Are low sun exposure and/or vitamin D risk factors for type 1 diabetes?

The global variation in type 1 diabetes (T1D) incidence rates is one of the most significant observed for any non-communicable disease. Geographical patterns in incidence suggest that low sun exposure may contribute to the wide disparity, with incidence rates generally increasing with distance from the Equator. T1D development is associated with hyperactivity of the adaptive immune system leading to autoimmune destruction of insulin-secreting pancreatic ß cells. Both exposure to ultraviolet radiation (UVR) and vitamin D, with their known immunosuppressive effects, have the potential to delay or inhibit the disease. Efforts to confirm the role of UVR by vitamin D dependent and independent pathways in the pathogenesis of T1D have been challenged by inconsistent results among studies. Human observational studies and animal and in vitro experiments indicate that at least some of the benefits of sun exposure come from improved vitamin D status. There is no evidence of benefit for T1D risk of vitamin D supplementation during pregnancy at current recommended levels (400 IU per day); but some evidence supports that higher sun exposure and/or vitamin D sufficiency in pregnancy, or supplementation in early life, decreases T1D risk. Further research is required to confirm an association between UVR exposure and T1D and clarify the mechanisms involved.

Psychiatric disorders during early adulthood in those with childhood onset type 1 diabetes: Rates and clinical risk factors from population-based follow-up.

AIM: To determine the incidence of and risk factors for psychiatric disorders in early adulthood in patients with childhood onset type 1 diabetes (T1D). METHODS: In this retrospective-cohort study, we identified a population-based childhood onset T1D cohort and an age and sex matched (5:1) non-diabetic comparison cohort. Data linkage was used to access inpatient hospitalization data, mental health support service data, and mortality data to follow-up both cohorts into early adulthood. RESULTS: The mean age of T1D diagnosis was 9.5 years (SD 4.1), with a mean age at end of follow-up of 26.4 years (SD 5.2, max 37.7). The diagnosis of any psychiatric disorder was observed for 187 of 1302 (14.3%) in the T1D cohort and 400 of 6422 (6.2%) in the comparison cohort [adjusted hazard ratio (HR) 2.3; 95% CI 1.9, 2.7]. Anxiety, eating, mood, and personality and behaviour disorders were observed at higher rates within the T1D cohort. Comorbid psychiatric disorders were more frequent, at the cohort level, within the T1D cohort (2-3 disorders 3.76% vs 1.56%) and service utilization was higher (15+ contacts 6.8% vs 2.8%); though these differences did not remain when restricted to only those individuals diagnosed during follow-up. A history of poor glycaemic control was associated with an increased risk of anxiety, mood, and 'any' disorder (HR ranging from 1.35 to 1.42 for each 1% increase in mean paediatric HbA1c). CONCLUSION: Our findings highlight the need for access to mental health support services as part of routine patient care for young adults with T1D, and for better predictive tools to facilitate targeting at-risk patients with early intervention programs.

Mesothelioma risk after 40†years since first exposure to asbestos: a pooled analysis.

BACKGROUND: The risk of malignant mesothelioma (MM) increases proportionally to the cumulative exposure, and to the 3rd or 4th power of time since first exposed, to asbestos. However, little is known about the risk of MM after more than 40 years since first exposure because most epidemiological studies do not have follow-up for sufficient periods of time. METHODS: The data from six cohort studies of exposed workers and two cohorts with residential exposure have been pooled. A nested case control design matched cases and controls on calendar period and age. Conditional logistic regression modelled the relationship between time since first exposure and risk of MM. RESULTS: The combined data consisted of 22,048 people with asbestos exposure (5769 women), 707 cases of pleural MM (165 in women) and 155 cases of peritoneal MM (32 in women). Median time since first exposure for pleural MM cases was 38.4 years (IQR 31.3-45.3). Median duration of exposure for pleural MM cases was 3.75 years (IQR 0.7-18.2). The rate and risk of pleural MM increased until 45 years following first exposure and then appeared to increase at a slower power of time since first exposure. The rate of increase in peritoneal MM over the 10-50 years since first exposure continued to increase. CONCLUSIONS: Exposure to asbestos confers a long-term risk of developing pleural and peritoneal mesothelioma which increases following cessation of exposure. While the rate of increase appears to start to level out after 40-50 years no one survives long enough for the excess risk to disappear.

