ORCID Profile
0000-0003-0930-1654
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In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Population And Ecological Genetics | Anthropological Genetics | Genetics | Genetic Immunology
Immune system and allergy | Health related to specific ethnic groups |
Publisher: Wiley
Date: 12-1998
DOI: 10.1002/(SICI)1099-0496(199812)26:6<380::AID-PPUL2>3.0.CO;2-I
Abstract: Atypical mycobacterial infection in HIV-negative children usually presents with cervical lymphadenopathy. We report on 10 children who are HIV-negative and who presented with pulmonary disease, in whom either culture-proven atypical mycobacterium infection (four), positive avian Mantoux test (five), or lack of response to human tuberculosis treatment (one) had been observed. One case was subsequently diagnosed as chronic granulomatous disease and illustrates that children with atypical mycobacterial pulmonary infection should have their immune status fully investigated. Bronchial obstruction was observed in eight cases, and of these, endobronchial disease was found in six children. The diagnosis of atypical mycobacterial disease is difficult, and a negative avian Mantoux test does not exclude the diagnosis. The availability of clarithromycin and rifabutin has offered new therapeutic options in treating atypical mycobacterial pulmonary infection, but management of these cases can be prolonged and difficult.
Publisher: European Respiratory Society (ERS)
Date: 12-1994
DOI: 10.1183/09031936.94.07122185
Abstract: Nebulized aerosols are commonly used to deliver drugs for the treatment of respiratory disease in children, but there are inadequate data on the dose of drug depositing in the lungs in this age group, and the effect of age on this dose. We therefore aimed to quantify total and regional deposition of nebulized aerosol in children of widely differing age. Twelve infants (median age 0.8 yrs, range 0.3-1.4 yrs) who were asleep, and eight older children (median age 10.8 yrs, range 6.3-18.0 yrs) with cystic fibrosis were studied. Radiolabelled normal saline aerosol was generated by a Turret nebulizer, with a driving flow of 9 l.min-1. All subjects inhaled aerosol via the nasal route, whilst the older children undertook a second study with inhalation via the oral route. Following aerosol inhalation, planar and single-photon emission computed tomography (SPECT) scans were obtained. For the nasal route, total lung deposition was lower in infants (median 1.3%, range 0.3-1.6%) than in older children (median 2.7%, range 1.6-4.4%). For the older children inhaling via the nasal or oral route, there was no influence of age on lung, upper respiratory tract, or the sum of upper respiratory tract and lung deposition. We conclude that the dose of a nasally inspired aerosol reaching the lungs of infants who are asleep is approximately half that for older children, when the nebulizer is operating at 9 l.min-1. Age does not affect deposition of nasally or orally inspired aerosols in older children.
Publisher: Elsevier BV
Date: 08-2019
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.PLEFA.2009.05.022
Abstract: Cysteinyl leukotrienes (cysLTs) are pro-inflammatory mediators with increasing evidence for a role in childhood acute asthma. This study examined the influence of polymorphisms in cysLT pathway genes on urinary leukotriene E(4) (uLTE(4)) levels and clinical status in acute asthmatic children. Children aged 2-16 years were recruited during an asthma attack (n=205). Where possible, asthma severity scores were assigned, ALOX5AP G-336A, ALOX5 G-1708A, LTC4S A-444C and G-1072A, GPX4 C718T, and CYSTLTR1 T927C genotypes were determined and uLTE(4) was measured in acute and convalescent s les. uLTE(4) levels were higher acutely compared with convalescence (acute GM: 115.7pg/mg creatinine 95% CI 88.6-151.1, convalescence GM: 66.4pg/mg creatinine 95% CI 51.5-85.6 n=50 paired s les, p=0.003) and paired s le analysis showed genotype-specific effects with significantly increased uLTE(4) for LTC(4)S-444AA (acute GM: 127.9pg/mg creatinine 95% CI 91.8-178.3, convalescence GM: 68.2pg/mg creatinine 95% CI 50.5-92.0 n=32, p=0.002), LTC(4)S-1072 GG (acute GM: 126.7pg/mg creatinine 95% CI 95.4-168.3, convalescence GM: 78.9pg/mg creatinine 95% CI 59.7-104.1 n=39, p=0.019) and CYSLTR1 927 TT/T_ (acute GM: 96.8pg/mg creatinine 95% CI 73.8-126.9, convalescence GM: 62.4pg/mg creatinine 95% CI 46.8-83.3 n=28, p=0.036) but not AC/CC, GA/AA, or TC/CC/C_, respectively. When we compared the allele frequencies of the CYSLTR1 SNP between asthmatics and non-asthmatics, the 927C allele was found to be a risk allele for asthma (OR=2.13, 95% CI: 1.06-4.26, p=0.033). Genotypes were not associated with acute or convalescent uLTE(4) levels alone and neither the SNPs nor uLTE(4) correlated with acute asthma severity. Leukotriene pathway gene polymorphisms may influence the magnitude of cysLT production during an attack, yet their influence alone may not be substantial enough to alter the severity of exacerbations.
Publisher: SAGE Publications
Date: 2006
DOI: 10.1191/1479972306CD100OA
Abstract: Adherence to recommended aerosol medicines and airway clearance techniques (ACT) for children with cystic fibrosis (CF) requires self-management skills. A multi-centre, randomized, controlled trial was conducted to investigate the effectiveness of a self-management education programme called ‘Airways’ for six-to 11-year old children with CF and their caregivers. Assessments were conducted immediately before and after the intervention period, and six and 12 months after the post-intervention assessment. The pen and paper education programme was completed by the child and caregiver together at home. Participants in the intervention and control groups had similar baseline characteristics. A per-protocol analysis was conducted and for variables that changed significantly, an additional intention-to-treat analysis was performed that included data from participants in the intervention group who withdrew from the study during the intervention period. The intervention group increased the percentage of prescribed aerosols taken (P 0.001) and this was maintained at 12-month follow-up (P 0.001). There was no change in the percentage of prescribed ACT performed, although when the child was unwell, caregivers in the intervention group increased the frequency and/or duration of ACT (P = 0.028) in the perprotocol analysis but not in the intention-to-treat analysis. Children in the intervention group increased their knowledge of ACT (P 0.001) which was maintained at 12-month follow-up (P 0.001) and felt more positively about their chest treatment regimens immediately following the intervention (P = 0.017) but not at 12-month follow-up. There were no significant changes in the control group for these variables over time. No significant changes occurred in the caregivers' reports of self-management behaviours and self-efficacy in either group. The positive results suggest that ‘Airways’ is a valuable educational tool for primary school-aged children with CF and their caregiver.
Publisher: Wiley
Date: 05-2005
DOI: 10.1002/PPUL.20191
Abstract: Newborn screening for cystic fibrosis has been used in Australia and New Zealand for over 20 years. In that time, considerable experience has been developed regarding the early diagnosis of cystic fibrosis after newborn screening. To date, there has not been a consensus on the process of screening and clinical evaluation leading to the diagnosis of cystic fibrosis in infants, many of whom are not symptomatic at time of notification of the screening result. The aim of this paper is to provide some consensus on the important issues of a cystic fibrosis diagnosis arising from newborn screening, based on the experience gained in Australia and New Zealand over the last 20 years.
Publisher: Public Library of Science (PLoS)
Date: 17-10-2019
Publisher: Wiley
Date: 21-10-2013
DOI: 10.1111/TAN.12226
Publisher: Springer Science and Business Media LLC
Date: 18-07-2018
DOI: 10.1038/S41598-018-29179-Y
Abstract: Using a well-designed longitudinal cohort, we aimed to identify cytokines that were protective against malaria and to explore how they were influenced by genetic and immunological factors. 349 Mozambican pregnant women and their newborn babies were recruited and followed up for malaria outcomes until 24 months of age. Six Th1 cytokines in cord blood were screened for correlation with malaria incidence, of which IL-12 was selected for further analyses. We genotyped IL-12 polymorphisms in children/mothers and evaluated the genotype-phenotype associations and genetic effects on IL-12 levels. Maternal IL-12 concentrations were also investigated in relation to Plasmodium infections and cord blood IL-12 levels. Our data showed that high background IL-12 levels were prospectively associated with a low incidence of clinical malaria, while IL-12 production after parasite stimulation had the opposite effect on malaria incidence. IL-12 genotypes ( IL-12b rs2288831/rs17860508) and the haplotype CGTTAGAG distribution were related to malaria susceptibility and background IL-12 levels. Maternal genotypes also exhibited an evident impact on host genotype-phenotype associations. Finally, a positive correlation in background IL-12 levels between maternal and cord blood was identified. Thus, cord blood background IL-12 concentrations are important for protecting children from clinical malaria, likely mediated by both genotypes (children& mothers) and maternal immunity.
Publisher: Elsevier BV
Date: 04-2017
Publisher: Elsevier BV
Date: 05-2016
Publisher: Springer Science and Business Media LLC
Date: 06-2016
DOI: 10.1007/S00431-016-2738-2
Abstract: The importance of good device technique to maximise delivery of aerosolised medications is widely recognised. Pressurised metered dose inhaler (pMDI)-spacer technique was investigated in 122 children, aged 2-7 years, with asthma. Eight in idual steps of device technique were evaluated before and after viewing an instructional video for correct device technique. Video measurements were repeated every three months for nine months. Device technique improved directly after video instruction at the baseline study visit (p < 0.001) but had no immediate effect at subsequent visits. Additionally, pMDI-spacer technique improved with successive visits over one year for the group overall as evidenced by increases in the proportion of children scoring maximal (p = 0.02) and near-maximal (p = 0.04) scores. Repeated video instruction over time improves inhaler technique in young children. • Correct device technique is considered essential for sufficient delivery of inhaled medication. • Poor inhaler use is common in young asthmatic children using pressurised metered dose inhalers and spacers. What is New: • Video instruction could be used as a strategy to improve device technique in young children.
Publisher: American Thoracic Society
Date: 15-08-2019
Publisher: The American Association of Immunologists
Date: 15-03-2019
Abstract: Asthma exacerbations are triggered by rhinovirus infections. We employed a systems biology approach to delineate upper-airway gene network patterns underlying asthma exacerbation phenotypes in children. Cluster analysis unveiled distinct IRF7
Publisher: Wiley
Date: 11-07-2018
DOI: 10.1111/ALL.13531
Publisher: American Thoracic Society
Date: 04-2021
Publisher: Elsevier BV
Date: 12-2005
DOI: 10.1086/497997
Publisher: Elsevier BV
Date: 2007
DOI: 10.1016/J.VACCINE.2006.07.024
Abstract: Significant differences in immune responses upon vaccination have been described, suggesting genetics are important in determining the magnitude of vaccine responses. The interleukin (IL)-4 pathway, including IL-4, IL-13 and the IL-4 receptor alpha chain (IL-4 Ralpha), is central to humoral responses and therefore could have an impact on vaccine responsiveness. To investigate whether single nucleotide polymorphisms (SNPs) in the IL-4, IL-13 and IL-4 RA genes influence pneumococcal serotype-specific IgG antibody responses. SNPs in the IL-4 gene (C -589T, G2979T), the IL-13 gene (G -1112A, Arg130Gln) and in the IL-4 RA gene (Ile50Val, Gln551Arg) were investigated in isolation and in combination, for their influence on serotype-specific IgG antibody responses upon combined pneumococcal conjugate and polysaccharide vaccinations in children with a history of recurrent otitis media. Lower antibody responses were observed for alleles previously associated with atopy, IL-4 -589T, IL-4 2979T and IL-4 Ralpha 551Gln. Effects were stronger in gene haplotype combinations or in multiple haplotype combination analyses. This study highlights the importance of host genetic factors in vaccine responses. Furthermore, it supports the approach of studying the effect of combinations of multiple alleles, in haplotypes or in combinations of haplotypes, on complex phenotypes within a biological pathway.
Publisher: Wiley
Date: 03-2007
DOI: 10.1111/J.1365-2222.2007.02668.X
Abstract: Early age at onset of atopy is associated with more severe asthma and increased airway responsiveness (AR) the underlying mechanism is unclear but may involve T cell responses. To test the hypothesis that enhanced T cell responses may be associated with early-onset atopy. In a longitudinal study, atopy was determined in infancy and at 6 and 11 years of age. In iduals were categorized as persistent infant-onset atopy (PIOA), early childhood-onset atopy (ECOA) and later childhood-onset atopy (LCOA). At 11 years of age, peripheral blood T cell cytokine responses, AR, exhaled nitric oxide (FE(NO)) and forced expiratory volume in 1 s were determined. The age at onset of atopy was determined for 60 children, of whom 15 had PIOA, 24 had ECOA and 21 had LCOA. An additional 76 children who were never atopic were also included. T cell responses to house dust mite, including interleukin-5, -9, -10 and tumour necrosis factor alpha, were higher among children with PIA and ECOA, and lower in children with LCOA, P<0.05. In contrast, those children with LCOA or who were not atopic had the highest IL-10 response to PHA (P=0.014). Children with PIOA and ECOA, but not LCOA, had higher AR and FE(NO) compared with non-atopic children (P<0.05). The group with PIOA were more likely among the atopic children to be admitted to hospital for asthma (P<0.05) and also had lower %FEV(1) compared with non-atopic children (P=0.023). Early age at sensitization is associated with enhanced T cell cytokine responses and indices of adverse asthma outcome. T cell cytokine responses might be programmed at the time of initial atopic sensitization.
Publisher: Elsevier BV
Date: 07-2008
DOI: 10.1016/J.VACCINE.2008.05.011
Abstract: Cytokine gene polymorphisms affect vaccine responses and gender-specific effects are known for many phenotypes. Therefore, this study investigated gender-specific effects of cytokine gene polymorphisms on vaccine responses. In 263 2-year-old subjects selected for parental history of atopy, boys with IL-4 C-589T and IL-4Ralpha I50V genotypes associated with atopy had increased Diptheria Toxoid (DiphTox) and Tetanus Toxoid (TetTox) responses compared with the remaining alleles (IL-4 C-589T: DipTox p=0.01, TetTox p=0.04 IL-4Ralpha.I50V: DipTox p=0.04, TetTox p=0.08). Contrastingly, girls with IL-10 -592C genotypes associated with atopy had lower levels of DiphTox (p=0.03) and TetTox (p=0.02) responses compared with the remaining allele. Additionally, interaction effects were found for IL-4 C-589T (p=0.01) and IL-4Ralpha I50V (p=0.04) polymorphisms. In conclusion, these findings support the interaction of primary genetic and modifying factors on vaccine responses and the importance of atopic genetics to these responses.
