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The Wittenoom crocidolite (blue asbestos) mine and mill ceased operating in 1966. The impact of this industry on asbestos-related disease in Western Australia has been immense. Use of the employment records of the Australian Blue Asbestos Company and records of the Wittenoom township residents has permitted two cohorts of people with virtually exclusive exposure to crocidolite to be assembled and studied. Follow-up of these two cohorts has been conducted through data linkage with available hospital, mortality and cancer records. The evolution of asbestos-related disease has been recorded and, with the establishment of exposure measurements, quantitative exposure-response relationships have been estimated. There has been an ongoing epidemic of mortality from lung cancer and malignant mesothelioma and, less so, from asbestosis. Wittenoom crocidolite was used extensively in asbestos-cement products in Western Australia. As a result, the state has recorded a higher malignant-mesothelioma mortality rate than in any other Australian state and in any defined general population in the world. Thus, the legacy of Wittenoom has extended beyond the mine and the town, and is still evident more than 50 years after the closure of the mine. [ABSTRACT FROM AUTHOR]

Malignant mesothelioma is an aggressive, treatment-resistant tumour, which is increasing in frequency throughout the world. Although the main risk factor is asbestos exposure, a virus, simian virus 40 (SV40), could have a role. Mesothelioma has an unusual molecular pathology with loss of tumour suppressor genes being the predominant pattern of lesions, especially the P16INK4A, and P14ARF, and NF2 genes, rather than the more common p53 and Rb tumour suppressor genes. Cytopathology of mesothelioma effusions or fine-needle aspirations are often sufficient to establish a diagnosis, but histopathology is also often required. Patients typically present with breathlessness and chest pain with pleural effusions. Median survival is now 12 months from diagnosis. Palliative chemotherapy is beneficial for mesothelioma patients with high performance status. The role of aggressive surgery remains controversial and growth factor receptor blockade is still unproven. Gene therapy and immunotherapy are used on an experimental basis only. Patterns identified from microarray studies could be useful for diagnosis as well as prognostication. [ABSTRACT FROM AUTHOR]

Malignant pleural mesothelioma (MPM) is an incurable cancer of the pleura that can be difficult to diagnose. Biomarkers for an easier and/or earlier diagnosis are needed. Approximately 90% of MPM patients develop a pleural effusion (PE). PEs are ideal sources of biomarkers as the fluid would almost always require drainage for diagnostic and/or therapeutic reasons. However, differentiating MPM PE from PE caused by other diseases can be challenging. MicroRNAs are popular biomarkers given their stable expression in tissue and fluid. MicroRNAs have been analysed in PE cytology samples for the diagnosis of MPM but have not been measured in frozen/fresh PE. We hypothesise that microRNAs expressed in PE are biomarkers for MPM. TaqMan OpenArray was used to analyse over 700 microRNAs in PE cells and supernatants from 26 MPMs and 21 other PE-causing diseases. In PE cells, combining miR-143, miR-210, and miR-200c could differentiate MPM with an area under the curve (AUC) of 0.92. The three-microRNA signature could also discriminate MPM from a further 40 adenocarcinomas with an AUC of 0.9887. These results suggest that the expression of miR-143, miR-210, and miR-200c in PE cells might provide a signature for diagnosing MPM. [ABSTRACT FROM AUTHOR]