Clinical and demographic risk factors associated with mortality during early adulthood in a population-based cohort of childhood-onset type 1 diabetes.

AIMS: To calculate standardized mortality ratios and to assess the association between paediatric clinical factors and higher risk of mortality during early adulthood in a population-based cohort of subjects with Type 1 diabetes. METHODS: Subjects with Type 1 diabetes were identified through the Western Australian Children's Diabetes Database and clinical data for those who reached 18 years of age (n = 1309) were extracted. An age- and sex-matched (without diabetes) comparison cohort (n = 6451) was obtained from the birth registry. Mortality records were obtained from the death registry. Participants were followed up until 31 January 2012. Associations of clinical factors (from clinic visits before 18 years of age) with mortality were assessed using Cox proportional hazard models. RESULTS: The standardized mortality ratio for all-cause mortality was 1.7 (95% CI 0.7-3.3) for male and 10.1 (95% CI 5.2-17.7) for female subjects with Type 1 diabetes (median age at end of study 25.6 years). The adjusted hazard ratio was 1.5 (95% CI 1.1-2.1) for a 1% increase in mean paediatric HbA1c level, 3.8 (95% CI 0.9-15.3) for four episodes of severe hypoglycaemia relative to zero episodes, and 6.21 (95% CI 1.4-28.4) for a low-level socio-economic background relative to a high-level background. CONCLUSIONS: People with childhood-onset Type 1 diabetes have higher mortality rates in early adulthood. At particularly high risk are women, those with a history of poor HbA1c levels, those with recurrent severe hypoglycaemia during paediatric management, and those from a low socio-economic background. These groups may benefit from intensified management during transition from paediatric to adult care facilities.

No dose-dependent increase in fracture risk after long-term exposure to high doses of retinol or beta-carotene.

UNLABELLED: Uncertainty remains over whether or not high intakes of retinol or vitamin A consumed through food or supplements may increase fracture risk. This intervention study found no increase in fracture risk among 2,322 adults who took a controlled, high-dose retinol supplement (25,000 IU retinyl palmitate/day) for as long as 16 years. There was some evidence that beta-carotene supplementation decreased fracture risk in men. INTRODUCTION: There is conflicting epidemiological evidence regarding high intakes of dietary or supplemental retinol and an increased risk for bone fracture. We examined fracture risk in a study administering high doses of retinol and beta-carotene (BC) between 1990 and 2007. METHODS: The Vitamin A Program was designed to test the efficacy of retinol and BC supplements in preventing malignancies in persons previously exposed to blue asbestos. Participants were initially randomised to 7.5 mg retinol equivalents (RE)/day as retinyl palmitate, 30 mg/day BC or 0.75 mg/day BC from 1990 to 1996; after which, all participants received 7.5 mg RE/day. Fractures were identified by questionnaire and hospital admission data up until 2006. Risk of any fracture or osteoporotic fracture according to cumulative dose of retinol and BC supplementation was examined using conditional logistic regression models adjusting for age, sex, smoking, body mass index, medication use and previous fracture. RESULTS: Supplementation periods ranged from 1 to 16 years. Of the 2,322 (664 females and 1,658 males) participants, 187 experienced 237 fractures. No associations were observed between cumulative dose of retinol and risk for any fracture (OR per 10 g RE=0.83; 95% CI, 0.63-1.08) or osteoporotic fracture (OR per 10 g RE=0.95; 95% CI 0.64-1.40). Among men, cumulative dose of BC was associated with a slightly reduced risk of any fracture (OR per 10 g=0.89; 95% CI 0.81-0.98) and osteoporotic fracture (OR per 10 g=0.84; 95% CI 0.72-0.97). CONCLUSIONS: This study observed no increases in fracture risk after long-term supplementation with high doses of retinol and/or beta-carotene.

Malignant mesotheliomas in former miners and millers of crocidolite at Wittenoom (Western Australia) after more than 50 years follow-up.

