Analysis of Sdhd and Mmp12 in an affected solar keratosis and control cohort

The incidence of Squamous Cell Carcinoma (SCG) is growing in certain populations to the extent that it is now the most common skin lesion in young men and women in high ultraviolet exposure regions such as Queensland. In terms of incidence up to 40% of the Australian population over 40 years of age is thought to possess the precancerous Solar Keratosis (SK) lesion and with a small, but significant, chance of progression into SCC, understanding the genetic events that play a role in this process is essential. The major aims of this study were to analyse whole blood derived samples for DNA aberrations in genes associated with tumour development and cellular maintenance, with the ultimate aim of identifying genes associated with non-melanoma skin cancer development. More specifically the first aim of this project was to analyse the SDHD and MMP12 genes via Dual-Labelled Probe Real-Time PCR for copy number aberrations in an affected Solar Keratosis and control cohort. It was found that 12 samples had identifiable copy-number aberrations in either the SDHD or MMP12 gene (this means that a genetic section of either of these two genes is aberrantly amplified or deleted), with five of the samples exhibiting aberrations in both genes. The significance of this study is the contribution to the knowledge of the genetic pathways that are malformed in the progression and development of the pre-cancerous skin lesion Solar Keratosis. © 2008 Springer Science+Business Media, LLC.

Estrogen receptor β activation impairs mitochondrial oxidative metabolism and affects malignant mesothelioma cell growth in vitro and in vivo

Estrogen receptor (ER)-β has been shown to possess a tumor suppressive effect, and is a potential target for cancer therapy. Using gene-expression meta-analysis of human malignant pleural mesothelioma, we identified an ESR2 (ERβ coding gene) signature. High ESR2 expression was strongly associated with low succinate dehydrogenase B (SDHB) (which encodes a mitochondrial respiratory chain complex II subunit) expression. We demonstrate that SDHB loss induced ESR2 expression, and that activated ERβ, by over-expression or by selective agonist stimulation, negatively affected oxidative phosphorylation compromising mitochondrial complex II and IV activity. This resulted in reduced mitochondrial ATP production, increased glycolysis dependence and impaired cell proliferation. The observed in vitro effects were phenocopied in vivo using a selective ERβ agonist in a mesothelioma mouse model. On the whole, our data highlight an unforeseen interaction between ERβ-mediated tumor suppression and energy metabolism that may be exploited to improve on the therapy for clinical management of malignant mesothelioma.

Rapid analysis of GSTM1, GSTT1 and GSTP1 polymorphisms using real-time polymerase chain reaction

Polymorphisms of glutathione transferases (GST) are important genetic determinants of susceptibility to environmental carcinogens (Rebbeck, 1997). The GSTs are a multigene family of dimeric enzymes involved in detoxification, and, in a few cases, the bioactivation of a variety of xenobiotics (Hayes et al., 1995). The cytosolic GST enzyme family consists of four major classes of enzymes, referred to as alpha, mu, pi and theta. Several members of this family (for example, GSTM1, GSTT1 and GSTP1) are polymorphic in human populations (Wormhoudt et al., 1999). Molecular epidemiology studies have examined the role of GST polymorphisms as susceptibility factors for environmentally and/or occupationally induced cancers (Wormhoudt et al., 1999). In particular, case-control studies showed a relationship between the GSTM1 null genotype and the development of cancer in association with smoking habits, which has been shown for cancers of the respiratory and gastrointestinal tracts as well as other cancer types (Miller et al., 1997). Only a few molecular epidemiological studies addressed the role of GSTT1 and GSTP1 polymorphisms in cancer susceptibility. Since GSTP1 is a key player in biotransformation/bioactivation of benzo(a)pyrene, GSTP1 may be even more important than GSTM1 in the prevention of tobacco-induced cancers (Harries et al., 1997; Harris et al., 1998). To date, this relationship has not been sufficiently addressed in humans. Comprehensive molecular epidemiological studies may add to the current knowledge of the role of GST polymorphisms in cancer susceptibility and extent of the knowledge gained from approaches that used phenotyping, such as GSTM1 activity as it relates to trans-stilbene oxide, or polymerase chain reaction (PCR) based genotyping of polymorphic isoenzymes (Bell et al., 1993; Pemble et al., 1994; Harries et al., 1997).