Publisher: American Society for Microbiology
Date: 07-2012
DOI: 10.1128/IAI.00261-12
Abstract: The role of interleukin-10 (IL-10) in malaria remains poorly characterized. The aims of this study were to investigate (i) whether genetic variants of the IL-10 gene influence IL-10 production and (ii) whether IL-10 production as well as the genotypes and haplotypes of the IL-10 gene in young children and their mothers are associated with the incidence of clinical malaria in young children. We genotyped three IL-10 single nucleotide polymorphisms in 240 children and their mothers from a longitudinal prospective cohort and assessed the IL-10 production by maternal peripheral blood mononuclear cells (PBMCs) and cord blood mononuclear cells (CBMCs). Clinical episodes of Plasmodium falciparum malaria in the children were documented until the second year of life. The polymorphism IL-10 A-1082G (GCC haplotype of three SNPs in IL-10) in children was associated with IL-10 production levels by CBMC cultured with P. falciparum -infected erythrocytes ( P = 0.043), with the G allele linked to low IL-10 production capacity. The G allele in children was also significantly associated with a decreased risk for clinical malaria infection in their second year of life ( P = 0.016). Furthermore, IL-10 levels measured in maternal PBMCs cultured with infected erythrocytes were associated with increased risk of malaria infection in young children ( P 0.001). In conclusion, IL-10 polymorphisms and IL-10 production capacity were associated with clinical malaria infections in young children. High IL-10 production capacity inherited from parents may diminish immunological protection against P. falciparum infection, thereby being a risk for increased malaria morbidity.
Publisher: Wiley
Date: 15-09-2015
DOI: 10.1111/CEA.12501
Abstract: Rhinoviruses from the Enterovirus genus cause frequent infections and induce remarkably high titres of anticapsid antigen antibodies in asthmatics, while the prevalence of neutralising antibodies to the gut-trophic echoviruses from the same genus is diminished. To assess the absolute and specific antibody titres to VP1 antigens of the gut-trophic enteroviruses, echovirus 30 and Sabin 1 poliovirus, in asthmatic and non-asthmatic children. Recombinant polypeptides representing the VP1 capsid antigens of echovirus 30 and Sabin poliovirus 1 were produced. Their ability to bind IgG1 antibodies from the plasma of asthmatic (n = 45) and non-asthmatic (n = 29) children were quantitated by immunoassays that incorporated immunoabsorptions to remove cross-reactivity. The IgG1 antibody titres and prevalence of antibody binding to echovirus 30 were significantly lower for asthmatic children compared to controls (P < 0.05) and inversely correlated with total IgE levels for the whole study population (r = -0.262 P < 0.05). There was no difference in the prevalence and titre between groups to the VP1 antigen of Sabin poliovirus. Anti-tetanus toxoid titres measured for comparison did not correlate with anti-echovirus or poliovirus, but correlated with anti-rhinovirus titres in controls but not asthmatics, where the titres were higher for the asthmatic group. The associations of lower antibody titres of asthmatic children to echovirus reported here and those of our previous findings of a heightened response to rhinovirus suggest a dichotomy where respiratory enterovirus infection/immunity increases the probability of developing asthma and enteric infections lower the risk. This provides further support for the concept of intestinal infection playing a key role in the development of allergic respiratory disease.
Publisher: S. Karger AG
Date: 2002
DOI: 10.1159/000064024
Abstract: i Objectives: /i The aim of this study was to compare subjective measures (overall health assessment both by the study physician and the child’s mother) with objective measurements of forced expiratory volumes (FEV sub t /sub ) and maximal flow at functional residual capacity & #118 & #775 sub max /sub FRC) in recurrently wheezy infants. i Methods: /i Sixteen wheezy infants (12 boys) aged 8–26 months were studied. A clinical assessment at visit 1 was followed by the run-in period during which day- and nighttime asthma symptom scores were obtained. The actual study period consisted of 2 visits when patient’s lung function was assessed. The first of which was during an acute exacerbation (visit 2), while the second was when the infant was asymptomatic (visit 3). FEV sub t /sub were obtained by the raised volume rapid thoracic compression technique (RVRTC) and & #118 & #775 sub max /sub FRC by the tidal volume rapid thoracic compression technique (TVRTC). i Results: /i Mean FEV sub t /sub but not mean & #118 & #775 sub max /sub FRC were significantly lower at visit 2 compared to visit 3 (FEV sub .5 /sub : p = 0.005, and FEV sub .75 /sub : p = 0.002 & #118 & #775 sub max /sub FRC: p = 0.15) and correlated well with overall health assessment by the study physician (FEV sub .5 /sub : r = 0.82, and FEV sub .75 /sub : r = 0.84), but not with the overall health assessment by the mother. i Conclusions: /i We have shown in the present study that objective measurements of FEV sub t /sub from a raised lung volume correlate well with the overall health assessment by the study physician this was in contrast to measurements of & #118 & #775 sub max /sub FRC in the tidal volume range. We therefore conclude that the RVRTC technique is a feasible method to assess and monitor obstructive lung disease in infancy.
Publisher: Elsevier BV
Date: 07-2018
Publisher: Wiley
Date: 11-08-2014
DOI: 10.1111/JPC.12705
Abstract: There are many current and evolving tools to assist clinicians in their daily work of phenotyping. In medicine, the term 'phenotype' is usually taken to mean some deviation from normal morphology, physiology and behaviour. It is ascertained via history, examination and investigations, and a primary aim is diagnosis. Therefore, doctors are, by necessity, expert 'phenotypers'. There is an inherent and partially realised power in phenotypic information that when harnessed can improve patient care. Furthermore, phenotyping developments are increasingly important in an era of rapid advances in genomic technology. Fortunately, there is an expanding network of phenotyping tools that are poised for clinical translation. These tools will preferentially be implemented to mirror clinical workflows and to integrate with advances in genomic and information-sharing technologies. This will synergise with and augment the clinical acumen of medical practitioners. We outline key enablers of the ascertainment, integration and interrogation of clinical phenotype by using genetic diseases, particularly rare ones, as a theme. Successes from the test bed or rare diseases will support approaches to common disease.
Publisher: Research Square Platform LLC
Date: 06-09-2023
Publisher: The American Association of Immunologists
Date: 07-2007
DOI: 10.4049/JIMMUNOL.179.1.132
Abstract: Severe bronchiolitis following respiratory syncytial virus (RSV) infection occurs in only a small subset of infected infants and the basis for variations in disease severity is not understood. Innate immune responses to RSV are mediated by TLR-4, and the 299Gly and 399Ile alleles of the TLR4 gene have been linked epidemiologically with increased severity of RSV disease in children. We hypothesized that cellular immune responses to RSV mediated by these variant forms of the receptor are defective relative to responses mediated via the common form of the receptor. Human bronchial epithelial cells were transfected with TLR4 constructs encoding the common TLR4 gene sequence (299Asp/399Thr), or the 299Gly or 399Ile alleles, and cytokine responses to in vitro RSV challenge were analyzed in the different transfected cells. Follow-up studies compared RSV-induced responses in PBMC from children expressing these same TLR4 genotypes. Human bronchial epithelial expressing 299Gly or 399Ile displayed normal levels of intracellular TLR4 but failed to efficiently translocate the receptor to the cell surface. This was associated with reduced NF-κB signaling post-TLR4 engagement, reduced production of IFNs, IL-8, IL-10, IL-12p35, IL-18, and CCL8, and the absence of acute-phase TNF-α. These findings were mirrored by blunted PBMC responses to RSV in children expressing the same TLR4 variants. Compromised first-line defense against RSV at the airway-epithelial surface of children expressing these TLR4 variants may thus confer increased susceptibility to severe infections with this virus.
Publisher: Elsevier BV
Date: 2009
DOI: 10.1016/J.JACI.2008.09.009
Abstract: Dendritic cells (DCs) are important in allergic diseases such as asthma, although little is known regarding the mechanisms by which DCs induce T(H)2-polarized responses in atopic in iduals. It has been suggested that intrinsic properties of allergens can directly stimulate T(H)2 polarizing functions of DCs, but little is known of the underlying mechanisms. To identify novel genes expressed by house dust mite (HDM) allergen-exposed DCs. We screened for allergen-induced gene expression by microarray, and validated differentially expressed genes at the mRNA and protein levels. Thrombomodulin (CD141, blood dendritic cell antigen 3) expression by microarray was higher on HDM-stimulated DCs from atopic (relative to nonatopic) in iduals. These findings were confirmed at both the mRNA and protein levels in an independent group. Purified thrombomodulin(+) DCs induced a strongly T(H)2-polarized cytokine response by allergen-specific T cells compared with DCs lacking thrombomodulin. In vivo, thrombomodulin(+) circulating DCs were significantly more frequent in subjects with HDM allergy and asthma, compared with control subjects. Furthermore, thrombomodulin expression in blood leukocytes was higher in children with acute asthma than at convalescence 6 weeks later. Thrombomodulin expression on DCs may be involved in the pathogenesis of atopy and asthma.
Publisher: Hindawi Limited
Date: 02-11-2012
DOI: 10.1002/HUMU.22219
Abstract: Three-dimensional (3D) facial analysis is ideal for high-resolution, nonionizing, noninvasive objective, high-throughput phenotypic, and phenomic studies. It is a natural complement to (epi)genetic technologies to facilitate advances in the understanding of rare and common diseases. The face is uniquely reflective of the primordial tissues, and there is evidence supporting the application of 3D facial analysis to the investigation of variation and disease including studies showing that the face can reflect systemic health, provides diagnostic clues to disorders, and that facial variation reflects biological pathways. In addition, facial variation has been related to evolutionary factors. The purpose of this review is to look backward to suggest that knowledge of human evolution supports, and may instruct, the application and interpretation of studies of facial morphology for documentation of human variation and investigation of its relationships with health and disease. Furthermore, in the context of advances of deep phenotyping and data integration, to look forward to suggest approaches to scalable implementation of facial analysis, and to suggest avenues for future research and clinical application of this technology.
Publisher: Wiley
Date: 13-07-2011
DOI: 10.1111/J.1399-3038.2011.01186.X
Abstract: We investigated the interactive effects of 11 innate immunity-related genes (IL10, IL12b, IL8, TLR2, TLR4, CD14, IFNGR, CC16, IFNg, CMA1, and TGFB) and four IgE response genes (IL4, IL13, IL4RA, and STAT6) with 'Western' or 'Eastern' environments/lifestyles on asthma and allergy in Karelian children. Karelian children (412 Finnish and 446 Russian) were recruited and assessed for a range of allergic conditions, with 24 single-nucleotide polymorphisms genotyped in 15 genes. The genotype-phenotype relationships differed in Finnish and Russian Karelian children. The interaction between polymorphisms and the variable representing 'Western' and 'Eastern' environments/ lifestyles was significant for IL10-1082 (p = 0.0083) on current rhinitis, IL12b 6408 on current conjunctivitis (p = 0.016) and atopy (p = 0.034), IL8 781 on atopic eczema (p = 0.0096), CD14 -550 on current rhinitis (p = 0.022), IFNgR1 -56 on atopic eczema(p = 0.038), and STAT6 2964 on current itchy rash (p = 0.037) and total serum IgE (p = 0.042). In addition, the G allele of IL13 130 was associated with a lower level of total serum IgE in Finnish (p = 0.003) and Russian (p = 0.01) children and overall (pooling the two populations together, p = 0.00006). After adjusting for multiple tests, the association between IL13 130 and IgE and the interactive effects of IL10-1082 on current rhinitis and IL8 781 on atopic eczema were significant by controlling a false-positive rate of 0.05 and 0.10, respectively. Living in an Eastern vs. Western environment was associated with a different genetic profile associated with asthma and allergy in the Karelian populations.
Publisher: Elsevier BV
Date: 07-2011
Publisher: Elsevier BV
Date: 06-2012
DOI: 10.1016/J.HUMIMM.2012.03.004
Abstract: Measles virus causes severe morbidity and mortality, despite the availability of measles vaccines. Successful defence against viral pathogens requires early recognition of virus-specific patterns by innate receptors like Toll-like receptor (TLR)3 and the RNA helicase, retinoic acid inducible gene-I (RIG-I). Genetic differences in these receptors may influence the primary immune responses to measles and the efficacy of measles vaccine. In 1-year-old Australian infants after their first measles vaccine dose, we investigated functional effects of TLR3 and RIG-I polymorphisms on intracellular protein expression using flow cytometry, cytokine responses to receptor ligands and measles lysate, and post-vaccination measles IgG levels. We found that TLR3 Leu412Phe was significantly associated with IFN-α/β response after stimulation with TLR3 ligand, poly(I:C) (P=0.024). Downregulation of TLR3 protein expression in NK cells after poly(I:C) was also associated with this variant (P=0.011). In contrast, measles-specific expression, cytokine responses and antibody responses were not associated with TLR3 polymorphisms. No associations were found with RIG-I variants. These results suggest that a TLR3 polymorphism has functional effects on receptor expression and cytokine response. However, this did not translate to an effect on specific responses to measles virus or vaccine. We found no evidence that RIG-I polymorphisms were involved in measles immune responses.
Publisher: Elsevier BV
Date: 08-2016
Publisher: Elsevier BV
Date: 02-2017
Publisher: European Respiratory Society (ERS)
Date: 06-08-2011
Publisher: Wiley
Date: 08-2003
DOI: 10.1034/J.1399-3038.2003.00065.X
Abstract: Exhaled nitric oxide (FENO) is raised in atopy. The mechanism for this is unclear. The aim of this study was to investigate whether the number of AAT repeats in intron 20 of the NOS1 gene, recently associated with variations in FENO in adults with asthma and cystic fibrosis, was associated with the raised FENO in healthy atopic children. Eighty-seven healthy children (44 girls, 42 atopic, age range 6-18 years) underwent measurements of FENO, spirometry, airway responsiveness and skin prick testing. Genotyping was carried out to determine the number of AAT repeats. There was no association between the number of AAT repeats and FENO in either the whole s le of healthy children (n = 87) or in the subs le of healthy atopics (n = 42). However, a greater number of atopic children had two high repeat alleles compared with non-atopic children (33.3% vs. 13.6%, respectively, p = 0.03). This suggests that variations in the NOS1 gene may contribute to atopy without this relationship being reflected by FENO.
