Early age exposure to moisture damage and systemic inflammation at the age of 6 years.

Cross-sectional studies have shown that exposure to indoor moisture damage and mold may be associated with subclinical inflammation. Our aim was to determine whether early age exposure to moisture damage or mold is prospectively associated with subclinical systemic inflammation or with immune responsiveness in later childhood. Home inspections were performed in children's homes in the first year of life. At age 6 years, subclinical systemic inflammation was measured by serum C-reactive protein (CRP) and blood leukocytes and immune responsiveness by ex vivo production of interleukin 1-beta (IL-1ß), IL-6, and tumor necrosis factor alpha (TNF-α) in whole blood cultures without stimulation or after 24 hours stimulation with phorbol 12-myristate 13-acetate and ionomycin (PI), lipopolysaccharide (LPS), or peptidoglycan (PPG) in 251-270 children. Moisture damage in child's main living areas in infancy was not significantly associated with elevated levels of CRP or leukocytes at 6 years. In contrast, there was some suggestion for an effect on immune responsiveness, as moisture damage with visible mold was positively associated with LPS-stimulated production of TNF-α and minor moisture damage was inversely associated with PI-stimulated IL-1ß. While early life exposure to mold damage may have some influence on later immune responsiveness, it does not seem to increase subclinical systemic inflammation in later life.

High IgE levels to α-lactalbumin, ß-lactoglobulin and casein predict less successful cow's milk oral immunotherapy.

BACKGROUND: A new treatment option for persistent cow's milk allergy (CMA) is oral immunotherapy (OIT). Not all patients develop tolerance during therapy, and markers to identify those who will benefit from it are needed. The objective was to study the IgE and IgG4 antibody profiles to milk and milk proteins before and after OIT in relation to clinical outcome. METHODS: Seventy-six children (5-17 years) with challenge-verified CMA were subjected to a 6-month OIT protocol. The treatment aimed at reaching a maintenance dose of 200 ml CM (high dose = HD). Those who did not reach target were analysed as a low-dose (LD) group. Sera were characterized before and after OIT regarding serum levels of IgE and IgG4 to milk and five milk allergen components evaluated together with clinical CMA symptoms and outcome of OIT. RESULTS: Fifty-five (72%) patients reached the maintenance dose (HD) during therapy. High specific IgE levels towards the milk allergens α-lactalbumin (P = 0.048), ß-lactoglobulin (P = 0.006) and casein (P = 0.015) before OIT start were associated with lower maintenance dose reached. Patients who developed desensitization had a larger increase in IgG4 levels to α-lactalbumin (P = 0.034), ß-lactoglobulin (P = 0.010), casein (P = 0.047) and lactoferrin (P = 0.030) during treatment than those who failed. CONCLUSIONS: Component-resolved diagnostics before OIT can help to identify children with lower probability of a successful OIT outcome, as high IgE levels to α-lactalbumin, ß-lactoglobulin and casein are associated with lower maintenance dose reached. An increase in the IgG4 concentration to milk components during treatment indicated effective desensitization.

Quantity and diversity of environmental microbial exposure and development of asthma: a birth cohort study.

BACKGROUND: Early-life exposure to environmental microbial agents may be associated with the development of allergies. The aim of the study was to identify better ways to characterize microbial exposure as a predictor of respiratory symptoms and allergies. METHODS: A birth cohort of 410 children was followed up until 6 years of age. Bacterial endotoxin, 3-hydroxy fatty acids, N-acetyl-muramic acid, fungal extracellular polysaccharides (EPS) from Penicillium and Aspergillus spp., ß-D-glucan, ergosterol, and bacterial or fungal quantitative polymerase chain reactions (qPCRs) were analyzed from dust samples collected at 2 months of age. Asthma, wheezing, cough, and atopic dermatitis were assessed using repeated questionnaires. Specific IgEs were determined at the age of 1 and 6 years. RESULTS: Only few associations were found between single microbial markers and the studied outcomes. In contrast, a score for the total quantity of microbial exposure, that is, sum of indicators for fungi (ergosterol), Gram-positive (muramic acid) bacteria, and Gram-negative (endotoxin) bacteria, was significantly (inverted-U shape) associated with asthma incidence (P < 0.001): the highest risk was found at medium levels (adjusted odds ratio (aOR) 2.24, 95% confidence interval (95% CI) 0.87-5.75 for 3rd quintile) and the lowest risk at the highest level (aOR 0.34, 95% CI 0.09-1.36 for 5th quintile). The microbial diversity score, that is, sum of detected qPCRs, was inversely associated with risk of wheezing and was significantly (inverted-U shape) associated with sensitization to inhalant allergens. CONCLUSION: Score for quantity of microbial exposure predicted asthma better than single microbial markers independently of microbial diversity and amount of dust. Better indicators of total quantity and diversity of microbial exposure are needed in studies on the development of asthma.

