European guideline (EuroGuiDerm) on atopic eczema: part I - systemic therapy.

The evidence- and consensus-based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty-nine experts (including clinicians and patient representatives) from 12 European countries participated. This first part of the guideline includes general information on its scope and purpose, the health questions covered, target users and a methods section. It also provides guidance on which patients should be treated with systemic therapies, as well as recommendations and detailed information on each systemic drug. The systemic treatment options discussed in the guideline comprise conventional immunosuppressive drugs (azathioprine, ciclosporin, glucocorticosteroids, methotrexate and mycophenolate mofetil), biologics (dupilumab, lebrikizumab, nemolizumab, omalizumab and tralokinumab) and janus kinase inhibitors (abrocitinib, baricitinib and upadacitinib). Part two of the guideline will address avoidance of provocation factors, dietary interventions, immunotherapy, complementary medicine, educational interventions, occupational and psychodermatological aspects, patient perspective and considerations for paediatric, adolescent, pregnant and breastfeeding patients.

European guideline (EuroGuiDerm) on atopic eczema - part II: non-systemic treatments and treatment recommendations for special AE patient populations.

The evidence- and consensus-based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty-nine experts (including clinicians and patient representatives) from 12 European countries participated. This second part of the guideline includes recommendations and detailed information on basic therapy with emollients and moisturizers, topical anti-inflammatory treatment, antimicrobial and antipruritic treatment and UV phototherapy. Furthermore, this part of the guideline covers techniques for avoiding provocation factors, as well as dietary interventions, immunotherapy, complementary medicine and educational interventions for patients with atopic eczema and deals with occupational and psychodermatological aspects of the disease. It also contains guidance on treatment for paediatric and adolescent patients and pregnant or breastfeeding women, as well as considerations for patients who want to have a child. A chapter on the patient perspective is also provided. The first part of the guideline, published separately, contains recommendations and guidance on systemic treatment with conventional immunosuppressive drugs, biologics and janus kinase (JAK) inhibitors, as well as information on the scope and purpose of the guideline, and a section on guideline methodology.

Predicting reactivity threshold in children with anaphylaxis to peanut.

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.

Report from the fifth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative).

This is the report from the fifth meeting of the Harmonising Outcome Measures for Eczema initiative (HOME V). The meeting was held on 12-14 June 2017 in Nantes, France, with 81 participants. The main aims of the meeting were (i) to achieve consensus over the definition of the core domain of long-term control and how to measure it and (ii) to prioritize future areas of research for the measurement of the core domain of quality of life (QoL) in children. Moderated whole-group and small-group consensus discussions were informed by presentations of qualitative studies, systematic reviews and validation studies. Small-group allocations were performed a priori to ensure that each group included different stakeholders from a variety of geographical regions. Anonymous whole-group voting was carried out using handheld electronic voting pads according to predefined consensus rules. It was agreed by consensus that the long-term control domain should include signs, symptoms, quality of life and a patient global instrument. The group agreed that itch intensity should be measured when assessing long-term control of eczema in addition to the frequency of itch captured by the symptoms domain. There was no recommendation of an instrument for the core outcome domain of quality of life in children, but existing instruments were assessed for face validity and feasibility, and future work that will facilitate the recommendation of an instrument was agreed upon.

Prenatal exposure to perfluoralkyl substances (PFASs) associated with respiratory tract infections but not allergy- and asthma-related health outcomes in childhood.

BACKGROUND: Prenatal exposure to perfluoralkyl substances (PFASs) has been reported to be associated with immunosuppression in early childhood, but with contradictory findings related to atopic and lung diseases. AIM: We aimed to determine if prenatal exposure to PFASs is associated with asthma or other allergic diseases or respiratory tract infections in childhood. METHODS: Nineteen PFASs were measured in cord blood available from 641 infants in the Environment and Childhood Asthma (ECA) prospective birth cohort study. The six most abundant PFASs were perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorooctanesulfonamide (PFOSA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), and perfluoroundecanoic acid (PFUnDA). Health outcomes were assessed at two and ten years of age, and included reported obstructive airways disease (wheeze by 10 years; asthma by 2 and 10 years; reduced lung function at birth; allergic rhinitis by 10 years), atopic dermatitis (AD) by 2 and 10 years, allergic sensitization by 10 years, and episodes of common respiratory tract infections (common cold by 2 years, lower respiratory tract infections (LRTI) by 10 years). The associations between exposure and health outcomes were examined using logistic and Poisson regression. RESULTS: The number of reported airways infections were significantly associated with cord blood concentrations of PFAS; common colds by two years with PFUnDA (ß = 0.11 (0.08-0.14)) and LRTIs from 0 to 10 years of age with PFOS (ß = 0.50 (0.42-0.57)), PFOA (ß = 0.28 (0.22-0.35)), PFOSA (ß = 0.10 (0.06-0.14)), PFNA (ß = 0.09 (0.03-0.14)) and PFUnDA (ß = 0.18 (0.13-0.23)) concentrations. Neither reduced lung function at birth, asthma, allergic rhinitis, AD nor allergic sensitization were significantly associated with any of the PFASs. CONCLUSION: Although prenatal exposure to PFASs was not associated with atopic or lung manifestations by 10 years of age, several PFASs were associated with an increased number of respiratory tract infections in the first 10 years of life, suggesting immunosuppressive effects of PFASs.

