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Background 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). Methods 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. Results 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. Conclusions 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.

Objectives Recent public awareness campaigns 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 samples 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. Methods Faecal samples 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. Results More than 90% of faecal samples from Chinese children tested positive for β-lactam, macrolide, tetracycline and aminoglycoside resistance genes, which was substantially higher than Australian samples. 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 blaTEM and tetM genes than children born and still living in Australia. Conclusions 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.

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.

Pneumonia is still the number one killer of young children globally, accounting for 18% of mortality in children under 5 years of age. An estimated 120 million new cases of pneumonia occur globally each year. In developing countries, management and prevention efforts against pneumonia have traditionally focused on bacterial pathogens. More recently however, viral pathogens have gained attention as a result of improved diagnostic methods, such as polymerase chain reaction, outbreaks of severe disease caused by emerging pathogens, discovery of new respiratory viruses as well as the decrease in bacterial pneumonia as a consequence of the introduction of highly effective conjugate vaccines. Although the epidemiology, etiology and clinical characterization of viral infections are being studied extensively in the developed world, little data are available from low- and middle-income countries. In this paper, we review the epidemiology, etiology, clinical and radiological features of viral pneumonia in developing countries.

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.

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.

To cite this article: Zhang G, Candelaria P, Makela JM, Khoo S-K, Hayden MC, von Hertzen L, Laatikainen T, Vartiainen E, Goldblatt J, Haahtela T, LeSouef NP. Disparity of innate immunity–related gene effects on asthma and allergy on Karelia. Pediatr Allergy Immunol 2011; 22: 621–630. Abstract Background: 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. Methods: 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. Results: 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. Conclusions: Living in an Eastern vs. Western environment was associated with a different genetic profile associated with asthma and allergy in the Karelian populations.

This study shows that CD14 DNA methylation is differentially regulated by environmental factors http://ow.ly/zlla30gxNWW

SummaryBackground Atopic sensitization to the house dust mite (HDM) is associated with alteredantibody responses to the nasopharyngeal colonizing bacterium Haemophilus influenzae andchildren admitted to the emergency department for asthma exacerbation have reduced IgGresponses to HDM allergens.Objective To investigate anti-bacterial and anti-allergen antibody responses duringconvalescence from asthma exacerbation and differences found in exacerbations associatedwith and without viral infection.Results IgE antibodies to the P6 bacterial antigen increased in 60% of sera duringconvalescence and for many children achieved titres as high as IgE titres to allergens. Incontrast IgEanti-HDM titres declined during convalescence. The anti-bacterial IgEtitres werethe same in subjects with and without virus infection while the anti-HDM IgE declined morerapidly invirus-infected subjects.IgG titres tothemajorHDM allergens showednoconsistentincrease and the overall IgG anti-HDM titres even declined in subjects without a virusinfection. Anti-bacterial IgG antibodies in contrast to IgE did not change. Patients withfrequent episodic or persistent asthma had similar IgE anti-bacterial titres to patients withinfrequent asthma during the acute phase, although they had reduced IgG titres to both thebacteria and the HDM.Conclusions During the period following an acute exacerbation of asthma there was a markedandspecificincreaseinanti-bacterialIgEcomparedwithareducedIgEresponsetoHDM.Thisprovides further support for the concept of T-helper type 2 responses to bacterial antigensplaying a role in asthma pathogenesis.Keywords asthma, bacteria, IgE, IgG, rhinovirusSubmitted 14 November 2008; revised 22 February 2009; accepted 24 February 2009

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.

Summary Background There is evidence that the specificity of the IgE binding in allergy tests can vary for different populations. Objective 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. Methods 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. Results 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 individual's atopic status, whereas in urban communities it is restricted to the major allergens and to atopic subjects. Conclusion 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.

There is a pattern of progressive facial dysmorphology in mucopolysaccharidosis type I (MPS I). Advances in 3D facial imaging have facilitated the development of tools, including dysmorphometrics, to objectively and precisely detect these facial phenotypes. Therefore, we investigated the application of dysmorphometrics as a noninvasive therapy-monitoring tool, by longitudinally scoring facial dysmorphology in a child with MPS I receiving enzyme replacement therapy (ERT) and bone marrow transplantation (BMT). Both dysmorphometric measures showed a decreasing trend, and the greatest differences were found in the severity of facial discordance (Z-RMSE), displaying scores >3 SD higher than the mean at their peak, in comparison to Z-RSD scores that mostly fell within the normative range (maximum; 1.5 SD from the mean). In addition to the general trend of reduced facial dysmorphology with treatment, initial fluctuations were also evident that may have related to transient subcutaneous facial fluctuations, in the context of conditioning for bone marrow transplant. These findings support the potential of our approach as a sensitive, noninvasive, and rapid means of assessing treatment response or failure in clinical trials, and for established therapies, and would be applicable for other inherited disorders of metabolism.