BACKGROUND: To report the number of malignant pleural and peritoneal mesotheliomas that have occurred in former Wittenoom crocidolite workers to the end of 2008, to compare this with earlier predictions, and to relate the mesothelioma rate to amount of exposure. METHODS: A group of 6489 men and 419 women who had worked for the company operating the former Wittenoom crocidolite mine and mill at some time between 1943 and 1966 have been followed up throughout Australia and Italy to the end of 2008. RESULTS: The cumulative number of mesotheliomas up to 2008 was 316 in men (268 pleural, 48 peritoneal) and 13 (all pleural) in women. There had been 302 deaths with mesothelioma in men and 13 in women, which was almost 10% of all known deaths. Mesothelioma rate, both pleural and peritoneal, increased with time since first exposure and appeared to reach a plateau after about 40 to 50 years. The mesothelioma rate increased with amount of exposure and the peritoneal mesotheliomas occurred preferentially in the highest exposure group, 37% compared with 15% overall. CONCLUSION: By the end of 2008, the number of mesothelioma deaths had reached 4.7% for all the male workers and 3.1% for the females. Over the past 8 years the numbers were higher than expected. It is predicted that about another 60 to 70 deaths with mesothelioma may occur in men by 2020.

Risk of childhood acute lymphoblastic leukaemia following parental occupational exposure to extremely low frequency electromagnetic fields.

BACKGROUND: Earlier studies have reported moderate increases in the risk of acute lymphoblastic leukaemia (ALL) among children whose mothers have been occupationally exposed to extremely low frequency (ELF) electromagnetic fields. Other studies examining parental occupational exposure to ELF and ALL have reported mixed results. METHODS: In an Australian case-control study of ALL in children aged < 15 years, parents were asked about tasks they undertook in each job. Exposure variables were created for any occupational exposure before the birth of the child, in jobs 2 years before birth, in jobs 1 year before birth and up to 1 year after birth. RESULTS: In all, 379 case and 854 control mothers and 328 case and 748 control fathers completed an occupational history. Exposure to ELF in all time periods was similar in case and control mothers. There was no difference in exposure between case and control fathers. There was no association between maternal (odds ratio (OR)=0.96; 95% CI=0.74-1.25) or paternal (OR=0.78; 95% CI=0.56-1.09) exposure to ELF any time before the birth and risk of childhood ALL. CONCLUSION: We did not find an increased risk of ALL in offspring of parents with occupational exposure to ELF.

Predicting survival in malignant mesothelioma.

Malignant mesothelioma (MM) of the pleura or peritoneum is a universally fatal disease attracting an increasing range of medical interventions and escalating healthcare costs. Changes in survival and the factors affecting survival of all patients ever diagnosed with MM in Western Australia over the past five decades and confirmed by the Western Australian Mesothelioma Registry to December 2005 were examined. Sex, age, date and method of diagnosis, site of disease and histological type were recorded. Date of onset of symptoms and performance status were obtained from clinical notes for a sample of cases. Cox regression was used to examine the association of the clinical variables and the 10-yr periods of disease onset with survival after diagnosis. Survival was inversely related to age, being worse for males (hazard ratio (HR) 1.4, 95% CI 1.2-1.6), and those with peritoneal mesothelioma (HR 1.4, 95% CI 1.1-1.7). Patients with sarcomatoid histology had worse prognosis than patients with epithelioid and biphasic histological subtypes. Survival improved after the 1970s and has made incremental improvements since then. Median (interquartile range) survival by decade, from 1960 until 2005, was 64 (0-198), 177 (48-350), 221 (97-504), 238 (108-502) and 301 (134-611) days; ~4 weeks of this apparent improvement can be attributed to earlier diagnosis. With increasing resources and treatment costs for MM over the past 40 yrs, there have been modest improvements in survival but no complete remissions.

Vitamin D and atopy and asthma phenotypes in children: a longitudinal cohort study.

Vitamin D has been linked in some studies with atopy- and asthma-associated phenotypes in children with established disease, but its role in disease inception at the community level is less clear. The aim of the present study was to investigate associations between vitamin D status and biological signatures indicative of allergy and asthma development in children aged 6 and 14 years in Perth, WA, Australia (latitude 32° S). Serum vitamin D was assayed in 989 6-yr-olds and 1,380 14-yr-olds from an unselected community birth cohort; 689 subjects were assessed at both ages. Vitamin D levels were assessed as a risk modifier for respiratory and allergic outcomes at both ages, using previously ascertained phenotypic data. The predictive value of vitamin D levels at age 6 yrs for development of clinical phenotypes at age 14 yrs was also examined. Serum vitamin D levels in children of both ages were negatively associated with concurrent allergic phenotypes; sex stratification revealed that this association was restricted mainly to males. Furthermore, vitamin D levels at age 6 yrs were significant predictors of subsequent atopy/asthma-associated phenotypes at age 14 yrs. In an unselected community setting, children (particularly males) with inadequate vitamin D are at increased risk of developing atopy, and subsequently bronchial hyperresponsiveness (BHR) and asthma. In a large unselected cohort, males with inadequate vitamin D at 6 and 14 yrs of age had increased atopy and BHR. Low vitamin D at age 6 yrs was a predictor of atopy and asthma at 14 yrs of age.

