Clinical Allergy and Immunology

 A bout of resistance-exercise induces acute changes in leukocyte counts  High-dose exertions appear to cause more rapid responses  Low-dose exertions appear to cause smaller, and or delayed responses  The timing of measures relative to the onset of exercise needs to be reported  A dose-response relationship appears to exist for resistance-exercise & leukocytes

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Fifty-four patients aged from 1 to 6 years with 22 previous wheezing attacks were prospectively followed for 3 months to assess the relation between allergen exposure, virus infections and wheezing episodes. Serum IgE was 22 SD above the normal in 31 patients. Skin prick tests with cat, dog and mite were positive in 19, 17 and 6 % of the patients, respectively. Pets in the homes were ram: one had a cat and none had a dog. Consequently, allergen levels in dust samples from the homes were low: major cat allergen, Fe1 d I 22 fig/g was detected in 4 96, dog allergens ~20.000 IU/g in 4 %, and a mite allergen, Der p I 22 fig/g in 10 56. Allergen exposure was not associated with the symptoms during the followup. Highest levels of allergens were detected in the homes of non-sensitized patients. Of the 73 wheezing episodes during the follow-up, 85 % were stated by the parents to be caused by an infection, and only 34 96 by an allergen exposure. Virus or Mycoplasma pneumoniae-infections were diagnosed in 29 (40 %) of the episodes. Tbe results suggest that proper allergen avoidance is feasible and that allergen induced wheezing may thus be minimized. The association of wheezing episodes with viral infections was confirmed.

BACKGROUNDThe aim of this study was to understand Australian donorsʼ and nondonorsʼ orientations toward 13 noncash incentives for blood and plasma donation and the associations between orientations and intention to donate (nondonors) and subsequent donation (donors).STUDY DESIGN AND METHODSA survey of 1028 donors and 1201 nondonors was conducted online and by telephone. Donors were randomly selected from the Australian Red Cross Lifeblood donor panel; nondonors were selected from randomly generated fixed line and mobile telephone numbers across Australia. Incentives were chosen to reflect a wide array of possible noncash incentives that might be introduced by blood donation organizations (BDOs). Differences between donors and nondonors, as well as other subgroups, were investigated.RESULTSOrientations toward most types of incentives were positive or neutral. No significant differences were observed between incentive orientations for whole blood versus plasma donations. Many subgroup...

RATIONALE: Reduced basophil histamine release is observed in patients treated with SCIT. We examined the effect of SCIT on intracellular protein concentrations of spleen tyrosine kinase (Syk) and SHIP-1, two key regulators of basophil releasability in the FcεRI-pathway. METHODS: We recruited patients with seasonal rhino-conjunctivitis (16 on SCIT for two years, 6 untreated allergic controls.). Blood basophils were purified both during offseason (spring) and the grass pollen season (summer). Purity of basophils (96.7%60.17%, mean 6 SEM) was assessed by flow cytometry (CD45 + , CD203c + , FcεRIa + ). Cell lysates were evaluated for Syk and SHIP-1 expression by quantitative Western blotting. Basophil activation test (BAT) was employed to assess allergen-specific releasability (log [grass pollen] required for half-maximal activation or LC 50 ). RESULTS: Basophil releasability (BAT) increased in untreated patients during pollen season (LC 50 -0.547 to-0.771, p5.04) while SCIT-treated patients maintained off-season releasability (-0.371 to -0.410, p50.46). There were no significant differences in offseason SHIP-1 levels in treated compared to untreated patients (p50.22). A fall in SHIP-1 levels was observed from offseason to the pollen season for untreated patients (31,17661,554 to 11,17162,251, p50.01) and treated patients showed a similar trend (45,249617,054 to 22,81764,819, p50.08). During the pollen season treated patients had elevated SHIP-1 levels compared to untreated patients (22,81764,819 vs. 11,17162,251, p50.03). We observed no significant changes in Syk expression. CONCLUSIONS: Natural allergen exposure in sensitized patients decreases basophil SHIP-1 predisposing them to enhanced releasability. Reduced basophil releasability and positive response to SCIT is significantly correlated with increased expression of SHIP-1, suggesting a new therapeutic approach.

RATIONALE: IL-9 is a Th 2 -cytokine implicated in allergic responses, but not yet investigated in gastrointestinal allergy. We hypothesize that IL-9 induces mastocytosis and increased intestinal permeability. METHODS: Intestinal permeability [mucosal to serosal paracellular flux of FITC-dextran and transcellular flux of HRP, and the inversely correlating transepithelial resistance (TER)] was measured using an Ussing Chamber system in wildtype (WT) and IL-9 intestinal transgenic (iFABP-IL-9-Tg) mice. Intestinal mast cell levels were determined by staining for chloroacetate esterase activity and serum levels of histamine and the mast cell activation marker, mouse mast cell protease-1 (mMCP-1), were measured using ELISA. To attenuate mast cell function, mice received intraperitoneal injections of 10 mg/kg cromolyn or PBS every 12 hours for 60 hours. RESULTS: Ectopic overexpression of IL-9 in the intestine was associated with intestinal mastocytosis (7.2060.327 vs 0.6860.075 mast cells/hpf; p<0.0001), elevated serum levels of mMCP-1 (41936905 vs 30.5612.0 ng/ml; p<0.02), and increased intestinal permeability (20646482 vs 2636100 ng/ml FITC-dextran, p<0.05; 65.7611.1 vs 6.862.0 ng/ml HRP, p<0.02; and 0.98260 vs 1.47360.054 kV/cm 2 , p<0.005) compared to WT mice. Cromolyn treatment of iFABP-IL-9-Tg mice reduced serum levels of mMCP-1 (13716211 vs 41936905 ng/ml, p<0.05) and histamine (169630 vs 484660 nM, p<0.008) compared to PBS treated mice. The reduction in mast cell mediators was associated with a significant decrease in intestinal permeability (498631 vs 20646482 ng/ml FITC-dextran, p<0.05; 18.4613.0 vs 65.7611.1 ng/ml HRP, p<0.05; and 1.5660.27 vs 0.98260 kV/cm 2 ). CONCLUSIONS: Collectively, these data establish that IL-9 overexpression in the intestine induces increased intestinal permeability, likely by a mast cell-dependent mechanism.