Background Advanced oxidation protein products (AOPP) are newly identified efficient oxidative stress biomarkers. In a longitudinal birth cohort the effects were investigated of genetic polymorphisms in five oxidative pathway genes on AOPP levels. Methods This study is part of a three-arm randomized, double-blind, placebo-controlled trial. Three hundred and twelve children were included in the present study with AOPP levels measured at 2.5, 5.5, 10.5, 15 and 24 months of age. Twelve polymorphisms were genotyped in five oxidative stress pathway genes: glutathione reductase (GSR), glutamylcysteine synthetase (GCLC), glutathione S-transferase (GST) P1, haem oxygenase 1 (HMOX1) and superoxide dismutase 2 (SOD2) in 298 children. There were 284 children assessed for anaemia and clinical malaria infection at the age of 24 months. Results Two principal components (PCA1 and PCA2) were derived from the AOPP levels measured at the five time points. PCA1 was significantly associated with anaemia (p = 0.0002), and PCA2 with clinical malaria infection (p = 0.047). In the K-Means Cluster Analysis based on levels of AOPP, children were clustered into two groups: Group A (lower AOPP levels) and Group B (higher AOPP levels). The cluster membership was significantly associated with anaemia (p =0.003) as well as with the GSR RS3594 polymorphism (p = 0.037). Mixed linear regression analyses found that the single nucleotide polymorphisms GCLC RS10948751 and HMOX1 RS17885925 were significantly associated with AOPP levels (p = 0.030 and p = 0.027, respectively). Conclusion Plasma AOPP levels were predictive for anaemia and oxidative stress markers for clinical malaria infection in two year old children. Several polymorphisms in GCLC, GSR and HMOX1 genes were associated with oxidative stress status of these children.

Background 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 β2-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. Objective 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. Methods 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 samples by direct sequencing. Multivariate analysis of the association between genotype and phenotype was then undertaken. Results 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. Conclusion 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.

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/phenotype 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. Individuals who were homozygous for Arg16 had significantly higher levels of specific IgE to Ascaris lumbricoides (P=0.002), significantly higher A. lumbricoides egg counts (P0.001) 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 individuals. 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.

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.

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.

To the Editors: Recently, the octopus Paul has attracted much attention through the general media by his accurate predictions in the FIFA 2010 World Cup. During the World Cup, Paul predicted the outcomes of eight matches with 100% success. Assuming that Paul has 50% accurate choices as independent coin flips, the probability for a continual eight success prediction is 0.0039. However, we may think that Octopus Paul is more likely to select the box with the German flag, for some reason. For example, when predicting the outcome of the Germany games Paul selected the box with the German flag five times out of seven, giving a percentage rating of 71.4% for selection of the German flag. Assuming Paul is more likely to select the German flag with a probability rate of 0.714, the probability for the correct predictions Paul achieved in FIFA 2010 World Cup is 0.0076 (0.714×0.714×0.714×0.714×0.714×0.286×0.286×0.5). In the academic world, we usually select a probability boundary of 0.05 or 0.01 to reject the null hypothesis 1. Therefore, we may conclude that Paul …

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.

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; p0.001). 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; p0.02). 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.

Background 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. Objective We sought to investigate the hypothesis that genetic variants associated with atopy and their interaction with PS influence infant vaccine responsiveness. Methods In 200 infants with parental atopic history, relationships were sought between polymorphisms in the IL-4, IL-4 receptor α (IL-4Rα), and IL-13 genes; PS; and immune responses to diphtheria/tetanus vaccination. Results Analyses stratified by PS unmasked negative associations between atopic alleles of these genes and vaccine outcomes. The most consistent involved the IL-4Rα 551 QR/QQ genotypes, which were associated with reduced IgG levels ( P = .02) and T-cell responses (IFN-γ, 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. Conclusion 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. Clinical implications PS interacts with genes associated with atopy to impair vaccine responses. These interactions might have vaccine design and public health implications.

Contains fulltext : 50782.pdf (Publisher’s version ) (Closed access) Innate immunity is of particular importance for protection against infection during early life, when adaptive immune responses are immature. CD14 plays key roles in innate immunity, including in defense against pathogens associated with otitis media, a major pediatric health care issue. The T allele of the CD14 C-159T polymorphism has been associated with increased serum CD14 levels. Our objective was to investigate the hypothesis that the CD14 C-159T allele is protective against recurrent acute otitis media in children. The association between the CD14 promoter genotype and the number of acute otitis media episodes was evaluated both retrospectively and prospectively in a cohort of 300 children. Serotype-specific immunoglobulin G (IgG) antibody responses after pneumococcal vaccinations were examined according to CD14 genotype to compare immune responsiveness across genotypes. An age-dependent association was found: compared with that for CC homozygotes aged between 12 to 24 months, TT homozygotes had fewer episodes of acute otitis media (79 versus 41%, respectively; P = 0.004); this relationship was absent in older children. Additionally, TT homozygotes showed higher serotype-specific anti-pneumococcal IgG antibody levels. Our data suggest that genetic variation in CD14, a molecule at the interface of innate and adaptive immune responses, plays a key role in the defense against middle ear disease in childhood and in pneumococcal vaccine responsiveness. These findings are likely to be important to these and other immune-mediated outcomes in early life.