There is evidence that dendritic cells (DCs) undergo age-related changes that modulate their function with their key role being priming antigen-specific effector T cells. This occurs once DCs develop into antigen-presenting cells in response to stimuli/danger signals. However, the effects of aging on DC responses to bacterial lipopolysaccharide (LPS), the pro-inflammatory cytokine interferon (IFN)-γ and CD40 ligand (CD40L) have not yet been systematically evaluated. We examined responses of blood myeloid (m)DC1s, mDC2s, plasmacytoid (p)DCs, and monocyte-derived DCs (MoDCs) from young (21–40 years) and elderly (60–84 years) healthy human volunteers to LPS/IFN-γ or CD40L stimulation. All elderly DC subsets demonstrated comparable up-regulation of co-stimulatory molecules (CD40, CD80 and/or CD86), intracellular pro-inflammatory cytokine levels (IFN-γ, tumour necrosis factor (TNF)-α, IL-6 and/or IL-12), and/or secreted cytokine levels (IFN-α, IFN-γ, TNF-α, and IL-12) to their younger counterparts. Furthermore, elderly-derived LPS/IFN-γ or CD40L-activated MoDCs induced similar or increased levels of CD8+ and CD4+ T cell proliferation, and similar T cell functional phenotypes, to their younger counterparts. However, elderly LPS/IFN-γ-activated MoDCs were unreliable in their ability to up-regulate chemokine (IL-8 and monocyte chemoattractant protein (MCP)-1) and IL-6 secretion, implying an inability to dependably induce an inflammatory response. A key age-related difference was that, unlike young-derived MoDCs that completely lost their ability to process antigen, elderly-derived MoDCs maintained their antigen processing ability after LPS/IFN-γ maturation, measured using the DQ-ovalbumin assay; this response implies incomplete maturation that may enable elderly DCs to continuously present antigen. These differences may impact on the efficacy of anti-pathogen and anti-tumour immune responses in the elderly. [ABSTRACT FROM AUTHOR]

Repetitive airway occlusion during sleep in patients with obstructive sleep apnoea (OSA) results in the generation of negative intrathoracic pressures and ends in arousal, both of which may predispose to reflux during sleep (nocturnal reflux). We aimed to determine and compare the prevalence of nocturnal reflux symptoms and their sleep-associated risk factors in untreated OSA patients, OSA patients using continuous positive airway pressure (CPAP) therapy, and the general population. Gastro-oesophageal reflux and sleep questionnaires were completed by 1116 patients with polysomnography diagnosed OSA and by 1999 participants of the 2007 Busselton population health survey. Of the OSA patients, 137 completed the reflux questionnaire before and after treatment. Risk of OSA in the general population was assessed using the Berlin score. The prevalence of frequent (>weekly) nocturnal reflux symptoms was increased ( P < 0.001) in OSA patients (10.2%) versus the general population (5.5%), in individuals from the general population at high (8.7%) versus low risk (4.3%) of OSA and in patients with severe (13.9%) versus mild OSA (5.1%). Frequent nocturnal reflux symptoms were associated with high risk (general population) (OR 1.9, P < 0.01) and severity of OSA (OSA population) OR 3.0, severe versus mild OSA, P < 0.001) after correcting for age, gender and body mass index. Treatment with CPAP decreased the prevalence of reflux symptoms significantly. In conclusion, the prevalence of nocturnal reflux symptoms is increased in those with or suspected of having OSA. This association is independent of other risk factors including age, gender and body mass index, suggesting a causal relationship between OSA and nocturnal reflux. [ABSTRACT FROM AUTHOR]

This study, notwithstanding limitations of its approach, provides the first comprehensive evaluation of adult patients at least 12 months following tPA/DNase treatment for pleural infection. Without a comparison group (e.g. those successfully treated without tPA/DNase or those treated with surgery only), it is difficult to determine if residual symptoms or defects are related to tPA/DNase.5,8 Patient recall biases are inevitable in cross-sectional studies. This cross-sectional multicentre cohort study reports, for the first time, long-term clinical, respiratory and functional outcomes >=12 months following tPA/DNase treatment for pleural infection. Keywords: deoxyribonuclease; intrapleural; pleural effusion; respiratory infection; tissue plasminogen activator EN deoxyribonuclease intrapleural pleural effusion respiratory infection tissue plasminogen activator 388 391 4 03/22/21 20210401 NES 210401 Abbreviations CP loss obliteration of costophrenic angle CXR chest radiograph DNase deoxyribonuclease FEV 1 forced expiratory volume in 1 s FVC forced vital capacity IQR interquartile range mMRC modified Medical Research Council QoL quality of life SF-36v2 36-item short form health survey TLC total lung capacity tPA tissue plasminogen activator Intrapleural tissue plasminogen activator/deoxyribonuclease (tPA/DNase) therapy has been rapidly adopted worldwide for treating pleural infection. [Extracted from the article]

