Antibody levels specific for capsular polysaccharides of Streptococcus pneumoniae and Haemophilus... more Antibody levels specific for capsular polysaccharides of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) and for tetanus toxoid were measured in serum samples of 386 age-stratified subjects. The study group consists of healthy adult blood donors and hospitalized children undergoing elective surgery, excluding individuals with a history of infection. In children, anti-tetanus toxoid antibody levels displayed two peaks of
International journal of hygiene and environmental health, 2013
The aim of the present study was to investigate to which extent environmental influences like ind... more The aim of the present study was to investigate to which extent environmental influences like indoor renovation activities affect the immune system of mother and child during the gestation period. Within the LINA (Lifestyle and Environmental Factors and their Influence on Newborn Allergy risk) birth cohort study blood samples of mothers during pregnancy and cord blood samples were analyzed for concentrations of the Th1/Th2 cytokines IL-4, IL-5, IL-13, IFN-γ and IgE. Data on indoor renovation activities (painting, flooring and new furniture) were assessed with questionnaires. Data on cytokine blood concentrations and exposure variables were available for 422 mother/child pairs. Neonates, who were strongly affected by renovation activities (especially floor covering and new furniture) during pregnancy, had significantly higher concentrations of IL-4 and IL-5 in cord blood. Among the single activities, new furniture, particularly flake board, were associated with increased IL-4 levels....
Subcutaneous immunoglobulin (SCIG) treatment provides stable serum immunoglobulin G (IgG) levels,... more Subcutaneous immunoglobulin (SCIG) treatment provides stable serum immunoglobulin G (IgG) levels, is associated with fewer systemic adverse events than intravenous immunoglobulin (IVIG) treatment, and offers the convenience of home therapy. In clinical practice, IVIG is still used preferentially for initiation of treatment in newly diagnosed patients with primary immunodeficiency (PI) and for immunomodulatory therapy, such as treatment of peripheral neuropathies, when high doses are believed to be necessary. The authors discuss recent experience in using SCIG in place of IVIG in these settings. SCIG has been successfully used for initiation of therapy in previously untreated PI patients. Seventeen of 18 PI patients achieved serum IgG levels ≥5 g/L after the loading phase. Daily treatment was well tolerated and provided opportunities for patient/parent training in selfinfusion. SCIG has been used for maintenance therapy in multifocal motor neuropathy (MMN) in three recent clinical trials, with good efficacy and tolerability results. Seven of eight MMN patients maintained serum IgG levels of 14-22 g/L with a mean dose of 272 mg/kg/week, had stable muscle strength, and felt comfortable polymyositis or dermatomyositis achieved improvement in serum creatine kinase levels and muscle strength with SCIG therapy. Recent experience with SCIG suggests that traditional concepts of immunoglobulin therapy may be challenged to increase available therapy options. SCIG can be used to achieve high IgG levels within several days in untreated PI patients and to maintain high serum levels, as shown in patients with MMN.
Redecoration of dwellings is a common behavior of expecting parents. Former studies gave evidence... more Redecoration of dwellings is a common behavior of expecting parents. Former studies gave evidence that early childhood exposure to volatile organic compounds (VOC) resulting from renovation activities may increase the risk for wheeze in infants. Objectives: The aim of the present study was to evaluate the impact of prenatal exposure on early wheeze and to identify sensitive time windows. Within the LINA birth cohort study data on renovation activities and respiratory outcomes were assessed via questionnaires during pregnancy and at children's age of one. At both timepoints, also indoor VOC concentrations were measured. The associations were studied by logistic regression analysis. Floor covering during pregnancy contributed to an increased risk for physician treated wheeze (adjusted odds ratio OR = 5.20, 95% confidence interval 1.8-15.2) during the first 12 months after birth in particular in children with an atopic predisposition. Thereby, wall-to-wall-carpets, PVC material, and laminate were the flooring materials which showed the strongest adverse associations. Floor covering was associated with enhanced concentrations of VOCs in the apartments. For the VOCs styrene, ethylbenzene, octane, 1-butanol, tridecane, and o-xylene, a significant association was found to the occurrence of wheezing symptoms. In contrast to pregnancy, exposure during the first 12 months after birth showed less detrimental associations. Only the association between wheezing and styrene as well as between wheezing and PVC flooring remained significant for exposure after birth. Redecoration during pregnancy, especially changing floor materials, increases the risk for respiratory diseases in early childhood and should therefore be avoided at least in families with a history of atopic diseases.