TSLP, IL-31, IL-33 and sST2 are new biomarkers in endophenotypic profiling of adult and childhood atopic dermatitis.

BACKGROUND: Recent years have seen growing interest in identifying new biomarkers in atopic dermatitis (AD) that could serve as indicators of disease severity and predictors of treatment response. OBJECTIVES: We compared serum levels of thymic stromal lymphopoietin (TSLP), interleukin(IL)-31, IL-33 and soluble(s)ST2 in AD patients and healthy controls, investigated the possible correlation with disease severity, investigated if other atopic comorbidities could play a role, and assessed their potential as biomarkers in AD. METHODS: Using standard enzyme-linked immunosorbent assay techniques, we measured target serum levels in 71 adults and 61 children with AD, and 31 adult controls. We characterized our cohort by disease severity, radioallergosorbent test status concerning both dietary and inhalant allergens, and anamnestic reports of food allergy, concomitant allergic asthma and/or allergic rhinitis. RESULTS: Serum levels of TSLP, IL-31 and IL-33, but not sST2, were significantly elevated in AD patients compared with controls. In AD patients, both IL-31 and IL-33 serum levels were higher in children than in adults, while the opposite was the case for sST2. We observed no correlation between disease severity and any of the investigated targets. While serum TSLP levels were unaffected by concomitant allergies and atopic comorbidities, serum levels of IL-31, IL-33 and sST2 were affected to a small extent. We found a positive correlation between TSLP, IL-31 and IL-33, and an inverse relationship between IL-33 and sST2. CONCLUSIONS: The studied targets hold little potential as indicators of disease severity. The serum values of our targets show robustness against atopic comorbidities, allergies and changes in disease severity. This robustness strengthens their potential use in biomarker-based stratification and could be instrumental in identifying subgroups and predicting the possible benefit of therapeutic and prevention approaches.

Cry1Ab protein from Bacillus thuringiensis and MON810 cry1Ab-transgenic maize exerts no adjuvant effect after airway exposure.

The genetically modified (GM) maize event MON810 has been inserted with a processed version of the transgene, cry1Ab, derived from the soil bacterium Bacillus thuringiensis (Bt) to express proteins with insecticidal properties. Such proteins may introduce new allergens and also act as adjuvants that promote allergic responses. While focus has been on safe consumption and hence the oral exposure to GM food and feed, little is known regarding inhalation of pollen and desiccated airborne plant material from GM crops. The aim of this study was to investigate whether plant material from the Cry1Ab-expressing maize variety MON810, or trypsin-activated Cry1Ab (trypCry1Ab) protein produced in recombinant bacteria, may act as adjuvants against the allergen ovalbumin (OVA) in a mouse model of airway allergy. A clear proallergic adjuvant effect of the mucosal adjuvant cholera toxin (CT) was demonstrated, determined as increased specific IgE, eosinophils and Th2 cytokines in MLN cell supernates, while no elevation in OVA-specific antibodies or cytokine release from MLN cells after stimulation with OVA were observed in mice receiving Cry1Ab-containing plant materials or the trypCry1Ab protein. Our data suggest that Cry1Ab proteins had no detectable systemic adjuvant effect in mice after airway exposure. Further experiments with purified plant proteins, as well as long-term exposures needs be conducted to further evaluate exposures experienced in real-life situations.

Suppression of allergen-specific IgE in offspring after preconceptional immunisation: maternal, paternal and genetic influences.

