First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B.

Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 × 10-8; odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10-5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 × 10-10; OR = 1.47; 95% CI, 1.38-1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 × 10-16; OR = 1.75; 95% CI, 1.64-1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% ± 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes.

Frequency and profile of Parkinson's disease prodromi in patients with malignant melanoma.

OBJECTIVE: The results of register studies suggest an association between Parkinson's disease (PD) and melanoma. We studied the frequency and profile of early markers of PD in patients with malignant melanoma. METHODS: 100 participants were enrolled in a prospective observational study, of whom 65 had a history of high-risk cutaneous (n=53) or uveal (n=12) melanoma (31 women; age, 61.2±14.9 years) and another 35 served as control participants (19 women; 54.6±20.5 years). Participants underwent assessments of motor function (Unified PD Rating Scale; keyboard tapping test), olfactory function, colour vision, depressive symptoms, the Non-Motor Symptoms Questionnaire, and transcranial brain sonography. Raters were blinded to the diagnosis and clinical data of study participants. RESULTS: Patients with melanoma showed increased frequency of substantia nigra hyperechogenicity and prodromal motor and non-motor features of PD, especially asymmetric motor slowing and apathy. Hyposmia and colour vision disturbance were, however, infrequent. Larger echogenicity of substantia nigra correlated with lower serum iron in patients with melanoma, similar to previously reported findings in PD, and independently from the earlier findings, with lighter skin pigmentation. Substantia nigra hyperechogenicity, combined with motor asymmetry or hyposmia, was present at baseline in all participants with mild or definite parkinsonism diagnosed after 1 year. Parkinsonism was specifically related to melanoma location at the sun-exposed skin of the head or neck. CONCLUSIONS: History of melanoma was associated with increased prevalence of prodromal markers of PD. Their predictive value needs to be established in long-term investigations. The similarity of serum iron characteristics found in patients with melanoma and PD deserves further research.

Rice-induced anaphylaxis: IgE-mediated allergy against a 56-kDa glycoprotein.

BACKGROUND: Although rice (Oryza sativa) is one of the most common cereals produced and consumed around the world, there have been only a few reports on immediate hypersensitivity reactions after ingestion of rice. Few clinical studies on rice allergy in Asia have been reported concerning rhinitis, asthma and atopic dermatitis. In this case study, we identify allergens presumably responsible for anaphylaxis after ingestion of rice in a German patient. METHODS: Prick-to-prick tests, determination of specific IgE and the basophil activation test (BAT) were performed to confirm IgE-mediated allergy. IgE reactivity was further analyzed by immunoblotting of protein extracts from cooked commercial rice products. Rice allergens were purified, subjected to N-terminal sequencing and characterized by IgE binding and IgE inhibition assays using additional sera from 8 subjects with sensitization to rice and/or a history of hypersensitivity symptoms after rice ingestion. RESULTS: Prick-to-prick tests were positive to raw and cooked rice (basmati rice and long-grain rice) and preparations of different rice extracts. Specific IgE against rice (f9) was 1.87 kU(A)/l. The BAT showed specific IgE-mediated activation of basophils after stimulation with rice extracts. Four IgE-reactive rice proteins with an apparent molecular weight of 49, 52, 56 and 98 kDa were identified. Interestingly, only binding to the 56-kDa glycoprotein was at least partially independent from cross-reactive carbohydrate determinants (CCD), whereas IgE binding to the other rice proteins was completely inhibited by pre-incubation with the CCD MUXF derived from bromelain. CONCLUSIONS: Yet unidentified high-molecular-weight allergens from rice seeds, predominantly a 56-kDa glycoprotein, seem to be responsible for anaphylaxis after consumption of rice in a German patient.

Wine allergy in a wine-growing district: tolerance induction in a patient with allergy to grape lipid-transfer protein.