Background: Methylotrophs are a diverse group of bacteria that can utilize single-carbon compound... more Background: Methylotrophs are a diverse group of bacteria that can utilize single-carbon compounds as a sole energy source, and are often catalase-positive. Known as environmental symbionts, they are emerging as disease-causing organisms in patients with CGD. Methods: We present a case of lymphadenitis due to Granulibacter bethesdensis, a facultative methylotroph, and review 8 other infections caused by methylotrophs in patients with CGD. Results: There have been 9 reported cases of infections due to methylotrophs in patients with CGD. Seven cases were due to G. bethesdensis, one was due to Acidomonas methanolica and one was due to a Methylobacter. In all cases, 16s rRNA gene sequencing was required for diagnosis. Conclusions: Methylotrophs are fastidious and difficult to identify. Although the mechanisms underlying susceptibility to infection with methylotrophs in CGD remain to be elucidated, these bacteria should be included in the spectrum of pathogens associated with infections ...
We aimed to describe if polymorphisms in xenobiotics-metabolizing genes modify the effect of mate... more We aimed to describe if polymorphisms in xenobiotics-metabolizing genes modify the effect of maternal exposure to fine particulate matter (PM2.5) on offspring birthweight. Among newborns from LISA cohort, we tested if polymorphisms of GSTT1, GSTP1, GSTM1, and CYP2D6 genes modified the effect measure of PM2.5 on term birthweight. Subsequently, we tested if polymorphisms modified the effect of other exposure factors with similar pathways of action (active or passive smoking). PM2.5 exposure above the median value (reference, below) was associated with birthweight changes by 76g in the homozygous wild type genotype (n=161), -90g in the heterozygous genotype (n=154) and -168g in children with GSTP1 *1B/*1B mutant genotype (n=39, interaction test, p=0.05). No effect measure modification with PM2.5 was detected for GSTT1, GSTM1 or CYP2D6 polymorphisms (p≥0.12). No effect measure modification with GSTP1 polymorphism was detected for active (p=0.71) nor for passive smoking effects on birthweight (p=0.13).
To analyse the association between socio-economic indicators and diet among 2-year-old children, ... more To analyse the association between socio-economic indicators and diet among 2-year-old children, by assessing the independent contribution of parental education and equivalent income to food intake. The analysis was based on data from a prospective birth cohort study. Information on diet was obtained using a semi-quantitative food-frequency questionnaire. Low and high intake of food was defined according to the lowest and the highest quintile of food consumption frequency, respectively. Four German cities (Munich, Leipzig, Wesel, Bad Honnef), 1999-2001. Subjects Subjects were 2637 children at the age of 2 years, whose parents completed questionnaires gathering information on lifestyle factors, including parental socio-economic status, household consumption frequencies and children's diet. Both low parental education and low equivalent income were associated with a low intake of fresh fruit, cooked vegetables and olive oil, and a high intake of canned vegetables or fruit, margarine, mayonnaise and processed salad dressing in children. Children with a low intake of milk and cream, and a high intake of hardened vegetable fat, more likely had parents with lower education. Low butter intake was associated with low equivalent income only. These findings may be helpful for future intervention programmes with more targeted policies aiming at an improvement of children's diets.
Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently ... more Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in populationbased samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85610 28 in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84610 27 ), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at ,1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.
Purpose The present study was designed to evaluate the efficacy and safety of a novel, 10% liquid... more Purpose The present study was designed to evaluate the efficacy and safety of a novel, 10% liquid formulation of intravenous immunoglobulin, stabilized with 250 mmol/L L-proline (Privigen®), in patients with primary immunodeficiency disease. Materials and Methods Eighty adults and children diagnosed with common variable immunodeficiency or X-linked agammaglobulinemia received intravenous Privigen® infusions (200-888 mg/kg) at 3-or 4-week intervals over a 12-month period, according to their previously established maintenance dose. The primary endpoint was the annual rate of acute serious bacterial infections. Results There were six episodes of acute serious bacterial infections, corresponding to an annual rate of 0.08; the annual rate for all infections was 3.55. Mean serum IgG trough levels were between 8.84 and 10.27 g/L. A total of 1,038 infusions were administered, most of them at the maximum rate permitted (8.0 mg kg −1 min −1 ). Temporally associated adverse events, possibly or probably related to
Sixty patients (16 children, 44 adults) participated in the study aiming at evaluating: (i) IgG l... more Sixty patients (16 children, 44 adults) participated in the study aiming at evaluating: (i) IgG levels when switching patients from intravenous IgG (IVIG) infusions in hospital to subcutaneous (SCIG) self-infusions at home using the same cumulative monthly dose, (ii) protections against infections, and (iii) safety of a new, ready-to-use 16% IgG preparation. All children and 33 adults had received IVIG therapy for >6 months at enrolment. Ten adults who had been on SCIG therapy for many years served as controls. Mean serum IgG trough levels increased in the pre-IVIG children from 7.8 to 9.2 g/L (non-inferiority: p < 0.001) and in the adults from 8.6 to 8.9 g/L (non-inferiority: p < 0.001). Totally 114 respiratory tract infections occurred, 90% of them mild. One serious bacterial infection (pneumonia) was reported for one adult. The annualized rate of serious infections was 0.04 episodes/patient. In total 2297 infusions were given and 28 systemic adverse reactions occurred, none of them severe. Local tissue reactions declined over time, this being particularly distinct after 8 to 10 weeks. In conclusion, the SCIG administration route was safe. High IgG levels were easily maintained resulting in a very good protection against infections.
