Summary
Background
Peanut allergy necessitates dietary restrictions, preferably individualized by determining reactivity threshold through an oral food challenge (OFC). However, risk of systemic ...reactions often precludes OFC in children with severe peanut allergy.
Objective
We aimed to determine whether clinical and/or immunological characteristics were associated with reactivity threshold in children with anaphylaxis to peanut and secondarily, to investigate whether these characteristics were associated with severity of the allergic reaction during OFC.
Methods
A double‐blinded placebo‐controlled food challenge (DBPCFC) with peanut was performed in 96 5‐ to 15‐year‐old children with a history of severe allergic reactions to peanut and/or sensitization to peanut (skin prick test SPT ≥3 mm or specific immunoglobulin E s‐IgE ≥0.35 kUA/L). Investigations preceding the DBPCFC included a structured interview, SPT, lung function measurements, serological immunology assessment (IgE, IgG and IgG4), basophil activation test (BAT) and conjunctival allergen provocation test (CAPT). International standards were used to define anaphylaxis and grade the allergic reaction during OFC.
Results
During DBPCFC, all 96 children (median age 9.3, range 5.1‐15.2) reacted with anaphylaxis (moderate objective symptoms from at least two organ systems). Basophil activation (CD63+ basophils ≥15%), peanut SPT and the ratio of peanut s‐IgE/total IgE were significantly associated with reactivity threshold and lowest observed adverse events level (LOAEL) (all P < .04). Basophil activation best predicted very low threshold level (<3 mg of peanut protein), with an optimal cut‐off of 75.8% giving a 93.5% negative predictive value. None of the characteristics were significantly associated with the severity of allergic reaction.
Conclusion and Clinical Relevance
In children with anaphylaxis to peanut, basophil activation, peanut SPT and the ratio of peanut s‐IgE/total IgE were associated with reactivity threshold and LOAEL, but not with allergy reaction severity.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
A crucial period for the development of the immune system occurs in utero. This results in a high fetal vulnerability to immunotoxic exposure, and indeed, immunotoxic effects have been reported, ...demonstrating negative effects on immune-related health outcomes and immune functionality. Within the NewGeneris cohort BraMat, a subcohort of the Norwegian Mother and Child Cohort Study (MoBa), immunotoxicity was demonstrated for polychlorinated biphenyls and dioxins, showing associations between estimated maternal intake levels and reduced measles vaccination responses in the offspring at the age of 3. The present study aimed to investigate this link at the transcriptomic level within the same BraMat cohort. To this end, whole-genome gene expression in cord blood was investigated and found to be associated with maternal Food Frequency Questionnaires-derived exposure estimates and with vaccination responses in children at 3 years of age. Because the literature reports gender specificity in the innate, humoral, and cell-mediated responses to viral vaccines, separate analysis for males and females was conducted. Separate gene sets for male and female neonates were identified, comprising genes significantly correlating with both 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and polychlorinated biphenyls (PCB) exposure and with measles vaccination response. Noteworthy, genes correlating negatively with exposure in general show positive correlations with antibody levels and vice versa. For both sexes, these included immune-related genes, suggesting immunosuppressive effects of maternal exposure to TCDD and PCB at the transcriptomic level in neonates in relation to measles vaccination response 3 years later.
