Childhood fish oil supplementation modifies associations between traffic related air pollution and allergic sensitisation.

BACKGROUND: Studies of potential adverse effects of traffic related air pollution (TRAP) on allergic disease have had mixed findings. Nutritional studies to examine whether fish oil supplementation may protect against development of allergic disease through their anti-inflammatory actions have also had mixed findings. Extremely few studies to date have considered whether air pollution and dietary factors such as fish oil intake may interact, which was the rationale for this study. METHODS: We conducted a secondary analysis of the Childhood Asthma Prevention Study (CAPS) birth cohort, where children were randomised to fish oil supplementation or placebo from early life to age 5 years. We examined interactions between supplementation and TRAP (using weighted road density at place of residence as our measure of traffic related air pollution exposure) with allergic disease and lung function outcomes at age 5 and 8 years. RESULTS: Outcome information was available on approximately 400 children (~ 70% of the original birth cohort). Statistically significant interactions between fish oil supplementation and TRAP were seen for house dust mite (HDM), inhalant and all-allergen skin prick tests (SPTs) and for HDM-specific interleukin-5 response at age 5. Adjusting for relevant confounders, relative risks (RRs) for positive HDM SPT were RR 1.74 (95% CI 1.22-2.48) per 100 m local road or 33.3 m of motorway within 50 m of the home for those randomised to the control group and 1.03 (0.76-1.41) for those randomised to receive the fish oil supplement. The risk differential was highest in an analysis restricted to those who did not change address between ages 5 and 8 years. In this sub-group, supplementation also protected against the effect of traffic exposure on pre-bronchodilator FEV1/FVC ratio. CONCLUSIONS: Results suggest that fish oil supplementation may protect against pro-allergic sensitisation effects of TRAP exposure. Strengths of this analysis are that supplementation was randomised and independent of TRAP exposure, however, findings need to be confirmed in a larger experimental study with the interaction investigated as a primary hypothesis, potentially also exploring epigenetic mechanisms. More generally, studies of adverse health effects of air pollution may benefit from considering potential effect modification by diet and other factors. TRIAL REGISTRATION: Australia New Zealand Clinical Trial Registry. www.anzctr.org.au Registration: ACTRN12605000042640 , Date: 26th July 2005. Retrospectively registered, trial commenced prior to registry availability.

Secreted-frizzled related protein 1 is a transcriptional repression target of the t(8;21) fusion protein in acute myeloid leukemia.

Secreted-frizzled related proteins (SFRPs) are modulators of the Wnt signaling pathway that is closely involved in normal and malignant hematopoiesis. Epigenetic deregulation of Wnt modulators leading to aberrant signaling has been reported in adult patients with acute myeloid leukemia (AML), but its occurrence in childhood patients with AML and the role of individual modulators are unclear. In this study, we examined SFRP1, SFRP2, SFRP4, and SFRP5 promoter methylation in 83 patients with AML (59 children and 24 adults) and found preferential SFRP1 methylation and mRNA down-regulation in the prognostically favorable subgroup of AML with t(8;21) translocation. Among the 4 genes, SFRP1 methylation independently predicted prolonged event-free and relapse-free survivals in childhood patients with nonacute promyelocytic leukemia with nonadverse cytogenetics. Mechanistically, we further demonstrated that RUNX1-ETO, the t(8;21) fusion product, specifically bound the SFRP1 promoter and repressed its transcription via a consensus RUNX binding site. In t(8;21)-leukemia cells, SFRP1 selectively inhibited canonical Wnt signaling and cellular proliferation that were associated with concomitant down-regulation of Wnt/ß-catenin target genes, including CCND1 and MYC. Taken together, we identified SFRP1 as a transcriptional repression target of the t(8;21) fusion protein and demonstrated a novel mechanism of Wnt activation in a specific subtype of AML.

A polymorphism in the 3'-untranslated region of the NPM1 gene causes illegitimate regulation by microRNA-337-5p and correlates with adverse outcome in acute myeloid leukemia.

Nucleophosmin, encoded by NPM1, is a haploinsufficient suppressor in hematologic malignancies. NPM1 mutations are mostly found in acute myeloid leukemia patients with normal karyotype and associated with favorable prognosis. A polymorphic nucleotide T deletion with unknown significance is present in the NPM1 3'-untranslated region. Here, we showed that the homozygous nucleotide T deletion was associated with adverse outcomes and could independently predict shortened survival in patients with de novo acute myeloid leukemia. Mechanistically, we demonstrated that the nucleotide T deletion created an illegitimate binding NPM1 for miR-337-5p, which was widely expressed in different acute myeloid leukemia subtypes and inhibited NPM1 expression. Accordingly, NPM1 levels were found to be significantly reduced and correlated with miR-337-5p levels in patients carrying a homozygous nucleotide T-deletion genotype. Together, our findings uncover a microRNA-mediated control of NPM1 expression that contributes to disease heterogeneity and suggest additional prognostic values of NPM1 in acute myeloid leukemia.