Th2-associated immunity to bacteria in teenagers and susceptibility to asthma.

Bacterial colonisation of the airways is associated with increased risk of childhood asthma. Immunoglobulin (Ig)E against bacterial antigens has been reported in some asthmatics, suggesting a role for bacterial-specific type-2 immunity in disease pathogenesis. We aimed to investigate relationships between bacterial-specific IgE amongst teenagers and asthma susceptibility. We measured titres of IgE against Haemophilus influenzae, Streptococcus pneumoniae and Staphylococcus aureus in 1,380 teenagers, and related these to asthma symptomatology and immunophenotypes. IgE titres against S. aureus-derived enterotoxins were highest amongst atopics and were associated with asthma risk. Surprisingly, IgE titres against H. influenzae and S. pneumoniae surface antigens were higher, not stratified by atopy and independently associated with decreased asthma risk. The positive association between type-2 immunity to S. aureus and asthma phenotypes probably reflects IgE-mediated effector cell activation via enterotoxin super antigens which are secreted in soluble form. The contrasting benign nature of type-2 immunity to H. influenzae and S. pneumoniae antigens may reflect their lower availability in soluble forms that can crosslink IgE receptors. We theorise that instead they may be processed by antigen presenting cells and presented to type-2 memory cells leading to mucosal secretion of interleukin (IL)-4/IL-13, a mechanism widely recognised in other tissues to attenuate T-helper-1 associated bacterial-induced inflammation.

Low-moderate prenatal alcohol exposure and risk to child behavioural development: a prospective cohort study.

OBJECTIVE: To examine the association of fetal alcohol exposure during pregnancy with child and adolescent behavioural development. DESIGN: The Western Australian Pregnancy Cohort (Raine) Study recruited 2900 pregnancies (1989-91) and the 14-year follow up was conducted between 2003 and 2006. SETTING: Tertiary obstetric hospital in Perth, Western Australia. POPULATION: The women in the study provided data at 18 and 34 weeks of gestation on weekly alcohol intake: no drinking, occasional drinking (up to one standard drink per week), light drinking (2-6 standard drinks per week), moderate drinking (7-10 standard drinks per week), and heavy drinking (11 or more standard drinks per week). Methods Longitudinal regression models were used to analyse the effect of prenatal alcohol exposure on Child Behaviour Checklist (CBCL) scores over 14 years, assessed by continuous z-scores and clinical cutoff points, after adjusting for confounders. MAIN OUTCOME MEASURE: Their children were followed up at ages 2, 5, 8, 10 and 14 years. The CBCL was used to measure child behaviour. RESULTS: Light drinking and moderate drinking in the first 3 months of pregnancy were associated with child CBCL z-scores indicative of positive behaviour over 14 years after adjusting for maternal and sociodemographic characteristics. These changes in z-score indicated a clinically meaningful reduction in total, internalising and externalising behavioural problems across the 14 years of follow up. CONCLUSIONS: Our findings do not implicate light-moderate consumption of alcohol in pregnancy as a risk factor in the epidemiology of child behavioural problems.

Dietary patterns and markers for the metabolic syndrome in Australian adolescents.