Mailed versus frozen transport of nasal swabs for surveillance of respiratory bacteria in remote Indigenous communities in Australia

Background Surveillance programs and research for acute respiratory infections in remote Australian communities are complicated by difficulties in the storage and transport of frozen samples to urban laboratories for testing. This study assessed the sensitivity of a simple method for transporting nasal swabs from a remote setting for bacterial polymerase chain reaction (PCR) testing. Methods We sampled every individual who presented to a remote community clinic over a three week period in August at a time of low influenza and no respiratory syncytial virus activity. Two anterior nasal swabs were collected from each participant. The left nare specimen was mailed to the laboratory via routine postal services. The right nare specimen was transported frozen. Testing for six bacterial species was undertaken using real-time PCR. Results One hundred and forty participants were enrolled who contributed 150 study visits and paired specimens for testing. Respiratory illnesses accounted for 10% of the reasons for presentation. Bacteria were identified in 117 (78%) presentations for 110 (79.4%) individuals; Streptococcus pneumoniae and Haemophilus influenzae were the most common (each identified in 58% of episodes). The overall sensitivity for any bacterium detected in mailed specimens was 82.2% (95% CI 73.6, 88.1) compared to 94.8% (95% CI 89.4, 98.1) for frozen specimens. The sensitivity of the two methods varied by species identified. Conclusion The mailing of unfrozen nasal specimens from remote communities appears to influence the utility of the specimen for bacterial studies, with a loss in sensitivity for the detection of any species overall. Further studies are needed to confirm our finding and to investigate the possible mechanisms of effect. Clinical trial registration Australia and New Zealand Clinical Trials Registry Number: ACTRN12609001006235. Keywords: Respiratory bacteria; RT-PCR; Specimen transport; Laboratory methods

Successful application of a simple specimen transport method for the conduct of respiratory virus surveillance in remote Indigenous communities in Australia

Objective Surveillance programs and research for acute respiratory infections in remote Aboriginal communities are complicated by difficulties in the storage and transport of frozen samples to urban laboratories for testing. This study assessed the sensitivity of a simple method for transporting respiratory samples from a remote setting for viral PCR compared with frozen specimens. Methods We sampled every individual who presented to a remote Aboriginal community clinic in a non-epidemic respiratory season. Two anterior nasal swabs were collected from each participant. The left nare specimen was mailed to the laboratory via routine postal services. The right nare specimen was transported frozen. Testing for 16 viruses was undertaken using real-time multiplex PCR. Results A total of 140 participants were enrolled who contributed 150 study visits. Respiratory illnesses accounted for 10% of the reasons for presentation. Sixty-one viruses were identified in 50 (33.3%) presentations for 40 (28.6%) individuals; bocavirus and rhinovirus were the most common viruses identified (14.0% and 12.6% of episodes respectively). The sensitivity for any virus detected in mailed specimens was 67.2% (95%CI 55.4, 78.9) compared to 65.6% (95%CI 53.7, 77.5) for frozen specimens. Conclusion The mailing of unfrozen nasal specimens from remote communities does not compromise the viability of the specimen for viral studies.

The impact of viral respiratory infection on the severity and recovery from an asthma exacerbation