Objectives An asbestos job-exposure matrix (AsbJEM) has been developed to systematically and cost-effectively evaluate occupational exposures in population-based studies. The primary aim of this study was to examine the accuracy of the AsbJEM in determining exposure–response relationships between asbestos exposure estimates and malignant mesothelioma (MM) incidence (indirect validation). The secondary aim was to investigate whether the assumptions used in the development of the original AsbJEM provided accurate asbestos exposure estimates. Methods The study population consisted of participants in an annual health surveillance program, who had at least 3-month occupational asbestos exposure. Calculated asbestos exposure indices included cumulative asbestos exposure and the average exposure intensity, estimated using the AsbJEM and duration of employment. Asbestos and MM exposure–response relationships were compared between the original AsbJEM and its variations based on manipulations of the intensity, duration and frequency of exposure. Twenty-four exposure estimates were calculated for both cumulative asbestos exposure and the average exposure intensity using three exposure intensities (50th, 75th and 90th percentile of the range of mode exposure), four peak durations (15, 30, 60 and 120 min) and two patterns of peak frequency (original and doubled). Cox proportional hazards models were used to describe the associations between MM incidence and each of the cumulative and average intensity estimates. Results Data were collected from 1602 male participants. Of these, 40 developed MM during the study period. There were significant associations between MM incidence and both cumulative and average exposure intensity for all estimates. The strongest association, based on the regression-coefficient from the models, was found for the 50th percentile of mode exposure, 15-min peak duration and the doubled frequency of peak exposure. Using these assumptions, the hazard ratios for mesothelioma were 1 (reference), 1.91, 3.24 and 5.37 for the quartiles of cumulative asbestos exposure and 1 (reference), 1.84, 2.31 and 4.40 for the quartiles of the average exposure intensity, respectively. Conclusion The well-known positive exposure–response relationship between MM incidence and both estimated cumulative asbestos exposure and average exposure intensity was confirmed. The strongest relationship was found when the frequency of peak exposure in the AsbJEM was doubled from the originally published estimates. [ABSTRACT FROM AUTHOR]

Background and objective: The relationship between vitamin D and respiratory disease was examined by cross-sectional analysis of a large community-based sample. Methods: Serum 25-hydroxyvitamin D (25OHD) and history of respiratory disease, symptoms (recorded by questionnaire) and spirometry were measured in 5011 adults aged 45-69 years. Adjustments were made for age, sex, season and smoking (Model A), plus body mass index (BMI) and physical activity level (Model B), plus history of chronic diseases (Model C). Results: Mean (SD) age was 58 (SD 6) years with 45% males, 10% current smokers and 12% taking vitamin D supplements. The prevalence of 25OHD level <50 nmol/L was 8.0%. In all the three models, 25OHD <50 nmol/L was significantly associated with asthma (Model C: odds ratio (OR): 1.32; 95% CI: 1.00, 1.73), bronchitis (1.54; 1.17, 2.01), wheeze (1.37; 1.10, 1.71) and chest tightness (1.42; 1.10, 1.83). Participants with vitamin D level > 100 nmol/L had higher forced vital capacity (FVC) in all the three models (1.17% higher, compared with the 50-100 nmol/L group in Model C). Conclusion: Low levels of serum 25OHD were independently associated with asthma, bronchitis, wheeze and chest tightness after three levels of adjustment for potential confounders. Higher vitamin D levels were associated with higher levels of lung function. [ABSTRACT FROM AUTHOR]