Publisher: American Society for Microbiology
Date: 22-02-2012
DOI: 10.1128/CVI.05652-11
Abstract: Despite the availability of measles vaccines, infants continue to die from measles. Measles vaccine responses vary between in iduals, and poor immunogenicity is likely to preclude protection against measles. CD46 is a ubiquitously expressed specific receptor for vaccine strains of measles virus. CD46 polymorphisms have not been functionally investigated but may affect CD46 protein expression, which in turn may mediate primary measles antibody responses in infants. In a cohort of children aged 12 to 14 months from Perth, Australia ( n = 137), after their first dose of measles-mumps-rubella (MMR) vaccine, CD46 polymorphisms were genotyped, and postvaccination measles IgG and CD46 protein expression before and after measles lysate stimulation of cells were measured. Three CD46 variants (rs7144, rs11118580, and rs2724384) were significantly associated with measles virus-specific IgG levels ( P = 0.008, P = 0.026, and P = 0.018, respectively). There were significant differences between CD46 rs7144 genotypes and CD46 protein expression on T cells, as well as the downregulation of CD46 and T-cell frequency after measles lysate stimulation. We show that CD46 polymorphisms were associated with primary measles antibody responses in naive infants. We also report the first association of a measles virus receptor polymorphism with functional effects on the receptor, suggesting a possible mechanism through which antibody responses are altered. Elucidating all of the interconnecting genetic factors that alter primary measles vaccine responses may be important for identifying children at risk of poor immunogenicity or vaccine failure and for the future design of vaccine strategies to help these children.
Publisher: Wiley
Date: 2009
DOI: 10.1111/J.1365-2222.2008.03102.X
Abstract: 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. The aim of this study was to determine the role of the SCGB1A1 gene in the development of the asthma phenotype. 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. 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). SCGB1A1 A38G may play a role in the development and persistence of the asthma phenotype in childhood.
Publisher: Wiley
Date: 21-09-2016
DOI: 10.1111/RESP.12905
Publisher: American Thoracic Society
Date: 12-1998
DOI: 10.1164/AJRCCM.158.6.9804037
Abstract: Asthma is a genetically complex disease, and the investigation of putative linkages to candidate loci in independent populations is an important part of the gene discovery process. This study investigated the linkage of microsatellite markers in the 5q and 11q regions to asthma-associated quantitative traits in 121 Australian Caucasian nuclear families. The families were recruited on the basis of a child proband: a cohort of 95 randomly recruited families of unselected probands (n = 442 subjects) and a cohort of 26 families of probands selected on the basis of severe symptomatic asthma (n = 134 subjects). The quantitative traits assessed included serum levels of total IgE and specific IgE to house dust mite and mixed grass, blood eosinophil counts, and the dose-response slope (DRS) of FEV1 to histamine provocation. Multipoint linkage analysis using Haseman-Elston sib-pair methods provided evidence of significant linkage between the chromosome 5q markers and loge total serum IgE levels, specific serum IgE levels, and loge blood eosinophil counts. The chromosome 11q markers showed evidence of significant linkage to specific serum IgE levels. Neither region demonstrated significant linkage to the loge DRS to histamine. Phenotypes were residualized for age and sex. These data are consistent with the existence of loci regulating asthma-associated quantitative traits in both the 5q31-33 and 11q13 chromosomal regions.
Publisher: Elsevier BV
Date: 09-2006
DOI: 10.1016/J.JACI.2006.05.009
Abstract: A novel IL4RA polymorphism, Ala57Thr, was identified in Greenlander Inuit. We sought to determine whether the novel Thr57 allele is population specific and to assess the associations of Ala57Thr and Ile50Val with atopy in 2 Inuit populations. Ala57Thr and Ile50Val were genotyped in 651 Inuit living in Denmark, 1295 Inuit living in Greenland, and 1329 in iduals from 7 populations from widely differing global locations. In Inuit the polymorphisms were evaluated for associations with atopy, rhinitis, asthma, and pulmonary function. Thr57 was in linkage disequilibrium with Ile50 (D' = 1, r(2) = 0.13) and was common (33%) in the Inuit but rare (<0.6%) in all other populations. In Inuit living in Denmark, the Thr57 allele (in a dose-dependent manner) and the Ile50/Thr57 haplotype were associated with lower risk of atopy (P(linear) = .003 and P = .034, respectively), with similar trends observed for atopic rhinitis and atopic asthma. In Inuit living in Greenland, Thr57 was not associated with atopy or atopic diseases, but Ile50 was weakly associated with lower risk of atopy. The novel IL4RA Ala57Thr was common in and population specific to Greenlander Inuit, with Thr57 associated with a lower risk of atopy in those living in Denmark. Hence a full investigation of genotype-phenotype relationships in a given population can only be achieved if each gene is screened for novel polymorphisms in that population. Clinical risk attributable to variations in a gene in an ethnic group requires that all variations of the gene are known for that group.
Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1016/J.JACI.2014.03.014
Abstract: Asthma exacerbations are associated with human rhinovirus (HRV) infections, and more severe exacerbations are associated with HRV-C. We have previously shown that the HRV-C-specific antibody response is low in healthy adult sera and that most of the antibody to HRV-C is cross-reactive with HRV-A. To compare the antibody response to each HRV species in asthmatic and nonasthmatic children in whom the type of HRV infection was known. Total and specific IgG₁ binding to HRV viral capsid protein antigens of HRV-A, -B, and -C were tested in the plasma from nonasthmatic children (n = 47) and children presenting to the emergency department with asthma exacerbations (n = 96). HRV, found in most of the children at the time of their exacerbation (72%), was analyzed using molecular typing. Asthmatic children had higher antibody responses to HRV. The titers specific to HRV-A, and to a lesser extent HRV-B, were higher than in nonasthmatic controls. The species-specific responses to HRV-C were markedly lower than titers to HRV-A and HRV-B in both asthmatic and nonasthmatic children (P < .001). The titers both at presentation and after convalescence were not associated with the HRV genotype detected during the exacerbation. The higher total anti-HRV antibody titers of asthmatic children and their higher anti-HRV-A and -B titers show their development of a heightened antiviral immune response. The low species-specific HRV-C titers found in all groups, even when the virus was found, point to a different and possibly less efficacious immune response to this species.
Publisher: Wiley
Date: 16-09-2017
DOI: 10.1111/RESP.12901
Abstract: Asthma in adults is associated with a persistent reduction in lung function from childhood, but this link has not been assessed back to infancy. Reduced infant lung function (ILF), a measure of antenatal and infant lung growth, is associated with asthma into adolescence. Our aim was to assess whether this link persists into adulthood and whether ILF can predict the remission of asthma symptoms in young adults. The study cohort was an unselected full-term birth cohort of 253 subjects enrolled antenatally with lung function assessments at 1, 6 and 12 months (maximum expiratory flow at functional residual capacity, V'maxFRC), and 6, 11, 18 and 24 years (spirometry) of age. Infants with V'maxFRC in the lowest quartile at 1 month had an OR of 5.1 (95% CI: 2-13, P = 0.001) for asthma at 24 years. Subjects with asthma at 24 years had a mean V'maxFRC at 1 month of 69% predicted (95% CI: 48-90%) versus 110% (95% CI: 101-119%) in non-asthmatic patients (P = 0.001). Subjects with current versus resolved asthma symptoms at 24 years had a mean V'maxFRC at 1 month of 69% predicted (95% CI: 53-84%) versus 105% (88-123%), respectively (P = 0.003). Subjects with current asthma at 24 years had persistently lower lung function from infancy with a mean reduction of 16.2% (95% CI: 8.1-24.3%, P < 0.0001). Reduced lung function in early infancy is predictive of persistent asthma in young adults and a persistent reduction in lung function, suggesting abnormal lung development and growth in utero or very early in life.
Publisher: Springer Science and Business Media LLC
Date: 24-07-0031
DOI: 10.1038/S41598-017-06791-Y
Abstract: The prevalence of asthma and allergic diseases is disproportionately distributed among different populations, with an increasing trend observed in Western countries. Here we investigated how the environment affected genotype-phenotype association in a genetically homogeneous, but geographically separated population. We evaluated 18 single nucleotide polymorphisms (SNPs) corresponding to 8 genes ( ADAM33 , ALOX5 , LT-α, LTC4S , NOS1, ORMDL3, TBXA2R and TNF-α ), the lung function and five respiratory/allergic conditions (ever asthma, bronchitis, rhinitis, dermatitis and atopy) in two populations of Inuit residing either in the westernized environment of Denmark or in the rural area of Greenland. Our results showed that lung function was associated with genetic variants in ORMDL3 , with polymorphisms having a significant interaction with place of residence. LT-α SNP rs909253 and rs1041981 were significantly associated with bronchitis risk. LT-α SNP rs2844484 was related to dermatitis susceptibility and was significantly influenced by the place of residence. The observed gene-phenotype relationships were exclusively present in one population and absent in the other population. We conclude that the genotype-phenotype associations relating to bronchitis and allergy susceptibility are dependent on the environment and that environmental factors/lifestyles modify genetic predisposition and change the genetic effects on diseases.
Publisher: European Respiratory Society (ERS)
Date: 12-2017
Publisher: Cambridge University Press (CUP)
Date: 08-2011
Abstract: For decades the relationships of twinning and alterations in body patterning, such as laterality and asymmetry, have been investigated. However, the tools to define and quantify these relationships have been limited and the majority of these studies have relied on associations with subjectively defined phenotypes. The emerging technologies of 3-dimensional (3D) facial scanning and geometric morphometrics are providing the means to establish objective criteria, including measures of asymmetry, which can be used for phenotypic classification and investigations. Additionally, advances in molecular epigenetics provide new opportunities for novel investigations of mechanisms central to early developmental processes, twinning and related phenotypes. We review the evidence for overlapping etiologies of twinning, asymmetry and selected monogenic and complex diseases, and we suggest that the combination of epigenetic investigations with detailed and objective phenotyping, utilizing 3D facial analysis tools, can reveal insights into the genesis of these phenomena.
Publisher: Wiley
Date: 12-09-2016
DOI: 10.1111/PAI.12612
Abstract: Finnish and Russian Karelian children have a highly contrasting occurrence of asthma and allergy. In these two environments, we studied associations between total serum immunoglobulin E (IgE) with methylation levels in cluster of differentiation 14 (CD14). Five hundred Finnish and Russian Karelian children were included in four groups: Finnish children with high IgE (n = 126) and low IgE (n = 124) as well as Russian children with high IgE (n = 125) and low IgE (n = 125). DNA was extracted from whole blood cells and pyrosequenced. Three CpG sites were selected in the promoter region of CD14. Methylation levels in two of the three CpG sites were higher in the Finnish compared to Russian Karelian children. In the promoter area of CD14, the Finnish compared to Russian children with low IgE had a significant (p < 0.0001) increase in methylation levels at the Amp5Site 2. Likewise, the Finnish compared to Russian children with high IgE had a significant (p = 0.003) increase in methylation levels at the Amp5Site 3. In Russian children with low vs. high IgE, there were significant differences in methylation levels, but this was not the case on the Finnish side. In the regression analysis, adding the methylation variation of CD14 to the model did not explain the higher asthma and allergy risk in the Finnish children. The methylation levels in the promoter region of CD14 gene were higher in the Finnish compared to Russian Karelian children. However, the methylation variation of this candidate gene did not explain the asthma and allergy contrast between these two areas.
Publisher: Springer Science and Business Media LLC
Date: 23-09-2011
DOI: 10.1007/S00251-011-0574-0
Abstract: Successful defence against viral pathogens requires the rapid recognition of virus-specific "danger signals" and the activation of both innate and adaptive immunity. Toll-like receptors (TLR) 7 and 8 play a critical role in the elimination of viruses by recognising the common viral component, single stranded (ss)RNA. Measles virus, an ssRNA virus, continues to cause serious morbidity and mortality worldwide despite available measles vaccines. TLR7 and TLR8 genetic variation may cause functional alterations that result in impaired responses to measles. In a population of 12-month-old Australian infants, receptor protein expression was examined to assess the functionality of TLR7 and TLR8 polymorphisms, and the effects of these polymorphisms on cellular and antibody responses after the first measles vaccine dose were investigated. TLR7 Leu11Gln showed associations with TNF-α responses after ligand (imiquimod) stimulation in males only (P = 0.040), and non-responders were more likely to be Gln males (P = 0.044). TNF-α non-responders after imiquimod also had higher percentages of TLR8 -4284TT (69.6%) (P = 0.001) and TLR8 -558CC (69.6%) (P = 0.002) in females. Receptor protein expression after imiquimod or measles stimulation was not significantly altered compared with baseline, nor was it affected by genotype. None of the TLR7 or TLR8 polymorphisms studied were associated with measles-specific cytokine levels or with measles IgG levels. In conclusion, we report gender-specific associations with TLR7 and TLR8 polymorphisms and TNF-α cellular responses to its ligand. However, we found no evidence of any functional effects of TLR7 or TLR8 polymorphisms on receptor expression, measles-specific cellular responses or measles vaccine antibody responses.
Publisher: Springer Science and Business Media LLC
Date: 23-06-2005
Publisher: Wiley
Date: 09-1999
DOI: 10.1046/J.1365-2222.1999.00570.X
Abstract: There are a number of candidate genes thought to play a role in the development of asthma. Polymorphisms at amino acid positions 16 (arginine to glycine) and 27 (glutamine to glutamic acid) of the beta2-adrenoreceptor (B2AR) gene are known to be functionally relevant and have been associated with more severe forms of asthma, nocturnal asthma and decreased airway responsiveness in asthmatic subjects. To determine if these polymorphisms contribute to the development of asthma by investigating the associations between the polymorphisms at amino acid positions 16 and 27 of the B2AR gene and asthma-related parameters in a large, phenotypically well-characterized population which was unselected for asthma. Subjects (n = 332) were characterized using physiological assessments, immuno-logical data and information obtained from questionnaire. PCR was used to generate a 229 base pair fragment spanning the mutations of interest. Genotype was determined using allele-specific oligonucleotide hybridization and confirmed in 10% of the s les by direct sequencing. Multivariate analysis of the association between genotype and phenotype was then undertaken. Homozygotes for Glu27 were significantly less responsive to histamine than Gln27 homozygotes. In addition, Arg16 homozygotes were more likely to 'wheeze during a cold', in comparison with Gly16 homozygotes. However, there was no association between either polymorphism and physician-diagnosed asthma, eczema, skin reactivity to common allergens or total and specific serum IgE levels. The two polymorphisms were found to be in significant linkage disequilibrium. The polymorphism at position 27 was associated with decreased airway responsiveness in the study population and the polymorphism at position 16 was associated with increased wheeze during respiratory infection, but neither was associated with physician-diagnosed asthma or any of the other variables considered.