Several legumes may induce allergy, and there is extensive serological cross‐reactivity among legumes. This cross‐reactivity has traditionally been regarded to have limited clinical relevance. ...However, the introduction of novel legumes to Western countries may have changed this pattern, and in some studies cross‐allergy to lupin has been reported in more than 60% of peanut‐allergic patients. We wanted to explore cross‐reactions among legumes using two newly established mouse models of food allergy. Mice were immunized perorally with fenugreek or lupin with cholera toxin as adjuvant. The mice were challenged with high doses of fenugreek, lupin, peanut or soy, and signs of anaphylactic reactions were observed. Cross‐allergic mechanisms were investigated using serum mouse mast cell protease‐1 (MMCP‐1), antibody responses, immunoblotting and ex vivo production of cytokines by spleen cells. Signs of cross‐allergy were observed for all the tested legumes in both models. The cross‐allergic symptoms were milder and affected fewer mice than the primary allergic responses. The cross‐allergy was reflected to a certain extent in the antibody and T‐cell responses, but not in serum MMCP‐1 levels. Cross‐allergy to peanut, soy, fenugreek and lupin was observed in lupin‐sensitized and fenugreek‐sensitized mice. Differences in serological responses between primary allergy and cross‐allergy might be due to mediation through different immune mechanisms or reflect different epitope affinity to IgE. These differences need to be further investigated.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Fenugreek is a legume mostly used as a spice in Indian‐style cooking. Although it has been used since ancient times, its allergenicity has only been reported in the last two decades. It poses special ...problems as an emerging and often hidden allergen. Fenugreek exposure may have serious implications also for individuals with peanut allergy because of cross‐reactivity. Because a new food requires a model specially designed for that particular food, the aim of our study was to develop a food allergy model of fenugreek in mice with anaphylaxis as the endpoint. Mice were immunized perorally using cholera toxin as adjuvant. A two‐compartment response surface design with immunoglobulin (Ig)E as the main variable was used to estimate the optimal sensitizing dose of fenugreek, which was further used to evaluate the model. The mice were challenged perorally with a high dose of fenugreek, and signs of anaphylactic reactions were observed. Challenged mice showed high levels of mouse mast cell protease‐1, developed specific IgE against several proteins in the fenugreek extract, had elevated levels of IgG1 and IgG2a and showed a general shift towards a Th2 response as determined by ex vivo production of cytokines. Total IgE levels were substantially decreased after challenge. In conclusion, we have established a mouse model of IgE‐mediated fenugreek allergy demonstrating anaphylactic reactions upon challenge. There is little information on fenugreek cross‐allergy to other legumes like peanut, soy and lupin, and we expect that this model will be a valuable tool in further research on legume allergy.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Particulate matter has been associated with a number of adverse health effects. Since combustion particles from vehicle exhaust and wood smoke are common constituents of ambient air, the morphology ...and elemental composition of particles from these two sources were analysed and compared using single particle analysis. Ambient air particles were collected in locations dominated by vehicle exhaust or residential wood smoke. To verify the source contributions to the ambient air samples, particles were collected directly from the combustion sources. All particulate samples were analysed on carbon extraction replica by transmission electron microscopy (TEM) and X-ray microanalysis (XRMA). The particles were classified into four groups based on morphology and elemental composition. Carbon aggregates were the only particles identified to originate from combustion sources and accounted for more than 88% of the particle numbers in the ambient air samples from both sources. The carbon aggregates were therefore further analysed with respect to morphology and elemental composition on germanium extraction replica. Carbon aggregates from vehicle exhaust were characterised by higher levels of Si and Ca compared to wood smoke aggregates that contained higher levels of K. The S content in aggregates from both sources was probably caused by interaction with gases in the air. Furthermore, the diameters of primary particles from vehicle exhaust were significantly smaller (27±7 nm) than the diameters for wood smoke (38±11 nm). The observed differences in elemental profiles and primary particle diameters for vehicle exhaust and wood smoke may influence the health effects caused by these particles.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The multiple intestinal neoplasia (Min)/+ mouse, which harbors only one functional allele of the Apc gene, is susceptible to environmental factors that disrupt this gene and subsequently trigger ...Apc-driven tumorigenesis in the colon. Aberrant crypt foci (ACF) are assumed to be preneoplastic lesions in colon carcinogenesis. Recently, we reported the absence of "classical" ACF in the colon of untreated Min/+ mice. Instead we identified flat dysplastic lesions, which we denoted ACF(Min) (J. E. Paulsen et al., Scand. J. Gastroenterol., 35: 534-539, 2000). In contrast to the classical type, ACF(Min) are not elevated above the surrounding mucosa, and their detection is totally dependent on methylene blue staining and transillumination. In the present study, we treated Min/+ mice with 5 mg/kg body weight azoxymethane (AOM) at weeks 1 and 2 and demonstrated induction of both types of lesions. However, only ACF(Min) appeared to be associated with the development of adenomas. Monocryptal ACF(Min), large ACF(Min), and adenomas showed a uniform histopathological picture of dysplasia and cytoplasmic overexpression of beta-catenin, indicating a qualitative relationship between these lesions. Also a quantitative relationship was suggested because the dramatic decrease in ACF(Min) number from week 7 to 11 was paralleled by a reciprocal increase in tumor number, indicating fast-crypt multiplication of ACF(Min). In AOM-treated +/+ (wild-type) littermates, a low number of ACF(Min) and tumors with the same characteristics as in Min/+ mice was seen. In contrast to ACF(Min), histopathological and immunohistochemical examination of classical ACF showed normal or hyperplastic crypts with normal levels of beta-catenin expression. In AOM-treated Min/+ mice, the number of classical ACF was virtually constant from week 7 to 11, and only a modest increase of crypt multiplicity was observed. The number of AOM-induced classical ACF at week 11 was not different in Min/+ mice and +/+ mice. In conclusion, we identified two distinct populations of altered crypts in the colon of Min/+ mice after AOM treatment. The ACF(Min), which resemble the dysplastic ACF described previously, clearly showed a continuous development from the monocryptal stage to adenoma, and they were characterized by fast-growing crypts with altered control of beta-catenin. In contrast, the classical ACF, which resemble the hyperplastic ACF described previously, were characterized by slow-growing crypts with normal beta-catenin expression, and they were probably not related to tumorigenesis.