Background: Malignant mesothelioma (MM) is a deadly cancer mainly caused by previous exposure to asbestos. With a latency period up to 50 years the incidence of MM is still increasing, even in countries that banned asbestos. Secondary prevention has been established to provide persons at risk regular health examinations. An earlier detection with tumor markers might improve therapeutic options. Previously, we have developed a new blood-based assay for the protein marker calretinin. Aim of this study was the verification of the assay in an independent study population and comparison with the established marker mesothelin.Methods: For a case-control study in men, a total of 163 cases of pleural MM and 163 controls were available from Australia, another 36 cases and 72 controls were recruited in Germany. All controls had asbestosis and/or plaques. Calretinin and mesothelin were determined by ELISA (enzyme-linked immunosorbent assay) in serum or plasma collected prior to therapy. We estimated the performance of both markers and tested factors potentially influencing marker concentrations like age, sample storage time, and MM subtype.Results: Calretinin was able to detect all major subtypes except for sarcomatoid MM. Calretinin showed a similar performance in Australian and German men. At a pre-defined specificity of 95% the sensitivity of calretinin reached 71% and that of mesothelin 69%, when excluding sarcomatoid MM. At 97% specificity, the combination with calretinin increased the sensitivity of mesothelin from 66% to 75%. Sample storage time did not influence the results. In controls the concentrations of calretinin increased 1.87-fold (95% CI 1.10-3.20) per 10 years of age and slightly more for mesothelin (2.28, 95% CI 1.30-4.00).Conclusions: Calretinin could be verified as a blood-based marker for MM. The assay is robust and shows a performance that is comparable to that of mesothelin. Retrospective analyses would not be limited by storage time. The high specificity supports a combination of calretinin with other markers. Calretinin is specific for epithelioid and biphasic MM but not the rarer sarcomatoid form. Molecular markers like calretinin and mesothelin are promising tools to improve and supplement the diagnosis of MM and warrant further validation in a prospective study. [ABSTRACT FROM AUTHOR]

Background: Progressive burden of diabetes mellitus is a major concern in India. Data on the predictors of poor glycemic control among diabetics are scanty. A population-based cross-sectional study nested in an urban cohort was thus conducted in West Bengal, India to determine the burden and correlates of total and uncontrolled abnormalities in glucose metabolism (AGM) in a representative population. Methods: From 9046 adult cohort-members, 269 randomly selected consenting subjects (non-response = 7.24%) were interviewed, examined [blood pressure (BP), anthropometry], tested for fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1C). Those having pre-diagnosed diabetes or FPG ≥126 or HbA1c≥6.5 were defined as diabetic. Among non-diabetics, subjects with FPG (mg/dl) = 100–125 or HbA1C(%) = 5.7–6.4 were defined as pre-diabetic. Pre-diagnosed cases with current FPG ≥126 were defined as uncontrolled AGM. Descriptive and regression analyses were conducted using SAS-9.3.2. Results: Among participants, 28.62% [95% Confidence Interval (95%CI) = 23.19–34.06)] were overweight [body mass index(BMI) = (25–29.99)kg/meter2], 7.81% (4.58–11.03) were obese(BMI≥30kg/meter2), 20.82% (15.93–25.70) were current smokers, 12.64% (8.64–16.64) were current alcohol-drinkers and 46.32% of responders (39.16–53.47) had family history of diabetes. 17.84% (13.24–22.45) had stage-I [140≤average systolic BP (AvSBP in mm of mercury)<160 or 90≤average diastolic BP (AvDBP)<100] and 12.64% (8.64–16.64) had stage-II (AvSBP≥160 or AvDBP≥160) hypertension. Based on FPG and HbA1c, 10.41% (6.74–14.08) were diabetic and 27.88% (22.49–33.27) were pre-diabetic. Overall prevalence of diabetes was 15.61% (11.25–19.98). Among pre-diagnosed cases, 46.43% (26.74–66.12) had uncontrolled AGM. With one year increase in age [Odds Ratio(OR) = 1.05(1.03–1.07)], retired subjects [OR = 9.14(1.72–48.66)], overweight[OR = 2.78(1.37–5.64)], ex-drinkers [OR = 4.66(1.35–16.12)] and hypertensives [ORStage I = 3.75(1.42–9.94); ORStage II = 4.69(1.67–13.17)] had higher odds of diabetes. Relatively older subjects [OR = 1.06(1.02–1.10)], unemployed [OR = 19.68(18.64–20.78)], business-owners [OR = 25.53(24.91–16.18)], retired [OR = 46.53(45.38–47.72)], ex-smokers [OR = 4.75(1.09–20.78)], ex-drinkers [OR = 22.43(4.62–108.81)] and hypertensives [ORStage II = 13.17(1.29–134.03)] were more likely to have uncontrolled AGM. Conclusions: Burden of uncontrolled AGM was high among participants. Efforts to curb the diabetes epidemic in urban India should include interventions targeting appropriate diabetic control among relatively older persons, unemployed, business-owners, retired, ex-smokers, ex-drinkers and hypertensives. [ABSTRACT FROM AUTHOR]