Background Viral respiratory illness triggers asthma exacerbations, but the influence of respiratory illness on the acute severity and recovery of childhood asthma is unknown. Our objective was to evaluate the impact of a concurrent acute respiratory illness (based on a clinical definition and PCR detection of a panel of respiratory viruses, Mycoplasma pneumoniae and Chlamydia pneumoniae) on the severity and resolution of symptoms in children with a nonhospitalized exacerbation of asthma. Methods Subjects were children aged 2 to 15 years presenting to an emergency department for an acute asthma exacerbation and not hospitalized. Acute respiratory illness (ARI) was clinically defined. Nasopharyngeal aspirates (NPA) were examined for respiratory viruses, Chlamydia and Mycoplasma using PCR. The primary outcome was quality of life (QOL) on presentation, day 7 and day 14. Secondary outcomes were acute asthma severity score, asthma diary, and cough diary scores on days 5, 7,10, and 14. Results On multivariate regression, presence of ARI was statistically but not clinically significantly associated with QOL score on presentation (B = 0.36, P = 0.025). By day 7 and 14, there was no difference between groups. Asthma diary score was significantly higher in children with ARI (B = 0.41, P = 0.039) on day 5 but not on presentation or subsequent days. Respiratory viruses were detected in 54% of the 78 NPAs obtained. There was no difference in the any of the asthma outcomes of children grouped by positive or negative NPA. Conclusions The presence of a viral respiratory illness has a modest influence on asthma severity, and does not influence recovery from a nonhospitalized asthma exacerbation.

Prevalence, codetection and seasonal distribution of upper airway viruses and bacteria in children with acute respiratory illnesses with cough as a symptom

Most studies exploring the role of upper airway viruses and bacteria in paediatric acute respiratory infections (ARI) focus on specific clinicaldiagnoses and/or do not account for virus–bacteria interactions. We aimed to describe the frequency and predictors of virus and bacteria codetection in children with ARI and cough, irrespective of clinical diagnosis. Bilateral nasal swabs, demographic, clinical and risk factor data were collected at enrollment in children aged <15 years presenting to an emergency department with an ARI and where cough was a symptom. Swabs were tested by polymerase chain reaction for 17 respiratory viruses and seven respiratory bacteria. Logistic regression was used to investigate associations between child characteristics and codetection of the organisms of interest. Between December 2011 and August 2014, swabs were collected from 817 (93.3%) of 876 enrolled children, median age 27.7 months (interquartile range13.9–60.3 months). Overall, 740 (90.6%) of 817 specimens were positive for any organism. Both viruses and bacteria were detected in 423 specimens (51.8%). Factors associated with codetection were age (adjusted odds ratio (aOR) for age <12 months = 4.9, 95% confidence interval (CI) 3.0, 7.9; age 12 to <24 months = 6.0, 95% CI 3.7, 9.8; age 24 to <60 months = 2.4, 95% CI 1.5, 3.9), male gender (aOR 1.46; 95% CI 1.1, 2.0), child care attendance (aOR 2.0; 95% CI 1.4, 2.8) and winter enrollment (aOR 2.0; 95% CI 1.3, 3.0). Haemophilus influenzae dominated the virus–bacteria pairs. Virus–H. influenzae interactions in ARI should be investigated further, especially as the contribution of nontypeable H. influenzae to acute and chronic respiratory diseases is being increasingly recognized.

Correcting for bias when estimating the cost of hospital-acquired infection : an analysis of lower respiratory tract infections in non-surgical patients

Hospital acquired infections (HAI) are costly but many are avoidable. Evaluating prevention programmes requires data on their costs and benefits. Estimating the actual costs of HAI (a measure of the cost savings due to prevention) is difficult as HAI changes cost by extending patient length of stay, yet, length of stay is a major risk factor for HAI. This endogeneity bias can confound attempts to measure accurately the cost of HAI. We propose a two-stage instrumental variables estimation strategy that explicitly controls for the endogeneity between risk of HAI and length of stay. We find that a 10% reduction in ex ante risk of HAI results in an expected savings of £693 ($US 984).

Collaboration and Engagement Throughout The Supply Chain : The Role of Government

Collaboration is acknowledged as a key to continued growth in the Australian construction industry. Government, as a major industry client, has an important role to play with respect to fostering collaboration and ensuring the global competitiveness of the industry. The paper draws upon data collected for the Construction 2020 study and aims to demonstrate that government can a) help to break down the adversarial situation that currently exists between clients, project managers and subcontractors; and b) allow the supply chain to collaborate more effectively in terms of satisfying the relational and financial needs of all parties. Government can also provide a clear set of guidelines (backed up by a functional dispute resolution system) that will promote confidence with respect to forging relationships. Thus, the paper will discuss the way in which public policy can be more closely aligned with actual industry needs in order to promote greater collaboration.