The significance of AhR signaling in immune regulation has been suggested, but its role in mast cells remains unknown. We hypothesized that AhR and its ligands may affect mast cells function and play an important role in the regulation of allergic diseases. METHODS: Mouse bone marrow-derived mast cells (BMMCs) were treated with several known AhR ligands including TCDD and FICZ. The levels of cytokines and mediators release in activated mast cells by IgE/Ag cross-linkage were analyzed. The in vivo effect was tested by passive cutaneous anaphylaxis (PCA). Reactive oxygen species (ROS) and intracellular calcium were detected by Flow cytometry. ERK and PKC phosphorylation was detected by Western blotting. RESULTS: Exposure of BMMCs to low-doses (< 10 nM) of AhR ligands significantly increased the levels of IL-13, degranulation, LTC 4 , and PCA response. Mechanistically, exposure of the cells to AhR ligands resulted in significantly increased levels of intracellular calcium and ROS, concomitant with enhanced activation of several signaling pathways involving ERK and PKC. Notably, the functional effects of AhR ligands could be reversed by the addition of an antioxidant, N-acetylcysteine, and calcium channel blockers. In addition, when BMMCs from AhR-null mice were analyzed, significant reductions in the numbers of BMMCs and in the levels of IL-3-induced proliferation were noted, as compared to those seen in wild-type mice. Mast cell deficiency was confirmed in various tissues and peritoneal cavity of AhR-null mice. CONCLUSIONS: These results thus provide evidence supporting critical roles of AhR signaling in maintaining the homeostasis, maturation and optimal activation of mast cells.

The Single Radial Haemolysis (SRH) assay is a serological method widely used for measuring antibodies against influenza viruses. Despite the broad application and recommendation by licensing authorities, the SRH assay has not been standardized. The aim of this study is to demonstrate how the SRH assay satisfies validation parameters of regulatory agencies in terms of specificity, precision, repeatability, intermediate precision, linearity, accuracy and robustness. This study shows that the SRH is a rapid, simple, reliable and reproducible assay, which requires only small volumes of serum samples and can be easily standardized.

The Single Radial Haemolysis (SRH) assay is a serological method widely used for measuring antibodies against influenza viruses. Despite the broad application and recommendation by licensing authorities, the SRH assay has not been standardized. The aim of this study is to demonstrate how the SRH assay satisfies validation parameters of regulatory agencies in terms of specificity, precision, repeatability, intermediate precision, linearity, accuracy and robustness. This study shows that the SRH is a rapid, simple, reliable and reproducible assay, which requires only small volumes of serum samples and can be easily standardised.

Background-The approach to the diagnosis of Severe Combined Immunodeficiency Disease (SCID) and related disorders varies among institutions and countries. Objectives-The Primary Immune Deficiency Treatment Consortium (PIDTC) attempted to develop a uniform set of criteria for diagnosing SCID and related disorders, and has evaluated the results as part of a retrospective study of SCID in North America. Methods-Clinical records from 2000 through 2009 at 27 centers in North America were collected on 332 children treated with hematopoietic cell transplant (HCT), enzyme replacement therapy (ERT) or gene therapy (GT) for SCID and related disorders. Eligibility for inclusion in the study and classification into disease groups were established by set criteria and applied by an expert review group. Result-Two hundred eighty-five (86%) of the patients were determined to be eligible and 47 (14%) were not eligible. Of the 285 eligible patients, 84% were classified as typical SCID; 13% were classified as leaky SCID, Omenn syndrome, or reticular dysgenesis; and 3% had a history of enzyme replacement or gene therapy. Detection of a genotype predicting a SCID phenotype was accepted for eligibility. Reasons for non-eligibility were failure to demonstrate either impaired lymphocyte proliferation or maternal T cell engraftment. Overall (n = 332) rates of testing were: proliferation to PHA 77%, maternal engraftment 35%, and genotype 79% (mutation identified in 62%). Conclusion-Lack of complete laboratory evaluation of patients prior to HCT presents a significant barrier to definitive diagnosis of SCID and related disorders and prevented inclusion of individuals in our observational HCT study. This lesson is critical for patient care as well as the design of future, prospective treatment studies for such children, since a well-defined and consistent study population is important for precision in outcomes analysis.

ASTERIA I was a 40-week, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of subcutaneous omalizumab as add-on therapy for 24 weeks in patients with chronic idiopathic urticaria/spontaneous urticaria (CIU/CSU) who remained symptomatic despite H 1 antihistamine treatment at licensed doses. Patients aged 12-75 years with CIU/CSU who remained symptomatic despite treatment with approved doses of H 1 antihistamines were randomized (1:1:1:1) in a double-blind manner to subcutaneous omalizumab 75 mg, 150 mg, or 300 mg or placebo every 4 weeks for 24 weeks followed by 16 weeks of followup. The primary end point was change from baseline in weekly itch severity score (ISS) at week 12. Among randomized patients (N ¼ 319: placebo n ¼ 80, omalizumab 75 mg n ¼ 78, 150 mg n ¼ 80, 300 mg n ¼ 81), 262 (82.1%) completed the study. Compared with placebo (n ¼ 80), mean weekly ISS was reduced from baseline to week 12 by an additional 2.96 points (95% confidence interval (CI): À 4.71 to À 1.21; P ¼ 0.0010), 2.95 points (95% CI: À 4.72 to À 1.18; P ¼ 0.0012), and 5.80 points (95% CI: À 7.49 to À 4.10; Po0.0001) in the omalizumab 75-mg (n ¼ 77), 150-mg (n ¼ 80), and 300-mg groups (n ¼ 81), respectively. The omalizumab 300-mg group met all nine secondary end points, including a significant decrease in the duration of time to reach minimally important difference response (X5-point decrease) in weekly ISS (Po0.0001) and higher percentages of patients with well-controlled symptoms (urticaria activity score over 7 days (UAS7) p6: 51.9% vs. 11.3%; Po0.0001) and complete response (UAS7 ¼ 0: 35.8% vs. 8.8%; Po0.0001) versus placebo. During the 24-week treatment period, 2 (2.9%), 3 (3.4%), 0, and 4 (5.0%) patients in the omalizumab 75-mg, 150-mg, 300-mg, and placebo groups, respectively, experienced a serious adverse event. Omalizumab 300 mg administered subcutaneously every 4 weeks reduced weekly ISS and other symptom scores versus placebo in CIU/CSU patients who remained symptomatic despite treatment with approved doses of H 1 antihistamines.