Background: Hyper-IgE syndromes (HIES) are primary immunodeficiency disorders characterized by St... more Background: Hyper-IgE syndromes (HIES) are primary immunodeficiency disorders characterized by Staphylococcus aureus abscesses, recurrent pneumonia, increased serum IgE levels, and eczema. The association of heterozygous signal transducer and activator of transcription 3 (STAT3) mutations with autosomal dominant (AD)-HIES allows the differentiation of AD-HIES from disorders associated with eczema and increased serum IgE levels, such as other primary immunodeficiencies and atopic dermatitis. Objective: To facilitate early diagnosis of AD-HIES to initiate appropriate therapy. Methods: The clinical phenotype (suggested by a National Institutes of Health [NIH] score of > _40 points), STAT3 genotype, and T H 17 cell counts were compared in a cohort of 78 patients suspected of having HIES.
Background: The influence of cat allergen exposure in early childhood on the development of sensi... more Background: The influence of cat allergen exposure in early childhood on the development of sensitization and allergic diseases is complex. Little is known about the natural course of the sensitization development within individuals. Objective: We investigated the association between cat allergen exposure in infancy and cat ownership and cat contact during childhood and the development of cat sensitization and allergic diseases up to age 6 years using a longitudinal analysis approach. Methods: Overall, 2166 children from an ongoing birth cohort study were included in the analysis. House dust samples were collected 3 months after birth. Cat allergen levels were extracted. Blood samples were collected when the children were 2 and 6 years old. Information on the allergic symptoms of
Background: A large number of children and adults with primary antibody deficiencies need lifelon... more Background: A large number of children and adults with primary antibody deficiencies need lifelong IgG replacement therapy. It is mostly unknown what effect the choice of replacement therapy has on the patients' health-related quality of life (HRQOL) and treatment satisfaction (TS). Objective: To investigate whether a switch from hospital-based intravenous IgG (IVIG) to home-based subcutaneous IgG (SCIG) therapy would improve the HRQOL and TS. Methods: Fifteen children (<14 years; hospital-based IVIG therapy at enrollment) and 32 adults (!14 years; 22 on hospital-based IVIG and 10 on home-based SCIG therapy at enrollment) were included. Questionnaires were completed at baseline and at 6 and 10 months: the Child Health Questionnaire-Parental Form 50 (children) or Short Form 36 (adults), the Life Quality Index, and questions regarding therapy preferences. Results: The SCIG home therapy was reported to give better health (P = .001) and improved school/social functioning (P = .02) for the children, reduced emotional distress (P = .02) and limitations on personal time for the parents (P = .004), and fewer limitations on family activities (P = .002). Adults switching therapy reported improved vitality (P = .04), mental health (P = .05), and social functioning (P = .01). Adults already on SCIG home therapy at enrollment retained high HRQOL and TS scores. The SCIG home therapy improved TS because it led to greater independence and better therapy convenience (P < .05). The patients preferred the SCIG administration route and having the treatment at home. Conclusions: Home-based SCIG therapy improves several important aspects of HRQOL and provides the patients with primary antibody deficiencies and their families with greater independence and better control of the therapy situation and daily life. SCIG home therapy is an appreciated therapeutic alternative for adults and children in need of lifelong IgG replacement therapy. (J Allergy Clin Immunol 2004;114:936-42.)