Publisher: American Thoracic Society
Date: 2010
Publisher: Wiley
Date: 06-02-2018
DOI: 10.1111/PAI.12859
Abstract: Significant differences exist in the prevalence, spectrum, and severity of allergic diseases between developing and developed countries and between subpopulations within single countries. These discrepancies likely result from a complex interaction between genetic and environmental factors. However, the precise nature of the contribution of ethnicity to genetic differences in the predisposition to allergic disease is not yet fully understood. In particular, there is a paucity of literature regarding the genetic determinants of allergic disease in people of black African origin with little or no genetic admixture. We aimed to analyze associations between 27 single nucleotide polymorphisms (SNPs) and allergy phenotypes in the local Xhosa population. A convenience s le of 213 Xhosa teenagers was enrolled at a local high school. Phenotypic data were collected in the form of a symptom questionnaire, skin prick tests for common food and aeroallergens, total serum IgE, and IgE to Ascaris lumbricoides. In addition, genotyping was performed to establish the prevalence of putative pro-inflammatory alleles. We demonstrated several significant associations between polymorphisms and allergy phenotypes. In particular, 2 polymorphisms in the IL-10 gene (IL10 -592A>C and IL10 -1082A>G) and 1 in the IL-4 gene (IL4 -589C>T) showed multiple associations with allergic sensitization and asthma phenotypes. Other polymorphisms, across a multitude of genes with discrepant functions, showed less consistent associations. This study represents an important first step in genotype henotype association in this population. Further research is required to confirm or refute our findings.
Publisher: European Respiratory Society (ERS)
Date: 14-03-2007
DOI: 10.1183/09031936.00123206
Abstract: The aim of the present study was to assess the effects of possible interactions between beta(2)-adrenoceptor gene polymorphisms and passive smoking on forced expiratory volume in one second (FEV(1)), forced vital capacity (FVC) and exhaled nitric oxide (eNO) in children aged 11 yrs. A cross-sectional analysis of the longitudinal cohort was conducted for associations between beta(2)-adrenoceptor gene polymorphisms and lung function and eNO with regard to passive smoking. Among children exposed to tobacco smoke, those with Arg16 (at least one Arg allele) exhibited lower adjusted mean FEV(1) (2.19 versus 2.38 L) and FVC (2.43 versus 2.64 L) than Gly16 homozygotes. Those with Gln27 (at least one Gln allele) also exhibited a lower adjusted mean FEV(1) relative to Glu27 homozygotes (2.24 versus 2.39 L). Among children with no exposure to smoking, those with Arg16 or Gln27 showed lower adjusted geometric mean eNO levels compared with Gly16 homozygotes (15.4 versus 30.9 ppb) and Glu27 homozygotes (18.0 versus 49.7 ppb). In conclusion, passive smoking had a significant effect on associations between beta(2)-adrenoceptor gene polymorphisms and asthma-related phenotypes, enhancing the relationship between Arg16 and lung function and removing the relationship between Arg16 or Gln27 and exhaled nitric oxide levels.
Publisher: Wiley
Date: 2006
DOI: 10.1002/PPUL.20529
Abstract: We evaluated the influence of haplotypes of beta(2)-adrenergic receptor (ADRB2) polymorphisms on lung function and airway responsiveness (AR) in a pediatric cohort recruited before birth and followed up to 11 years of age. The subjects (180) were the participants in a prospective study of lung function and AR. They have been assessed five times (at 1 month, 6 months, 12 months, 6 and 11 years of age) for lung function and AR. The two ADRB2 single nucleotide polymorphisms (SNPs): Arg16Gly and Gln27Glu were genotyped by PCR-RLFP and their haplotypes inferred using the program PHASE. An association between the haplotype arg16gln27 and the prevalence of positive AR was found at age 6 years (P = 0.009). The gly16gln27 haplotype was associated with higher FEV1 (P = 0.015) at age 6 and both higher FEV1 and FVC (P = 0.018 and P = 0.001, respectively) at age 11. In contrast, arg16gln27 was associated with both lower FEV1 and FVC (P = 0.028 and P = 0.011, respectively) at age 11. Children with the gly16gln27 haplotype were less likely to have asthma-ever or doctor-diagnosed asthma at age 11 (OR: 0.38 P = 0.019 and OR: 0.31 P = 0.041, respectively). In conclusion, haplotypes of beta(2)-adrenoceptor polymorphisms are associated with lung function, AR, and asthma susceptibility in childhood.
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.VACCINE.2012.07.063
Abstract: Despite an effective vaccine, measles remains a major health problem globally, particularly in developing countries. More than 30% of children show primary vaccine failure and therefore remain vulnerable to measles. Genetic variation in key innate pathogen recognition receptors, such as the measles cell entry receptors CD46 and SLAM, measles attachment receptor DC-SIGN, the antiviral toll-like receptors (TLR)3, TLR7 and TLR8, and the cytosolic antiviral receptor RIG-I, may significantly affect measles IgG antibody responses. Measles is still highly prevalent in developing countries such as those in Africa however there is no previous data on the effect of these innate immune genes in a resident African population. Polymorphisms (n=29) in the candidate genes were genotyped in a cohort of vaccinated children (n=238) aged 6 months-14 years from Mozambique, Africa who either had vaccine failure and contracted measles (cases n=66) or controls (n=172). Contrasting previous associations with measles responses in Caucasians and/or strong evidence for candidacy, we found little indication that these key innate immune genes affect measles IgG responses in our cohort of Mozambican children. We did however identify that CD46 and TLR8 variants may be involved in the occurrence of measles vaccine failure. This study highlights the importance of genetic studies in resident, non-Caucasian populations, from areas where determining the factors that may affect measles control is of a high priority.
Publisher: Wiley
Date: 05-01-2010
DOI: 10.1111/J.1398-9995.2009.02145.X
Abstract: Genetic and environmental influences and their interactions are central to asthma pathogenesis. This study aimed to investigate the effects of different macro-environments on asthma genotype-phenotype associations in two geographically separated populations with common ancestry. To accomplish this, two unselected populations of Inuit were recruited, one living in Greenland (n = 618) and the other in Denmark (n = 739). Subjects were genotyped for CD14 C-159T, SCGB1A1 A38G, ADRB2 Arg16Gly and Gln27Glu. The resulting genetic data were analysed for relationships with asthma-related parameters including lung function, ever asthma, atopy, rhinitis and dermatitis. The results showed contrasting magnitude and direction of genetic associations between the two geographically separate Inuit populations. In Greenland, the ADRB2 16Arg allele was associated with male-specific lower lung function, but in Denmark the same allele was associated with male-specific higher lung function. This allele was also associated with higher incidence of ever asthma in Denmark but not in Greenland. The SCGB1A1 38A allele was associated with lower rhinitis prevalence in Greenland but not in Denmark. These associations suggest that environment interacts with candidate asthma genes to modulate asthma pathogenesis in the Inuit.
Publisher: Wiley
Date: 26-07-2016
DOI: 10.1111/TMI.12743
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2000
Publisher: Wiley
Date: 03-08-2020
DOI: 10.1111/RESP.13661
Publisher: BMJ
Date: 12-2003
DOI: 10.1136/THORAX.58.12.1048
Abstract: Exhaled nitric oxide (FE(NO)) is raised in asthmatic children, but there are inconsistencies in the relationship between FE(NO) and characteristics of asthma, including atopy, increased airway responsiveness (AR), and airway inflammation. The aim of this study was to investigate the relationship between FE(NO) and asthma, atopy, and increased AR in children. One hundred and fifty five children (79 boys) of mean age 11.5 years underwent an assessment that included FE(NO) measurements, spirometric tests, inhaled histamine challenge, and a skin prick test. Blood was collected for eosinophil count. Current and past asthma like symptoms were determined by questionnaire. In multiple linear regression analyses FE(NO) was associated with atopy (p<0.001), level of AR (p = 0.005), blood eosinophil count (p = 0.007), and height (p = 0.002) but not with physician diagnosed asthma (p = 0.1) or reported wheeze in the last 12 months (p = 0.5). Separate regression models were conducted for atopic and non-atopic children and associations between FE(NO) and AR, blood eosinophils and height were only evident in atopic children. Exhaled NO was raised in children with a combination of atopy and increased AR independent of symptoms. Raised FE(NO) seems to be associated with an underlying mechanism linking atopy and AR but not necessarily respiratory symptoms.
Publisher: Wiley
Date: 07-06-2010
Publisher: Wiley
Date: 15-06-2012
Publisher: BMJ
Date: 25-10-2012
DOI: 10.1136/ARCHDISCHILD-2012-302312
Abstract: Adherence to prescribed inhaled medication is often low in young children. Poor adherence to medication may contribute to lack of symptom control. Doctors are not good at predicting the adherence rates of their patients, and parental report of adherence does not correlate with objective measures of adherence. The objective of this study was to investigate whether parental admission of non-adherence and reasons given for non-adherence correlated with objectively measured adherence. Adherence to prescribed inhaled corticosteroid treatment was monitored electronically in 132 children aged 2–6 years who were participating in a randomised controlled trial comparing different inhaler devices. Follow-up was carried out every 3 months for a year. Parental answers to simple questions about adherence were compared to electronically measured adherence. Mean adherence ranged from zero to 100%. Intra-participant adherence varied throughout the year-long study period (mean variance for in idual children between quarterly periods was 28.5%). Parents who reported missed doses, generally missed at least half of the prescribed doses. Parents who reported that not a single prescribed dose was missed, still missed 20% of doses on average. Adherence was particularly low when parents cited initiating their own trial off medication as a reason for missing doses. By examining parental response to questions enquiring whether any doses were missed, healthcare providers can gain a modest degree of insight into their patients’ true adherence to prescribed medication. Adherence to prescribed asthma medication is extremely variable in young children. Data from this study were derived from a randomised controlled trial (ACTRN12608000294358).
Publisher: Wiley
Date: 10-10-2008
DOI: 10.1111/J.1398-9995.2008.01804.X
Abstract: This review considers the data from studies analysing associations between the CD14C-159T single nucleotide polymorphism (SNP) and asthmatic phenotypes and discusses the variability of the conclusions. By searching PubMed and EMBASE for articles on CD14C-159T -related population or family-based association studies, 47 were identified up till September 2007. Collectively, the studies reviewed herein consistently showed population differences in frequencies of the alleles of the SNP, with African descent having the highest C allele frequencies, followed by Caucasians and Asians. The T allele of the SNP was associated with increased sCD14 in some studies but not in others. Inconsistently, the C allele, or even occasionally the T allele, was associated with atopic phenotypes in a population subgroup. There are several explanations for these inconsistencies, including lack of power, linkage disequilibrium, gene-gene interactions, population admixture and gene-environment interactions. If the SNP was associated with functional changes to the coded protein and thus modulating susceptibility to allergic disease, its effect may be modest and dependent on other co-existent, ethnicity-specific, genetic or environmental risk factors.
Publisher: Wiley
Date: 27-05-2018
DOI: 10.1002/PPUL.24062
Abstract: Increasing evidence suggests that poor lung function in adulthood is determined very early in life. Our study aims were: (1) identify factors associated with early infant lung function (2) quantify the link between early infant lung function and early adult lung function and (3) identify environmental and inherited factors which predict lung function throughout the post-natal growth period. In this longitudinal study, 253 in iduals were recruited antenatally. Lung function and allergy testing occurred at 1, 6, 12 months, 6, 11, 18, and 24 years of age. The relationship between lung function at 1 month (V'maxFRC) and spirometry variables at each follow-up was evaluated. Early life predictors of spirometry were assessed longitudinally using linear mixed models. V'maxFRC correlated positively with FEF25-75% at every assessment from 6 to 24 years and FEV Lung airflow measurements track from birth into early adulthood, suggesting a permanent and stable airway framework is laid down in the antenatal period. Lower infant airway function is associated with respiratory symptoms into adulthood, indicating the link is clinically important. Antenatal and early life exposures must be addressed in order to maximize airway growth and reduce lifelong respiratory compromise.
Publisher: American Society for Microbiology
Date: 12-2016
DOI: 10.1128/JVI.01701-16
Abstract: Rhinovirus (RV) species A and C are the most frequent cause of respiratory viral illness worldwide, and RV-C has been linked to more severe exacerbations of asthma in young children. Little is known about the immune responses to the different RV species, although studies comparing IgG1 antibody titers found impaired antibody responses to RV-C. Therefore, the aim of this study was to assess whether T-cell immunity to RV-C is similarly impaired. We measured T-cell proliferation to overlapping synthetic peptides covering the entire VP1 capsid protein of an RV-A and RV-C genotype for 20 healthy adult donors. Human leukocyte antigen (HLA) was typed in all the donors in order to investigate possible associations between the HLA type and RV peptide recognition. Total and specific IgG1 antibody titers to the VP1 proteins of both RV-A and RV-C were also measured to examine associations between the antibody and T-cell responses. We identified T-cell epitopes that are specific to and representative of each RV-A and RV-C species. These epitopes stimulated CD4 + -specific T-cell proliferation, with similar magnitudes of response for both RV species. All the donors, independent of their HLA-DR or -DQ type, were able to recognize the immunodominant RV-A and -C regions of VP1. Furthermore, the presence or absence of specific antibody titers was not related to changes in T-cell recognition. Our results indicate a dissociation between the antibody and T-cell responses to rhinoviruses. The species-representative T-cell epitopes identified in this study are valuable tools for future studies investigating T-cell responses to the different RV species. IMPORTANCE Rhinoviruses (RVs) are mostly associated with the common cold and asthma exacerbations, although their contributions to most upper and lower respiratory tract diseases have increasingly been reported. Species C (RV-C) has been associated with more frequent and severe asthma exacerbations in young children and, along with RV-A, is the most clinically relevant species. Little is known about how our immune system responds to rhinoviruses, and there are limited tools to study specific adaptive immunity against each rhinovirus species. In this study, we identified immunodominant T-cell epitopes of the VP1 proteins of RV-A and RV-C, which are representative of each species. The study found that T-cell responses to RV-A and RV-C were of similar magnitudes, in contrast with previous findings showing RV-C-specific antibody responses were low. These findings will provide the basis for future studies on the immune response to rhinoviruses and can help elucidate the mechanisms of severity of rhinovirus-induced infections.