The possible effects of immunization on subsequent development of asthma and atopy remains a matter of controversy. Although some studies have suggested that immunization might increase the risk for atopic disease, a number of studies have found no association or have even reported a protective effect for immunization against atopy. Recent studies have provided evidence that ethnicity might affect the susceptibility to the immunomodulatory effects of vaccination. In this review the association between immunization and atopy and the effect of ethnicity on this association are briefly outlined. The focus will be particularly on BCG vaccination. (J Allergy Clin Immunol 2004;113:401-6.

The maxillary sinuses are the first sinuses form in the embryonic period and begin to be pneumatized from 4 th year of life. Sinusitis is a common disease in children and its on-time diagnosis and treatment is very important to prevent relevant side effects. Unfortunately, in some medical centers Waters' radiography is routinely prescribed for the diagnosis of sinusitis, regardless of the trend of sinuses evolution in children. The aim of this study was to evaluate the efficacy of Waters' radiography in diagnosis of children's sinusitis. This study was an observational, cross-sectional, and retrospective study. The samples included 180 of 0-12 years old children with sinusitis who had referred to Isfahan city clinics and the physicians had prescribed Waters' radiography for them. Required information was gathered via examination and enquiry into the patients' records. The radiographs were blindly surveyed by two radiologists (an oral and a general radiologist) and the data were statistically analyzed using the Chi-square and Kruskal -Wallis statistical tests. The coefficient of agreement between clinical signs and Waters' radiographic features in the samples was 52%.The greatest frequency rate of non -pneumatized sinuses was reported in the group of 3-years-olds and under. 30% of the maxillary sinuses were found to be normal in radiography (P=0.0005). No difference was observed between sinusitis radiographic results, based on the time of involvement (P=0.219) and sex (P=0.546).Cough (%89.4) and nasal purulent excretions (%53.2) were the most common clinical symptoms of sinusitis. However, clinical signs in 2 groups of with positive radiographic results and with normal sinuses showed no statistically significant difference (0.11<P<0.83). Discussion: Waters' radiography is recommended not to be routinely used for children for some reasons such as non -pneumatization of sinuses, especially in the group of 3-years-olds and under; non -observation of sinuses; and a high percent of normal radiographic findings in Waters' radiographs, in spite of the existence of sinusitis clinical signs, except for special cases.

RATIONALE: Obesity, as determined by BMI, has been shown to impact upon lung function in both asthmatic and non-asthmatic patients. We sought to determine the impact of adiposity upon lung function. METHODS: We evaluated 29 asthmatic and non-asthmatic obese adolescents (62% male, 77% African-American, average age 13years) who were taking part in a study of the mechanisms of airway inflammation. Dual-Energy X-ray Absorptiometry (DEXA) and Peak Expiratory Flow Rate (PEFR) were measured. Protocol had IRB approval. RESULTS: BMI, Total fat %, Trunk fat %, Ankle fat %, Total fat (kg), and Trunk fat (kg), sex, and race were not significantly different in the obese asthmatic and obese non-asthmatic groups. BMI did not correlate with the PEFR in the obese asthmatic and obese non-asthmatic groups (r 5 0.267, p 5 0.402; r 5 0.393, p 5 0.164, respectively). Total fat %, trunk fat %, and ankle fat % correlated in an inverse manner with PEFR in the obese asthmatic group (r 5 -0.618, p 5 0.043; r 5 -0.580, p 5 0.061; r 5 -0.675, p 5 0.023 respectively) but not in the obese non-asthmatic group. CONCLUSION: In adolescents, the degree of adiposity seems to correlate with lung dysfunction in obese asthmatics but not in obese non-asthmatics. Adiposity, may enhance pulmonary dysfunction in asthmatic patients, and may be a valuable indicator to study the contribution of obesity to airway inflammation Funding: NIH/NCRR general clinical research center; NIH center of biomedical research excilence COBRE.

• Etymologiquement, le terme épigénétique provient de l'association (épi-) signifiant ce qui est « sur » et génétique • L'épigénétique est l'étude des changements stables et héritables, de l'expression des gènes au cours des divisions cellulaires sans modification de la séquence primaire de l'ADN. • Ces changements épigénétiques sont tissuspécifiques, permettant la diversification cellulaire chez un même individu

Objectives Twenty-eight genetic loci are associated with serum urate levels in Europeans. Evidence for association with gout at most loci is absent, equivocal or not replicated. Our aim was to test the loci for association with gout meeting the American College of Rheumatology gout classification criteria in New Zealand European and Polynesian case-control sample sets. Methods 648 European cases and 1550 controls, and 888 Polynesian (Ma ¯ori and Pacific) cases and 1095 controls were genotyped. Association with gout was tested by logistic regression adjusting for age and sex. Power was adequate (>0.7) to detect effects of OR>1.3. Results We focused on 24 loci without previous consistent evidence for association with gout. In Europeans, we detected association at seven loci, one of which was the first report of association with gout (IGF1R). In Polynesian, association was detected at three loci. Meta-analysis revealed association at eight locitwo had not previously been associated with gout (PDZK1 and MAF). In participants with higher Polynesian ancestry, there was association in an opposing direction to Europeans at PRKAG2 and HLF (HLF is the first report of association with gout). There was obvious inconsistency of gout association at four loci (GCKR, INHBC, SLC22A11, SLC16A9) that display very similar effects on urate levels. Conclusions We provide the first evidence for association with gout at four loci (IGF1R, PDZK1, MAF, HLF). Understanding why there is lack of correlation between urate and gout effect sizes will be important in understanding the aetiology of gout.