Background: Previous studies have shown a protective effect of early exposure to cats and dogs on... more Background: Previous studies have shown a protective effect of early exposure to cats and dogs on the development of atopic eczema, asthma, allergic rhinitis, and atopic sensitization in later life. In particular, a higher microbial exposure to endotoxin in early childhood might contribute to this effect. Objective: We examined the associations between bacterial endotoxin in house dust and atopic eczema, infections, and wheezing during the first year of life in an ongoing birth cohort study (LISA). Methods: Data of 1884 term and normal-weight neonates with complete information on exposure to biocontaminants and confounding variables were analyzed. House dust from the mothers' and the children's mattresses was sampled 3 months after birth. Endotoxin content was quantified by using a chromogenic kinetic limulus amoebocyte lysate test. Results: During the first 6 months of life, the risk of atopic eczema was significantly decreased by endotoxin exposure in dust from mothers' mattresses in the fifth quintile (odds ratio [OR], 0.50; 95% CI, 0.28-0.88), whereas the risk was increased for respiratory infections (OR, 1.69; 95% CI, 1.25-2.28) and cough with respiratory infection, bronchitis, or both (OR, 1.73; 95% CI, 1.28-2.33). The risk of wheezing was also significantly increased during the first 6 months of life (OR, 2.37; 95% CI, 1.40-4.03). For the entire first year of life, these associations attenuated, except for the risk of wheezing, which remained significant (OR, 1.60; 95% CI, 1.10-2.30). Conclusion: Our findings support the hygiene hypothesis that exposure to high concentrations of endotoxin very early in life might protect against the development of atopic eczema within the first 6 months of life, along with an increased prevalence of nonspecific respiratory diseases. (J Allergy Clin Immunol 2001;108:847-54.)
There is evidence that microRNAs (miRNAs) are sensitive to environmental stressors, including tob... more There is evidence that microRNAs (miRNAs) are sensitive to environmental stressors, including tobacco smoke. On the other hand, miRNAs are involved in immune regulation, such as regulatory T (Treg) cell differentiation. The aim of the present study was to investigate the association between prenatal tobacco smoke exposure, miRNAs, and Treg cell numbers. Within a prospective mother-child study (Lifestyle and Environmental Factors and Their Influence on Newborns Allergy Risk), we analyzed the expression of miR-155 and miR-223 together with Treg cell numbers in maternal blood during pregnancy, as well as in cord blood (n = 441). Tobacco smoke exposure was assessed based on questionnaire answers and maternal urine cotinine levels. Additionally, the concentration of smoking-related volatile organic compounds was measured in dwellings of study participants. Both maternal and cord blood miR-223 expressions were positively correlated with maternal urine cotinine levels. An association was also found between maternal miR-223 expression and indoor concentrations of benzene and toluene. High miR-223 expression was associated with lower Treg cell numbers in maternal and cord blood. Furthermore, children with lower Treg cell numbers at birth had a higher risk of atopic dermatitis during the first 3 years of life. The concentration of the toluene metabolite S-benzylmercapturic acid in maternal urine was associated with decreased cord blood, but not maternal blood, miR-155 expression. A relationship between miR-155 expression and Treg cell numbers was not found. For the first time, we show that maternal tobacco smoke exposure during pregnancy correlates with the level of miRNA-223 expression in blood, with an effect on children&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s cord blood Treg cell numbers and subsequent allergy risk.
Background: Several studies showed a protective effect of elder siblings on eczema development, w... more Background: Several studies showed a protective effect of elder siblings on eczema development, which is in line with the hygiene hypothesis. However, findings are not consistent, and there might exist different causal pathways for the development of eczema. Especially barrier disturbances as found in children with mutations in the filaggrin gene (FLG) seem to play an important role. Objectives: To investigate the interaction between FLG mutations and the presence of elder siblings on the development of eczema in 2 independent birth cohorts. Methods: We used data from 2 German birth cohorts (LISAplus, GINIplus) up to the age of 6 years. Genotyping for FLG mutations (R501X, 2282del4) was performed in 1039 (LISAplus) and 1828 (GINIplus) children. Data on eczema (diagnosis and symptoms) and elder siblings were obtained by parental questionnaires. The association among eczema, FLG mutations, and elder siblings was analyzed longitudinally by using generalized estimating equations. Results: We found no protective effect of elder siblings on eczema development. On the contrary, children with FLG mutations had a significantly higher risk for eczema if they had elder siblings. Attending day care centers lessened this effect. After excluding 303 children who attended early day care, the odds ratio for interaction between FLG mutations and elder siblings was 3.27 (95% CI, 1.14-9.36) in LISAplus and 2.41 (95% CI, 1.06-5.48) in GINIplus. Conclusion: Our findings did not confirm a protective sibling effect. The prevalence of eczema in children with filaggrin deficiency was higher if elder siblings were present. Our results give evidence for complex skin-driven pathogenic mechanisms that might be different depending on children's genetic backgrounds. (J Allergy Clin Immunol 2010;125:1254-60.)