Immunisation of female mice with the allergen ovalbumin (OVA) during pregnancy reduces the OVA-specific IgE response in adult offspring. To approach primary prevention strategies for allergy, we investigated to what extent genetic, paternal and maternal factors influence this suppressive effect on allergic sensitisation in offspring and investigated the possibility of pregestational immunisation. Maternal allergen immunisation reduced OVA-specific IgE levels in immunised offspring, even after maternal immunisation up to 8 weeks before conception without further allergen exposure. Immunisation of immunodeficient BALB/c severe combined immune deficiency (SCID) dams mated with wild type males did not lead to IgE suppression in offspring, indicating the importance of a functional maternal immune system. Immunisation of male mice before the relevant spermatogenesis did not cause antibody suppression in offspring. OVA-specific IgG1, presumably of maternal origin, was present in naïve offspring only from immunised dams and was associated with suppressed IgE responses after offspring immunisation. The IgE-suppressive effect of maternal immunisation was demonstrated in all three immunocompetent strains tested (NIH/OlaHsd, BALB/cA and C57BL/6 mice). In conclusion, suppression of allergen-specific IgE production in offspring could not be induced by paternal immunisation, and genetic factors were of minor importance. In contrast, we demonstrate the necessity of maternal factors, possibly allergen-specific IgG1, resulting from a functional adaptive immune response, for the IgE-suppressive effect in offspring. These maternal factors could be induced by immunisation of female mice even before conception.

Transcriptomic fingerprints in human peripheral blood mononuclear cells indicative of genotoxic and non-genotoxic carcinogenic exposure.

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 20 h 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.

Determinants of experimental allergic responses: interactions between allergen dose, sex and age.

The prevalence of allergic diseases is influenced by sex and age. Although mouse models are widely used in allergy research, few experimental studies have examined the interaction effects of sex and age on allergy outcomes. Our aim was to investigate the individual and combined effects of sex and age on allergic sensitization and inflammation in two mouse models: an intraperitoneal (i.p.) and an intranasal (i.n.) sensitization model. We also investigated how the allergen immunization dose interacted with age and sex in the i.p. model. Female and male mice were immunized i.p. or i.n. with ovalbumin when 1, 6 or 20 weeks old. In both models, allergen challenges were performed by i.n. delivery. Serum antibodies, draining lymph node cytokine release and airway inflammatory responses were assessed. In the i.p. model, the antibody and cytokine levels and airway inflammation were highly influenced by immunization dose and age. The responses increased with age when using a low immunization dose, but decreased with age when using a high immunization dose. In the i.n. model, antibody production and airway tissue inflammation increased with age. Female compared with male mice generally developed more pronounced antibody and inflammatory responses. Relative to older mice, juvenile mice had augmented airway inflammation to allergen exposures. The study demonstrates that immunization dose, sex and age are highly influential on allergy outcomes. To better mimic different life stages of human allergic airway disease, murine models, therefore, require careful optimization.

Erythropoietin does not attenuate renal dysfunction or inflammation in a porcine model of endotoxemia.

BACKGROUND: Erythropoietin (EPO) is a multifunctional cytokine with anti-apoptotic, anti-inflammatory, and organ protective effects. EPO protects against ischemia-reperfusion injuries, and recent reports suggest that EPO also prevents organ dysfunction in experimental sepsis. The aims of this study were to determine whether EPO prevents endotoxemia-induced organ dysfunction in a porcine model and to characterize the immunomodulatory and anti-apoptotic effects of EPO. METHODS: Twenty-eight pigs were randomly assigned to three groups: (1) endotoxemia treated with EPO 5000 IU/kg, (2) endotoxemia treated with placebo, and (3) a sham group anesthetized and submitted to sham operation without treatment. A laparotomy was performed, and a flow probe was placed around the left renal artery, which allowed renal blood flow (RBF) measurements. Endotoxemia was induced by an infusion of lipopolysaccharide. After 2 h, the infusion was reduced to a maintenance dose and the animals were fluid resuscitated. The glomerular filtration rate (GFR), RBF, renal oxygen consumption, and plasma cytokines [interleukin (IL)-1ß, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha] were analyzed. Renal biopsies were analyzed for cytokine content and apoptosis. RESULTS: Endotoxemia elicited impaired renal function, estimated as GFR, and increased the levels of renal apoptotic cells, with no modifying effect of EPO. Furthermore, EPO had no effect on RBF, renal oxygen consumption, or the systemic hemodynamic response to endotoxemia. EPO did not modify the inflammatory response, measured as changes in cytokine levels in plasma and organs. CONCLUSION: EPO did not confer renal protection in this fluid-resuscitated porcine model of endotoxemia, and EPO did not modify the inflammatory response.