Background: Epigallocatechin gallate (EGCG), a component of green tea catechin with the strongest biological activity, has been focused in recent years because of its anti-inflammatory and immunomodulatory activities. Dendritic cells (DCs) are professional antigen-presenting cells, capable of priming naive T cells, and play the key roles in the activation of T-cell-mediated immune responses. Objective: We aimed to investigate the effect of EGCG on human monocyte-derived DCs (MODCs) and, consequently, on the T-cell-mediated immune response. Methods: The induction of apoptosis, and the detailed phenotypic and functional changes of MODCs, generated by culture of peripheral blood monocytes in the presence of GM-CSF and IL-4, induced by EGCG was investigated and compared with the effects of dexamethasone. Results: Epigallocatechin gallate induced apoptosis and affected the phenotype of the developing DCs. The expressions of CD83, CD80, CD11c, and MHC class II, which are molecules essential for antigen presentation by DCs, were downregulated by EGCG. EGCG also suppressed the endocytotic ability of immature DCs, whereas dexamethasone-treated DCs had higher endocytotic ability than control DCs. Most importantly, mature DCs treated with EGCG inhibited stimulatory activity toward allogeneic T cells while secreting high amounts of IL-10. Conclusion: Epigallocatechin gallate induces immunosuppressive alterations on human MODCs, both by induction of apoptosis and suppression of cell surface molecules and antigen presentation.

Bowel wall fibrosis is associated with a complicated disease behavior in patients with Crohn's disease (CD). The quantitative assessment of fibrosis severity in CD-affected bowel can help clinical decision making. Our aim was to evaluate the feasibility, reliability, and reproducibility of ultrasound elasticity imaging (UEI) toward the assessment of ileal fibrosis in CD patients. Methods: Twenty-three consecutive patients with ileal or ileocolonic CD, elected for surgical resection of the terminal ileum, underwent bowel ultrasound and UEI. Twenty inflammatory CD patients without complications were enrolled as controls. Bowel wall stiffness was evaluated with UEI by means of color scale and quantitative strain ratio measurement. The severity of bowel wall fibrosis and inflammation were evaluated on histological sections by semiquantitative and quantitative image analysis and used as a reference standard. The UEI strain ratio measurement was significantly correlated with the severity of bowel fibrosis at both semiquantitative and quantitative histological image analysis: it was characterized by an excellent discriminatory ability for severe bowel fibrosis (area under the receiver operating characteristic curve: 0.917; 95% confidence interval, 0.788-1.000). UEI strain ratio measurements were characterized by an excellent interrater agreement. At multivariate analysis, bowel wall fibrosis proved the only independent determinant of the strain ratio. The ileal strain ratio of inflammatory CD patients was significantly lower than in operated CD patients with severe fibrosis. Conclusions: UEI can be used to assess ileal fibrosis in CD patients.

The epidemiology of Hymenoptera stings and allergic reactions varies in different studies. We investigated the prevalence of stings and allergic reactions in mid schoolchildren across Israel. METHODS: A modified version of the International Study of Asthma and Allergies in Childhood written questionnaire was administered to a national sample of 13-14 yr-old schoolchildren, across Israel. Questions regarding Hymenoptera stings, allergic reactions, and hospital attendance were added. The questionnaire was filled by the children themselves. The parents of the children received an explanatory letter with a reply slip that served as an informed consent. RESULTS: There were 10,021 complete questionnaires available for analysis. 5,644 children (56.3%) were stung at least once in their lifetime, 60% of them were stung more than once. Boys, Arab children, and rural residents were stung significantly more often (p<0.0001). 11.5% of the children reported having had large local reaction (LLR), 6.5% mild (cutaneous) systemic reaction (MSR) and 2.5% had moderate to severe systemic reaction (SSR). After adjustment for various potential risk factors, having been stung more than once and Arab population group, were significant risk factors for LLR, MSR,and SSR. LLR was strongly associated with SSR (OR 6.26, 95% CI,) and with MSR (OR 5.15, 95% CI,. The prevalence of stings is high among schoolchildren in Israel. More stings associated with more allergic reactions. Systemic reactions were reported higher than previously described in children and were associated with LLR. Arab children have more allergic reactions from all kinds, independent of the number of stings.

The cytokine of granulocyte macrophage colony stimulating factor (GM-CSF) is a glycoprotein, which is synthesized in the female reproductive tract and has embryonic trophic effect in mammals. The objective of this study was to examine the optimal dosage of GM-CSF to improve the mouse embryo development in vitro. To collect two and eight cells embryos, the pregnant NMRI mice were sacrificed by cervical dislocation at 48 h and 72 h post hCG injections, respectively. The embryos were cultured randomlly in T6 medium supplemented with 5 mg /ml bovine serum albumin (BSA) and 0, 2, and 10 ng / ml human rGM-CSF. The data of blastocyst formation and hatching in different groups of embryo culture were compared by chi-square analysis. The results showed that the developmental rates of 2 and 8 cells embryos to hatching blastocyst in the presence of 2 ng/ml of GM-CSF their control groups (51.5% and 49.7%, respectively) were more than those in the other groups, but insignificant. It seems more researches are necessary to confirm this suggestion that the GM-CSF with 2 ng/ml concentration may have a better potential, not only to enhance the developmental rates of 2 and 8 cells embryos but also for decreasing the degeneration of those embryos.