Mesothelioma is an almost invariably fatal tumor with chemotherapy extending survival by a few months. One immunotherapeutic strategy is to target dendritic cells (DCs), key antigen-presenting cells involved in antigen presentation, to induce antigen-specific T cell responses. However, DC-targeting will only be effective if DCs are fit-for-purpose, and the functional status of DCs in mesothelioma patients was not clear. We found that mesothelioma patients have significantly decreased numbers of circulating myeloid (m)DC1 cells, mDC2 cells and plasmacytoid (p)DCs relative to healthy age and gender-matched controls. Blood monocytes from patients could not differentiate into immature monocyte-derived DCs (MoDCs), indicated by a significantly reduced ability to process antigen and reduced expression of costimulatory (CD40, CD80 and CD86) and MHC (HLA-DR) molecules, relative to controls. Activation of mesothelioma-derived MoDCs with LPS+/-IFNγ generated partially mature MoDCs, evident by limited upregulation of the maturation marker, CD83, and the costimulatory markers. Attempts to rescue mesothelioma-derived DC function using CD40Ligand(L) also failed, indicated by maintenance of antigen-processing capacity and limited upregulation of CD40, CD83, CD86 and HLA-DR. These data suggest that mesothelioma patients have significant numerical and functional DC defects and that their reduced capacity to process antigen and reduced expression of costimulatory molecules could induce anergized/tolerized T cells. Nonetheless, survival analyses revealed that individuals with mesothelioma and higher than median levels of mDC1s and/or whose MoDCs matured in response to LPS, IFNγ or CD40L lived longer, implying their selection for DC-targeting therapy could be promising especially if combined with another treatment modality. [ABSTRACT FROM AUTHOR]

Objectives Lower circulating androgens and poorer lung function are associated with increased cardiovascular risk and mortality in men. The association between androgens and lung function is unclear. We tested the hypothesis that circulating testosterone (T) and its metabolites dihydrotestosterone ( DHT) and oestradiol (E2) are differentially associated with lung function in men. Methods Early-morning serum T, DHT and E2 were assayed using mass spectrometry in 1768 community-dwelling men from Busselton, Western Australia. Forced expiratory volume in 1 s ( FEV1) and forced vital capacity ( FVC) were measured using spirometry. Linear regression models adjusting for age, height, smoking, exercise, body mass index, respiratory conditions and cardiovascular risk factors were used. Results Mean age was 50.1 ± 16·8 years. 16·0% were current smokers, 14·1% reported a history of asthma and 2·7% reported chronic obstructive pulmonary disease. Current smokers had higher T compared with never smokers (age-adjusted mean 14·5 vs 13·5 nmol/l, P = 0·002) and higher E2 (65·3 vs 60·1 pmol/l, P = 0·017). In fully adjusted analyses, T was associated with FEV1 (51 ml per 1 SD increase, P < 0·001) as was DHT (62 ml, P < 0·001), E2 was not ( P = 0·926). Similar results were seen for FVC (T: 76 ml, P < 0·001; DHT: 65 ml, P < 0·001; E2 P = 0·664). Higher DHT was marginally associated with the ratio FEV1/ FVC (0·3% per 1 SD increase, P = 0·047). Conclusions Both T and DHT were independently associated with higher FEV1 and FVC in predominantly middle-aged community-dwelling men. Androgens may contribute to, or be biomarkers for, better lung function in men. Further research is needed to clarify whether androgens preserve lung function in ageing men. [ABSTRACT FROM AUTHOR]