Publisher: Wiley
Date: 26-01-2010
DOI: 10.1111/J.1440-1843.2009.01700.X
Abstract: Despite major advances in the understanding of the pathogenesis of asthma and improvements in management, the accompanying benefits from public health initiatives and clinical practice have arguably been less than expected. For ex le, there are no effective public health strategies or treatment regimes that reduce the risk of developing asthma or influence its natural history. These represent priority areas for future translational research, which would need to investigate genetic and environmental interactions and vaccine strategies. In terms of asthma management it is tempting to focus on novel drug therapies however, a case can be made that the priority is to undertake research that leads to improvements in the use of existing treatments through public health and primary care initiatives. Guidelines represent an important component of this approach, with recommendations for asthma imbedded within respiratory guidelines that can be implemented in the developing world where other acute and chronic respiratory disorders are common. This approach offers the best opportunity to close the gap between what is currently achieved in asthma management and that which is potentially achievable.
Publisher: Springer Science and Business Media LLC
Date: 09-10-2009
DOI: 10.1038/JHG.2009.97
Abstract: In the era of genome-wide association (GWA) studies, delineating pathogenic asthma genetic pathways has provided both challenges and opportunities. Initial GWA studies on asthma and asthma-like phenotypes provided some successes in terms of ascertaining new potential asthma candidate genes. However, due to asthma having a heterogeneous etiology, replications of these genotype-phenotype association studies are generally lacking. Furthermore, genes by environment interactions are generally not considered when GWA studies are conducted. Therefore, there is a need for extensive collaborations in multi-disciplinary research fields, including different environments and populations, to investigate the functional importance of variations in the human genome in relation to asthma pathogenesis.
Publisher: Wiley
Date: 16-04-2020
DOI: 10.1111/ALL.14277
Publisher: American Society for Clinical Investigation
Date: 09-04-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2001
DOI: 10.1097/00008571-200102000-00008
Abstract: The polymorphisms of the important xenobiotic metabolizing enzymes CYP2D6, CYP2C19 and CYP2E1 have been studied extensively in a large number of populations and show significant heterogeneity in the frequency of different alleles/genotypes and in the prevalence of the extensive and poor metabolizer phenotypes. Understanding of inter-ethnic differences in genotypes is important in prediction of either beneficial or adverse effects from therapeutic agents and other xenobiotics. Since no data were available for Australian Aborigines, we investigated the frequencies of alleles and genotypes for CYP2D6, CYP2C19 and CYP2E1 in a population living in the far north of Western Australia. Because of its geographical isolation, this population can serve as a model to study the impact of evolutionary forces on the distribution of different alleles for xenobiotic metabolizing enzymes. Twelve CYP2D6 alleles were analysed. The wild-type allele *1 was the most frequent (85.81%) and the non-functional alleles (*4, * 5, * 16) had an overall frequency of less than 10%. Only one subject (0.4%) was a poor metabolizer for CYP2D6 because of the genotype *5/*5. For CYP2C19, the frequencies of the *1 (wild-type) and the non-functional (*2 and *3) alleles were 50.2%, 35.5% and 14.3%, respectively. The combined CYP2C19 genotypes (*2/*2, *2/*3 or *3/*3) correspond to a predicted frequency of 25.6% for the CYP2C19 poor metabolizer phenotype. For CYP2EI, only one subject had the rare c2 allele giving an overall allele frequency of 0.2%. For CYP2D6 and CYP2C19, allele frequencies and predicted phenotypes differed significantly from those for Caucasians but were similar to those for Orientals indicating a close relationship to East Asian populations. Differences between Aborigines and Orientals in allele frequencies for CYP2D6* 10 and CYP2E1 c2 may have arisen through natural selection, or genetic drift, respectively.
Publisher: European Respiratory Society (ERS)
Date: 27-09-2007
DOI: 10.1183/09031936.00051106
Abstract: The aim of the present study was to measure airway, oropharyngeal and gastrointestinal deposition of (99m)Tc-labelled hydrofluoroalkane-beclomethasone dipropionate after inhalation via a pressurised metered-dose inhaler and spacer (Aerochamber Plus) in asthmatic children. A group of 24 children (aged 5-17 yrs) with mild asthma inhaled the labelled drug. A total of 12 children took five tidal breaths after each actuation (tidal group). The other 12 children used a slow maximal inhalation followed by a 5 - 10-s breath-hold (breath-hold group). Simultaneous anterior and posterior planar gamma-scintigraphic scans (120-s acquisition) were recorded. For the tidal group, mean+/-sd lung deposition (% ex-actuator, attenuation corrected) was 35.4+/-18.3, 47.5+/-13.0 and 54.9+/-11.2 in patients aged 5-7 (n = 4), 8-10 (n = 4) and 11-17 yrs (n = 4), respectively. Oropharyngeal and gastrointestinal deposition was 24.0+/-10.5, 10.3+/-4.4 and 10.1+/-6.2. With the breath-hold technique, lung deposition was 58.1+/-6.7, 56.6+/-5.2 and 58.4+/-9.2. Oropharyngeal and gastrointestinal deposition was 12.9+/-3.2, 20.1+/-9.5 and 20.8+/-8.8. Inhalation of the extrafine formulation with the breath-hold technique showed significantly improved lung deposition compared with tidal breathing across all ages. Oropharyngeal and gastrointestinal deposition was markedly decreased, regardless of which inhalation technique was applied, compared with a previous paediatric study using the same formulation delivered via a breath-actuated metered-dose inhaler.
Publisher: The American Association of Immunologists
Date: 15-08-2009
Abstract: Severe asthma exacerbations in children requiring hospitalization are typically associated with viral infection and occur almost exclusively among atopics, but the significance of these comorbidities is unknown. We hypothesized that underlying interactions between immunoinflammatory pathways related to responses to aeroallergen and virus are involved, and that evidence of these interactions is detectable in circulating cells during exacerbations. To address this hypothesis we used a genomics-based approach involving profiling of PBMC subpopulations collected during exacerbation vs convalescence by microarray and flow cytometry. We demonstrate that circulating T cells manifest the postactivated “exhausted” phenotype during exacerbations, whereas monocyte/dendritic cell populations display up-regulated CCR2 expression accompanied by phenotypic changes that have strong potential for enhancing local inflammation after their recruitment to the atopic lung. Notably, up-regulation of FcεR1, which is known to markedly lify capacity for allergen uptake resentation to Th2 effector cells via IgE-mediated allergen capture, and secondarily programming of IL-4/IL-13-dependent IL-13R+ alternatively activated macrophages that have been demonstrated in experimental settings to be a potent source of autocrine IL-13 production. We additionally show that this disease-associated activation profile can be reproduced in vitro by cytokine exposure of atopic monocytes, and furthermore that IFN-α can exert both positive and negative roles in the process. Our findings suggest that respiratory viral infection in atopic children may initiate an atopy-dependent cascade that lifies and sustains airway inflammation initiated by innate antiviral immunity via harnessing underlying atopy-associated mechanisms. These interactions may account for the unique susceptibility of atopics to severe viral-induced asthma exacerbations.
Publisher: Cold Spring Harbor Laboratory
Date: 17-12-2021
DOI: 10.1101/2021.12.16.21267946
Abstract: Although average contraceptive use has increased globally in recent decades, an estimated 222 million (26%) of women of child-bearing age worldwide face an unmet need for family planning — defined as a discrepancy between fertility preferences and contraception practice, or failing to translate desires to avoid pregnancy into preventative behaviours and practices. While many studies have reported relationships between availability of contraception, infant mortality, and fertility, these relationships have not been evaluated quantitatively across a broad range of low- and middle-income countries. Using publicly available data from 46 low- and middle-income countries, we collated test and control variables in six themes: ( i ) availability of family planning, ( ii ) quality of family planning, ( iii ) maternal education, ( iv ) religion, ( v ) mortality, and ( vi ) socio-economic conditions. We predicted that higher nation-level availability/quality of family-planning services, maternal education, and wealth reduce average fertility, whereas higher infant mortality and religious adherence increase it. Given the s le size, we first constructed general linear models to test for relationships between fertility and the variables from each theme, from which we retained those with the highest explanatory power within a final general linear model set to determine the partial correlation of dominant test variables. We also applied boosted regression trees, generalised least-squares models, and a generalised linear mixed-effects models to account for non-linearity and spatial autocorrelation. On average among all countries, we found an association between all main variables and fertility, with reduced infant mortality having the strongest relationship with reduced fertility. Access to contraception was the next-highest correlate with reduced fertility, with female secondary education, home health visitations, and adherence to Catholicism having weak, if any, explanatory power. Our models suggest that decreasing infant mortality and increasing access to contraception will have the greatest effect on decreasing global fertility. We thus provide new evidence that progressing the United Nation’s Sustainable Development Goals for reducing infant mortality can be accelerated by increasing access to any form of family planning.
Publisher: European Respiratory Society (ERS)
Date: 22-10-2015
DOI: 10.1183/13993003.00397-2015
Abstract: The Perth Infant Asthma Follow-up (PIAF) study involves a birth cohort of unselected subjects who have undergone longitudinal assessments of airway responsiveness at 1, 6 and 12 months and 6, 11 and 18 years of age. The aim of this study was to determine the relationship between increased airway responsiveness throughout childhood and asthma in early adult life. Airway responsiveness to histamine, assessed as a dose–response slope (DRS), and a respiratory questionnaire were completed at 1, 6 and 12 months and 6, 11 and 18 years of age. 253 children were initially recruited and studied. Airway responsiveness was assessed in 203, 174, 147, 103, 176 and 137 children at the above-mentioned time points, respectively (39 participants being assessed on all test occasions). Asthma at 18 years was associated with increased airway responsiveness at 6, 12 and 18 years, but not during infancy (slope 0.24, 95% CI 0.06–0.42 p=0.01 slope 0.25, 95% CI 0.08–0.49 p=0.006 and slope 0.56, 95% CI 0.29–0.83 p .001, respectively). Increased airway responsiveness and its association with asthma at age 18 years is established between infancy and 6 years. We propose that airway responsiveness in early life reflects the initial airway geometry and airway responsiveness later in childhood increasingly reflects immunological responses to environmental influences.
Publisher: Wiley
Date: 30-09-2017
DOI: 10.1002/JMV.24684
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.VACCINE.2011.05.068
Abstract: Despite the use of measles vaccine, measles virus continues to circulate and cause severe disease. Immune responses to the measles vaccine are variable between in iduals, with up to 10% failing to produce a sufficient protective response post-vaccination. Signaling lymphocyte activation molecule (SLAM) and dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN CD209) are specific measles receptors: SLAM binds and permits entry of the virus into the cell, DC-SIGN acts as an attachment receptor, increasing viral binding efficiency and transmission. Genetic variations in these receptor genes may alter measles vaccine antibody and cellular responses. In 12-month-old infants from Perth, Western Australia after their first measles vaccine dose as part of the combination measles-mumps-rubella (MMR) vaccine, 7 SLAM and DC-SIGN polymorphisms were genotyped and associations were investigated with measles IgG antibody levels and in vitro measles cytokine responses. The DC-SIGN promoter variant -336C/T was associated with overall IFN-γ responses after measles stimulation (P=0.002) and three DC-SIGN polymorphisms (-336C/T, -139C/T and -871C/T) were associated with the proportion of cytokine non-responders to measles (P=0.001, P=0.021 and P=0.036, respectively). However, no associations were found between the DC-SIGN or SLAM polymorphisms and measles IgG antibody levels. The results suggest that DC-SIGN -139C/T, -336C/T and -871C/T polymorphisms may modulate cytokine (but not antibody) responses to the measles component of MMR vaccine. Furthermore, contrasting previous studies, SLAM polymorphisms do not appear to affect measles antibody or cytokine responses in this cohort.
Publisher: Elsevier BV
Date: 04-2012
DOI: 10.1016/J.MEHY.2012.01.016
Abstract: We propose that, given shared evolutionarily factors mediate vaccine response and facial development, objective, high-resolution 3D facial analysis can be employed to investigate phenomena underlying vaccine response/failure. To account for ontological processes, the optimal prospective cohort would be ascertained in early life and followed longitudinally. Additionally, the non-invasive and relatively inexpensive nature of these technologies is ideally suited for novel investigations of existing cohorts and for use in developing countries.
Publisher: Springer Berlin Heidelberg
Date: 2015
Publisher: Elsevier BV
Date: 11-2004
Abstract: Raised exhaled nitric oxide (Feno) levels have been associated with asthma. However, we have found that in children, Feno was increased in atopic children with increased airway responsiveness (AR), and this was independent of a diagnosis of asthma. The current study was designed to test the hypothesis that in adults there is no association between Feno and asthma after controlling for atopy and AR. One hundred fifteen adults (77 women mean age, 41 years) underwent an assessment that included Feno measurements, spirometry, skin-prick testing, blood eosinophil count, and inhaled histamine challenge (results are expressed as a dose-response slope [DRS]). When only atopic in iduals were considered (n = 73), Feno was positively associated with the DRS (p = 0.003), male gender (0.02), and negatively associated with current smoking (p = 0.09). Only male gender (p = 0.03) was associated with Feno among nonatopic in iduals (n = 36). In multivariate analysis, there was no association between Feno and current asthma, current wheeze, or asthma ever. We conclude that in adult subjects, elevated Feno measurements are associated with a phenotype characterized by atopy and increased AR regardless of the presence of asthma or asthma-like symptoms.