Exposure to dogs is associated with a decreased tumour necrosis factor-α-producing capacity in early life.

BACKGROUND: It appears that contacts with furred animals early in life and already during gestation contribute to the immunological development in humans, but the mechanisms and relevant exposures are not clear. OBJECTIVE: To investigate whether exposure to animals during pregnancy and the first year of life is associated with early immune development, determined as stimulated cytokine responses of children at birth and at age 1 year. METHODS: Cord blood (n=228) and peripheral venous blood (n=200) samples 1 year after birth were collected and stimulated with Gram-positive superantigen Staphylococcal enterotoxin B, Gram-negative bacterial lipopolysaccharide (LPS) and the combination of mitogenic phorbol 12-myristate 13-acetate and calcium ionophore ionomycin (P/I) for 24 and 48 h. TNF-α, IFN-γ, IL-5, IL-8 and IL-10 responses were measured by ELISA. For each cytokine, the time-point with the highest response was chosen for further analyses. Animal contacts were surveyed by self-administered questionnaires. RESULTS: Dog ownership was associated with decreased TNF-α-producing capacity at birth (P/I: median 841 vs. 881 pg/10(6) WBC, P=0.05) and 1 year after birth (P/I: 1290 vs. 1530, P=0.01; LPS: 425 vs. 508, P=0.02). Associations remained significant after adjustment for potential confounders. Cat ownership was not associated with cytokine production. CONCLUSION: Having a dog in the household in infancy and already during pregnancy may be associated with reduced innate immune responses in early childhood. The observed attenuation of cytokine production may help in preventing exaggerated immune responses against harmless antigens later in life. Thus, intensive exposure to dogs in early life may be beneficial during normal immune maturation.

Specific IgE to allergens in cord blood is associated with maternal immunity to Toxoplasma gondii and rubella virus.

BACKGROUND: Various studies have found reduced prevalences of atopic sensitization and atopic diseases in children previously exposed to infections or living conditions with a high microbial burden, such as the farming environment. OBJECTIVE: We sought to determine the relationships of cord blood immunoglobulin E (IgE) with maternal health conditions before and during pregnancy. METHODS: Pregnant women living in rural areas in five European countries were recruited in the third trimester of pregnancy. Information on maternal health during pregnancy was collected from maternity records and by questionnaires (n = 497). Specific IgE for inhalant and food allergens was assessed in cord blood and peripheral blood samples of the mothers. RESULTS: Inverse associations of cord blood IgE to seasonal allergens with positive maternal records for Toxoplasma gondii (adjusted odds ratio = 0.37 [0.17-0.81]) and rubella virus (adjusted odds ratio = 0.35 [0.13-0.96]) were found. The previously described effect of prenatal farm exposure on IgE to seasonal allergens was partly confounded by a positive maternal record for T. gondii. The number of maternal siblings, maternal contact to cats during pregnancy or during her first year of life, predicted a positive maternal record for T. gondii. CONCLUSIONS: Maternal immunity to T. gondii and rubella may impact on atopic sensitization in the fetus. A positive T. gondii record explained the previously identified effect of prenatal farm exposure on IgE to seasonal allergens only to a minor extent.

High birth weight, asthma and atopy at the age of 16 yr.