Introduction: Occupational exposure data on asbestos are limited and poorly integrated in Australia so that estimates of disease risk and attribution of disease causation are usually calculated from data that are not specific for local conditions. Objective: To develop a job-exposure matrix (AsbJEM) to estimate occupational asbestos exposure levels in Australia, making optimal use of the available exposure data. Methods: A dossier of all available exposure data in Australia and information on industry practices and controls was provided to an expert panel consisting of three local industrial hygienists with thorough knowledge of local and international work practices. The expert panel estimated asbestos exposures for combinations of occupation, industry, and time period. Intensity and frequency grades were estimated to enable the calculation of annual exposure levels for each occupation-industry combination for each time period. Two indicators of asbestos exposure intensity (mode and peak) were used to account for different patterns of exposure between occupations. Additionally, the probable type of asbestos fibre was determined for each situation. Results: Asbestos exposures were estimated for 537 combinations of 224 occupations and 60 industries for four time periods (1943-1966; 1967-1986; 1987-2003; ≥2004). Workers in the asbestos manufacturing, shipyard, and insulation industries were estimated to have had the highest average exposures. Up until 1986, 46 occupation-industry combinations were estimated to have had exposures exceeding the current Australian exposure standard of 0.1 f ml−1. Over 90% of exposed occupations were considered to have had exposure to a mixture of asbestos varieties including crocidolite. Conclusion: The AsbJEM provides empirically based quantified estimates of asbestos exposure levels for Australian jobs since 1943. This exposure assessment application will contribute to improved understanding and prediction of asbestos-related diseases and attribution of disease causation. [ABSTRACT FROM AUTHOR]

Mesothelioma is principally caused by asbestos and may be preventable because there is a long latent period between exposure and disease development. The most at-risk are a relatively well-defined population who were exposed as a consequence of their occupations. Although preventative agents investigated so far have not been promising, discovery of such an agent would have a significant benefit world-wide on healthcare costs and personal suffering. Statins are widely used for management of hypercholesterolemia and cardiovascular risk; they can induce apoptosis in mesothelioma cells and epidemiological data has linked their use to a lower incidence of cancer. We hypothesised that statins would inhibit the development of asbestos-induced mesothelioma in mice and humans. An autochthonous murine model of asbestos-induced mesothelioma was used to test this by providing atorvastatin daily in the feed at 100 mg/kg, 200 mg/kg and 400 mg/kg. Continuous administration of atorvastatin did not alter the rate of disease development nor increase the length of time that mice survived. Latency to first symptoms of disease and disease progression were also unaffected. In a parallel study, the relationship between the use of statins and development of mesothelioma was investigated in asbestos-exposed humans. In a cohort of 1,738 asbestos exposed people living or working at a crocidolite mine site in Wittenoom, Western Australia, individuals who reported use of statins did not have a lower incidence of mesothelioma (HR = 1.01; 95% CI = 0.44–2.29, p = 0.99). Some individuals reported use of both statins and non-steroidal anti-inflammatory drugs or COX-2 inhibitors, and these people also did not have an altered risk of mesothelioma development (HR = 1.01; 95% CI = 0.61–1.67, p = 0.97). We conclude that statins do not moderate the rate of development of mesothelioma in either a mouse model or a human cohort exposed to asbestos. [ABSTRACT FROM AUTHOR]