Nitrogen dioxide: no influence on allergic sensitization in an intranasal mouse model with ovalbumin and diesel exhaust particles.

The role of traffic-related air pollution in the development of allergic diseases is still unclear. We therefore investigated if NO2, an important constituent of traffic-related air pollution, promotes allergic sensitization to the allergen ovalbumin (OVA). We also examined if NO2 influenced the allergy adjuvant activity of diesel exhaust particles (DEP). For this purpose, mice were exposed intranasally to OVA with or without DEP present, immediately followed by exposure to NO2 (5 or 25 parts per million [ppm]) or room air for 4 h in whole body exposure chambers. Eighteen hours after the last of three exposures, the lungs of half of the animals were lavaged with saline and markers of lung damage and lung inflammation in the bronchoalveolar lavage fluid (BALF) were measured. Three weeks later, after intranasal booster immunizations with OVA, the levels of OVA-specific IgE and IgG2a antibodies in serum were determined. Both NO2 (25 ppm) and DEP gave lung damage, measured as increased total protein concentration in BALF, whereas only NO2 seemed to stimulate release of the proinflammatory cytokine tumor necrosis factor alpha (TNF-α). In contrast, only DEP significantly increased the number of neutrophils. Furthermore, DEP in combination with OVA stimulated the production of serum allergen-specific IgE antibodies. NO2, however, neither increased the production of allergen-specific IgE antibodies, nor influenced the IgE adjuvant activity of DEP. Thus, based on our findings, NO2 seems to be of less importance than combustion particles in the development of allergic diseases after exposure to traffic-related air pollution.

Perfluoroalkyl substances, airways infections, allergy and asthma related health outcomes - implications of gender, exposure period and study design.

INTRODUCTION: Exposure to perfluoroalkyl substances (PFASs) has been inconsistently associated with asthma, allergic diseases and airways infections in early childhood. The aim of the study was, therefore, to investigate the effect of childhood exposure to PFASs on asthma and allergy related outcomes and on airways infections before and during puberty using the prospective birth cohort Environment and Childhood Asthma (ECA) Study. Aspects of gender, exposure period and study design (cross-sectional and longitudinal) were also taken into consideration. MATERIAL AND METHODS: Included in the study was 378 participants with PFAS measurements at age 10 years and follow-up data at ages 10 years (cross sectional data) and 16 years (longitudinal data). Eight PFASs with at least 70% of measurements above the limit of quantification (LOQ) in the child's serum were included in the present study: perfluoroheptanoate (PFHpA), perfluorooctanoate (PFOA), perfluourononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnDA), perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS) and perfluorooctane sulfonate (PFOS). The PFAS levels were converted into interquartile range (IQR). In addition, perfluorooctane sulfonamide (PFOSA) detected in 60% of the samples, was recoded into "not detected /detected". Binomial, multinomial and linear regression were used, followed by Bonferroni adjustment to correct for multiple comparisons. Sensitivity analyses evaluating the effect of extreme PFAS values and gender were performed. RESULTS: In the cross sectional data at 10 years a positive statistically significant association was seen between PFHpA and asthma in girls. In the longitudinal data, PFNA, PFDA and PFUnDA were inversely associated with atopic dermatitis (AD) in girls and with PFHxS in all participants and in boys. Further, PFNA and PFHpS were positively associated with rhinitis in girls and with PFOA in all participants. There seems to be a suggestive pattern of increased risk of allergic sensitisation in all participants and a decreased risk in boys, but due to different results in main and sensitivity analyses these findings should be interpreted with caution. No associations were found between PFASs and lung function. For airways infections and longitudinal data, PFDA was inversely associated with common cold, while positive association was found for PFHpA, PFOA, PFHpS and PFOS and lower respiratory tract infections (LRTI). DISCUSSION AND CONCLUSION: Our results lend further support for an immunosuppressive effect of PFASs on AD and LRTI. Gender seems to be important for some exposure-health associations. No clear pattern in exposure-health associations was observed with regard to exposure period or study design, with the exception of asthma where significant findings have mostly been reported in cross-sectional studies.

Particle size determines activation of the innate immune system in the lung.