On the influence of vector design on antibody phage display.

Phage display technology is an established technology particularly useful for the generation of monoclonal antibodies (mAbs). The isolation of phagemid-encoded mAb fragments depends on several features of a phage preparation. The aims of this study were to optimize phage display vectors, and to ascertain if different virion features can be optimized independently of each other. Comparisons were made between phagemid virions assembled by g3p-deficient helper phage, Hyperphage, Ex-phage or Phaberge, or corresponding g3p-sufficient helper phage, M13K07. All g3p-deficient helper phage provided a similar level of antibody display, significantly higher than that of M13K07. Hyperphage packaged virions at least 100-fold more efficiently than did Ex-phage or Phaberge. Phaberge's packaging efficiency improved by using a SupE strain. Different phagemids were also compared. Removal of a 56 base pair fragment from the promoter region resulted in increased display level and increased virion production. This critical fragment encodes a lacZ'-like peptide and is also present in other commonly used phagemids. Increasing display level did not show statistical correlation with phage production, phage infectivity or bacterial growth rate. However, phage production was positively correlated to phage infectivity. In summary, this study demonstrates simultaneously optimization of multiple and independent features of importance for phage selection.

Weighted road density and allergic disease in children at high risk of developing asthma.

BACKGROUND: Evidence for an association between traffic-related air pollution and allergic disease is inconsistent, possibly because the adverse effects may be limited to susceptible subgroups and these have not been identified. This study examined children in the Childhood Asthma Prevention Study (CAPS), potentially susceptible to air pollution effects because of a family history of asthma. METHODS: We examined cross-sectional associations at age eight years between road density within 75 m and 50 m of home address weighted by road type (traffic density), as a proxy for traffic-related air pollution, on the following allergic and respiratory outcomes: skin prick tests (SPTs), total and specific serum IgE, pre- and post-bronchodilator lung function, airway hyperresponsiveness, exhaled NO, and reported asthma and rhinitis. RESULTS: Weighted road density was positively associated with allergic sensitisation and allergic rhinitis. Adjusted relative risk (RR) for house dust mite (HDM) positive SPT was 1.25 (95% CI: 1.06-1.48), for detectable house dust mite-specific IgE was 1.19 (95% CI: 1.01-1.41) and for allergic rhinitis was 1.30 (95% CI: 1.03-1.63) per 100 m local road or 33.3 m motorway within 50 m of home. Associations were also seen with small decrements of peak and mid-expiratory flows and increased risk of asthma, current wheeze and rhinitis in atopic children. CONCLUSION: Associations between road density and allergic disease were found in a potentially susceptible subgroup of children at high risk of developing atopy and asthma.

Occupational asthma in New South Wales (NSW): a population-based study.

BACKGROUND: The proportion of asthma in adults that is due to occupational exposures is not known. AIM: To examine the contribution of workplace exposures to the development of asthma in adults in New South Wales (NSW) in a cross sectional, population-based study. METHODS: A randomly selected population of 5,331 18- to 49-year olds completed and returned a mailed questionnaire (response rate 37%). In adult-onset asthmatics we examined the association of asthma with reported exposure, within 1 year of asthma onset, to a list of occupations and exposures known to be at risk for occupational asthma (high-risk jobs and exposures). RESULTS: Among 910 subjects (18%) with asthma, 383 (7%) subjects reported adult-onset disease. After adjusting for sex, age and smoking, working in any high-risk job or exposure at the time of asthma onset was significantly associated with adult-onset asthma (OR 1.51, 95% CI 1.19-1.92). The population attributable risk (PAR) of adult-onset asthma for either a high-risk job or an exposure was 9.5%. Sudden onset, irritant or reactive airways dysfunction syndrome type exposures were associated with adult-onset asthma (OR 4.65, 95% CI 1.64-13.2). The PAR of adult-onset asthma for these exposures was 0.2%. CONCLUSION: Reported adult onset of asthma is common and occupational exposures may be associated with 9.5% of prevalent cases of adult-onset asthma in NSW.

Presence and timing of cat ownership by age 18 and the effect on atopy and asthma at age 28.

