on the personal income of a cohort of individuals with RA in Australia. METHODS: A cross-sectional study of a sample of 497 working age people with RA in Adelaide, South Australia was carried out. RESULTS: The average personal income of an individual with RA in our cohort in 2003-2004 was $A22 400 compared with the Australian mean annual income of $A38 000. When standardized, the income of our cohort was 66% that of the average income of the Australian population. Overall one-third of the RA cohort relied principally on the social security system for their income and more than 75% of the cohort estimated they had lost greater than $A10 000 per annum in personal income as a result of their disease. Individuals with RA who were not working had annual incomes on average of more than $A20 000 less than those who continued to work. CONCLUSION: The personal income loss associated with RA in Australia is of enormous significance. It reduces a large population of individuals to relative financial poverty and potentially limits their access to a range of services including private health services.

Medical emergencies in dental practice - management requirements and international practitioner proficiency. A scoping review.

The management of medical emergencies is widely considered a requisite skill for all dentists. Timely intervention of an emergency can significantly alter the outcome for a patient's morbidity and possible mortality. This scoping review examines the prevalence of medical emergencies in dental practice, as well as dentists' attitude, confidence, and competence, of medical emergency management within a dental setting. Key findings include a lack of preparedness towards medical emergencies, despite a universal recognition of the importance and desire to improve key medical skills.

An advance notification letter increases participation in colorectal cancer screening.

OBJECTIVES: To determine the impact of novel invitation strategies on population participation in faecal immunochemical test (FIT)-based colorectal cancer (CRC) screening. SETTING: A community screening programme in Adelaide, South Australia. METHODS: In total, 2400 people aged 50-74 years were randomly allocated to one of four CRC screening invitation strategies: (a) CONTROL: standard invitation-to-screen letter explaining risk of CRC and the concept, value and method of screening; (b) Risk: invitation with additional messages related to CRC risk; (c) Advocacy: invitation with additional messages related to advocacy for screening from previous screening programme participants and (d) Advance Notification: first, a letter introducing CONTROL letter messages followed by the standard invitation-to-screen. Invitations included an FIT kit. Programme participation rates were determined for each strategy relative to control. Associations between participation and sociodemographic variables were explored. RESULTS: At 12 weeks after invitation, participation was: CONTROL: 237/600 (39.5%); Risk: 242/600 (40.3%); Advocacy: 216/600 (36.0%) and Advance Notification: 290/600 (48.3%). Participation was significantly greater than CONTROL only in the Advance Notification group (Relative risk [RR] 1.23, 95% confidence interval [CI] 1.06-1.43). This effect was apparent as early as two weeks from date of offer; Advance Notification: 151/600 (25.2%) versus CONTROL: 109/600 (18.2%, RR 1.38, 95% CI 1.11-1.73). CONCLUSIONS: Advance notification significantly increased screening participation. The effect may be due to a population shift in readiness to undertake screening, and is consistent with the Transtheoretical Model of behaviour change. Risk or lay advocacy strategies did not improve screening participation. Organized screening programmes should consider using advance notification letters to improve programme participation.

Superficial heat or cold for low back pain.

BACKGROUND: Heat and cold are commonly utilised in the treatment of low-back pain by both health care professionals and people with low-back pain. OBJECTIVES: To assess the effects of superficial heat and cold therapy for low-back pain in adults. SEARCH STRATEGY: We searched the Cochrane Back Review Group Specialised register, the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2005), MEDLINE (1966 to October 2005), EMBASE (1980 to October 2005) and other relevant databases. SELECTION CRITERIA: We included randomised controlled trials and non-randomised controlled trials that examined superficial heat or cold therapies in people with low-back pain. DATA COLLECTION AND ANALYSIS: Two authors independently assessed methodological quality and extracted data, using the criteria recommended by the Cochrane Back Review Group. MAIN RESULTS: Nine trials involving 1117 participants were included. In two trials of 258 participants with a mix of acute and sub-acute low-back pain, heat wrap therapy significantly reduced pain after five days (weighted mean difference (WMD) 1.06, 95% confidence interval (CI) 0.68 to 1.45, scale range 0 to 5) compared to oral placebo. One trial of 90 participants with acute low-back pain found that a heated blanket significantly decreased acute low-back pain immediately after application (WMD -32.20, 95%CI -38.69 to -25.71, scale range 0 to 100). One trial of 100 participants with a mix of acute and sub-acute low-back pain examined the additional effects of adding exercise to heat wrap, and found that it reduced pain after seven days. There is insufficient evidence to evaluate the effects of cold for low-back pain, and conflicting evidence for any differences between heat and cold for low-back pain. AUTHORS' CONCLUSIONS: The evidence base to support the common practice of superficial heat and cold for low back pain is limited and there is a need for future higher-quality randomised controlled trials. There is moderate evidence in a small number of trials that heat wrap therapy provides a small short-term reduction in pain and disability in a population with a mix of acute and sub-acute low-back pain, and that the addition of exercise further reduces pain and improves function. The evidence for the application of cold treatment to low-back pain is even more limited, with only three poor quality studies located. No conclusions can be drawn about the use of cold for low-back pain. There is conflicting evidence to determine the differences between heat and cold for low-back pain.

