Ethical considerations relating to healthcare resource allocation decisions.

Public policy decisions about patients' access to limited healthcare resources must be defensible and responsive to the interests of those affected. Decision-makers should articulate their reasoning and recommendations so that citizens can judge them. While the context of policy decisions will differ, their legitimacy depends upon the transparency of the reasoning, the accountability of the decision-makers, the testability of the evidence used to inform the decision-making and the inclusive recognition of those the decision affects. An example of applying this framework to resource allocation is that of approving effective high-cost anticancer drugs in a timely fashion.

Transthyretin uptake in placental cells is regulated by the high-density lipoprotein receptor, scavenger receptor class B member 1.

Transfer of thyroid hormone into cells is critical for normal physiology and transplacental transfer of maternal thyroid hormones is essential for normal fetal growth and development. Free thyroid hormone is known to enter cells through specific cell surface transport proteins, and for many years this uptake of unbound thyroid hormones was assumed to be the only relevant mechanism. Recently, evidence has emerged of alternate pathways for hormone entry into cells that are dependent on hormone binding proteins. In this study we identify the high-density lipoprotein receptor Scavenger Receptor class B member 1 (SR-B1) as important in the uptake and transport of transthyretin-bound thyroid hormone by placental trophoblast cells. High-density lipoprotein increases expression of SR-B1 in placental cells but also reduces uptake of transthyretin-thyroid hormone through the SR-B1 transporter. SR-B1 is expressed in many cells and this study suggests that SR-B1 may be universally important in thyroid hormone uptake. Further investigation of SR-B1-TTR interactions may fundamentally change our understanding of hormone biology and have important clinical consequences.

Sex Hormone Binding Globulin Modifies Testosterone Action and Metabolism in Prostate Cancer Cells.

Sex Hormone Binding Globulin (SHBG) is the major serum carrier of sex hormones. However, growing evidence suggests that SHBG is internalised and plays a role in regulating intracellular hormone action. This study was to determine whether SHBG plays a role in testosterone uptake, metabolism, and action in the androgen sensitive LNCaP prostate cancer cell line. Internalisation of SHBG and testosterone, the effects of SHBG on testosterone uptake, metabolism, regulation of androgen responsive genes, and cell growth were assessed. LNCaP cells internalised SHBG by a testosterone independent process. Testosterone was rapidly taken up and effluxed as testosterone-glucuronide; however this effect was reduced by the presence of SHBG. Addition of SHBG, rather than reducing testosterone bioavailability, further increased testosterone-induced expression of prostate specific antigen and enhanced testosterone-induced reduction of androgen receptor mRNA expression. Following 38 hours of testosterone treatment cell morphology changed and growth declined; however, cotreatment with SHBG abrogated these inhibitory effects. These findings clearly demonstrate that internalised SHBG plays an important regulatory and intracellular role in modifying testosterone action and this has important implications for the role of SHBG in health and disease.

Validation of the QTNM staging system for cancer-specific survival in patients with differentiated thyroid cancer.

An Australian state database was used to test the validity of the Quantitative tumor/node/metastasis (QTNM) staging system for assessing prognosis of differentiated thyroid cancer (DTC) on the basis of four variables quantified at diagnosis (histopathology, age, node involvement, and tumor size). Using the Queensland Cancer Registry (QCR), we identified 788 cases of DTC diagnosed from 1982 to 2006 with complete staging information. Causes of death were ascertained by linking the QCR database with the Australian National Death Index. Subjects were staged according to AJCC TNM 7th edition and QTNM, and cancer-specific survival (CSS) was calculated by the Kaplan-Meier method. Cancer-specific mortality was observed in 22 (2.8 %) patients, with 10-year CSS for the cohort of 97.0 % at a median follow-up of 262.8 months. QTNM stage specific cancer survival at 10 years was 99.6, 97.0, and 78.6 % for low-, intermediate-, and high-risk groups, respectively. This was comparable to the original US dataset in which the QTNM was initially studied, and it fared better at discriminating survival than the standard TNM system, where there was overlap in survival between stages. The current study validates the QTNM system in an Australian cohort and shows at least equivalent discriminatory capacity to the current TNM staging system. The QTNM utilized prognostic variables of significance to produce an optimal three-stage stratification scheme. Given, its advantage in clearly discriminating between prognostic groups, clinical relevance and simplicity of use, we recommend that TNM be replaced with QTNM for risk stratification for both recurrence and CSS.

Pregnancy-induced Cushing's syndrome in recurrent pregnancies: case report and literature review.