1 Department of Morphology, Genetics and Aquatic Biology, Norwegian College of Veterinary Medicine, Oslo
2 Section of Virology, Central Veterinary Laboratory, PO Box 8156 Dep., 0033 Oslo
and 3 ...Electron Microscopy Unit, National Institute of Public Health, Oslo, Norway
A long-term cell line (SHK-1) supporting replication of the causal virus of infectious salmon anaemia (ISA) has been established. The cell line was developed from a culture of Atlantic salmon ( Salmo salar L.) head kidney cells. CPE was observed in SHK-1 cells 1214 days after inoculation with ISA-infective tissue material. The time for CPE to develop decreased after repeated passages of medium from infected cell cultures to new cultures. Transmission trials demonstrated that Atlantic salmon parr developed ISA after intraperitoneal injection of preparations made from infected cells and growth medium. The ISA infectivity of the cell preparations increased with incubation time of inoculated cells. Cell cultures in a second passage were found to have a higher infectivity than the primary inoculated cultures. Virus particles with a diameter of approximately 100120 nm, and which contained an external envelope and granules were seen in electron micrographs of thin sections of infected cells. Most of the virus particles were located extracellularly close to the cell surface, and in some cases, a connection between virus and plasma membrane could be observed. This indicates that virus particles were released by budding. Enveloped virus particles of 45140 nm in diameter were seen in abundance in electron micrographs of a negatively stained purified virus preparation. Large, highly pleomorphic particles up to 700 nm in the longest dimension were occasionally observed in unpurified preparations. The evidence is therefore strong that the virus isolated in SHK-1 cells is the aetiological agent of ISA.
* Author for correspondence (mail should be sent to the Central Veterinary Laboratory address). Fax +47 22 460034.
Received 28 November 1994;
accepted 7 February 1995.
► Existing genotoxicity biomarkers provide limited mechanistic insight. ► Furthermore, they do not allow detection of exposure to non-genotoxic carcinogens. ► Potentially, transcriptomics can ...overcome these limitations. ► We investigate transcriptomic responses to (non-) genotoxic exposure in human PBMC. ► Profiles indicative of genotoxic and non-genotoxic exposure were identified.
For evaluating genotoxic exposure in human populations a number of biomarkers has been successfully applied over the last 30 years to determine early biological effects due to exposure to carcinogens. Despite their success, these early biological effect markers provide limited mechanistic insight, and do not allow detection of exposure to non-genotoxic carcinogens. Gene expression profiling forms a promising tool for the development of new biomarkers in blood cells to overcome these limitations. The aim of our research was to identify novel genomics-based candidate markers for genotoxic and non-genotoxic carcinogen exposure in human peripheral blood cells (PBMC). Whole genome gene expression changes were investigated following 20h of in vitro exposure to a high and low concentration of eight genotoxic and three non-genotoxic carcinogenic compounds using whole genome microarrays. Per condition, PBMC of five independent donors were exposed, all in the presence of human liver S9. Sets of genes, as well as biological pathways indicative of genotoxic exposure and of non-genotoxic carcinogenic exposure were identified. Furthermore, networks were built using the genotoxic and non-genotoxic gene sets, showing the majority of the genes to be interlinked and revealing distinctive transcription factors for both classes. The identification of these potential candidate marker genes might contribute to the development of genomic based biomarkers of carcinogen exposure.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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