Antibody levels specific for capsular polysaccharides of Streptococcus pneumoniae and Haemophilus... more Antibody levels specific for capsular polysaccharides of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) and for tetanus toxoid were measured in serum samples of 386 age-stratified subjects. The study group consists of healthy adult blood donors and hospitalized children undergoing elective surgery, excluding individuals with a history of infection. In children, anti-tetanus toxoid antibody levels displayed two peaks of
International journal of hygiene and environmental health, 2013
The aim of the present study was to investigate to which extent environmental influences like ind... more The aim of the present study was to investigate to which extent environmental influences like indoor renovation activities affect the immune system of mother and child during the gestation period. Within the LINA (Lifestyle and Environmental Factors and their Influence on Newborn Allergy risk) birth cohort study blood samples of mothers during pregnancy and cord blood samples were analyzed for concentrations of the Th1/Th2 cytokines IL-4, IL-5, IL-13, IFN-γ and IgE. Data on indoor renovation activities (painting, flooring and new furniture) were assessed with questionnaires. Data on cytokine blood concentrations and exposure variables were available for 422 mother/child pairs. Neonates, who were strongly affected by renovation activities (especially floor covering and new furniture) during pregnancy, had significantly higher concentrations of IL-4 and IL-5 in cord blood. Among the single activities, new furniture, particularly flake board, were associated with increased IL-4 levels....
Subcutaneous immunoglobulin (SCIG) treatment provides stable serum immunoglobulin G (IgG) levels,... more Subcutaneous immunoglobulin (SCIG) treatment provides stable serum immunoglobulin G (IgG) levels, is associated with fewer systemic adverse events than intravenous immunoglobulin (IVIG) treatment, and offers the convenience of home therapy. In clinical practice, IVIG is still used preferentially for initiation of treatment in newly diagnosed patients with primary immunodeficiency (PI) and for immunomodulatory therapy, such as treatment of peripheral neuropathies, when high doses are believed to be necessary. The authors discuss recent experience in using SCIG in place of IVIG in these settings. SCIG has been successfully used for initiation of therapy in previously untreated PI patients. Seventeen of 18 PI patients achieved serum IgG levels ≥5 g/L after the loading phase. Daily treatment was well tolerated and provided opportunities for patient/parent training in selfinfusion. SCIG has been used for maintenance therapy in multifocal motor neuropathy (MMN) in three recent clinical trials, with good efficacy and tolerability results. Seven of eight MMN patients maintained serum IgG levels of 14-22 g/L with a mean dose of 272 mg/kg/week, had stable muscle strength, and felt comfortable polymyositis or dermatomyositis achieved improvement in serum creatine kinase levels and muscle strength with SCIG therapy. Recent experience with SCIG suggests that traditional concepts of immunoglobulin therapy may be challenged to increase available therapy options. SCIG can be used to achieve high IgG levels within several days in untreated PI patients and to maintain high serum levels, as shown in patients with MMN.
Redecoration of dwellings is a common behavior of expecting parents. Former studies gave evidence... more Redecoration of dwellings is a common behavior of expecting parents. Former studies gave evidence that early childhood exposure to volatile organic compounds (VOC) resulting from renovation activities may increase the risk for wheeze in infants. Objectives: The aim of the present study was to evaluate the impact of prenatal exposure on early wheeze and to identify sensitive time windows. Within the LINA birth cohort study data on renovation activities and respiratory outcomes were assessed via questionnaires during pregnancy and at children's age of one. At both timepoints, also indoor VOC concentrations were measured. The associations were studied by logistic regression analysis. Floor covering during pregnancy contributed to an increased risk for physician treated wheeze (adjusted odds ratio OR = 5.20, 95% confidence interval 1.8-15.2) during the first 12 months after birth in particular in children with an atopic predisposition. Thereby, wall-to-wall-carpets, PVC material, and laminate were the flooring materials which showed the strongest adverse associations. Floor covering was associated with enhanced concentrations of VOCs in the apartments. For the VOCs styrene, ethylbenzene, octane, 1-butanol, tridecane, and o-xylene, a significant association was found to the occurrence of wheezing symptoms. In contrast to pregnancy, exposure during the first 12 months after birth showed less detrimental associations. Only the association between wheezing and styrene as well as between wheezing and PVC flooring remained significant for exposure after birth. Redecoration during pregnancy, especially changing floor materials, increases the risk for respiratory diseases in early childhood and should therefore be avoided at least in families with a history of atopic diseases.