The association between high birth weight and asthma has been suggested. The Northern Finland Birth Cohort 1986, a longitudinal cohort originally including 9479 participants, has been followed up since birth until the age of 16 yr. Using the data of this study, we analyzed the association of high birth weight with asthma and atopic sensitization at the age of 16 yr. The analysis included the 5995 subjects with complete skin prick test data and the 5500 subjects with data on doctor-diagnosed asthma (written questionnaire) at the age of 16 yr. Atopy was defined as at least one positive skin prick test reaction, which definition was also used to separate atopic and non-atopic asthma. There was a significant association between high birth weight (>4510 g) and asthma among the atopic subjects (OR 2.40, 95% CI 1.33-4.32). When looking at atopy, the highest risk was observed among the subjects with highest birth weight category (>4510 g) (OR 1.44, 95% CI 1.05-1.97) and the adjacent (4200-4500 g) birth weight category (OR 1.24, 95% CI 1.01-1.53), when compared with the reference category (2500-3340 g). Our results support the notion that high birth weight is associated with an increased risk of asthma and suggest that the association is mostly explained by an increased risk of atopy. The biological mechanisms behind the associations are unknown, but they could be related to obesity.

Effect of farming environment on sensitisation to allergens continues after childhood.

AIMS: The farming environment in childhood has been reported to decrease the risk of sensitisation to allergens. The purpose of the present study was to explore whether later exposure to a farming environment also could affect this sensitisation. METHODS: A population based sample of 202 women who did not live on a farm and 231 who did. The subjects filled in a questionnaire and underwent skin prick tests for several common and farming related allergens. RESULTS: The prevalence of sensitisation to any of the allergens was similar in the two groups (37.1 v 34.6% (p = NS). However, compared with women who did not live on a farm, the women who lived on a dairy farm showed a low prevalence of sensitisation to pollens (4.4 v 17.3%, p = 0.01) and cats (3.5 v 10.4%, p = 0.047). The risk of sensitisation to pollens and pets was lowest among women with both a childhood and adulthood farming environment and was dose dependently associated with current contact with farm animals. However, this contact increased the risk of sensitisation to bovine dander. CONCLUSION: The farming environment may reduce sensitisation to common allergens also after early childhood. However, it may also increase sensitisation to farm allergens.

Radiobiological depth of subcutaneous induration.

The incidence of subcutaneous induration in 23 breast cancer patients with postmastectomy radiotherapy was investigated. The patients were treated with three different radiotherapy schedules 7. 9-9.8 years ago. The incidence was correlated with the biological effective dose (BED) at different depths from the skin surface and a best fit was obtained using an alpha/beta ratio of 2 Gy. The most representative depth at which to assess dose for subcutaneous induration was 2 mm which is near the subcutaneous fat/dermis interface.

Respiratory morbidity 20 years after RSV infection in infancy.

Epidemiological data suggest that respiratory syncytial virus (RSV) infection in early life is a risk factor for later asthma. There are no prospective studies on RSV infection starting from infancy progressing through childhood into adulthood. We followed up a cohort of children, hospitalized for RSV bronchiolitis or RSV pneumonia before age 24 months, until age 18-20 years. The aim of the study was to evaluate early RSV infection as a risk factor for asthma, bronchial reactivity, and lung function abnormalities in young adults. The participants filled in a questionnaire on asthma and asthma-like symptoms. The clinical study included flow-volume spirometry (FVS), methacholine inhalation challenge (MIC), home PEF (peak expiratory flow) monitoring, and skin prick tests (SPT) to common allergens. Asthma was present in 17-22% of 36 index subjects, depending on asthma definition, compared to 11% of 45 controls. Furthermore, FEV% and MEF25 were lower, and MEF50 tended to be lower, in index than in control subjects. One or more abnormal lung function results were found in 16 (44%) index subjects, but only in 5 (11%) controls (P < 0.01). Bronchial reactivity (PD20 <4,900 microg methacholine) was demonstrated in 16 (46%) index subjects and 14 (32%) controls (NS). At least one positive SPT result was present in 21 (60%) index subjects; 6 (29%) had asthma (NS vs. nonatopic index subjects); 13 (62%) had abnormal lung function (P < 0.05); and 14 (67%) had bronchial reactivity (P < 0.01). In the logistic regression adjusted for atopy, as defined by SPT positivity, RSV infection in infancy was an independent risk factor for lung function abnormality (one or more abnormal results in FVS; OR, 5.27; 95% CI, 1.60-17.36), and also for decreased FEV% and MEF50 when these were analyzed separately. However, RSV infection in infancy was not a significant risk factor for asthma or bronchial reactivity. In young adults, lung function abnormalities may be associated with RSV infection which required hospitalization in infancy.