Early acquisition of Pseudomonas aeruginosa is associated with a poorer prognosis in patients with cystic fibrosis. We investigated whether polymorphisms in CD14, the lipopolysaccharide receptor, increase the risk of early infection. Forty-five children with cystic fibrosis were investigated with annual bronchoalveolar lavage (BAL) and plasma sCD14 levels. Plasma sCD14 levels were significantly lower in children from whom P.aeruginosa was subsequently isolated (492.75 μg/ml vs. 1339.43 μg/ml, p = 0.018). Those with the CD14 -159CC genotype had a significantly increased risk of early infection with P.aeruginosa suggesting that CD14 C-159T plays a role in determining the risk of early infection with P.aeruginosa.

Summary Background Reduced levels of interferon gamma (IFNγ) mRNA and protein have been detected in the bronchoalveolar lavage fluid of atopic asthmatics. IFNγ is secreted by TH1 cells while IL-4 and IL-5 are secreted by TH2 cells and an imbalance in the TH1/TH2 response may be responsible for atopic asthma. The gene for IFN4gM is located on chromosome 12; a region of the genome which has been shown in linkage studies to be associated with asthma. Objective To determine if there are any mutations present in the coding exons and 5’flanking region of the IFNγ gene in atopic asthmatic subjects compared with controls to explain the lower levels of this cytokine as an inherited, rather than acquired, factor in the asthmatic subjects. Methods The four exons and 5’flanking region of the IFNγ gene were amplified by polymerase chain reaction (PCR) from genomic DNA of 265 individuals from a Western Australian and a Venezuelan population. The PCR products were examined by single strand conformational polymorphism and heteroduplex analyses to see if there were any changes in the DNA migration patterns which would suggest the presence of a sequence variation. Results The four exons and the 5’flanking region of the IFNγ gene were amplified from 265 individuals from two populations. Single strand conformational polymorphism and heteroduplex analyses did not reveal any mutations in the regions examined. Conclusions The gene for IFNγ appears to be highly conserved as no sequence variations were detected in 265 individuals. These results suggest that mutations of the IFNγ gene are unlikely to be a significant cause of an inherited asthma diathesis.

Establishing the contribution of genetics to the acquisition of asthma is likely to be essential in allowing fundamental questions regarding asthma etiology to be answered. Some topics that could be addressed include determination of different types of asthma, individuals who have the potential to become asthmatics, and the effect of environmental factors to cause asthma in genetically susceptible individuals. Epidemiological and immunological evidence has shown that there is an increased prevalence of asthma within families, and twin studies have shown greater concordance for asthma in monozygotic than dizygotic twins. Similar findings have been reported for IgE and IgE-related parameters. These observations strongly suggest a genetic component to asthma, but the strength of this influence has been difficult to ascertain due to the inevitable sharing of environment and genes in family studies. Recent work has focused on determining genes involved in asthma. Several genome searches have now been completed and regions in 16 of the 22 autosomal chromosomes have been associated with various asthma-related phenotypic factors, including total and specific IgE production, airway hyperresponsiveness, and symptoms of asthma. Polymorphisms associated with changes in phenotype have been described for several genes, including the genes for interleukin-4, tumor necrosis factor-alpha, the beta-chain of the high-affinity receptor for IgE, and the beta 2-adrenoreceptor. These findings indicate that the molecular genetics of asthma is highly complex and that much more work will be needed to allow the genetic susceptibility of asthma to be defined at the molecular level.

Although most wheezy infants are considered asthmatic, they generally respond poorly to antiasthma treatment, and there is inadequate knowledge about the pathologic mechanisms that cause wheezing at this age. The aim of this study was to determine whether the strong association between wheezing and bronchial responsiveness (BR) seen in older subjects was also present in infants. We compared BR with inhaled histamine in 19 recurrently wheezy infants with a group of age-, height-, weight-, and sex-matched control infants. Maximal flow at FRC (VmaxFRC) was determined from partial expiratory flow-volume curves generated using the "squeeze" technique. Histamine was delivered during 1 min of tidal breathing in doubling concentrations from 0.125 g/L to a maximum of 8 g/L or until VmaxFRC fell by 40% (PC40). The median baseline VmaxFRC for the wheezy infants was 100.0 ml/s compared with 182.0 ml/s for the control infants (p less than 0.01). However, there was no significant difference in the PC40 between the two groups (2.1 versus 2.3 g/L).