Background: Methylotrophs are a diverse group of bacteria that can utilize single-carbon compound... more Background: Methylotrophs are a diverse group of bacteria that can utilize single-carbon compounds as a sole energy source, and are often catalase-positive. Known as environmental symbionts, they are emerging as disease-causing organisms in patients with CGD. Methods: We present a case of lymphadenitis due to Granulibacter bethesdensis, a facultative methylotroph, and review 8 other infections caused by methylotrophs in patients with CGD. Results: There have been 9 reported cases of infections due to methylotrophs in patients with CGD. Seven cases were due to G. bethesdensis, one was due to Acidomonas methanolica and one was due to a Methylobacter. In all cases, 16s rRNA gene sequencing was required for diagnosis. Conclusions: Methylotrophs are fastidious and difficult to identify. Although the mechanisms underlying susceptibility to infection with methylotrophs in CGD remain to be elucidated, these bacteria should be included in the spectrum of pathogens associated with infections ...
We aimed to describe if polymorphisms in xenobiotics-metabolizing genes modify the effect of mate... more We aimed to describe if polymorphisms in xenobiotics-metabolizing genes modify the effect of maternal exposure to fine particulate matter (PM2.5) on offspring birthweight. Among newborns from LISA cohort, we tested if polymorphisms of GSTT1, GSTP1, GSTM1, and CYP2D6 genes modified the effect measure of PM2.5 on term birthweight. Subsequently, we tested if polymorphisms modified the effect of other exposure factors with similar pathways of action (active or passive smoking). PM2.5 exposure above the median value (reference, below) was associated with birthweight changes by 76g in the homozygous wild type genotype (n=161), -90g in the heterozygous genotype (n=154) and -168g in children with GSTP1 *1B/*1B mutant genotype (n=39, interaction test, p=0.05). No effect measure modification with PM2.5 was detected for GSTT1, GSTM1 or CYP2D6 polymorphisms (p≥0.12). No effect measure modification with GSTP1 polymorphism was detected for active (p=0.71) nor for passive smoking effects on birthweight (p=0.13).
To analyse the association between socio-economic indicators and diet among 2-year-old children, ... more To analyse the association between socio-economic indicators and diet among 2-year-old children, by assessing the independent contribution of parental education and equivalent income to food intake. The analysis was based on data from a prospective birth cohort study. Information on diet was obtained using a semi-quantitative food-frequency questionnaire. Low and high intake of food was defined according to the lowest and the highest quintile of food consumption frequency, respectively. Four German cities (Munich, Leipzig, Wesel, Bad Honnef), 1999-2001. Subjects Subjects were 2637 children at the age of 2 years, whose parents completed questionnaires gathering information on lifestyle factors, including parental socio-economic status, household consumption frequencies and children&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s diet. Both low parental education and low equivalent income were associated with a low intake of fresh fruit, cooked vegetables and olive oil, and a high intake of canned vegetables or fruit, margarine, mayonnaise and processed salad dressing in children. Children with a low intake of milk and cream, and a high intake of hardened vegetable fat, more likely had parents with lower education. Low butter intake was associated with low equivalent income only. These findings may be helpful for future intervention programmes with more targeted policies aiming at an improvement of children&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s diets.
Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently ... more Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in populationbased samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85610 28 in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84610 27 ), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at ,1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.
Purpose The present study was designed to evaluate the efficacy and safety of a novel, 10% liquid... more Purpose The present study was designed to evaluate the efficacy and safety of a novel, 10% liquid formulation of intravenous immunoglobulin, stabilized with 250 mmol/L L-proline (Privigen®), in patients with primary immunodeficiency disease. Materials and Methods Eighty adults and children diagnosed with common variable immunodeficiency or X-linked agammaglobulinemia received intravenous Privigen® infusions (200-888 mg/kg) at 3-or 4-week intervals over a 12-month period, according to their previously established maintenance dose. The primary endpoint was the annual rate of acute serious bacterial infections. Results There were six episodes of acute serious bacterial infections, corresponding to an annual rate of 0.08; the annual rate for all infections was 3.55. Mean serum IgG trough levels were between 8.84 and 10.27 g/L. A total of 1,038 infusions were administered, most of them at the maximum rate permitted (8.0 mg kg −1 min −1 ). Temporally associated adverse events, possibly or probably related to
Sixty patients (16 children, 44 adults) participated in the study aiming at evaluating: (i) IgG l... more Sixty patients (16 children, 44 adults) participated in the study aiming at evaluating: (i) IgG levels when switching patients from intravenous IgG (IVIG) infusions in hospital to subcutaneous (SCIG) self-infusions at home using the same cumulative monthly dose, (ii) protections against infections, and (iii) safety of a new, ready-to-use 16% IgG preparation. All children and 33 adults had received IVIG therapy for >6 months at enrolment. Ten adults who had been on SCIG therapy for many years served as controls. Mean serum IgG trough levels increased in the pre-IVIG children from 7.8 to 9.2 g/L (non-inferiority: p < 0.001) and in the adults from 8.6 to 8.9 g/L (non-inferiority: p < 0.001). Totally 114 respiratory tract infections occurred, 90% of them mild. One serious bacterial infection (pneumonia) was reported for one adult. The annualized rate of serious infections was 0.04 episodes/patient. In total 2297 infusions were given and 28 systemic adverse reactions occurred, none of them severe. Local tissue reactions declined over time, this being particularly distinct after 8 to 10 weeks. In conclusion, the SCIG administration route was safe. High IgG levels were easily maintained resulting in a very good protection against infections.