RATIONALE: Birch, alder, hazel, and oak are members of the birch homologous group based on IgE cross-reactivity to the major allergen Bet v 1. Treatment effects of tree sublingual immunotherapy (SLIT)tablets containing standardized birch pollen extract in participants with birch pollen-induced allergic rhinitis with or without conjunctivitis (AR/C) were evaluated during alder/hazel and oak pollen seasons. METHODS: In a randomized, multinational, double-blind trial (EudraCT-2015-004821-15), 634 participants (12-65 years) with birch pollen-induced AR/C with or without asthma received daily tree SLITtablets (12 SQ-Bet) or placebo before and during tree pollen season (TPS; start of alder/hazel pollen season through birch pollen season). Rescue medication was allowed. The primary endpoint was the total combined score (TCS; sum of rhinoconjunctivitis daily symptom score [DSS] and daily medication score [DMS]) during birch pollen season. TCS, DSS, and DMS during alder/hazel and oak pollen seasons and the continuous TPS (all days during TPS regardless of pollen counts) were analyzed post-hoc. RESULTS: Relative improvements in TCS with tree SLIT-tablets versus placebo were 39.6%, 29.7%, and 36.0% during birch, alder/hazel, and oak pollen seasons, respectively, and 35.0% for continuous TPS (all p≤0.002). Relative improvements in DSS versus placebo were 36.8%, 26.0%, and 31.6% during birch, alder/hazel, and oak pollen seasons, and 31.6% for continuous TPS (all p≤0.003) and in DMS were 49.2%, 43.8%, 45.9%, and 45.3%, respectively (all p≤0.002). CONCLUSIONS: Improvements with tree SLIT-tablets versus placebo during alder/hazel and oak pollen seasons showed internal consistency across seasons and support the clinical relevance of the immunologic crossreactivity between birch pollen homologous allergens.

RATIONALE: Introduction of baked milk (BM) is a mainstay in the management of cow's milk allergy. We sought to characterize predictors of BM tolerance and progression to baked cheese and direct milk among patients undergoing BM oral food challenges (OFC). METHODS: 126 patients challenged to BM from 2009-2011 were reviewed. OFC success was defined as consumption of ¼ cup BM. Logistic regression was performed utilizing milk-IgE level (log-transformed), age, gender, duration of follow-up, and OFC outcome to determine predictors of subsequent milk intake. RESULTS: 99 patients (4 months-18 years) old were included. Median duration of follow-up was 51 months (range 1.9-85 months). 65% passed the BM OFC. Among those failing, 91% were permitted to introduce specified quantities of BM. Of those passing, 75% progressed to unlimited BM or more, 61% advanced to baked cheese or more, and 38% advanced to direct milk, compared to 48%, 40%, and 26% of those failing the BM challenge (p50.004,0.046, and 0.234, respectively). Milk-IgE was significantly associated with OFC outcome (OR 0.19, p50.001) and progression to unlimited BM (OR 0.35, p50.046) or baked cheese (OR 0.38, p50.05) but not direct milk (OR 0.96, p50.16). Patients with milk-IgE >10kU/L were less likely to tolerate unlimited BM (10% vs 54%, p50.015), baked cheese (8% vs 45%, p50.04), or direct milk (4% vs 29% p50.06). Gender, duration of follow-up, and age were not significant predictors. CONCLUSIONS: OFC outcome and milk-IgE were the most important predictors of persistent tolerance to BM or more concentrated forms of milk.

RATIONALE: There is not a published case report describing a common variable immunodeficiency (CVID) patient presenting with pigmented villonodular synovitis (PVNS). Commonly, PVNS presents in the knee or hip. Presentation with ankle involvement is much rarer, with only a few such cases reported. Progression to bilateral ankle involvement appears to have not been previously documented. METHODS: 27 year old female with CVID and clinical features of McCune-Albright Syndrome developed PVNS with bilateral ankle involvement. Physical examination showed caf e au lait spots, short stature and round facies. Fibrous dysplasia of the skull and long bones was notable on imaging. We explored the possibility of an immunologic connection between these disease states through a review of literature, laboratory results and imaging studies. RESULTS: Routine karyotype and genetic testing of the GNAS locus were normal. Two chromosomal microarray analyses have showed a 743.8 kb interstitial gain at 12p13.33 gene locus. PHA lymphocyte stimulation testing was normal. B and T cell counts were normal at 500/mcL and 356/ mcL respectively. NK cell count was low at 60/mcL with normal NK cell function. Serum immunoglobulins showed low IgA of 32 mg/dL, normal IgM of 43 mg/dL and IgG of 992 mg/dL on weekly subcutaneous immunoglobulin. CONCLUSIONS: A defect at the 12p13.33 locus may cause the phenotype of CVID and McCune-Albright syndrome, with PVNS.

Background: Allergic disease is the most frequent chronic health issue in children and has been linked to early-life gut microbiome dysbiosis. Many lines of evidence suggest that microbially derived short-chain fatty acids, and particularly butyrate, can promote immune tolerance. Objective: We sought to determine whether bacterial butyrate production in the gut during early infancy is protective against the development of atopic disease in children. Methods: We used shotgun metagenomic analysis to determine whether dysbiosis in butyrate fermentation could From a the