Screening for colorectal cancer by faecal occult blood test: why people choose to refuse.

To better understand the personal barriers that limit participation in faecal occult blood test (FOBT) screening for colorectal cancer, non-participants from a recent screening initiative were sent detailed questionnaires, defining their reasons for not participating, as well as how to make screening more attractive. The important barrier was procrastination. The type of FOBT kit offered influenced the reasons for not participating. Convenient FOBT and greater general practitioner involvement may be important for optimizing community acceptance of FOBT-based screening.

Scleroderma in South Australia: further epidemiological observations supporting a stochastic explanation.

The aim of this study was to determine the incidence, prevalence, survival and selective demographic characteristics of scleroderma occurring in South Australia over the 10-year period 1993-2002. Analysis of the database of the South Australian Scleroderma Register: a population-based register established in 1993. Patients with scleroderma resident in South Australia (n = 353 at 2002) were ascertained from multiple sources and clinical and demographic data were obtained from mailed questionnaire and from review of computerized hospital databases, case notes or referring letters. Time-space cluster analysis was carried out according to the Knox method. Control data were obtained from the Australian Bureau of Statistics census. The mean prevalence was 21.4 per 10(5) (95% confidence interval 20.2-22.6) and the mean cumulative incidence of 1.5 per 10(5) (95% confidence interval 1.32-1.73) with no significant change in incidence over the study period (P = 0.13). Cumulative survival improved over the study period, with patients with diffuse disease having significantly reduced survival (as compared with limited disease, P < 0.001). The proportion with diffuse disease ( approximately 22%) remained steady. There was a small but significant predisposition in patients with a continental European birthplace (P < 0.001). A family history of scleroderma was noted in 1.6% with lambda1 (familial risk) of 14.3 (95% confidence interval 5.9-34.5). However, a family history of systemic autoimmunity (especially rheumatoid arthritis) was more common (6%). No socioeconomic stratification, temporal clustering nor spatio-temporal clustering was observed either at time of initial symptom or at 10 years before disease onset. Scleroderma occurs relatively infrequently in South Australia with no significant change in incidence observed over the 10-year study period. However, cumulative survival has improved. Identified risk factors include family history of scleroderma (risk approximately 14-fold), female sex (risk approximately 5-fold) and European birthplace (risk approximately 2.5-fold); however, the majority of the disease variance appears unexplained. A stochastic explanation based on genetic instability is favoured to explain this paradox.

Long-term effects of cancer treatment and consequences of cure: cancer survivors enjoy quality of life similar to their neighbours.

To assess the long-term effects of cancer treatment and consequences of cure, 102 index cancer cases were compared with 95 neighbourhood controls of similar age and sex and with 78 cardiac controls. The quality of life experienced by these three groups was examined using multiple instruments with proven psychometric properties. All the major quality of life domains (physical, psychological and social) were covered. The findings revealed that the index cases were similar to their neighbours in areas of subjective well-being. However, the index cases exhibited more sexual dysfunction, were more conscientious, determined and emotionally disciplined, and applied the defence mechanisms of displacement and reaction formation more often than the neighbourhood controls. The cardiac controls were older, more anxious, more conventional/less imaginative and used suppression as a defence mechanism to a greater degree than the index cases. In conclusion, young adult cancer survivors enjoy a quality of life similar to their neighbours, whereas coronary bypass survivors adjust less well psychosocially.

The effect of hypoxia on term trophoblast: hormone synthesis and release.