Publisher: Springer Science and Business Media LLC
Date: 03-04-2014
Publisher: American Society for Microbiology
Date: 20-05-2020
Abstract: Gene expression profiling of the host response to HIV infection has promised to fill the gaps in our knowledge and provide new insights toward vaccine and cure. However, despite 20 years of research, the biggest questions remained unanswered. A literature review identified 62 studies examining gene expression dysregulation in s les from in iduals living with HIV. Changes in gene expression were dependent on cell/tissue type, stage of infection, viremia, and treatment status. Some cell types, notably CD4 + T cells, exhibit upregulation of cell cycle, interferon-related, and apoptosis genes consistent with depletion.
Publisher: European Respiratory Society (ERS)
Date: 31-10-2010
Publisher: BMJ
Date: 03-2008
Abstract: A study was undertaken to examine factors that might influence lung function during infancy and to test the hypothesis that change in weight during infancy is negatively associated with change in lung function. Weight, length and maximal flow at functional residual capacity (V'maxFRC) were measured at ages 1 and 12 months. V'maxFRC was adjusted for length. Asthma symptoms and age at introduction of formula feeds were identified from questionnaires. Groups were dichotomised by V'maxFRC at 1 month and change in V'maxFRC. 154 infants were assessed at ages 1 and 12 months. The change in V'maxFRC was inversely associated with change in weight (r = -0.18, r2 = 0.13, p<0.001). The group with lower V'maxFRC at 1 month and reduced change in V'maxFRC over infancy had the greatest weight gain (p = 0.003) and increased risk for asthma symptoms by 3 years (p = 0.017) but not afterwards. Exclusive breast feeding to 6 months was associated with a mean reduction in weight gain at age 12 months in comparison with earlier introduction of formula milk (mean difference 0.65 kg, p = 0.001), and was also associated with reduced asthma symptoms at 3 years (odds ratio 0.44, p = 0.043) but not at 6 or 11 years of age. Weight gain in infancy is inversely associated with change in lung function during infancy. Postnatal weight gain may be indirectly associated with early transient asthma symptoms via an influence on lung growth during infancy, and this is potentially modifiable by breast feeding. These associations could be relevant to the clinically recognised syndrome of the "fat happy wheezer".
Publisher: Wiley
Date: 08-12-2009
DOI: 10.1111/J.1651-2227.2009.01508.X
Abstract: A recently proposed method for classifying preschool wheeze is to describe it as either episodic (viral) wheeze or multiple trigger wheeze. In research studies, phenotype is generally determined by retrospective questionnaire. To determine whether recently proposed phenotypes of preschool wheeze are stable over time. In all, 132 two to six-year-old children with doctor diagnosed asthma on maintenance inhaled corticosteroids were classified as having episodic (viral) wheeze or multiple trigger wheeze at a screening visit and then followed up at three-monthly intervals for a year. At each follow-up visit, standardized questionnaires were used to determine whether the subjects wheezed only with, or also in the absence of colds. Stability of the phenotypes was assessed at the end of the study. Phenotype as determined by retrospective parental report at the start of the study was not predictive of phenotype during the study year. Phenotypic classification remained the same in 45.9% of children and altered in 54.1% of children. When children with preschool wheeze are classified into episodic (viral) wheeze or multiple trigger wheeze based on retrospective questionnaire, the classification is likely to change significantly within a 1-year period.
Publisher: Elsevier BV
Date: 2015
Publisher: Mary Ann Liebert Inc
Date: 10-2010
Abstract: Output from spacers (or valved holding chambers) is sensitive to changes in breathing pattern. Different spacers have unique characteristics that may influence breathing. A method used for breathing simulation, where the simulated breathing can be recorded on subjects while they are using spacers, may allow for more accurate in vitro estimation of drug delivery in specific populations, using specific spacers. A flow chamber was used to record breathing while salbutamol was administered to two adult subjects through different spacers. Each subject performed a series of breathing patterns over a range of different inhalation volumes and flows. Salbutamol "inhaled" by subjects was captured on inspiratory filters and quantified by ultraviolet spectrophotometry. Recorded breathing patterns were simulated and ex vivo drug delivery was compared to in vitro drug delivery. Three equipment configurations were used to validate different aspects of the methodology. Configuration 1: breathing recorded by pneumotachometer placed directly between a human subject and the spacer. Breathing simulation performed with an identical setup. Configuration 2: spacer enclosed within a flow-chamber while breathing was recorded. Breathing simulation performed with an identical setup. Configuration 3: spacer enclosed in flow chamber to record breathing, but not when simulating breathing. In each configuration, the ex vivo and in vitro (simulated) filter doses were compared. Configuration 1: the median difference between ex vivo and in vitro filter doses was 0.4% (range: -12.2 to 6.9%). Configuration 2: the median difference was -2.3% (range: -9.0 to 5.0%). Configuration 3: the median difference was 1.7% (range: -11.5 to 3.9%). Our results indicate that in vitro simulated drug delivery using this method of recording using a flow chamber, closely approximates ex vivo total drug delivery. This technique allows for recording of breathing on patients while they are using spacers, with minimum increase in dead space or resistance, and no physical alteration in the patient-device interface.
Publisher: American Thoracic Society
Date: 15-03-2006
Publisher: Wiley
Date: 05-2000
DOI: 10.1002/(SICI)1099-0496(200005)29:5<331::AID-PPUL1>3.0.CO;2-A
Abstract: In a prospective, longitudinal, population-based cohort study of familial and environmental influences on the development of wheezing respiratory illness in early childhood, we identified infant length, weight, gender, and exposure to maternal cigarette smoking as significant determinants of lung function during the first year of life. A cohort of 237 infants (106 females: 131 males) was evaluated, and 496 lung function measurements were made between the ages of 1-12 months. Respiratory function was assessed using the rapid thoracic compression technique to obtain maximum expiratory flow at functional residual capacity (V'maxFRC). Parental history of asthma and smoking habits during pregnancy were obtained by questionnaire. Data were analyzed using a longitudinal random effects model. Infants with a parental history of asthma and/or in utero passive smoke exposure were compared to a reference group of infants who had no parental history of asthma and in whom neither parent smoked pre- or postnatally. Boys were found to have a consistently lower V'maxFRC (-21.05 mL.s(-1)) throughout the first year of life in comparison to girls (P < 0.05). Maternal smoking during pregnancy was associated with a lower V'maxFRC in both genders in comparison to unexposed infants (P < 0.05). V'maxFRC was unaffected by parental history of asthma. Gender-specific normative equations for V'maxFRC throughout the first year of life were derived for the infant cohort as a whole and also for subgroups of infants, based on parental asthma and smoking history. We conclude that lung function during the first year of life differs between genders and is adversely affected by in utero passive tobacco smoke exposure. Gender-specific predictive equations for V'maxFRC should be used during infancy.
Publisher: Wiley
Date: 12-2000
DOI: 10.1046/J.1440-1754.2000.00565.X
Abstract: This paper provides specific guidelines on the management of tuberculosis infection and disease, covering general principles, recommended drug regimens and discuss the evidence to support these. It also covers use of corticosteroids, intermittent therapy, directly observed therapy and an approach to the management of a patient with drug-resistant tuberculosis.
Publisher: Wiley
Date: 22-05-2019
DOI: 10.1111/PAI.13063
Abstract: Antigen‐specific IgE binds the Fcε receptor I (FcεRI) expressed on several types of immune cells, including dendritic cells (DCs). Activation of FcεRI on DCs in atopics has been shown to modulate immune responses that potentially contribute to asthma development. However, the extent to which DC subsets differ in FcεRI expression between atopic children with or without asthma is currently not clear. This study aimed to analyse the expression of FcεRI on peripheral blood mononuclear cells (PBMCs) from atopic children with and without asthma, and non‐atopic/non‐asthmatic age‐matched healthy controls. We performed multiparameter flow cytometry on PBMC from 391 children across three community cohorts and one clinical cohort based in Western Australia. We confirmed expression of FcεRI on basophils, monocytes, plasmacytoid and conventional DCs, with higher proportions of all cell populations expressing FcεRI in atopic compared to non‐atopic children. Further, we observed that levels of FcεRI expression were elevated across plasmacytoid and conventional DC as well as basophils in atopic asthmatic compared to atopic non‐asthmatic children also after adjusting for serum IgE levels. Our data suggest that the expression pattern of FcεRI on DC and basophils differentiates asthmatic from non‐asthmatic atopic children. Given the significant immune modulatory effects observed as a consequence of FcεRI expression, this altered expression pattern is likely to contribute to asthma pathology in children.
Publisher: Elsevier BV
Date: 06-2014
Publisher: Wiley
Date: 09-1993
Abstract: Limited information exists regarding the repeatability of lung function and bronchial challenge tests using the rapid thoracic compression technique (RTC) in infants. To determine the repeatability of lung function and histamine challenge test results using the RTC technique and to compare the results obtained for bronchial challenges using histamine (H) and methacholine (M). Twelve infants [7 healthy, 5 with cystic fibrosis (CF) had pairs of H challenges 1 week apart. Eleven infants (7 healthy, 4 CF) had one H and one M challenge a week apart. The provocative concentration of H or M to cause a 40% fall in maximum flow at functional residual capacity (PC40) was determined using the RTC technique. Twenty-three comparisons were possible between maximal expiratory flow at functional residual capacity (VmaxFRC) measurements made 1 week apart. The mean difference between pairs of VmaxFRC measurements was 6.4% of baseline, and the coefficient of repeatability was 31.1% of baseline. The mean difference between PC40(H) measurements was 0.163 doubling concentrations, with a coefficient of repeatability of 1.66 doubling concentrations. The mean difference between PC40(H) and PC40(M) was 0.75 doubling concentrations, with 95% of PC40(H) between -0.18 to 1.69 doubling concentrations of the PC40(M). Although the repeatability of VmaxFRC using the RTC technique is less than for voluntary forced expiratory flow parameters in older children, similar results were obtained for infants as observed in older subjects for repeatability of H challenges and agreement between measures of bronchial responsiveness using H or M.
Publisher: Wiley
Date: 16-12-2016
DOI: 10.1002/EM.21989
Abstract: Several human diseases and conditions are disproportionally distributed in the world with a significant "Western-developed" vs. "Eastern-developing" gradient. We compared genome-wide DNA methylation of peripheral blood mononuclear cells in 25 newly arrived Chinese immigrants living in a Western environment for less than 6 months ("Newly arrived") with 23 Chinese immigrants living in the Western environment for more than two years ("Long-term") with a mean of 8.7 years, using the Infinium HumanMethylation450 BeadChip. In a sub-group of both subject groups (n = 12 each) we also investigated genome-wide gene expression using a Human HT-12 v4 expression beadChip. There were 62.5% probes among the total number of 382,250 valid CpG sites with greater mean Beta (β) in "Long-term" than in "Newly arrived". In the regions of CpG islands and gene promoters, compared with the CpG sites in all other regions, lower percentages of CpG sites with mean methylation levels in "Long-term" greater than "Newly arrived" were observed, but still >50%. The increase of methylation was associated with a general decrease of gene expression in Chinese immigrants living in the Western environment for a longer period of time. After adjusting for age, gender and other confounding factors the findings remained. Chinese immigrants living in Australia for a longer period of time have increased overall genome methylation and decreased overall gene expression compared with newly arrived immigrants.
Publisher: European Respiratory Society (ERS)
Date: 05-07-2018
Publisher: Public Library of Science (PLoS)
Date: 07-03-2012
Publisher: Wiley
Date: 29-12-2020
DOI: 10.1002/JMV.26730
Publisher: Elsevier BV
Date: 02-2017
Publisher: Elsevier BV
Date: 06-2008
Abstract: The airways in patients with cystic fibrosis (CF) are characterized by the accumulation of tenacious, dehydrated mucus that is a precursor for chronic infection, inflammation, and tissue destruction. The clearance of mucus is an integral component of daily therapy. Inhaled mannitol is an osmotic agent that increases the water content of the airway surface liquid, and improves the clearance of mucus with the potential to improve lung function and respiratory health. To this end, this study examined the efficacy and safety of therapy with inhaled mannitol over a 2-week period. This was a randomized, double-blind, placebo-controlled, crossover study. Thirty-nine subjects with mild-to-moderate CF lung disease inhaled 420 mg of mannitol or placebo twice daily for 2 weeks. Following a 2-week washout period, subjects were entered in the reciprocal treatment arm. Lung function, respiratory symptoms, quality of life, and safety were assessed. Mannitol treatment increased FEV(1) from baseline by a mean of 7.0% (95% confidence interval [CI], 3.3 to 10.7) compared to placebo 0.3% (95% CI, - 3.4 to 4.0 p < 0.001). The absolute improvement with mannitol therapy was 121 mL (95% CI, 56.3 to 185.7), which was significantly more than that with placebo (0 mL 95% CI, - 64.7 to 64.7). The forced expiratory flow in the middle half of the FVC increased by 15.5% (95% CI, - 6.5 to 24.6) compared to that with placebo (increase, 0.7% 95% CI, - 8.3 to 9.7 p < 0.02). The safety profile of mannitol was adequate, and no serious adverse events related to treatment were observed. Inhaled mannitol treatment over a period of 2 weeks significantly improved lung function in patients with CF. Mannitol therapy was safe and well tolerated. (ClinicalTrials.gov) Identifier: NCT00455130.
Publisher: Mary Ann Liebert Inc
Date: 05-2018
Abstract: To assess if the difference in species-specific immune response to RV-C correlates with a higher frequency of reinfection, shorter time to reinfection, or different symptom severity than infections with RV-A or RV-B. Forty-three patients were enrolled of which 34 were successfully tracked longitudinally over 3 months, with nasal swabs and symptom questionnaires provided every 2 weeks to identify rhinovirus (RV) strains and the concurrent symptomatology. No difference was found in the time to reinfection with an RV species between RV-C and RV-A or RV-B (p = 0.866). There was a trend toward more rapid reinfection with the same species in RV-C than RV-A (55.1 days vs. 67.9 days), but this failed to reach statistical significance (p = 0.105). RV infections were generally associated with only minor symptoms, with rhinorrhea being the only significantly associated symptom (p = 0.01). RV-C was shown to have higher levels of lethargy and wheeze than other RV species. Time to reinfection with subsequent RV is not influenced by the species of the preceding RV.