-Eosinophils -Airway hyperresponsiveness -Serum immunoglobulin -Lung edema Inflammation Resolution LTD 4 CysLT1 MCTR, maresin conjugate in tissue regeneration, LTD 4 , leukotriene D 4 ; Ova, ovalbumin; HDM, house dust mite MCTRs Reduce Leukotrienes' Pro-phlogistic Lung Responses MCTR3 MCTR1 MCTR2 MCTR3 Human airways in precision cut lung sections Allergic Airway Responses (Ova or HDM) MCTR3 MCTR2 MCTR1 13S,14S-epoxy-maresin 14S-hydroperoxy-intermediate DHA LOX (14S-lipoxygenation) GSTM4 or LTC4S GGT DPEP MCTR biosynthetic pathway Background: Cysteinyl leukotrienes (CysLTs) are potent prophlogistic mediators in asthmatic patients; however, inhibition of CysLT receptor 1 is not a consistently effective treatment, suggesting additional regulatory mechanisms. Other cysteinyl-containing lipid mediators (LMs) derived from docosahexaenoic acid, namely maresin conjugates in tissue regeneration (MCTRs), were recently discovered. Therefore their production and actions in the lung are of considerable interest. Objective: We sought to determine MCTR production, bioactions, and mechanisms in the human lung and in patients with experimental allergic airway inflammation. Methods: LM metabololipidomic profiling of the lung was performed by using liquid chromatography with tandem mass spectrometry. Donor-derived human precision-cut lung slices were exposed to leukotriene (LT) D 4 , MCTRs, or both before determination of airway contraction. The actions of exogenous MCTRs on murine allergic host responses were determined in the setting of ovalbumin-and house dust mite-induced lung inflammation. Results: Lipidomic profiling showed that the most abundant cysteinyl LMs in healthy human lungs were MCTRs, whereas CysLTs were most prevalent in patients with disease. MCTRs blocked LTD 4 -initiated airway contraction in human From a the Pulmonary and Critical Care Medicine

High consumption of fruits and vegetables has been associated with a lower risk of pancreatic cancer in many case-control studies. However, cohort studies on this relationship are limited and do not support an association. We examined the associations of overall consumption of fruits and vegetables and consumption of certain subgroups of fruits and vegetables with the incidence of pancreatic cancer among 81,922 women and men in the Swedish Mammography Cohort and the Cohort of Swedish Men. Hazard ratios (HR) with 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models. During an average follow-up of 6.8 years (1998)(1999)(2000)(2001)(2002)(2003)(2004), 135 incident pancreatic cancer cases were diagnosed. After adjustment for age and other risk factors for pancreatic cancer, the HRs for the highest compared with the lowest category of intake were 1.13 (95% CI, 0.66-1.94) for total fruits and vegetables, 1.10 (95% CI, 0.64-1.88) for total fruits, and 1.08 (95% CI, 0.63-1.85) for total vegetables. Among specific subgroups of fruits and vegetables, a nonsignificant inverse association was observed with cruciferous vegetable consumption (z3 servings/wk versus <1 serving/wk: HR, 0.70; 95% CI, 0.43-1.13). Cabbage consumption was associated with a statistically significant lower risk of pancreatic cancer (z1 serving/wk versus never consumption: HR, 0.62; 95% CI, 0.39-0.99). Findings from this prospective study do not support a relationship of overall fruit and vegetable consumption with pancreatic cancer risk. The association between consumption of cruciferous vegetables and pancreatic cancer risk warrants further investigation. (Cancer Epidemiol Biomarkers Prev 2006;15(2):301 -5)

ELISA and by multiplex array using a single universal allergen standard containing purified natural allergens. RESULTS: Linear regression analysis showed a highly significant quantitative correlation between the multiplex array and ELISA for each of the allergens: R 2 values >0.90, p<0.001 for all allergens. The limits of detection of the multiplex array are an order of magnitude greater than ELISA, <0.1 ng/mL, and interassay CVs are less than 20%. CONCLUSIONS: The simultaneous quantification of multiple allergens in a high throughput multiplex array has been developed. The array will be applicable to large population studies where the assessment of multiple allergens is required. The array will allow for greater efficiency, reproducibility and standardization in the measurement of indoor allergens.

The nickel and cobalt disperse alloy deposits of five different compositions were obtained by electrodeposition on Cu substrates in the galvanostatic regime from an ammonium sulfate-chloride solution. The effect of cathodic current density and Ni2+/Co2+ ions concentration ratio in the electrolyte on the composition, microstructure, morphology and mechanical properties of Ni–Co alloys were investigated. Conditions for formation of nanostrustured disperse deposits and surface roughness was determined by 3D SEM reconstruction of the specimen surface. It was established that formation of the disperse deposits with highly developed structures is favored from bath with equal Ni2+/Co2+ ions concentration ratio in the electrolyte. Cathodic polarization diagrams determined for all investigated alloys have shown shift of the cathodic potential for alloy deposition to the more negative values with increasing Ni2+/Co2+ ions concentration ratio in the electrolyte. An increase of in the cobalt co...

Immune Biomarker Reference Range Estimation for Healthy Paediatric Patients in South Africa Steve Bicko Cygu Department of Mathematical Sciences, University of Stellenbosch, Private Bag X1, Matieland 7602, South Africa. Thesis: MSc. (Mathematics) March 2017 Understanding and quantifying human peripheral blood T-lymphocyte immunophenotypes is necessary for the diagnosis and treatment of immune and haematological disorders. This is only possible if comparison to control-data from healthy subjects is available for all the biomarkers of interest. Historical empirical studies in industrialized countries have described normal reference ranges for such biomarkers in children by grouping particular age ranges into ‘age-blocks’. Since such markers change with age this has resulted in a loss of precision in determining whether patients that lie close to the limits of age-ranges are normal or not. Previous studies have relied on fitting single exponential models to such data, which makes the s...

The impact of baseline HIV-1 reverse transcriptase (RT) polymorphisms on response to first-line modern HAART containing tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) was evaluated. The impact of each RT polymorphism on virological success (VS) was evaluated in 604 HIV-1 subtype B-infected patients starting TDF+FTC-containing HAART. TDF and FTC antiviral activity was also tested in PBMCs infected by mutagenised HIV. Structural analysis based on docking simulations was performed. A98S was the only mutation significantly correlated with an increased proportion of patients achieving VS at 24 weeks (94.0% vs. 84.3%; P=0.03). Multivariate regression and Cox model analyses confirmed this result. At concentrations close to the minimal concentration achieved in patient plasma, TDF and FTC exhibited higher potency in the presence of A98S-mutated virus compared with wild-type (IC90,TDF, 8.6±1.1 vs. 19.3±3.5nM; and IC90,FTC, 12.4±7.7 vs. 16.8±9.8nM, respectively). The efficacy of ...