Objective: Observational studies suggest that moderate intakes of retinol and increased circulating retinol levels may increase fracture risk. Easy access to supplements, combined with an aging population, makes this a potentially important association. The aim of this study was to investigate plasma retinol and total carotene concentrations in relation to fracture risk after long-term supplementation with retinol and/or beta-carotene in 998 adults between 1990 and 2007. Methods: Participants were 663 men and 335 women in a cancer prevention program who were initially randomized to a retinol (7.5 mg RE/d) or beta-carotene (30 mg/d) supplement between 1990 and 1996. After 1996, all participants received the retinol supplement only. Plasma retinol and total carotene, medication use and various lifestyle factors were measured at annual clinic visits. Fractures were identified by self-report in 2007. The risk for any fracture or osteoporotic fracture was modeled using Cox proportional hazard models. Results: Over a median follow-up of 7.8 y, 123 participants with plasma samples reported an incident fracture. Although plasma retinol concentrations were markedly higher than those reported in observational studies, no association was observed between plasma retinol and risk for any fracture (hazard ratio [HR], 0.86 mmol/L; 95% confidence interval [CI], 0.65-1.14) or osteoporotic fracture (HR, 0.97 µmol/L; 95% CI, 0.66-1.43). A lower risk for any fracture was suggested with increasing plasma total carotenes (HR, 0.85 µmol/L; 95% CI, 0.71-1.01). Conclusions: This study does not support earlier reports of an increased fracture risk associated with increased plasma retinol concentration. The potential for carotenes to prevent fractures deserves further investigation. [ABSTRACT FROM AUTHOR]

Abstract: Background: Malignant mesothelioma (MM), a primarily asbestos-induced tumour, has a poor prognosis, with over-all 5-year survival less than 5%. Tumour biomarkers are being intensely investigated in MM as aids to diagnosis and prognosis. Hyaluronic acid (HA) is produced in MM but its role in prognostication remains uncertain. Materials and methods: HA concentrations were determined in matching serum and pleural effusion of 96 MM patients, 26 lung cancer patients and 42 patients with benign effusions resulting from infectious, cardiac, renal, liver and rheumatoid diseases and compared to the current ‘best practice’ biomarker, mesothelin. Liver and kidney function were determined for each patient. Diagnostic accuracy was determined by area under the receiver operator characteristic curve (AUC) analysis following logistic regression modelling. Difference in survival between groups was determined by both log-rank test and Cox proportional hazards regression modelling. Results: For effusion HA, the AUC (IQ range) was 0.89 (0.82–0.94) and for effusion mesothelin, it was 0.85 (0.78–0.90). Serum HA was not diagnostically useful. A combined measure of effusion HA, and serum and effusion mesothelin had an AUC of 0.92 (0.86–0.96), which was significantly higher than effusion mesothelin alone. Effusion HA had a biphasic distribution in MM patients, dichotomised at a concentration of 75mg/L. The median survival of MM patients with high effusion HA was 18.0 (13.7–22.4) months, significantly longer than those with low HA effusion levels (12.6 months (8.4–16.8), p =0.004). Serum HA, and effusion and serum mesothelin were not significant prognostic indicators. Conclusion: This study demonstrates that a combined biomarker panel has greater diagnostic accuracy than effusion mesothelin alone, and that significant prognostic information is provided by effusion HA. [Copyright &y& Elsevier]

Haplotypes in the promoter region of the prostanoid DP receptor ( PTGDR) gene have been shown to functionally influence gene transcription and to be associated with asthma in two previous case-control studies in Caucasians. This study tested the association of PTGDR haplotypes with asthma phenotypes in two large Caucasian-Australian populations. These results were incorporated in a meta-analysis with previously published data to determine the overall role for these haplotypes in the risk of asthma. Three PTGDR promoter-region single nucleotide polymorphisms (SNP) were genotyped in 368 individuals from the Western Australian Twin Child Health study and 2988 individuals from the Busselton Health Study. Logistic regression and transition disequilibrium tests were used to assess whether SNP genotypes and three SNP haplotypes were associated with doctor-diagnosed asthma or intermediate quantitative traits. Longitudinal data from the Busselton Health Study were used to examine whether PTGDR influences changes in lung function over time. Meta-analysis incorporated the findings of this study with those of two previous studies in Caucasian populations. Cross-sectional associations between PTGDR haplotypes and asthma phenotypes were non-significant ( P > 0.05) in both populations. Longitudinal analyses of PTGDR and lung function were also non-significant. Meta-analysis, however, suggested that haplotype TCT was significantly associated with decreased risk of asthma (OR = 0.76; P = 0.02) while haplotype CCC was not significantly associated with asthma (OR = 1.30; P = 0.07). These results suggest that despite the non-significant findings in the present study populations, PTGDR promoter haplotypes may account for a small but significant proportion of the risk of asthma in Caucasian populations. Functional haplotypes in the PTGDR gene have been linked to asthma in Caucasians. In this study they were not significantly associated with asthma phenotypes or longitudinal decline in lung function in two Australian populations. A meta-analysis of previous studies in Caucasians demonstrated small but significant effects consistent with functional data. [ABSTRACT FROM AUTHOR]