Publisher: Elsevier BV
Date: 03-2004
Publisher: Informa UK Limited
Date: 11-2010
DOI: 10.1080/02770903.2010.508856
Abstract: The glutathione S-transferase enzymes (GSTs) play an important role in the detoxification of environmental tobacco smoke (ETS), which contributes to airway inflammation, a key component of asthma. Genetic variation in GST genes may influence in iduals' ability to detoxify environmental pollutants. To examine the role of polymorphisms in GSTP1 (Ile105Val and Ala114Val), alone and in combination with ETS exposure, on atopy and asthma severity. GSTP1 Ile105Val and Ala114Val were genotyped and ETS exposure was assessed by parental questionnaire, which was validated by urinary cotinine measurements. Associations between ETS exposure, GSTP1 polymorphisms, and their interaction on atopy and asthma severity were investigated. For the functional GSTP1 105 SNP, those with the Ile/Ile genotype had odds for atopy of 2.77 (p = .054) when assessed by genotype alone, which increased to 9.02 (p = .050) when ETS was included, relative to in iduals with other genotypes. Likewise, compared to children with other GSTP1 114 genotypes, those with Ala/Ala genotype had a 5.47-fold (p = .002) increased risk of atopy (p = .020) when assessed by genotype alone, increasing to 9.17-fold when ETS was included. The 105 Ile/Ile in iduals all had the AA (105 Ile/Ile and 114 Ala/Ala) haplotype group therefore, the odds for atopy were the same. In iduals without any *C haplotype (105 Val and 114 Val allele) who were exposed to ETS had a 9.17-fold increased risk of atopy when compared with in iduals with at least one *C haplotype and not exposed to ETS (p = .020). There were significant interactions between GSTP1 SNPs, atopy, and ETS exposure in this cohort.
Publisher: Elsevier BV
Date: 07-2020
Publisher: Springer Science and Business Media LLC
Date: 14-01-0003
DOI: 10.1007/S00251-005-0778-2
Abstract: The gene for Clara cell 16-kDa (CC16) protein is a promising candidate for asthma susceptibility. The CC16 38A allele has been associated with decreased CC16 plasma levels and increased incidence of asthma in Australian children. To date these results have not been replicated in adults. Therefore, potential links between CC16 A38G, asthma and atopy were investigated in an unselected population of young adult Danes. Four hundred sixty-four Danes, aged 19-29 years, from Copenhagen participated in an asthma and allergy phenotype-genotype study. Genotyping was done by Sau96I restriction digestion of PCR products spanning the A38G polymorphism. Potential A38G genotype and asthma-related phenotype associations were investigated using regression analysis, adjusting for potential confounders where appropriate. Adults with the 38AA genotype had higher odds of current asthma (OR 3.2, P=0.013) and ever asthma (OR 2.2, P=0.045) compared with those with the 38GG genotype. Adjusting for atopy had minimal effect on this relationship. A positive linear trend was evident between the 38A allele and atopic dermatitis (OR 1.67, P=0.02). No associations were found between the A38G polymorphism and rhinitis, atopy, forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC), airway responsiveness (AR) to histamine or peripheral blood eosinophil level (PBEL). An atopy-independent association between CC16 38AA and asthma prevalence was identified, suggesting the CC16 38A allele predisposes to adult asthma independent of Th1/Th2 processes. This finding is consistent with previous studies in children, but is the first reported association between CC16 A38G and asthma in adults. CC16 38A also displayed a positive linear trend with atopic dermatitis.
Publisher: American Academy of Pediatrics (AAP)
Date: 12-2010
Abstract: The goal was to determine the number of breaths required to inhale salbutamol from different spacers/valved holding chambers (VHCs). Breathing patterns were recorded for 2- to 7-year-old children inhaling placebo from 4 different spacers/VHCs and were simulated by a flow generator. Drug delivery with different numbers of tidal breaths and with a single maximal breath was compared. With tidal breathing, mean inhalation volumes were large, ranging from 384 mL to 445 mL. Mean values for drug delivery with an Aerochamber Plus (Trudell, London, Canada) were 40% (95% confidence interval [CI]: 34%–46%) and 41% (95% CI: 36%–47%) of the total dose with 2 and 9 tidal breaths, respectively. Mean drug delivery values with these breath numbers with a Funhaler (Visiomed, Perth, Australia) were 39% (95% CI: 34%–43%) and 38% (95% CI: 35%–42%), respectively. With a Volumatic (GlaxoSmithKline, Melbourne, Australia), mean drug delivery values with 2 and 9 tidal breaths were 37% (95% CI: 33%–41%) and 43% (95% CI: 40%–46%), respectively (P = .02) there was no significant difference in drug delivery with 3 versus 9 tidal breaths. With the modified soft drink bottle, drug delivery. Drug delivery was not improved with a single maximal breath with any device. For young children, tidal breaths through a spacer/VHC were much larger than expected. Two tidal breaths were adequate for small-volume VHCs and a 500-mL modified soft drink bottle, and 3 tidal breaths were adequate for the larger Volumatic VHC.
Publisher: Elsevier BV
Date: 10-1996
DOI: 10.1016/S0140-6736(96)04446-7
Abstract: Infants of mothers who smoke have reduced respiratory function and are more likely to develop wheezing. Little evidence is available on the effect of in-utero cigarette-smoke exposure as opposed to postnatal exposure to environmental tobacco smoke. We used a previously validated non-invasive method to measure the time to peak tidal expiratory flow (tPTEF) as a proportion of expiratory time (tE) in newborn infants soon after birth to examine the effects of a family history of asthma and in-utero cigarette-smoke exposure on the infants' respiratory function. We collected respiratory-function data from 500 healthy infants of mothers taking part in the Western Australia Pregnancy Cohort Study. During behaviourally defined quiet sleep, measurements were obtained a median of 58 h (range 26-159) after the infants were born. We used uncalibrated inductance plethysmography. The uncalibrated volume signal was differentiated to flow and used to calculate respiratory rate, total inspiratory time, tE, and tPTEF. Mothers answered questionnaires on demographic, medical, and pregnancy characteristics, including smoking history. Serum cotinine measurements were available to validate self-reported smoking history in a subset of mothers (238). Data suitable for analysis were obtained from 461 infants. In multivariate regression analysis, lower values of tPTEF/tE were independently associated with respiratory rate (beta coefficient per 10 breaths/min 0.018 [SE 0.005], p < 0.01), age (beta coefficient per 10 h -0.008 [0.003], p 10 cigarettes daily beta coefficient -0.049 [0.022], p < 0.05), maternal hypertension during pregnancy (-0.037 [0.015], p < 0.02), and a family history of asthma (-0.028[0.014], p < 0.05). In-utero smoke exposure, a family history of asthma, and maternal hypertension during pregnancy are associated with reduced respiratory function after birth. We speculate that these factors adversely affect lung development in utero.
Publisher: Wiley
Date: 11-2021
DOI: 10.1111/JPC.15822
Abstract: Dire forecasts predict that an increasingly hostile environment globally will increase the threats to human health. Infants and young children are especially at risk because children are particularly vulnerable to climate‐related stressors. The childhood diseases most affected, the breadth and magnitude of future health problems and the time frame over which these problems will manifest remain largely unknown. To review the possibility that spacially explicit analyses can be used to determine how climate change has affected children's health to date and whether these analyses can be used for future projections. As an ex le of whether these objectives can be achieved, all available Australian environmental and health databases were reviewed. Environmental and health data in Australia have been collected for up to 30 years for the same spatial areas at ‘Statistical Area level 1’ (SA1) scale. SA1s are defined as having a population of between 200 and 800 people and collectively they cover the whole of Australia without gaps or overlap. Although the SA1 environmental and health data have been collected separately, they can be merged to allow detailed statistical analyses that can determine how climate change has affected the health of children. The availability of environmental and health datasets that share the same precise spatial coordinates provides a pathway whereby past and emerging effects on child health can be measured and predicted into the future. Given that the future health and well‐being of children is one of society's greatest concerns, this information is urgently needed.
Publisher: BMJ
Date: 09-2019
DOI: 10.1136/BMJOPEN-2019-029968
Abstract: We sought to test hypotheses regarding the principal correlates of child-health performance among African nations based on previous evidence collected at finer spatial scales. Retrospective, cross-sectional study. All countries in Africa, excluding small-island nations. We defined a composite child-health indicator for each country comprising the incidence of stunting, deaths from respiratory disease, deaths from diarrhoeal disease, deaths from other infectious disease and deaths from injuries for children aged under 5 years. We also compiled national-level data for Africa to test the effects of country-level water quality, air pollution, food supply, breast feeding, environmental performance, per capita wealth, healthcare investment, population density and governance quality on the child-health indicator. Across nations, child health was lowest when water quality, improved sanitation, air quality and environmental performance were lowest. There was also an important decline in child health as household size (a proxy for population density) increased. The remaining variables had only weak effects, but in the directions we hypothesised. These results emphasise the importance of continued investment in clean water and sanitation services, measures to improve air quality and efforts to restrict further environmental degradation, to promote the UN’s Sustainable Development Goal 3 target to ‘… end preventable deaths of newborns and children under 5’ and Goal 6 to ‘… ensure access to water and sanitation for all’ by 2030.
Publisher: Wiley
Date: 09-05-2017
DOI: 10.1111/CEA.12935
Publisher: Wiley
Date: 22-07-2007
DOI: 10.1111/J.1365-2222.2007.02786.X
Abstract: There is evidence that the specificity of the IgE binding in allergy tests can vary for different populations. We aimed to examine the allergenic specificity of IgE binding in sera from house dust mite (HDM)-atopic subjects in a tropical Australian Aboriginal community. Sera shown to contain IgE antibodies to an HDM extract of Dermatophagoides pteronyssinus were examined for IgE binding to a panel of nine purified HDM allergens from this mite species by quantitative microtitre assays. IgG antibody binding (IgG1 and IgG4) was also measured. The IgE-binding activity in the sera from the Aboriginal community was not directed to the expected major groups 1 and 2 HDM allergens but instead to the group 4 amylase allergen. There was also little IgE binding to the potentially cross-reactive tropomyosin (Der p 10) or arginine kinase (Der p 20) allergens. The IgG4 antibody was rarely detected and limited to the Der p 4 allergen. IgG1 antibody binding was frequently measured to all the allergens regardless of an in idual's atopic status, whereas in urban communities it is restricted to the major allergens and to atopic subjects. The high IgE anti-HDM response of Australian Aboriginals predominantly bound Der p 4 and not the Der p 1 and 2 allergens, showing a distinctive allergy that could affect the disease outcome and diagnosis.
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.JPEDS.2011.06.025
Abstract: To examine the influence of viral respiratory infection (VRI) on treatment response in acute asthma in children. A total of 218 children (mean age, 6.6 years) with acute asthma were recruited. Symptoms were recorded, an asthma severity score was determined, and whenever possible, a per-nasal aspirate was obtained for detection of viruses. Each child's response to inhaled β(2)-agonists was assessed after 6, 12, and 24 hours. The 168 children with VRI symptoms received more treatment with inhaled β(2)-agonists after 6 hours (P = .010), 12 hours (P = .002), and 24 hours (P = .0005) compared with the 50 children without such symptoms. Asthma severity did not differ between the 2 groups. A per-nasal aspirate was obtained from 77% of the children. The most frequently identified virus was rhinovirus (61.4%). Among children with symptoms of a VRI, those with rhinovirus had an impaired response to β(2)-agonists at 6 hours (P = .032). Children with acute asthma and symptoms of VRI respond less effectively to β(2)-agonists after 6, 12, or 24 hours and thus may benefit from more intense therapy and monitoring.
Publisher: Wiley
Date: 09-07-2009
Publisher: Cold Spring Harbor Laboratory
Date: 03-05-2023
DOI: 10.1101/2023.04.29.23289314
Abstract: Recurrent wheezing disorders including asthma are complex and heterogeneous diseases that affect up to 30% of all children, contributing to a major burden on children, their families, and global healthcare systems. It is now recognized that a dysfunctional airway epithelium plays a central role in the pathogenesis of recurrent wheeze, although the underlying mechanisms are still not fully understood. This prospective birth cohort aims to bridge this knowledge gap by investigating the influence of intrinsic epithelial dysfunction on the risk for developing respiratory disorders and the modulation of this risk by maternal morbidities, in utero exposures, and respiratory exposures in the first year of life. The Airway Epithelium Respiratory Illnesses and Allergy (AERIAL) study is nested within the ORIGINS Project and will monitor 400 infants from birth to five years. The primary outcome of the AERIAL study will be the identification of epithelial endotypes and exposure variables that influence the development of recurrent wheezing, asthma, and allergic sensitisation. Nasal respiratory epithelium at birth to six weeks, one, three, and five years will be analysed by bulk RNA-seq and DNA methylation sequencing. Maternal morbidities and in utero exposures will be identified on maternal history and their effects measured through transcriptomic and epigenetic analyses of the amnion and newborn epithelium. Exposures within the first year of life will be identified based on infant medical history as well as on background and symptomatic nasal s ling for viral PCR and microbiome analysis. Daily temperatures and symptoms recorded in a study-specific Smartphone App will be used to identify symptomatic respiratory illnesses. Ethical approval has been obtained from Ramsey Health Care HREC WA-SA (#1908). Results will be disseminated through open-access peer-reviewed manuscripts, conference presentations, and through different media channels to consumers, ORIGINS families, and the wider community.
Publisher: The Korean Academy of Asthma, Allergy and Clinical Immunology and The Korean Academy of Pediatric Al
Date: 2014
Publisher: Informa UK Limited
Date: 08-2018
DOI: 10.2147/JAA.S170285
Publisher: Wiley
Date: 09-2009
DOI: 10.1111/J.1398-9995.2009.02006.X
Abstract: Finnish Karelians have a higher prevalence of allergic disease than Russian Karelians. As both populations are generally from the same ethnic group, the Karelian population offers a unique opportunity to analyse genetic and allergic disease interactions between 'Western' and 'Eastern' environments. We investigated associations between allergic diseases and CD14 and CC16 polymorphisms in Finnish vs Russian Karelian women. Adult female Karelians (330 Finnish and 274 Russian) were recruited, examined for a range of symptoms and conditions including rhinitis, itchy rash, asthma and atopy and genotyped for CD14 C-159T and CC16 A38G. For both CD14 C-159T and CC16 A38G, the risk allele for atopic phenotypes in Finnish Karelia was the protective allele in Russian Karelia. For CD14 C-159T, an interactive effect on ever itchy rash (P(interaction) = 0.004), itchy rash <12 mo (P(interaction) = 0.001) and dry cough at night in the past 12 months (<12 months) (P(interaction) = 0.011) was found the risk allele was C in Russians and T in Finns. For CC16 A38G, an interaction was significant for ever rhinitis (P(interaction) = 0.006), rhinitis <12 mo (P(interaction) = 0.004), and marginally significant for ever hayfever (P(interaction) = 0.07), allergic eye symptoms <12 mo (P(interaction) = 0.09) their risk allele was G in Russians and A in Finns. An Eastern vs Western environment appears to exert an effect via opposite alleles on risk of allergic diseases in adult women.