Background: Hyper-IgE syndromes (HIES) are primary immunodeficiency disorders characterized by St... more Background: Hyper-IgE syndromes (HIES) are primary immunodeficiency disorders characterized by Staphylococcus aureus abscesses, recurrent pneumonia, increased serum IgE levels, and eczema. The association of heterozygous signal transducer and activator of transcription 3 (STAT3) mutations with autosomal dominant (AD)-HIES allows the differentiation of AD-HIES from disorders associated with eczema and increased serum IgE levels, such as other primary immunodeficiencies and atopic dermatitis. Objective: To facilitate early diagnosis of AD-HIES to initiate appropriate therapy. Methods: The clinical phenotype (suggested by a National Institutes of Health [NIH] score of > _40 points), STAT3 genotype, and T H 17 cell counts were compared in a cohort of 78 patients suspected of having HIES.
Background: The influence of cat allergen exposure in early childhood on the development of sensi... more Background: The influence of cat allergen exposure in early childhood on the development of sensitization and allergic diseases is complex. Little is known about the natural course of the sensitization development within individuals. Objective: We investigated the association between cat allergen exposure in infancy and cat ownership and cat contact during childhood and the development of cat sensitization and allergic diseases up to age 6 years using a longitudinal analysis approach. Methods: Overall, 2166 children from an ongoing birth cohort study were included in the analysis. House dust samples were collected 3 months after birth. Cat allergen levels were extracted. Blood samples were collected when the children were 2 and 6 years old. Information on the allergic symptoms of
Background: A large number of children and adults with primary antibody deficiencies need lifelon... more Background: A large number of children and adults with primary antibody deficiencies need lifelong IgG replacement therapy. It is mostly unknown what effect the choice of replacement therapy has on the patients' health-related quality of life (HRQOL) and treatment satisfaction (TS). Objective: To investigate whether a switch from hospital-based intravenous IgG (IVIG) to home-based subcutaneous IgG (SCIG) therapy would improve the HRQOL and TS. Methods: Fifteen children (<14 years; hospital-based IVIG therapy at enrollment) and 32 adults (!14 years; 22 on hospital-based IVIG and 10 on home-based SCIG therapy at enrollment) were included. Questionnaires were completed at baseline and at 6 and 10 months: the Child Health Questionnaire-Parental Form 50 (children) or Short Form 36 (adults), the Life Quality Index, and questions regarding therapy preferences. Results: The SCIG home therapy was reported to give better health (P = .001) and improved school/social functioning (P = .02) for the children, reduced emotional distress (P = .02) and limitations on personal time for the parents (P = .004), and fewer limitations on family activities (P = .002). Adults switching therapy reported improved vitality (P = .04), mental health (P = .05), and social functioning (P = .01). Adults already on SCIG home therapy at enrollment retained high HRQOL and TS scores. The SCIG home therapy improved TS because it led to greater independence and better therapy convenience (P < .05). The patients preferred the SCIG administration route and having the treatment at home. Conclusions: Home-based SCIG therapy improves several important aspects of HRQOL and provides the patients with primary antibody deficiencies and their families with greater independence and better control of the therapy situation and daily life. SCIG home therapy is an appreciated therapeutic alternative for adults and children in need of lifelong IgG replacement therapy. (J Allergy Clin Immunol 2004;114:936-42.)