Serum eosinophil cationic protein (ECP) and eosinophil protein X (EPX) in childhood asthma: the influence of atopy.

The purpose of this study was to determine the value of serum measurements of eosinophil cationic protein (ECP) and eosinophil protein X (EPX) in diagnosing asthma in children, and to investigate the influence of concomitant allergic diseases and atopic sensitization, assessed by skin prick tests (SPT), on these markers. ECP and EPX were determined in 36 children with asthma, in 33 children with other symptoms from lower airways disease (OSLA), and in 166 control children. Sixteen children with asthma but no anti-inflammatory therapy had significantly higher concentrations of ECP and EPX (ECP: 27.5 microg/L, P < 0.001; EPX: 59.9 microg/L, P < 0.001) than the control children (ECP: 11.2 microg/L; EPX: 26.2 microg/L). In the 20 children on anti-inflammatory therapy, ECP values were similar to those of controls. The children with OSLA (ECP: 13.6 microg/L, P < 0.01; EPX: 47.2 microg/L, P < 0.001) differed significantly from controls. When using the value of 24.7 microg/L (97.5 percentile in the 68 non-atopic controls) as a pathologic upper limit for ECP, 10 (63%) of the 16 asthmatic children on no maintenance medication, two (10%) of the 20 asthmatics on maintenance therapy, and 11 (33%) of the 33 children with OSLA had high ECP; the same figure was only 18 (11%) in the 166 control children. Both ECP and EPX had a significant association with allergic disorders and with SPT reactivity. In multivariate logistic regression analysis, an elevated ECP was significantly associated with asthma (OR 2.3, 95%CI 1.1-4.9) and atopic dermatitis (2.9, 1.2-6.9), and an elevated EPX was significantly associated with asthma (2.61, 1.19-5.74) and allergic rhinoconjunctivitis (5.23, 1.46-18.73). We conclude that serum concentrations of both ECP and EPX are higher in asthmatic than in healthy children. However, other allergic diseases, such as allergic rhinoconjunctivitis, atopic dermatitis, and allergic skin sensitization also raise the concentrations of these markers. This limits their usefulness in the diagnosis of childhood asthma.

Antimicrobial effects of Finnish plant extracts containing flavonoids and other phenolic compounds.

Plant phenolics, especially dietary flavonoids, are currently of growing interest owing to their supposed functional properties in promoting human health. Antimicrobial screening of 13 phenolic substances and 29 extracts prepared from Finnish plant materials against selected microbes was conducted in this study. The tests were carried out using diffusion methods with four to nine microbial species (Aspergillus niger, Bacillus subtilis, Candida albicans, Escherichia coli, Micrococcus luteus, Pseudomonas aeruginosa, Saccharomyces cerevisiae, Staphylococcus aureus and Staphylococcus epidermidis). Flavone, quercetin and naringenin were effective in inhibiting the growth of the organisms. The most active plant extracts were purple loosestrife (Lythrum salicaria L.) against Candida albicans, meadowsweet (Filipendula ulmaria (L.) Maxim.), willow herb (Epilobium angustifolium L.), cloudberry (Rubus chamaemorus L.) and raspberry (Rubus idaeus L.) against bacteria, and white birch (Betula pubescens Ehrh.), pine (Pinus sylvestris L.) and potato (Solanum tuberosum. L.) against gram-positive Staphylococcus aureus.

Antimicrobial activity of some coumarin containing herbal plants growing in Finland.

Antimicrobial screening against selected Gram-positive and Gram-negative bacteria, yeasts, mold, as well as plant pathogenic fungi, with emphasis on method optimization was carried out on methanol extracts prepared from seven plants grown in Finland. Sensitivity to the extracts was found to vary considerably among the micro-organisms, the extract from Petroselinum crispum and Ruta graveolens showing the highest toxicity against Rhizoctonia solani. The growth of Heterobasidium annosum was inhibited, whereas that of Phytophtora (cactorum) was promoted by all the extracts. The antibacterial and antifungal activities of six natural coumarin compounds were weak, except for the inhibitory effect against Fusarium culmorum.

Neuropeptide S receptor 1 (NPSR1) activates cancer-related pathways and is widely expressed in neuroendocrine tumors.