Pregnancy in women with Cushing's syndrome (CS) is uncommon. It is associated with significant maternal and fetal complications. Pregnancy-induced Cushing's syndrome is exceptionally rare with fewer than ten cases reported in the world literature and none in Australia or New Zealand. We describe a woman with possible recurrent pregnancy-induced CS complicating five pregnancies over a 7-year period. We discuss the changes in the hypothalamic-pituitary-adrenal axis during normal pregnancy together with the diagnosis, aetiology and management of CS in pregnancy.

Determinants of body fat in infants of women with gestational diabetes mellitus differ with fetal sex.

OBJECTIVE: Neonatal adiposity is a well-recognized complication of gestational diabetes mellitus (GDM). This study aimed to identify factors influencing adiposity in male and female infants of women treated for GDM. RESEARCH DESIGN AND METHODS: This was a prospective study of 84 women with GDM. Daily blood glucose levels (BGLs) were retrieved from glucose meters, and overall mean fasting and mean 2-h postprandial BGLs were calculated for each woman. Infant body composition was measured at birth, and regression analysis was used to identify significant predictors of infant body fat separately in male and female infants. RESULTS: Maternal fasting BGL was the major predictor of adiposity in male infants but had little relationship to adiposity in female infants. In male infants, percent fat was increased by 0.44% for each 0.1 mmol/L increase in mean maternal fasting BGL. Maternal BMI was the primary predictor in female infants but had little effect in males. In female infants, percent fat was increased by 0.11% for each 1 kg/m(2) increase in maternal prepregnancy BMI. CONCLUSIONS: Fetal sex may influence the impact that treatment strategies for GDM have on infant adiposity.

Delivery of maternal thyroid hormones to the fetus.

Thyroid hormones (THs) play an essential role in ensuring normal fetal development, particularly that of the central nervous system. Before 16 weeks gestation, the fetus relies solely on transplacental delivery of maternal T(4), and clinical studies suggest that even mild maternal thyroid hormone deficiency adversely affects the intellectual function of offspring. Maternofetal TH transfer is regulated by trophoblast cell membrane transporters, which mediate influx and efflux of THs, placental deiodinases D3 and D2, which control intraplacental TH levels, and TH-binding proteins (transthyretin), which provide transport roles in the placenta. This review discusses new information about mechanisms of transplacental delivery of T(4) to the fetus, providing insight into complex processes that are vitally important for normal fetal development.

Effect of oxygen concentrations on sodium iodide symporter expression and iodide uptake and hCG expression in human choriocarcinoma BeWo cells.

Normal human fetal development requires an adequate supply of thyroid hormone from conception. Until about 16 wk gestation this is supplied entirely by placental transfer of maternal hormone. Subsequently, the fetal thyroid synthesizes thyroid hormones, requiring a supply of maternal iodide. Trophoblast iodide transfer is mediated by the apical sodium iodide symporter (NIS). Placental oxygen levels are low in early pregnancy (~1%), rising with placental vascularisation to a plateau of ~8% at about 16 wk. Although the impact of these changing oxygen levels on placental implantation is well recognized, effects on trophoblast materno-fetal exchange are less understood. We investigated expression of the NIS regulator hCG, NIS mRNA expression, and I(125) uptake in choriocarcinoma BeWo cells (a model of the trophoblast) cultured in 1 and 8% oxygen and in room air (21% oxygen). Expression of NIS and hCG mRNA and protein was low at 1% oxygen but rose significantly at 8 and at 21%. This was reflected in significant increases in I(125) uptake. Desferrioxamine, an iron chelator and hypoxia mimic, decreased NIS and hCG expression and I(125) uptake in BeWo cells. NIS expression and I(125) uptake in cells grown at 1% oxygen were not increased by addition of hCG (2,500 IU/l). We infer that placental NIS mRNA and protein expression are regulated by oxygen, rising with vascularization of the placenta in the late first trimester, a time when fetal iodide requirements are increasing.

Histoplasmosis in Australia: report of 16 cases and literature review.

We describe 16 previously unreported patients with histoplasmosis from Queensland and northern New South Wales, Australia, and review all previous Australian reports, providing 63 cases in total to study (17 cases of acute pulmonary histoplasmosis, 2 cases of chronic pulmonary disease, and 44 cases of systemic disease, including 17 cases of single-organ infection and 27 instances of disseminated disease). All acute pulmonary disease was acquired in Australia, with 52% of systemic disease definitely autochthonous. Most cases of single-organ disease occurred in immunocompetent patients (76%), and were oropharyngeal (53%) in location. Forty-one percent of disseminated disease occurred in patients with human immunodeficiency virus (HIV). Patients with HIV had high rates of systemic symptoms, pancytopenia, fungemia, and hepatosplenomegaly. Oropharyngeal and adrenal involvement as well as systemic symptoms were prominent in immunocompetent patients with disseminated disease, with 6 of 7 cases of adrenal involvement leading to Addison disease. Most systemic disease was diagnosed by culture of Histoplasma capsulatum. Where serology was assessed in cases other than acute pulmonary disease, it was positive in only 32%.Prognosis for patients with single-organ disease was excellent. Disseminated disease was associated with recurrence in 30% and death in 37%. The results of this study confirm several previously known patterns of disease but also provide new insights into this rare but endemic condition in Australia.