Publisher: Elsevier BV
Date: 02-2007
DOI: 10.1016/J.JACI.2006.09.018
Abstract: Gene-environment interactions play central roles in controlling postnatal maturation of immune function, but their effects on infant vaccine responses are unknown. Genetic variants associated with atopy and the environmental factor of exposure to parental smoking (PS) of tobacco independently alter immune responses. We sought to investigate the hypothesis that genetic variants associated with atopy and their interaction with PS influence infant vaccine responsiveness. In 200 infants with parental atopic history, relationships were sought between polymorphisms in the IL-4, IL-4 receptor alpha (IL-4Ralpha), and IL-13 genes PS and immune responses to diphtheria/tetanus vaccination. Analyses stratified by PS unmasked negative associations between atopic alleles of these genes and vaccine outcomes. The most consistent involved the IL-4Ralpha 551 QR/QQ genotypes, which were associated with reduced IgG levels (P = .02) and T-cell responses (IFN-gamma, P = .002 IL-10, P = .01 1L-13, P = .01 IL-5, P = .06) to tetanus toxoid and parallel reductions in polyclonal T-cell responses and innate immune responses in PS-exposed infants. PS potentiates suppressive effects of variants in immune response genes in children. These effects are not observed in the absence of this exposure. Ultimately, this finding might have implications for infant vaccination in countries with high smoking rates. It might also have broader implications in relation to environmental toxicology because it demonstrates specific mechanisms through which the developing immune system might be differentially sensitive to low-level toxicant exposures. PS interacts with genes associated with atopy to impair vaccine responses. These interactions might have vaccine design and public health implications.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2012
Publisher: Wiley
Date: 07-1995
DOI: 10.1111/J.1365-2222.1995.TB01111.X
Abstract: It is widely held that in vitro T cell responses to allergens are more prominent in atopic than in normal in iduals, though this conclusion is based upon culture techniques which fail to detect proliferative responses in a significant minority of atopics and many normals. Study allergen-specific proliferative responses of T cells cultured in serum-free medium (SFM). Examine associations between atopic status, age and T cell reactivity. Initially, peripheral blood mononuclear cells were stimulated with allergens or antigens in SFM, and compared with cells cultured in RPMI + 10% fetal calf serum or human AB serum. Subsequently, T cell reactivity was studied in 34 adults (20-49 years), 27 children (2-13 years), and 19 infants (< or = 10 weeks) using SFM alone. Compared with serum-supplemented medium, SFM enhanced net T cell proliferation, both in bulk culture and when cloning at limiting dilution. In many subjects, SFM unmasked T cell reactivity to allergens which was not otherwise evident, and lowered the threshold allergen levels required for in vitro T cell triggering. For most allergens, T cell proliferative responses did not differ between adults who had specific IgE, and those who did not. The most vigorous responses observed were to ubiquitous inhalant allergens, which stimulated T cells from close to 100% of adults and children, and over 60% of infants. In contrast, responses to the 'vaccine' antigen tetanus toxoid were completely absent in the latter age group, but present in the majority of adults and children. These findings suggest that the extent of active T cell recognition of environmental allergens has been hitherto underestimated, and further that these responses may frequently be initiated in very early life. Additionally, these findings reinforce the notion that qualitative (as opposed to quantitative) variations in specific T cell reactivity ultimately determine allergen responder phenotype.
Publisher: Springer Science and Business Media LLC
Date: 25-07-2020
DOI: 10.1186/S13223-020-00465-7
Abstract: Human microbiota plays a fundamental role in modulating the immune response. Western environment and lifestyle are envisaged to alter the human microbiota with a new microbiome profile established in Chinese immigrants, which fails to prime the immune system. Here, we investigated how differences in composition of oropharyngeal microbiome may contribute to patterns of interaction between the microbiome and immune system in Chinese immigrants living in Australia. We recruited 44 adult Chinese immigrants: newly-arrived (n = 22, living in Australia 6 months) and long-term Chinese immigrants (n = 22, living in Australia 5 years), with age and gender matched. Oropharyngeal swabs, serum and whole blood were collected. The 16 s ribosomal RNA gene from the swabs was sequenced on the Illumina MiSeq platform. Innate immune responses were determined by 23 Toll-like receptors (TLR) pathway cytokines, while adaptive immune responses were determined by IgG-associated response to specific microbial/viral pathogens. The relative abundance of the genus Leptotrichia was higher in long-term immigrants as compared to that in newly-arrived Chinese immigrants, while the genus Deinococcus was significantly lower in long-term Chinese immigrants. The genera uncultured Lachnospiraceae , Erysipelotrichaceae UCG - 007 , Veillonella , and Actinomycetales_ambiguous taxa were negatively correlated with cytokine IL-6 in long-term Chinese immigrants (rho range: − 0.46 ~ − 0.73). With respect to adaptive immunity, several microbial taxa were significantly associated with IgG1 responsiveness to microbial antigens in long-term immigrants, while a significant correlation with IgG1 responsiveness to viral antigens was detected in newly-arrived immigrants. The composition of the oropharyngeal microbiome varies between newly-arrived and long-term Chinese immigrants. Specific microbial taxa are significantly associated with immunological parameters but with different association patterns between newly-arrived and long-term Chinese immigrants.
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.JGAR.2018.03.003
Abstract: Recent public awareness c aigns on the risk of antibiotic resistance in pathogenic microbes has placed pressure on governments to enforce stricter antimicrobial stewardship policies on hospitals and the agricultural industry. In this study, faecal s les from Australian and Chinese children were screened for the presence of antimicrobial resistance genes (ARGs) in order to identify demographics at risk of carriage of these genes and to examine antimicrobial stewardship policies from the two countries that may influence carriage. Faecal s les from 46 Australian and 53 Chinese children were screened by PCR for the presence of six clinically relevant ARGs. Clinical and demographic data were also collected from each patient. More than 90% of faecal s les from Chinese children tested positive for β-lactam, macrolide, tetracycline and aminoglycoside resistance genes, which was substantially higher than Australian s les. Besides country of origin, no clear trend could be seen to predict carriage of ARGs. The exception to this was Chinese-born children who immigrated to Australia having higher rates of carriage of bla These data indicate that Chinese children are more likely to carry certain ARGs than Australian children. The Chinese government has recently implemented strict policies to control the overuse of antibiotics in hospitals. However, many of these policies do not extend to the agricultural industry, which could explain the differences seen in this study.
Publisher: Informa UK Limited
Date: 2008
DOI: 10.1080/02770900801971792
Abstract: The aim of this study was to determine the influence of single nucleotide polymorphisms in the beta(2)-adrenoceptor gene, on the response to inhaled beta(2)-agonists in children with acute asthma. We hypothesised that children with polymorphisms that generate enhanced receptor downregulation in vitro, Gly16 and Gln27, would have a slower response to beta(2)-agonist therapy during acute asthma. One hundred and forty-eight children with acute asthma were recruited and genotyped for beta(2)Arg16Gly and beta(2)Gln27Glu. For Gln27Glu, in iduals Gln27Gln took longest to stretch out to 1, 2 and 4 hourly beta(2)-agonists, followed by heterozygotes who were intermediate and Glu27Glu who responded most rapidly (1 hourly: 2.6 hr vs. 2.0 vs. 1.4, p = 0.02 2 hourly: 10.6 hr vs. 10.7 vs. 6.8, p = 0.07 4 hourly: 29.8 hr vs. 28.5 vs. 24.3, p = 0.30). The ability to prospectively identify children who respond less effectively to beta (2)-agonists during an acute asthma attack has the potential to allow the generation of genotype-specific treatment pathways.
Publisher: European Respiratory Society (ERS)
Date: 14-05-2008
DOI: 10.1183/09031936.00002108
Abstract: There is poor agreement on definitions of different phenotypes of preschool wheezing disorders. The present Task Force proposes to use the terms episodic (viral) wheeze to describe children who wheeze intermittently and are well between episodes, and multiple-trigger wheeze for children who wheeze both during and outside discrete episodes. Investigations are only needed when in doubt about the diagnosis. Based on the limited evidence available, inhaled short-acting beta(2)-agonists by metered-dose inhaler/spacer combination are recommended for symptomatic relief. Educating parents regarding causative factors and treatment is useful. Exposure to tobacco smoke should be avoided allergen avoidance may be considered when sensitisation has been established. Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze benefits are often small. Montelukast is recommended for the treatment of episodic (viral) wheeze and can be started when symptoms of a viral cold develop. Given the large overlap in phenotypes, and the fact that patients can move from one phenotype to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost any preschool child with recurrent wheeze, but should be discontinued if there is no clear clinical benefit. Large well-designed randomised controlled trials with clear descriptions of patients are needed to improve the present recommendations on the treatment of these common syndromes.
Publisher: Springer Science and Business Media LLC
Date: 09-04-1900
Abstract: The diminishing incidence of parasitic infection in westernised societies has been suggested to result in an increased prevalance of asthma. Asthma is a polygenic disease and genome screens have shown that genes on chromosome 5q31-33 are strongly linked to the disease. The gene for the beta2-adrenoreceptor is located in this region and two polymorphisms have been identified that result in amino acid changes at positions 16 (ArgGly) and 27 (GlnGlu). To determine whether these polymorphisms influence asthma and parasitic infection, a genotype henotype study has been performed on a cohort of 126 children from Coche Island in Venezuela. There is a high incidence of asthma on the island and intestinal helminthiasis is endemic. Genotyping for both polymorphisms was carried out by using the polymerase chain reaction and allele-specific oligonucleotide hybridisation. Genotype frequencies in this cohort were consistent with other studies and both polymorphisms were in significant linkage disequilibrium. In iduals who were homozygous for Arg16 had significantly higher levels of specific IgE to Ascaris lumbricoides (P=0.002), significantly higher A. lumbricoides egg counts (P<0.001) and significantly larger wheal sizes following skin-prick testing with A. lumbricoides allergen (P=0.008). There was no association between either polymorphism and total serum IgE or asthma in this population. A combination of mast cell degranulation and the lung migratory phase of A. lumbricoides larvae may result in bronchoconstriction in infected in iduals. These results suggest that the Gly 16 allele confers resistance to high levels of parasitic infection in this population. An alternative explanation for the association is that it may be the result of linkage disequilibrium with other genes in the chromosome 5q31-33 region.
Publisher: Springer Berlin Heidelberg
Date: 2012
Publisher: Mary Ann Liebert Inc
Date: 09-2017
Abstract: Despite effective measles vaccines, measles still causes severe morbidity and mortality worldwide, particularly in developing countries. The Th2 pathway involving interleukin (IL)-4 and IL-13 cytokines, and their receptor IL-4Rα, play important roles in the Th1/Th2 balance and antibody production. A Th2 skewing of the cytokine milieu may affect vaccine responses. We investigated IL-4, IL-13, and IL-4Rα polymorphisms and their impact on measles IgG responses and measles vaccine failure, in two separate cohorts: 12-month-old Australian children immunized with measles-mumps-rubella vaccine (n = 137) and a case/control cohort of children aged 6 months-14 years from Mozambique, Africa (n = 89), some of whom were vaccinated, but still contracted measles (vaccine failure). We found that IL-4Rα haplotypes for Val75Ile, Ser503Pro, and Arg576Gln were associated with measles IgG in Mozambican children (p = 0.016 and p = 0.032 for Val.Pro.Arg and Val.Ser.Arg, respectively), but not Australian children. IL-4Rα 503Pro was more prevalent in Mozambique vaccine failure cases compared with controls (p = 0.008). We showed that the impact of Th2 genes on measles vaccine responses differs between ethnicities and IL-4Rα polymorphisms may work in combination to affect measles antibody responses and vaccine failure in Mozambican children. Studies in this area are particularly important in developing countries like Mozambique where measles is still a major health issue.
Publisher: Wiley
Date: 18-02-2009
DOI: 10.1111/J.1399-0039.2008.01185.X
Abstract: The ST2 gene is a member of the interleukin-1 receptor family and is located on chromosome 2q12, an area of the genome that has been associated with asthma. The soluble product of the ST2 gene, serum ST2 (sST2), has previously been shown to be elevated in adult asthmatic patients. This study investigated the potential role of ST2 in children with acute asthma. Children aged 2-16 years (n = 186) were recruited on presentation with acute asthma in the emergency department. Blood was obtained on presentation and during convalescence. Variables assessed included sST2 levels, a comprehensive assembly of clinical parameters and two polymorphisms in the ST2 gene, -26999G/A, located in the distal promoter region, and ala78glu polymorphism, on exon 3. The A allele of the -26999G/A polymorphism occurred more frequently in asthmatics compared with an unselected control group (P = 0.031). Serum ST2 levels were substantially higher during acute asthma compared with levels after the attack: 0.29 ng/ml (95% confidence interval: 0.23-0.36) and 0.14 ng/ml (0.12-0.17), respectively (P = 0.001) and were inversely related to eosinophil counts during an acute asthma attack (P = 0.002). The -26999AA genotype, as well as the AC haplotype, was associated with asthma severity scores (P = 0.05 and 0.02) compared with the -26999GA and GG genotypes. Serum ST2 levels were not associated with any of the studied genotypes or haplotypes. The observed associations of ST2 genotypes and haplotypes with acute asthma and asthma severity scores as well as the phenotypic differences associated with ST2 polymorphisms suggest that ST2 may play a role in the pathophysiology of asthma.
Publisher: Elsevier BV
Date: 04-2018
No related organisations have been discovered for Peter Le Souef.
Start Date: 07-2006
End Date: 06-2010
Amount: $310,000.00
Funder: Australian Research Council
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