Our knowledge about particle size in relation to activation of the innate immune system is limited. Therefore, the acute effect of particle exposure on the innate immune system was studied in a lung model using the intracellular bacterium Listeria monocytogenes. Female Balb/cA mice were instilled intratracheally with polystyrene particles (PSP) of different diameters (0.064, 0.202, 1.053 and 4.646 mum) simultaneously with or 1 day prior to inoculation of 10(5) bacteria. Mice were sacrificed 1 day after Listeria challenge, and the numbers of viable bacteria in the lungs and the spleen were determined as a measure of cellular activation. In separate experiments, bronchoalveolar lavage (BAL) fluid was collected. Only mice exposed to the smallest PSP (0.064 and 0.202 mum) had significantly reduced bacterial numbers in the lung after particles and Listeria were given simultaneously. When particles were given 1 day prior to Listeria challenge also the largest 4.646 mum PSP, but not the medium size 1.053 mum PSP, reduced bacterial numbers. The number of neutrophils in BAL fluid was increased for all PSP-exposed groups after 24 h, and tended to be highest in the group exposed to 4.646 mum PSP. TNF-alpha, IL-1beta and MIP-2 were significantly increased in BAL fluid after exposure to the largest compared with the smallest PSP. In conclusion, activation of the innate immune system by chemical-free particles was size-dependent. Ultrafine and coarse particles appeared to activate cells by different mechanisms, which implies qualitative differences between the health effects of ambient air particulate matter size fractions.

A community-based long-term follow up of women undergoing obstetric fistula repair in rural Ethiopia.

OBJECTIVES: To assess urinary and reproductive health and quality of life following surgical repair of obstetric fistula. DESIGN: Follow-up study. SETTING: A newly established fistula clinic (2004) at Gimbie Adventist Hospital, a 71-bedded district general hospital in West Wollega Zone, in rural Western Ethiopia. POPULATION: Thirty-eight women (86%) of 44 who had undergone fistula repair were identified in their community. METHODS: Community-based structured interviews 14-28 months following fistula repair, using a customised questionnaire addressing urinary health, reproductive health and quality of life. MAIN OUTCOME MEASURES: Urinary health at follow up was assessed as completely dry, stress or urge incontinence, or fistula. King's Health Questionnaire was modified and used for the quality-of-life assessment. RESULTS: At follow up, 21 women (57%) were completely dry, 13 (35%) suffered from stress or urge incontinence and three (8%) had a persistent fistula. Surgery improved quality of life and facilitated social reintegration to a level comparable to that experienced before fistula development for both women who were dry and those with residual incontinence (P = 0.001). For women still suffering from fistula no change was seen (P = 0.1). Four women became pregnant following their surgery, among which there was one maternal death, three stillbirths and one re-occurrence of fistula. CONCLUSION: Community-based, long-term follow up after fistula repair succeeded in Western rural Ethiopia. Despite one-third still suffering stress or urge incontinence, the women reported improved quality of life and social reintegration after fistula closure.

Increased nuchal translucency with normal karyotype: a follow-up study of 100 cases supplemented with CGH and MLPA analyses.

OBJECTIVE: To evaluate whether high-resolution comparative genomic hybridization (HR-CGH) and subtelomeric and syndrome-specific multiplex ligation-dependent probe amplification (MLPA) would detect minor chromosomal aberrations in fetuses with increased nuchal translucency thickness (NT) and normal karyotype on conventional karyotyping. METHODS: Chorionic villus samples from 100 fetuses with NT > or = 99(th) percentile and normal G-banding analysis and MLPA for detection of aneuploidies for chromosomes 13, 18, 21, X and Y were included. Examinations were supplemented by HR-CGH and MLPA for syndromes and subtelomeric regions. Pregnancy outcome was followed up. RESULTS: Among 80 liveborn children who were followed up, three (4%) had syndromes involving mental retardation, including a case of Sotos syndrome caused by a de novo mutation. 15% of fetuses were lost during pregnancy due to abnormalities and termination. The rate of adverse outcome overall was 18%. HR-CGH and MLPA did not detect any chromosomal aberrations associated with the syndromes. CONCLUSION: The rate of adverse outcome was similar to levels recorded in the literature. Using CGH and MLPA did not increase the detection rate of genetic disease, which supports the current approach of repeated ultrasound examinations in these high-risk pregnancies.

Maternal levels of perfluoroalkyl substances (PFASs) during pregnancy and childhood allergy and asthma related outcomes and infections in the Norwegian Mother and Child (MoBa) cohort.