Carrier-mediated thyroid hormone transport into placenta by placental transthyretin.

CONTEXT: The serum protein transthyretin (TTR) plays an important role in the transport of thyroid hormone and retinol, which are critical for normal development of the human fetus. TTR is not only synthesized and secreted into the circulation by the liver and other tissues but is also synthesized by placental trophoblasts, which separate the maternal and fetal circulations. Whether it is secreted or taken up by these cells and whether it carries thyroid hormone is unknown. OBJECTIVE AND METHODS: Our objective was to study placental handling of TTR and determine whether TTR participates in placental thyroid hormone transport. We investigated the capacity of human placenta and choriocarcinoma cell lines to secrete and internalize TTR and its ligands by Western blotting, immunofluorescence, and uptake of radiolabeled TTR. RESULTS: Human placental explants and TTR expressing JEG-3 cells secrete TTR. JEG-3 cells grown in bicameral chambers secrete TTR, predominantly from the apical surface. Human placental explants and JEG-3 cells internalize Alexa Fluor488-labeled TTR and (125)I-TTR. Furthermore, binding to thyroid hormones (T(4), T(3)) increases (125)I-TTR uptake by enhancing tetramer formation. Cross-linking experiments confirm internalization of the TTR-(125)I-T(4) complex. CONCLUSIONS: Our results suggest that human placenta and choriocarcinoma cells secrete transthyretin, which binds extracellular T(4), and that T(4) binding results in increased internalization of TTR-T(4) complex. TTR production by trophoblasts may represent a mechanism to allow transfer of maternal thyroid hormone to the fetal circulation that could have important implications for fetal development.

Pathology in education and practice: a time for integration?

While there has been a strong history of pathology in understanding disease, in recent years we have seen less appreciation of the value of pathology in clinical practice. Divisions at the clinical level, with pathology delivered from isolated buildings at the periphery of hospitals rather than within the heart of it, confirms in the mind of the new graduate the lack of importance of the discipline, despite using the service daily. We argue that it is time for a reintegration of pathology services.

Effect of Iodide on Human Choriogonadotropin, Sodium-Iodide Symporter Expression, and Iodide Uptake in BeWo Choriocarcinoma Cells.

CONTEXT: Active placental transport of maternal iodide by the thyroidal sodium iodide symporter (NIS) provides an essential substrate for fetal thyroid hormone synthesis. NIS is expressed in trophoblast and is regulated by human choriogonadotropin (hCG). In thyroid, iodide down-regulates expression of several genes including NIS. Placentas of iodine-deficient rats demonstrate up-regulation of NIS mRNA, suggesting a role for iodide in regulating placental NIS. OBJECTIVES AND METHODS: The objectives were to examine effects of iodide on expression of NIS and hCG in BeWo choriocarcinoma cells. Gene expression was studied by quantitative real-time PCR. Effects on NIS protein expression were assessed by Western blotting. Functional activity of NIS was measured by (125)I uptake. Expression of hCG protein was assessed by immunoassay of secreted hormone. RESULTS: Iodide inhibited NIS mRNA and membrane protein expression as well as (125)I uptake, which were paralleled by decreased betahCG mRNA expression and protein secretion. Iodide had no effects on pendrin expression. Addition of hCG increased NIS mRNA expression. This effect was partially inhibited by addition of iodide. The inhibitory effects of iodide on NIS mRNA expression were abolished by propylthiouracil and dithiothreitol. CONCLUSIONS: We conclude that expression of placental NIS is modulated by maternal iodide. This may occur through modulation of hCG effects on NIS and hCG gene expression.

Are Australian children iodine deficient? Results of the Australian National Iodine Nutrition Study.