BACKGROUND AND AIMS: Overweight and other risk factors for cardiovascular disease (CVD) as well as their clustering, are increasingly prevalent among adolescents. We examined dietary patterns, CVD risk factors, and the clustering of these risk factors in 1139 14-year-olds living in Western Australia. METHODS AND RESULTS: Usual dietary intake was assessed using a food frequency questionnaire. Two dietary patterns, 'Western' and 'Healthy', were identified using factor analysis. Associations between these dietary patterns and BMI, waist circumference, systolic blood pressure, fasting levels of serum glucose, insulin, total cholesterol, HDL-C, LDL-C, triglycerides and insulin resistance were assessed using ANOVA. Cluster analysis identified a high risk group (the 'high risk metabolic cluster') with features akin to adult metabolic syndrome. Belonging to the 'high risk metabolic cluster' was examined in relation to dietary patterns using logistic regression, adjusting for aerobic fitness and socio-demographic factors. Higher 'Western' dietary pattern scores were associated with greater odds for the 'high risk metabolic cluster' (p for trend=0.02) and greater mean values for total cholesterol (p for trend=0.03), waist circumference (p for trend=0.03) and BMI (p for trend=0.02) in girls, but not boys. Scores for the 'Healthy' dietary pattern were not related to the 'high risk metabolic cluster' but were inversely associated with serum glucose in boys and girls (p for trend=0.01 and 0.04, respectively) and were positively associated with HDL-C in boys (p for trend=0.02). CONCLUSIONS: Dietary patterns are associated with CVD risk factors and the clustering of these risk factors in adolescence.

Fetal growth and risk of childhood acute lymphoblastic leukemia: results from an Australian case-control study.

The relation between intrauterine growth and risk of childhood acute lymphoblastic leukemia was investigated in an Australian population-based case-control study that included 347 cases and 762 controls aged <15 years recruited from 2003 to 2006. Information on proportion of optimal birth weight, a measure of the appropriateness of fetal growth, was collected from mothers by questionnaire. Data were analyzed by using logistic regression. Risk of acute lymphoblastic leukemia was positively associated with proportion of optimal birth weight; the odds ratio for a 1-standard-deviation increase in proportion of optimal birth weight was 1.18 (95% confidence interval: 1.04, 1.35) after adjustment for the matching variables and potential confounders. This association was also present among children who did not have a high birth weight, suggesting that accelerated growth, rather than high birth weight per se, is associated with risk of acute lymphoblastic leukemia. Similar associations between proportion of optimal birth weight and acute lymphoblastic leukemia were observed for both sexes and across age groups and leukemia subtypes. Results of this study confirm earlier findings of a positive association between rapidity of fetal growth and subsequent risk of acute lymphoblastic leukemia in childhood, and they are consistent with a role for insulin-like growth factors in the causal pathway.

The PHF11 gene is not associated with asthma or asthma phenotypes in two independent populations.

BACKGROUND: Numerous areas of the human genome have previously been associated with asthma and asthma-related phenotypes, but few positive findings have been successfully replicated in independent populations. Initial studies have reported strong associations of variants in the plant homeodomain zinc finger protein 11 (PHF11) gene with serum IgE levels, asthma, airway hyper-responsiveness and childhood atopic dermatitis. OBJECTIVES: To investigate the association of variants in the PHF11 gene with asthma and associated intermediate phenotypes in two independent Western Australian population-based samples. METHODS: A linkage-disequilibrium (LD)-tagging set of 20 single nucleotide polymorphisms (SNPs) was genotyped in PHF11 in two separate populations (total n = 2315), a family-based twin study consisting of 230 families (n = 992 subjects) and a population-based nested case-control study consisting of 617 asthma cases and 706 controls. Information regarding asthma, respiratory physiology, atopy and environmental exposures was collected. Transmission disequilibrium tests, variance components models and generalised linear models were used to test for association between PHF11 SNPs and selected asthma outcomes (including longitudinal change in lung function). RESULTS: After correction for multiple testing, no statistically significant (p < 0.05) associations were found between PHF11 and either asthma or total serum IgE levels in either population. No statistically significant associations were found with any other asthma-associated phenotypes in either population. CONCLUSIONS: Previously reported associations of PHF11 with asthma outcomes were not replicated in this study. This study suggests that PHF11 is unlikely to contain polymorphic loci that have a major impact on asthma susceptibility in our populations.

Cross-sectional and longitudinal association of the secretoglobin 1A1 gene A38G polymorphism with asthma phenotype in the Perth Infant Asthma Follow-up cohort.