The article discusses the study which aims to determine the CA125 which improves the sensitivity of mesothelin in diagnosing mesothelioma. The study shows that combining CA125 and mesothelin serum levels does not improve the accuracy of diagnosis of malignant mesothelioma over the mesothelin marker. Moreover, the use of mesothelin and CA125 biomakers increases the number of patients who can be monitored.

BACKGROUND:: As antitumoral immunity requires the generation of local immunity directed against tissue proteins, we attempted to recreate within tumors the same environment found within tissues affected by autoimmune diseases (i.e., prolonged cytokine expression). Vaccinia virus (VV) has not been widely used as a cytokine gene therapy vector because of presumed high immunogenicity that would likely make repeated injections impossible; therefore, we modified it by inserting the cytokine gene into the thymidine kinase region, rendering it replication-restricted. The cytokine chosen was human interleukin-2 (IL-2), a molecule with powerful antitumoral effects. METHODS:: Six patients with the treatment-resistant tumor malignant mesothelioma received intratumoral (i.t.) VV-IL-2 therapy for 12 weeks by injection of 107 plaque-forming units of VV-IL-2 per dose. Serial tumor biopsies, sputum, urine, and blood samples were tested for VV-IL-2 mRNA expression; VV culture and T-cell infiltrates were evaluated by immunohistochemistry. Patients and contacts of patients were monitored for changes in VV immunoglobulin G (IgG) levels and clinical evidence of VV infection. RESULTS:: VV-IL-2 was not excreted and was only cultured in one patient from tumor biopsies. A T-cell infiltrate was detected in 50% of tumor biopsies. VV-IL-2 mRNA expression was highest on days 1–3 postinjection and was detected for up to 3 weeks after each injection even though VV IgG levels rose in all patients. No significant toxicities, infection of patient contacts, or tumor regressions were observed. CONCLUSIONS:: I.t. VV-IL-2 administration is safe, is associated with minimal toxicity, and results in i.t. expression of VV-IL-2 for up to 3 weeks postinjection regardless of the level of anti-VV IgG titers generated. This suggests that VV may be a good vector for repeated cytokine gene therapy of solid human cancer. [ABSTRACT FROM AUTHOR]

Purpose: Few studies have investigated the association of childhood obesity with respiratory disease-related outcomes in adulthood and findings are inconsistent. The aim of this study was to examine the associations of body mass index (BMI) in childhood with the occurrence of respiratory events in adulthood.Methods: We analyzed a cohort of 4537 school-aged children who attended the Busselton Health Study. Height and weight were measured and generated BMI z-scores were categorized into four groups. Participants were followed for respiratory disease-related hospital admissions or death using the Western Australia Data Linkage System. The associations between childhood BMI and respiratory events in adulthood were investigated using Cox regression models. A subgroup of 2196 that reattended a survey in young adulthood was also analyzed.Results: During the 122,781 person-years of follow-up, 810 participants experienced a respiratory event. Childhood BMI group was not associated with risk of respiratory event in adulthood (hazard ratio for BMI z ≥ 1 vs. < -1 = 0.90; 95% CI, 0.70-1.17; P = .295) and this persisted after adjustment for selected confounders in the subgroup (hazard ratio 0.80; 95% CI, 0.43-1.48; P = .476).Conclusions: Childhood BMI is not associated with risk of respiratory events in adulthood. [ABSTRACT FROM AUTHOR]