BACKGROUND: Asthma and allergic sensitization to cats frequently coexist, although recent studies show less atopic disease among people who had pets in infancy. However, no longterm evaluations have been performed thus far. OBJECTIVE: We sought to evaluate the relationship between cat ownership at different age periods (< 18, > 18, and both periods and atopic disease at age 28. METHODS: Australian school children aged 8 to 10 years were recruited in 1982 and participated in follow-up surveys until 2002. Cat ownership was defined by surveys in 1992 and 2002 as having a cat before age 18 only, after age 18 only, or in both periods of life. Health outcomes were defined at a mean age of 28.5 years. RESULTS: Complete data were available for 224 subjects, 50 of whom had a cat before 18 years of age only, 14 after age 18 only, and 70 in both periods. Compared with 90 subjects that never had a cat, having a cat before age 18 protected against atopy to outdoor allergens, airway hyperresponsiveness (AHR) to histamine, current wheeze, and current asthma (P < .05). In contrast, subjects who acquired their first cat after age 18 showed a trend toward higher prevalence rates for asthma symptoms and AHR (P > .10). CONCLUSIONS: Having had a cat before 18 years of age protects against adult asthma and atopy.

The effect of neonatal BCG vaccination on atopy and asthma at age 7 to 14 years: an historical cohort study in a community with a very low prevalence of tuberculosis infection and a high prevalence of atopic disease.

BACKGROUND: There are conflicting reports on the effect of BCG vaccination on the subsequent development of atopy and asthma. There are no data on the effects of neonatal BCG vaccination on cytokine responses of lymphocytes that are exposed in vitro to allergens. OBJECTIVES: We sought to test the hypothesis that neonatal BCG vaccination or, alternatively, evidence of an immunologic memory of this vaccination is associated with a reduced prevalence of allergic sensitization, asthma, eczema, and hay fever during childhood. METHODS: An historical cohort study was conducted among 7- to 14-year-old children who were born in 2 districts in Sydney, Australia, and whose mothers were born in southeast Asia. One district had routinely administered BCG vaccination to infants born to overseas-born mothers and the other had not. Eligible subjects were identified from birth registers. Consenting subjects completed questionnaires, performed spirometric and airway hyperresponsiveness testing, and had allergen skin prick testing and tuberculin skin testing. Blood was collected to measure total serum IgE levels and for in vitro lymphocyte culture in the presence of an extract of house dust mite, the dominant allergen in this region, and purified protein derivative of Mycobacterium tuberculosis (tuberculin). IL-4, IL-5, IL-10, and IFN-gamma were measured in the culture supernatant. RESULTS: The cohort included 309 BCG-vaccinated subjects and 442 non-BCG-vaccinated subjects. BCG-vaccinated subjects did not have a lower rate of allergic sensitization than nonvaccinated subjects. However, among the subgroup of subjects with a family history of rhinitis or eczema, BCG vaccination was associated with a lower prevalence of current asthma (defined as recent wheezing plus airway hyperresponsiveness; relative risk, 0.46; 95% CI, 0.22-0.95). BCG vaccination was also associated with lower levels of allergen-stimulated IL-10 production in vitro. Among the BCG-vaccinated subjects, the 44 (14.3%) who had tuberculin skin test reaction sizes of 5 mm or greater and the 31 (18.3%) who demonstrated an in vitro IFN-gamma response to purified protein derivative of M tuberculosis did not have lower rates of allergic sensitization and, overall, did not have a lower prevalence of allergic disease than tuberculin skin test or IFN-gamma nonreactors. CONCLUSION: We conclude that neonatal BCG vaccination has an effect on T-cell allergen responsiveness 7 to 14 years after vaccination and that among a subgroup of subjects with an inherited predisposition to allergic disease, this is associated with clinically relevant beneficial effects. The findings of this study encourage the view that external influences on the immune system in the neonatal period have consequences that extend into later childhood and influence the expression of asthma. Genetic factors are likely to modify the effect of those external factors.

An evidence-based specialist breast nurse role in practice: a multicentre implementation study.

The objective of this study was to examine the feasibility, implementation, acceptability and impact of an evidence-based specialist breast care nurse (SBN) model of care in Australia. Primary data were collected from four diverse Australian breast cancer treatment centres over a 12-month period. The design was a multicentre demonstration project. Information about the provision of care and patient needs was collected through prospective logs. Structured interviews were conducted with women who received the SBN intervention (N = 167) and with a control group of women treated prior to the intervention period (N = 133). Health professionals (N = 47) were interviewed about their experience of the SBN. Almost all women had contact with an SBN at five scheduled consultations and 67% of women in the intervention group requested at least one additional consultation with the SBN. Women in the intervention group were more likely to receive hospital fact sheets and to be told about and participate in clinical trials. Ninety-eight per cent of women reported that the availability of an SBN would affect their choice of hospital, with 48% indicating that they would recommend only a hospital with a SBN available. Health professionals reported that SBNs improved continuity of care, information and support for the women, and resulted in more appropriate referrals and use of the time of other members of the team. In conclusion, the SBN model is feasible and acceptable within diverse Australian treatment centres; there is evidence that some aspects of care were improved by the SBN.