OBJECTIVE: To document the population iodine nutritional status in Australian schoolchildren. DESIGN AND SETTING: Cross-sectional survey of schoolchildren aged 8-10 years, based on a one-stage random cluster sample drawn from all Year 4 school classes in government and non-government schools in the five mainland Australian states of New South Wales, Victoria, South Australia, Western Australia and Queensland. The study was conducted between July 2003 and December 2004. PARTICIPANTS: 1709 students from 88 schools (881 boys and 828 girls), representing 85% of the estimated target number of students. The class participation rate was 65%. MAIN OUTCOME MEASURES: (i) Urinary iodine excretion (UIE) levels (compared with the criteria for the severity of iodine deficiency of the World Health Organization/International Council for the Control of Iodine Deficiency Disorders: iodine replete, UIE > or = 100 microg/L; mild iodine deficiency, UIE 50-99 microg/L; moderate iodine deficiency, UIE 20-49 microg/L; severe iodine deficiency, UIE < 20 microg/L); (ii) Thyroid volumes measured by ultrasound (compared with new international reference values). RESULTS: Overall, children in mainland Australia are borderline iodine deficient, with a national median UIE of 104 microg/L. On a state basis, NSW and Victorian children are mildly iodine deficient, with median UIE levels of 89 microg/L and 73.5 microg/L, respectively. South Australian children are borderline iodine deficient, with a median UIE of 101 microg/L. Both Queensland and Western Australian children are iodine sufficient, with median UIE levels of 136.5 microg/L and 142.5 microg/L, respectively. Thyroid volumes in Australian schoolchildren are marginally increased compared with international normative data obtained from children living in iodine sufficient countries. There was no significant association between UIE and thyroid volume. CONCLUSION: Our results confirm the existence of inadequate iodine intake in the Australian population, and we call for the urgent implementation of mandatory iodisation of all edible salt in Australia.

Synthesis of thyroid hormone binding proteins transthyretin and albumin by human trophoblast.

CONTEXT: Mechanisms regulating materno-fetal transfer of thyroid hormone are not well understood. Modulation of trophoblast type 3 iodothyronine deiodinase (D3) may play an important role. OBJECTIVE: The objective of this study was to investigate trophoblast thyroid hormone binding proteins that may modulate interactions between D3 and T4. DESIGN: Placentas were obtained by informed consent from women delivering normal infants by repeat cesarean section at 38-40 wk gestation. T4 and T3 binding was examined in human placenta. Serum thyroid hormone binding proteins were identified by Western blotting, and their mRNA was examined by RT-PCR. Presence of these proteins in trophoblast was determined by immunocytochemistry and immunofluorescence. Cytosol was progressively purified to reveal additional thyroid hormone binding proteins that were identified by matrix-assisted laser desorption/ionization time of flight mass spectrometry. Effects of mefenamic acid on placental deiodination were examined by HPLC. RESULTS: We detected high-affinity T4 and T3 binding in human placental cytosol. All three major serum-binding proteins, T4 binding globulin (TBG), transthyretin (TTR), and albumin, were present in cytosol. TTR mRNA and albumin mRNA were detected in human placenta, and TTR and albumin were identified histochemically in syncytiotrophoblasts. Neither TBG mRNA nor TBG was detected, suggesting that plasma TBG had contaminated the cytosol preparation. Low-affinity thyroid hormone binding proteins alpha-1-antitrypsin and alpha-1-acid glycoprotein were also identified. Addition of mefenamic acid, a potent inhibitor of thyroid hormone binding, to placental cytosol significantly enhanced deiodination of T4 by D3. CONCLUSIONS: Placenta produces a series of thyroid hormone binding proteins that may modify thyroid hormone deiodination and materno-fetal thyroid hormone transport.

Lessons from the Clinical Support Systems Program: facilitating better practice through leadership and team building.

The increasing array of strategies and models for improving clinical practice and patient outcomes can be confusing for clinicians. The Clinical Support Systems (CSS) model has proved to be effective in local environments because it demystifies the design and implementation of evidence-based practice improvement projects. The CSS model is simple and has a wide scope. It provides a broad framework with minimalist specifications, enabling clinicians to design their own systems of care that cut across fragmented organisational structures. Implementing simple rules can be an effective strategy for change in complex care systems. These rules do not impose solutions on clinicians, but rather, help them to find creative solutions that have meaning for them and are contextually relevant.

6: Thyroid nodules and thyroid cancer.

Thyroid nodules are common clinically (prevalence, about 5%) and even more common on ultrasound examination (about 25%). About 5% of thyroid nodules are malignant. Most thyroid cancers are well-differentiated papillary or follicular tumours with an excellent prognosis (10-year survival, 80%-95%). The incidence of papillary thyroid cancer appears to be increasing on the east coast of Australia. Fine-needle aspiration biopsy of the thyroid is the most cost-effective diagnostic tool. Recommended initial management of all follicular carcinomas and of papillary carcinomas > 1.0 cm is total thyroidectomy followed by radioiodine ablation. Most patients should be managed postoperatively with doses of thyroid hormone sufficient to suppress plasma levels of thyroid-stimulating hormone. Recurrences can occur many years after initial therapy, and follow-up should be lifelong. Thyroid nodules are very common, but have a relatively low risk of malignancy