Background: Epigenetic signatures in the nasal epithelium, which is a primary interface with the environment and an accessible proxy for the bronchial epithelium, might provide insights into mechanisms of allergic disease. Objective: We aimed to identify and interpret methylation signatures in nasal epithelial brushes associated with rhinitis and asthma. Methods: Nasal epithelial brushes were obtained from 455 children at the 16-year follow-up of the Dutch Prevention and Incidence of Asthma and Mite Allergy birth cohort study. Epigenome-wide association studies were performed on children with asthma, rhinitis, and asthma and/or rhinitis (AsRh) by using logistic regression, and the top results were replicated in 2 independent cohorts of African American and Puerto Rican children. Significant CpG sites were related to environmental exposures (pets, active and passive smoking, and molds) during secondary school and were correlated with gene expression by RNA-sequencing (n 5 244). Results: The epigenome-wide association studies identified CpG sites significantly associated with rhinitis (n 5 81) and AsRh (n 5 75), but not with asthma. We significantly replicated 62 of 81 CpG sites with rhinitis and 60 of 75 with AsRh, as well as 1 CpG site with asthma. Methylation of cg03565274 was negatively associated with AsRh and positively associated with exposure to pets during secondary school. DNA methylation signals associated with AsRh were mainly driven by specific IgE-positive subjects. DNA methylation related to gene transcripts that were enriched for immune pathways and expressed in immune and epithelial cells. Nasal CpG sites performed well in predicting AsRh. Conclusions: We identified replicable DNA methylation profiles of asthma and rhinitis in nasal brushes. Exposure to pets may affect nasal epithelial methylation in relation to asthma and rhinitis. (

Sleep disorders in children are a significant health issue that can affect their development and quality of life. One factor that is suspected to contribute to sleep disturbances is food allergies. This article reviews the connection between food allergies and sleep disorders in children, focusing on the underlying cellular immunopathophysiology, clinical manifestations, and management through the Oral Food Challenge (OFC) procedure. A deeper understanding of this mechanism is crucial for accurate diagnosis and appropriate therapy to improve children's quality of life. Food allergies are an abnormal immune response to specific proteins in foods, which can affect various organ systems, including the central nervous system. Some studies suggest that children with food allergies are at a higher risk of developing sleep disorders compared to children without allergies. These sleep disorders can manifest as difficulty falling asleep, frequent nighttime awakenings, or non-restorative sleep. Sleep disorders in children can negatively impact their concentration, mood, and daily behavior. Therefore, it is essential to understand the relationship between food allergies and sleep disorders, as well as the underlying immunopathophysiological mechanisms, to provide effective management and improve children's quality of life.

Sleep disorders in children are a significant health issue that can affect their development and quality of life. One factor that is suspected to contribute to sleep disturbances is food allergies. This article reviews the connection between food allergies and sleep disorders in children, focusing on the underlying cellular immunopathophysiology, clinical manifestations, and management through the Oral Food Challenge (OFC) procedure. A deeper understanding of this mechanism is crucial for accurate diagnosis and appropriate therapy to improve children's quality of life. Food allergies are an abnormal immune response to specific proteins in foods, which can affect various organ systems, including the central nervous system. Some studies suggest that children with food allergies are at a higher risk of developing sleep disorders compared to children without allergies. These sleep disorders can manifest as difficulty falling asleep, frequent nighttime awakenings, or non-restorative sleep. Sleep disorders in children can negatively impact their concentration, mood, and daily behavior. Therefore, it is essential to understand the relationship between food allergies and sleep disorders, as well as the underlying immunopathophysiological mechanisms, to provide effective management and improve children's quality of life.

Headaches and migraines are common complaints among adults. Many chronic migraine cases are treated with pain relievers without investigating their underlying causes. One often overlooked trigger is food allergy. Food allergic reactions do not always manifest through skin or gastrointestinal symptoms but can present as neurological manifestations such as headaches. This article aims to explain the connection between food allergies and headaches and migraines in adults, diagnosis through Oral Food Challenge (OFC), and management focusing on the elimination of trigger foods rather than merely symptomatic treatments.

Recurrent Aphthous Stomatitis (RAS) adalah kondisi inflamasi kronis berulang di mukosa mulut yang ditandai dengan munculnya ulkus superfisial nyeri, berbatas tegas, dan dikelilingi area eritema. Meskipun penyebab pasti RAS belum diketahui, bukti klinis dan epidemiologis menunjukkan hubungan signifikan antara RAS dan alergi makanan. Reaksi imun terhadap protein makanan tertentu dapat memicu lesi aftosa, terutama pada individu yang mengalami sensitisasi terhadap susu sapi, telur, gandum, dan makanan laut. Pendekatan diagnosis melalui eliminasi makanan dan oral food challenge (OFC) menunjukkan peran penting alergi makanan dalam patogenesis RAS. Artikel ini bertujuan mengeksplorasi hubungan imunopatogenetik dan klinis antara RAS dan alergi makanan, serta mendiskusikan strategi penanganan berbasis eliminasi makanan dan OFC.

Sialorrhea atau air liur berlebihan sering kali dianggap sepele, tetapi pada anak usia besar, kondisi ini bisa menjadi tanda gangguan sistemik yang perlu dicermati. Salah satu penyebab yang kerap diabaikan adalah hipersensitivitas saluran cerna akibat alergi makanan. Artikel ini membahas hubungan antara alergi makanan dan sialorrhea, termasuk anatomi dan fisiologi kelenjar ludah, tanda dan gejala, serta pendekatan diagnostik dan penanganan melalui eliminasi makanan provokatif dengan metode Oral Food Challenge (OFC).