Neuroendocrine tumors (NETs) arise from disseminated neuroendocrine cells and express general and specific neuroendocrine markers. Neuropeptide S receptor 1 (NPSR1) is expressed in neuroendocrine cells and its ligand neuropeptide S (NPS) affects cell proliferation. Our aim was to study whether NPS/NPSR1 could be used as a biomarker for neuroendocrine neoplasms and to identify the gene pathways affected by NPS/NPSR1. We collected a cohort of NETs comprised of 91 samples from endocrine glands, digestive tract, skin, and lung. Tumor type was validated by immunostaining of chromogranin-A and synaptophysin expression and tumor grade was analyzed by Ki-67 proliferation index. NPS and NPSR1 expression was quantified by immunohistochemistry using polyclonal antibodies against NPS and monoclonal antibodies against the amino-terminus and carboxy-terminus of NPSR1 isoform A (NPSR1-A). The effects of NPS on downstream signaling were studied in a human SH-SY5Y neuroblastoma cell line which overexpresses NPSR1-A and is of neuroendocrine origin. NPSR1 and NPS were expressed in most NET tissues, with the exception of adrenal pheochromocytomas in which NPS/NPSR1 immunoreactivity was very low. Transcriptome analysis of NPSR1-A overexpressing cells revealed that mitogen-activated protein kinase (MAPK) pathways, circadian activity, focal adhesion, transforming growth factor beta, and cytokine-cytokine interactions were the most altered gene pathways after NPS stimulation. Our results show that NETs are a source of NPS and NPSR1, and that NPS affects cancer-related pathways.

Allergen-specific sensitization in asthma and allergic diseases in children: the study on farmers' and non-farmers' children.

BACKGROUND: Farmers' children are less frequently sensitized to common allergens than the non-farmers' children, but less is known about their sensitization to other allergens and its association with clinical diseases. OBJECTIVE: To examine the association of farm environment with atopic sensitization, allergic diseases, expression of allergen-induced symptoms, and the importance of specific sensitization against 'common' (timothy, dog, cat, birch, Dermatophagoides pteronyssimus, mugwort) and 'other' (cockroach, horse, Lepidoglyphus destructor, cow) allergens for asthma and allergic diseases in children. METHODS: A cross-sectional study including 344 farmers' and 366 non-farmers' children aged 6-13 years in eastern Finland, using a self-administered written questionnaire and skin prick tests against the above-mentioned allergens. RESULTS: Farmers' children had less asthma and allergic diseases and were less often sensitized against common allergens than the non-farmers' children. However, little difference was observed in sensitization against the other allergens between the farmers' (17.2%) and non-farmers (14.5%) children [adjusted odds ratios (aOR) 1.11 (0.71-1.72)]. Being sensitized against only other allergens, without sensitization against common allergens, was unrelated to asthma or allergic diseases. Among the single allergens, sensitization against pets or pollen, or against horse or cow, had the strongest association with asthma, hayfever, and atopic eczema; no such association was seen in D. pteronyssimus, mugwort, cockroach, or L. destructor. Farmers' children had significantly less often symptoms of allergic rhinitis in contact with dog (aOR 0.32%, 95% confidence interval (CI) 0.15-0.67), cat (aOR 0.45, 0.22-0.88), or pollen (aOR 0.58%, 95% CI 0.37-0.90) than the non-farmers' children. CONCLUSION: Farm environment reduces the occurrence of asthma, allergic diseases, and atopic sensitization in children, and also the occurrence of allergen-induced rhinitis. Remarkable differences were observed between single allergens in their association with allergic disease, stressing the importance of allergen selection when defining atopy in epidemiological studies.

Serum procalcitonin in pneumococcal pneumonia in children.