BACKGROUND: Associations between Clara cell secretory protein gene variants (SCGB1A1, also known as CC16, CC10, CCSP and uteroglobin) and the asthma phenotype have been found in five out of eight studies world-wide. No study has investigated the contribution of SCGB1A1 polymorphisms to the development and/or persistence of the asthma phenotype in a birth cohort followed over time. OBJECTIVE: The aim of this study was to determine the role of the SCGB1A1 gene in the development of the asthma phenotype. METHODS: The Perth Infant Asthma Follow-up (PIAF) cohort (n=231 unrelated infants, unselected for asthma and recruited at birth) were seen at 1 month, 6 and 11 years of age, and had a questionnaire, lung function, airway responsiveness (AR) and skin prick tests (SPTs) completed. Blood was taken at 6 and 11 years for total and specific immunoglobulin E (sIgE) and DNA extraction. SPT positivity had at least one positive SPT. SIgE>4 kU/L had at least one sIgE above 4 kU/L. SCGB1A1 A38G (rs3741240), that alters gene transcription, was genotyped using Sau96I restriction digestion of exon 1 PCR products. RESULTS: At 6 and 11 years of age, 33.0% and 29.7% of those genotyped had doctor-diagnosed asthma, and 35.8% and 52.1% had SPT positivity. In cross-sectional analyses, children with 38G/38A or 38A/38A had increased AR at 1 month (1.72-fold, P=0.013); sIgE>4 kU/L [odds ratio (OR)=6.95, 95% confidence interval (CI)=1.35-35.91, P=0.021]; house dust mite (HDM) SPT positivity (OR=7.21, 95% CI=1.09-47.78, P=0.041) and sIgE (4.57-fold, P=0.045) at 6 years; and doctor-diagnosed asthma (OR=3.93, 95% CI=1.24-12.47, P=0.02) and cat SPT positivity (OR=4.34, 95% CI=1.01-18.77, P=0.049) at 11 years. Longitudinal analyses of 6 and 11 years paired data showed that children with 38A/38A had increased persistent sIgE>4 kU/L (OR=11.87, 95% CI=1.97-71.53, P=0.007) and persistent HDM SPT positivity (OR=7.84, 95% CI=1.04-58.92, P=0.045). CONCLUSION: SCGB1A1 A38G may play a role in the development and persistence of the asthma phenotype in childhood.

Predicted mortality from malignant mesothelioma among women exposed to blue asbestos at Wittenoom, Western Australia.

INTRODUCTION: Nearly 3000 women and girls were documented to have lived at the blue asbestos mining and milling town of Wittenoom in Western Australia between 1943 and 1992. Eight per cent of deaths among these women to the end of 2004 have been from malignant mesothelioma of the pleura. AIM: To predict future mortality from mesothelioma to 2030 in this cohort. METHODS: Mesothelioma mortality rates incorporating parameters for cumulative exposure, a power of time since first exposure and annual rates of fibre clearance from the lung were calculated from maximum likelihood estimates. These rates plus age specific mortality rates for Western Australian females incorporating an excess lung cancer risk were then applied to all Wittenoom cohort women surviving to the end of 2004, in yearly increments, to predict the future numbers of cases of mesothelioma to 2030. RESULTS: There were 40 deaths from mesothelioma among the Wittenoom women to the end of 2004. Using a range of models that incorporate time since first exposure, competing risks from other diseases, latency periods and clearance of mesothelioma from the lungs we predict 66 (lowest estimate) to 87 (highest estimate) deaths from mesothelioma until 2030. This represents one and a half to two and a half times the number of deaths that have already occurred to the end of 2004. CONCLUSION: The high toll from mesothelioma in this cohort of women and girls will continue well into the future.

Mortality of former crocidolite (blue asbestos) miners and millers at Wittenoom.

BACKGROUND: Blue asbestos was mined and milled at Wittenoom in Western Australia between 1943 and 1966. METHODS: Nearly 7000 male workers who worked at the Wittenoom mine and mill have been followed up using death and cancer registries throughout Australia and Italy to the end of 2000. Person-years at risk were derived using two censoring dates in order to produce minimum and maximum estimates of asbestos effect. Standardised mortality ratios (SMRs) compare the mortality of the former Wittenoom workers with the Western Australian male population. RESULTS: There have been 190 cases of pleural and 32 cases of peritoneal mesothelioma in this cohort of former workers at Wittenoom. Mortality from lung cancer (SMR = 1.52), pneumoconiosis (SMR = 15.5), respiratory diseases (SMR = 1.58), tuberculosis (SMR = 3.06), digestive diseases (SMR = 1.47), alcoholism (SMR = 2.24) and symptoms, signs and ill defined conditions (SMR = 2.00) were greater in this cohort compared to the Western Australian male population. CONCLUSION: Asbestos related diseases, particularly malignant mesothelioma, lung cancer and pneumoconiosis, continue to be the main causes of excess mortality in the former blue asbestos miners and millers of Wittenoom.