Alergi makanan telah diakui sebagai faktor yang berpotensi berkontribusi pada berbagai kelainan saluran napas atas, termasuk hipertrofi adenoid pada anak-anak. Hipertrofi adenoid dapat memperburuk gangguan pernapasan dan meningkatkan risiko infeksi telinga berulang. Penanganan alergi makanan yang tepat, termasuk dengan pendekatan oral food challenge (OFC), lebih akurat dibandingkan pemeriksaan laboratorium serologi seperti tes panel IgE spesifik. Penggunaan obat antialergi hanya memberikan perbaikan gejala sementara tanpa mengatasi penyebab dasar. Pemahaman hubungan ini sangat penting untuk diagnosis dan terapi yang lebih efektif.

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

T-lymphocytes express not only the cell membrane calcium ORAI1 but also voltage-dependent Cav1 channels. In excitable cells, these channels are composed of the ion forming pore α1 and auxiliary subunits (β and α2δ) needed for proper trafficking and activation of the channel. We previously disclosed the role of Cav1.2 α1 in mouse and human Th2- but not Th1-cell functions and showed that knocking-down Cav1 α1 prevents experimental asthma OBJECTIVE: We investigated the role of β and α2δ auxiliary subunits on Cav1 α1 function in Th2 lymphocytes and on the development of acute allergic airway inflammation. We used antisense oligonucleotides (CavβAS) to knockdown Cavβ and gabapentin, a drug that binds to and inhibits α2δ1 and α2δ2, to test their effects on Th2 functions and their capacity to reduce allergic airway inflammation. Mouse and human Th2-cells express mainly Cavβ1, β3 and α2δ2 subunits. CavβAS reduces TCR-driven calcium responses and cytokine production by mouse and human Th2, w...

Severe cutaneous adverse reactions (SCARs) are very rare but clinically important diseases because of their significant morbidity and mortality. Causative agents and susceptible subjects may be different according to countries. However, little has been known about SCARs in Korea. METHODS: Medical records of patients with SCARs treated in Seoul National University Hospital from 2005 to 2010 were retrospectively reviewed. RESULTS: During the study period, patients with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) were 58 and those with drug reaction with eosinophilia and systemic symptoms (DRESS) were 39. Mortality rates were 6.9% and 5.1% among patients with SJS/ TEN and DRESS respectively. The most frequently involved drugs were allopurinol (SJS/TEN: 11.6%, DRESS: 35.7%) and carbamazepine (SJS/ TEN: 11.6%, DRESS: 16.2%). Cutaneous manifestations were found in most patients with SJS/TEN (98%) and DRESS (84%). Mucosal involvements were more prevalent in SJS/TEN (84%) compared with DRESS (30%). Lymphadenopathy was more frequently found in DRESS compared SJS/TEN (18.9% vs. 5.8%). Although eosinophilia and organ involvement were major features of DRESS (78.9% and 87.2%), considerable number of patients with SJS/TEN also had these phenotypes (34.5% and 66.1%). Seasonal patterns were observed in the development of SCARs (31.4% of SJS/TEN in winter, 47.1% of DRESS in spring). The outcome was not different according to treatment modalities (conservative management, systemic corticosteroid, and intravenous immunoglobulin). CONCLUSIONS: Among patients with SCARs, mortality rate was 6.2% and the most common causative agents were allopurinol and carbamazepine. Overlapped features of SJS/TEN and DRESS were frequently observed.

The underlying mechanism of successful immunotherapy has not been fully identified. The aim of the present work was to study the potential mechanisms of ASIT in bronchial asthma. METHODS: thirty asthmatic subjects and 10 healthy controls were subjected to the following assays (before & one year after immunotherapy): flowcytometric analysis of CD95 (Fas) on T-lymphocytes in fresh blood samples, serum total IgE, IL-4, and IFN-gamma. RESULTS: After one year of immunotherapy a significant increase of IFN-gamma was evident (p < 0.001), with concomitant reduction of serum IgE and IL-4 (p 5 0.0001) indicate restoring Th1/Th2 balance. A statistically non significant down-regulation of Fas expressed on T cells (p 5 0.4) was demonstrated which could contribute in part to resolution of airway allergic inflammation and enhanced delayed T-cell apoptosis. CONCLUSIONS: Immunotherapy is a multifaceted effective modality in controlling asthma symptoms and allergic inflammation through skewing the cytokine profile to restore the balance between Th1/Th2 as evidenced by significant increase of IFN-gamma and decreased T-cell Fas expression.

RATIONALE: Eosinophilic esophagitis (EoE) can be treated with various combinations of a proton pump inhibitor (PPI), topical steroid (TS), and elimination diet (D). This study assessed which treatments patients were using and sought to determine patient/caregiver ratings of EoE symptoms, response to treatment, and tolerability of therapy. METHODS: After IRB approval, patients with biopsy proven EoE followed in our allergy clinic were selected for a questionnaire based phone survey and chart review. Severity of symptoms before and after treatment and overall response to treatment were rated on a scale from 0-5, with 0 being lowest. RESULTS: Survey data were obtained for 79 out of 138 patients (ages 9-76 yrs, mean 36 yrs 6 20.1). Dysphagia (76%), food impaction (63%), and regurgitation (46%) were the most common moderate/severe pre-treatment symptoms, with these decreasing to 11%, 14%, and 8% post-treatment, respectively. Overall, moderate/severe symptoms decreased by 82% with treatment. The most commonly reported treatment regimens were PPI+TS (27%), PPI alone (22%), and PPI+TS+D (15%). Topical steroid containing treatment groups as a whole had significantly higher treatment response ratings than the non-topical steroid containing treatment groups (average ratings 4.20/5 vs 3.46/5, p50.003). Only 0.07% of patients on TS reported side effects (oral thrush or dryness), 0.05% of patients on a PPI reported side effects (GI symptoms, rash), while 28% rated their EoE diet impossible or near impossible to follow. CONCLUSIONS: Overall, responses to EoE treatment were good. Use of a topical steroid was associated with significantly higher treatment response ratings and very few side effects.