Serum procalcitonin (PCT), a marker of bacterial infection, was measured in children with pneumonia to examine whether PCT can be used to screen pneumococcal (PNC) from viral pneumonia. The number of patients was 132; mean age 3.0 yrs, and 64% were males. In all cases, pneumonia was radiologically confirmed, being alveolar in 46 and interstitial in 86 cases. The aetiology of infection was studied by a panel of serological tests for PNC, for five other respiratory bacteria and for seven common respiratory viruses. PNC infection was found in 25, mixed viral-PNC infections in 13 and viral infection in 17 cases. In general, serum PCT was not associated with the type or aetiology of pneumonia. PCT values were >1.0 mg.L(-1) in 40% of PNC cases, as compared to 12-15% in viral or mixed cases, respectively (p<0.05). PCT values were significantly higher in >2 yrs old children than in younger ones. The cut-off limits of 0.5 ng.mL(-1), 1.0 ng.mL(-1) and 2.0 ng.mL(-1) were tested for screening between PNC and viral pneumonia. The highest sensitivity of 55% was found at the 0.5 ng.mL(-1) cut-off level, whereas the highest specificity of 88% was reached at the level of 1.0 ng.mL(-1). The likelihood ratios, however, were far from optimal for both the positive and negative results. Although marginally higher in pneumococcal pneumonia than in viral pneumonia, serum procalcitonin cannot be used to discriminate between these two types of pneumonia.

Asthma and atopy in schoolchildren in a defined population.

We investigated the frequency of allergic disorders, the pattern of allergen sensitization and serum total IgE concentration in a population-based sample of schoolchildren screened on the basis of respiratory symptoms (N = 244). The children were classified on clinical grounds into three groups, asthma (N = 43), other symptoms from lower airways (OSLA; N = 34) and control children (N = 167). The frequency of allergic disorders (allergic rhinitis, conjunctivitis or dermatitis) differed significantly between children with asthma (81%), children with OSLA (62%) and in control children (48%) (p < 0.001). The presence of at least one positive skin prick test result was equally common in children with asthma or OSLA (77%), but lower in control children (40%) (p < 0.001). Serum total IgE concentrations did not differ between the three groups. Two conclusions can be drawn: (i) there is a strong association between clinical allergy, skin reactivity and asthma in school age children, and (ii) a similar association is present between allergy and asthma-like conditions.

Outcome of children with respiratory symptoms without objective evidence of asthma: a two-year, prospective, follow-up study.

This study evaluated the outcome of 33 children with asthma-like symptoms without objective evidence of asthma, and the role of certain factors in predicting the development of clinical asthma in these children. Data on symptom histories, lung functions (flow-volume spirometry, free running test and methacholine inhalation challenge test) and atopic sensitization (skin prick tests and markers of eosinophilic inflammation) were collected twice with an interval of 2 y, and the diagnoses were re-evaluated after the follow-up period. Based on the results, it was concluded that one-third of the children with prolonged or recurrent lower airway symptoms, such as cough or wheeze, either have mild asthma or will develop asthma in the near future. Children who had a significant response [> or = 10% fall in forced expiratory volume in 1 s (FEV1)] in the free running test formed a risk group for active asthma, whereas other baseline characteristics seemed not to predict the outcome.

Which factors explain the lower prevalence of atopy amongst farmers' children?

BACKGROUND: The inverse association between farming and atopy in children has been attributed to microbial exposure, especially through livestock. Very little is known about other potential explanatory factors. OBJECTIVE: To explore potential differences in lifestyle and environmental factors between farmer and non-farmer families, and whether these factors could explain the association between farming and childhood atopy. METHODS: A cross-sectional study, including 366 farmers' and 344 non-farmers' children in eastern Finland. Information regarding exposure and background characteristics was gathered by a written questionnaire. Atopy was defined as having one or more positive skin prick test reactions (> 3 mm) against the six common aeroallergens. RESULTS: Regardless of the current farming type, atopy was less frequent among the farmers' children than the non-farmers' children (aOR 0.56, 95% CI 0.40-0.78). Remarkable differences were seen in many lifestyle factors (including diet) between the farmer and non-farmer families, but only a few of the explored factors were associated with atopy. The frequency of current livestock contacts seemed to have an inverse, dose-dependent association with atopy (aOR 0.46, 95% CI 0.22-0.97 for daily vs. no contact). Having lived on a dairy farm in infancy (aOR 0.51, 95% CI 0.28-0.93), or having had cats or dogs in infancy (aOR 0.60, 95% CI 0.42-0.85), decreased the risk of atopy at school age. The inverse association between farming and atopy was not explained by the sociodemographic factors, or by differences in conventional risk factors of atopy. Animal contacts explained partially, but not completely, the association. CONCLUSION: Higher frequency of animal contacts is one factor, but probably not the only one, explaining the inverse association of farming and atopy in children. The importance of early life exposures may have recently been over-emphasized, and current exposures discounted, when studying the risk factors of childhood atopy.