Background: Previous studies have shown a protective effect of early exposure to cats and dogs on... more Background: Previous studies have shown a protective effect of early exposure to cats and dogs on the development of atopic eczema, asthma, allergic rhinitis, and atopic sensitization in later life. In particular, a higher microbial exposure to endotoxin in early childhood might contribute to this effect. Objective: We examined the associations between bacterial endotoxin in house dust and atopic eczema, infections, and wheezing during the first year of life in an ongoing birth cohort study (LISA). Methods: Data of 1884 term and normal-weight neonates with complete information on exposure to biocontaminants and confounding variables were analyzed. House dust from the mothers' and the children's mattresses was sampled 3 months after birth. Endotoxin content was quantified by using a chromogenic kinetic limulus amoebocyte lysate test. Results: During the first 6 months of life, the risk of atopic eczema was significantly decreased by endotoxin exposure in dust from mothers' mattresses in the fifth quintile (odds ratio [OR], 0.50; 95% CI, 0.28-0.88), whereas the risk was increased for respiratory infections (OR, 1.69; 95% CI, 1.25-2.28) and cough with respiratory infection, bronchitis, or both (OR, 1.73; 95% CI, 1.28-2.33). The risk of wheezing was also significantly increased during the first 6 months of life (OR, 2.37; 95% CI, 1.40-4.03). For the entire first year of life, these associations attenuated, except for the risk of wheezing, which remained significant (OR, 1.60; 95% CI, 1.10-2.30). Conclusion: Our findings support the hygiene hypothesis that exposure to high concentrations of endotoxin very early in life might protect against the development of atopic eczema within the first 6 months of life, along with an increased prevalence of nonspecific respiratory diseases. (J Allergy Clin Immunol 2001;108:847-54.)
There is evidence that microRNAs (miRNAs) are sensitive to environmental stressors, including tob... more There is evidence that microRNAs (miRNAs) are sensitive to environmental stressors, including tobacco smoke. On the other hand, miRNAs are involved in immune regulation, such as regulatory T (Treg) cell differentiation. The aim of the present study was to investigate the association between prenatal tobacco smoke exposure, miRNAs, and Treg cell numbers. Within a prospective mother-child study (Lifestyle and Environmental Factors and Their Influence on Newborns Allergy Risk), we analyzed the expression of miR-155 and miR-223 together with Treg cell numbers in maternal blood during pregnancy, as well as in cord blood (n = 441). Tobacco smoke exposure was assessed based on questionnaire answers and maternal urine cotinine levels. Additionally, the concentration of smoking-related volatile organic compounds was measured in dwellings of study participants. Both maternal and cord blood miR-223 expressions were positively correlated with maternal urine cotinine levels. An association was also found between maternal miR-223 expression and indoor concentrations of benzene and toluene. High miR-223 expression was associated with lower Treg cell numbers in maternal and cord blood. Furthermore, children with lower Treg cell numbers at birth had a higher risk of atopic dermatitis during the first 3 years of life. The concentration of the toluene metabolite S-benzylmercapturic acid in maternal urine was associated with decreased cord blood, but not maternal blood, miR-155 expression. A relationship between miR-155 expression and Treg cell numbers was not found. For the first time, we show that maternal tobacco smoke exposure during pregnancy correlates with the level of miRNA-223 expression in blood, with an effect on children&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s cord blood Treg cell numbers and subsequent allergy risk.
Background: Several studies showed a protective effect of elder siblings on eczema development, w... more Background: Several studies showed a protective effect of elder siblings on eczema development, which is in line with the hygiene hypothesis. However, findings are not consistent, and there might exist different causal pathways for the development of eczema. Especially barrier disturbances as found in children with mutations in the filaggrin gene (FLG) seem to play an important role. Objectives: To investigate the interaction between FLG mutations and the presence of elder siblings on the development of eczema in 2 independent birth cohorts. Methods: We used data from 2 German birth cohorts (LISAplus, GINIplus) up to the age of 6 years. Genotyping for FLG mutations (R501X, 2282del4) was performed in 1039 (LISAplus) and 1828 (GINIplus) children. Data on eczema (diagnosis and symptoms) and elder siblings were obtained by parental questionnaires. The association among eczema, FLG mutations, and elder siblings was analyzed longitudinally by using generalized estimating equations. Results: We found no protective effect of elder siblings on eczema development. On the contrary, children with FLG mutations had a significantly higher risk for eczema if they had elder siblings. Attending day care centers lessened this effect. After excluding 303 children who attended early day care, the odds ratio for interaction between FLG mutations and elder siblings was 3.27 (95% CI, 1.14-9.36) in LISAplus and 2.41 (95% CI, 1.06-5.48) in GINIplus. Conclusion: Our findings did not confirm a protective sibling effect. The prevalence of eczema in children with filaggrin deficiency was higher if elder siblings were present. Our results give evidence for complex skin-driven pathogenic mechanisms that might be different depending on children's genetic backgrounds. (J Allergy Clin Immunol 2010;125:1254-60.)
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