Altered glucose metabolism in childhood pre-B acute lymphoblastic leukaemia.

The cells of solid tumours are known to have an altered metabolism, with high rates of glucose uptake and glycolysis, which results in the excessive production of lactate. To date there has been no definitive research documenting metabolic changes in acute lymphoblastic leukaemia (ALL) cells. In order to investigate whether ALL cells have an altered metabolism, we initially compared the transcriptional profiles of 22 specimens from paediatric patients diagnosed with ALL to five CD34+ specimens isolated from bone marrow, which was verified in an independent cohort of 101 specimens. Profiling revealed the upregulation of genes facilitating glycolysis in the ALL specimens compared to the CD34+ specimens, while those involved in the tricarboxylic acid cycle were downregulated. Functional studies supported the microarray findings threefold: (1) higher expression of the glucose transport protein glucose transporter 1 in ALL compared to CD34+ specimens, (2) the excessive production of lactate in ALL cell lines and (3) sensitivity of ALL cell lines to the glycolysis inhibitor 2-deoxy-D-glucose. While metabolic alterations have been well documented in solid tumours, this is the first study to provide direct evidence for the existence of metabolic changes in the leukaemic cells of ALL patients. The finding offers new options for targeted therapy for ALL patients.

The risk of lung cancer with increasing time since ceasing exposure to asbestos and quitting smoking.

OBJECTIVES: To examine if the risk of lung cancer declines with increasing time since ceasing exposure to asbestos and quitting smoking, and to determine the relative asbestos effect between non-smokers and current smokers. METHODS: A cohort study of 2935 former workers of the crocidolite mine and mill at Wittenoom, who responded to a questionnaire on smoking first issued in 1979 and on whom quantitative estimates of asbestos exposure are known. Conditional logistic regression was used to relate asbestos exposure, smoking category, and risk of lung cancer. RESULTS: Eighteen per cent of the cohort reported never smoking; 66% of cases and 50% of non-cases were current smokers. Past smokers who ceased smoking within six years of the survey (OR = 22.1, 95% CI 5.6 to 87.0), those who ceased smoking 20 or more years before the survey (OR = 1.9, 95% CI 0.50 to 7.2), and current smokers (<20 cigarettes per day (OR = 6.8, 95% CI 2.0 to 22.7) or >20 cigarettes per day (OR = 13.2, 95% CI 4.1 to 42.5)) had higher risks of lung cancer compared to never smokers after adjusting for asbestos exposure and age. The asbestos effect between non-smokers and current smokers was 1.23 (95% CI 0.35 to 4.32). CONCLUSION: Persons exposed to asbestos and tobacco but who subsequently quit, remain at an increased risk for lung cancer up to 20 years after smoking cessation, compared to never smokers. Although the relative risk of lung cancer appears higher in never and ex-smokers than in current smokers, those who both smoke and have been exposed to asbestos have the highest risk; this study emphasises the importance of smoking prevention and smoking cessation programmes within this high risk cohort.

Etiology of common acquired melanocytic nevi: constitutional variables, sun exposure, and diet.

Associations were sought between prevalence of nevi on the arms and other variables in controls from a case-control study of cutaneous malignant melanoma. The prevalence of nevi was higher in women than men, fell with age up to about 35 years of age, and was low in those born outside Australia. Among pigmentary characteristics, there was strong evidence only of an association with skin color of the upper inner arm. The highest prevalence of nevi was in those with skin of intermediate darkness. Peak prevalence of nevi was also seen in intermediate categories of variables indicating sun exposure, particularly mean annual hours of bright sunlight at places of residence when 10-24 years of age, total outdoor exposure time per week in the summer at 10-24 years of age, and usual summer suntan on the arms in the last 10 years. These dose-effect patterns may indicate conflicting effects of sun exposure on appearance and disappearance of nevi. The protective effect of birthplace outside Australia appeared to be due to the corresponding low mean annual hours of bright sunlight at places of residence when 10-24 years of age. The prevalence of nevi was comparatively lower in those who drank alcohol and in those who had average or high daily intakes of retinol. These associations were not explained by those of any of the other variables.