Isolated trophoblast in culture remained viable when exposed to severe hypoxia (Po2 12-14 mmHg) for at least 72 h as indicated by trypan blue exclusion and the synthesis and secretion of metabolically labelled proteins. However, release of hCG, hPL, progesterone and estradiol was reduced to < 10 per cent when compared to trophoblast in normoxia (Po2 120-130 mmHg). hCG mRNA was also reduced demonstrating interruption of synthesis at transcription. Acute exposure to hypoxia (2 h) suppressed progesterone release but not hCG, whereas inhibitors of oxidative phosphorylation suppressed hCG release but not progesterone. hCG release increases progressively during culture in normoxia, peaking at 72 h. Exposure of trophoblast to hypoxia for 48 h after 24, 48 and 72 h in normoxia interrupted this progression but did not suppress hCG release. Progesterone release, in contrast, was reduced by hypoxia. Exogenous dibutyryl cAMP increased hCG and progesterone release by normoxic trophoblast but not by hypoxic cells. Trophoblast returned to normoxia after 24 h in hypoxia increased hCG and progesterone release, suggesting early recovery. Conservation of oxygen and ATP by reducing hormone synthesis may contribute to survival of trophoblast in hypoxia.

Synthesis and secretion of apolipoprotein E by human placenta and choriocarcinoma cell lines.

The synthesis and secretion of apolipoproteins (apos) by cells from a human choriocarcinoma cell line, JAR, were examined by [35S]-methionine labeling followed by immunoprecipitation and SDS/PAGE. Apo E, but not apos A-I, A-IV, or B, was synthesized and secreted. Apo E was also synthesized by fragments of chorionic villi from human placenta and by another choriocarcinoma line, BeWo. Pulse-chase experiments with JAR cells revealed that apoE was initially synthesized as a 33 kDa protein followed by a 34 KDa protein, probably the result of glycosylation. The latter was secreted into the medium where it was detected coincident with a 21/22 kDa doublet, possibly proteolytic fragments of apo E. Approximately 50 per cent of the apo E in the medium was complexed with lipid as indicated by ultracentrifugation at a density of 1.21 g/ml. The amount of apo E produced by JAR was not affected by preincubation with dibutyryl cAMP and theophylline, or by the cholesterol content of the cells. Following perfusion of an isolated lobule of human placenta with [14C]-amino acids, [14C]-apo E was detected by immunoprecipitation of the maternal and fetal perfusates with 88 per cent in the maternal perfusate. These studies suggest that apo E, which promotes receptor-mediated lipoprotein uptake, is secreted by the trophoblast to facilitate uptake of maternal lipoproteins.

The effect of hypoxia on human trophoblast in culture: morphology, glucose transport and metabolism.

The response to hypoxia of trophoblast isolated from term placenta and maintained in culture was studied. Trophoblast exposed to normoxic (PO2 120-130 mmHg) or hypoxic (PO2 12-14 mmHg) conditions were examined by electron microscopy. After 48 h, the cytoplasm of the hypoxic cells was more electron-dense with increased numbers of mitochondria, lysosomes and vacuoles. Compared to normoxic cells, the surface microvilli of the hypoxic cells were sparse, short and unevenly distributed. [3H]thymidine incorporation by both hypoxic and normoxic trophoblast fell rapidly and equivalently after 2 days in culture. The percentage of cells with the proliferation-associated nuclear antigen, Ki 67, also decreased, but remained higher in hypoxic cells suggesting that hypoxia retarded completion of the cell cycle (normoxia, 10.80 +/- 2.51 s.e.; hypoxia, 19.87 +/- 2.73, P < 0.01). Glucose consumption was elevated in hypoxia (3.73 +/- 1.07 s.e. mumol/10(6) cells/24 h) as compared to normoxia (1.46 +/- 0.83, P = 0.01). Although lactate production was consistently higher in hypoxia, the difference was not statistically significant (hypoxia 5.38 +/- 1.54 mumol/10(6) cells/24 h versus normoxia, 1.52 +/- 0.29, P = 0.07). After 48 h, uptake of [3H]2-deoxglucose ([3H]2DG) by hypoxic cells was reduced to 12 per cent +/- 4.3 s.e. of that in normoxic cells; return to normoxia resulted in recovery within 10 min. Lineweaver-Burk plots of [3H]2DG uptake indicated high affinity (KM 2.2 +/- 0.4 x 10(-4) M) and low affinity transporters (KM 4.5 +/- 1.6 x 10(-3) M). Northern blot analysis identified mRNA for GLUT1 and GLUT3. In hypoxia, steady-state GLUT1 and GLUT3 mRNA were approximately three- and 10-fold higher than in normoxia respectively. Inhibitors of oxidative metabolism of glucose increased the uptake of [3H]2DG within 2 h, whereas hypoxia reduced uptake. Hence, trophoblast in culture survives in extreme hypoxia, but manifests striking changes in morphology and in glucose metabolism and transport. Completion of cell cycle appears to be retarded.