INTRODUCTION: Prenatal exposure to perfluoroalkyl substances (PFASs) has been inconsistently associated with asthma and allergic diseases and increased number of infections in early childhood. We examined the association of PFASs measured in pregnancy with childhood asthma, allergies and common infectious diseases in a prospective pregnancy cohort followed to age 7 years. MATERIAL AND METHODS: Six PFASs (out of 19 measured) with at least 80% of measurements above the limit of quantification (LOQ) in maternal plasma during pregnancy in two subcohorts of the Norwegian Mother and Child Cohort Study (MoBa) were analyzed in relation to health outcomes: perfluorooctane sulfonic acid (PFOS), acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), perfluoroundecanoic acid (PFUnDA), and perfluoroheptane sulfonic acid (PFHpS). Follow-up questionnaires were completed at 3 years by 1270 women and at 7 years by 972 women among the 1943 with pregnancy questionnaire and PFAS measures. Health outcomes included parent reports of child's symptoms or doctor diagnosed asthma and allergic conditions at age 7 years and parent-reported frequency of various infections at 3 and 7 years of age. Logistic and Poisson regression were used. The false discovery rate was controlled at 5%. Sensitivity analyses on gender were performed. RESULTS: Among the allergy and asthma outcomes, a statistically significant inverse association was seen between PFUnDA concentrations and ever having atopic eczema in girls. PFUnDA also tended to be inversely associated with both wheeze and asthma. For infections from 0 to 3 and 6 to 7 years, 11 significant positive associations were seen between PFASs and airways infections (bronchitis/pneumonia, throat infection, pseudocroup), ear infection and gastric flu/diarrhea; whereas 6 inverse associations were seen for pseudocroup, ear infections and urinary tract infections. The majority of the findings with respect to infectious diseases were found in girls only. DISCUSSION: With the exception of an inverse association between PFUnDA and eczema, and a tendency of a similar association for wheeze and asthma, maternal PFAS levels during pregnancy showed little association with asthma or allergy related outcomes. Findings from the present study suggest immunosuppressive effects of PFASs on airways infections, such as bronchitis/pneumonia and throat infections, as well as diarrhea/gastric flu. Our results indicate a possible role of gender in the PFAS-health outcome associations.

Dose reduction of coadministered 6-mercaptopurine decreases myelotoxicity following high-dose methotrexate in childhood leukemia.

High-dose methotrexate (HDM) given concurrently with oral 6-mercaptopurine (6 MP) may be followed by myelotoxicity, which may necessitate treatment interruption and thus interfere with the efficacy of the treatment of childhood acute lymphoblastic leukemia (ALL). Through inhibition of purine de novo synthesis and enhancement of the bioavailability, HDM may increase the incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6 MP.A total of 26 children diagnosed 3/1996-4/2001 with ALL received five courses of HDM (5 g/m(2)/24 h with leucovorin rescue) at 8 weeks intervals during their first year of maintenance therapy with oral methotrexate (20 mg/m(2)/week) and 6MP (75 mg/m(2)/day). The dose of oral 6MP was reduced to a median of 51% (75% range: 39-62%, maximum 74%) of the standard dose from 2 weeks prior to until 2 weeks after HDM, because the previous HDM had led to a thrombocyte nadir < or =60 x 10(9)/l and/or a neutrophil nadir < or =0.7 x 10(9)/l. The 6MP dose reductions raised the median thrombocyte nadir following HDM from 46 x 10(9)/l (range: 6-214) to 133 x 10(9)/l (range: 21-305; P<0.001) and the median neutrophil nadir from 0.5 x 10(9)/l (range: 0.0-1.4) to 0.9 x 10(9)/l (range: 0.2-3.2; P<0.001). The effect of 6MP dose reductions was not significantly related to risk group, gender, age, or thiopurine methyltransferase genotype. With 6MP dose reductions, the median duration of treatment interruption following HDM was reduced from 8 to 0 days (P < 0.001). The reduction of 6MP dosage during HDM can significantly reduce the risk of severe myelotoxicity and prevent treatment interruptions.

Polycyclic aromatic hydrocarbons, tobacco smoke, and epigenetic remodeling in asthma.

Environmental determinants including aerosolized pollutants such as polycyclic aromatic hydrocarbons (PAHs) and tobacco smoke have been associated with exacerbation and increased incidence of asthma. The influence of aerosolized pollutants on the development of immune dysfunction in asthmatics has been suggested to be mediated through epigenetic remodeling. Genome accessibility and transcription are regulated primarily through DNA methylation, histone modification, and microRNA transcript silencing. Epigenetic remodeling has been shown in studies to be associated with Th2 polarization and associated cytokine and chemokine regulation in the development of asthma. This review will present evidence for the contribution of the aerosolized pollutants PAH and environmental tobacco smoke to epigenetic remodeling in asthma.