BACKGROUND: : An IgE-mediated allergy against a lipid-transfer protein of grapes was the cause of repeated severe anaphylaxis in a patient after consumption of grapes, wine, and raisins. OBJECTIVE: : Although the patient was aware of her grape allergy, avoidance proved difficult and accidental anaphylaxis occurred. Furthermore, wine allergy in a wine-growing district means a non-negligible restriction of quality of life. METHODS: : Although there is little data on specific oral tolerance induction (SOTI) in lipid-transfer protein (LTP) allergy, SOTI with increasing doses starting from approximately 20 mg of grapes was done. For follow-up, skin tests, grape-specific IgE and IgG4, basophil activation tests, and immunoblotting were performed. RESULTS: : Within 3 days the patient reached tolerance to the daily maintenance dose of 20 g of grapes (about 3 grape pieces) without anaphylaxis symptoms. Two months later, a controlled challenge with a total of 66.5 mL of white wine was tolerated. Grape-specific IgE stayed stable at 2.37 kU/L (class 2) and grape-specific IgG4 was first detectable 21 months after SOTI. Prick-to-prick skin tests continued to be positive to grapes, to raisins, and to white and red wine. The basophil activation test still showed strong IgE-mediated activation of basophils after stimulation with grape extract. Immunoblotting still detected IgE binding to a 8-kDa protein. CONCLUSIONS: : We performed SOTI in a patient with severe IgE-mediated allergy against the LTP Vit v 1 of grapes and reduced the risk of anaphylaxis because of accidental intake of any kind of grapes. However, underlying mechanisms of SOTI and maintenance of the established tolerance are still not known.

Chromated metal products may be hazardous to patients with chromate allergy.

BACKGROUND: Hidden allergen exposure may contribute to persistence and relapse of chromate dermatitis. According to case reports, chromated metal products, such as screws, fittings, etc., may be relevant allergen sources for patients sensitized to chromate. OBJECTIVES: To examine concomitant patch test reactivity to potassium dichromate 0.5% petrolatum (pet.) and three different types of chromated metal rings. PATIENTS/METHODS: Patients with proven or suspected chromate allergy were patch tested with potassium dichromate 0.5% pet. and three different types of chromated metal rings (yellow, olive, and black). Hexavalent chromium Cr(VI) release from the patch tested rings was chemically analysed. RESULTS: Ninety-five patients were tested: 49/95 (52%) reacted to potassium dichromate and 25/95 (26%) reacted to black chromated rings. Reactions to chromated rings exclusively occurred in patients reacting to potassium dichromate. Of 20 patients with a strong reaction to potassium dichromate, 14 reacted to black chromated rings. These were shown to have a high Cr(VI) release. Only two patients reacted to the other chromated rings, which had a very low Cr(VI) release. CONCLUSIONS: Handling chromated metal products must be regarded a hazard to chromate-sensitive patients, in particular those with a strong sensitization.

Anaphylaxis to iodinated contrast material: nonallergic hypersensitivity or IgE-mediated allergy?

OBJECTIVE: Contrast material is generally well tolerated although approximately 1% of patients who receive low-osmolar nonionic contrast material will develop anaphylaxis symptoms. Because most anaphylactic reactions are mild and nonallergic, clinically mimicking immunoglobulin E (IgE)-mediated allergy, diagnostic skin testing has been discussed controversially in the past and prophylactic pretreatment drug regimens are recommended instead. In the past 6 years, all patients with contrast material-induced anaphylaxis have been subjected to allergologic diagnostic procedures to clearly differentiate allergic and nonallergic anaphylaxis. Thus the purpose of our study was to identify and differentiate IgE-mediated allergy and nonallergic contrast material-induced hypersensitivity. Furthermore, the objective of our diagnostic procedures was not only to identify the culprit contrast material but also to find alternative contrast material for future radiologic interventions. SUBJECTS AND METHODS: We evaluated 96 patients with anaphylaxis symptoms after contrast material application using standardized intradermal skin testing. In patients with positive skin tests, the IgE-mediated allergy was further evaluated with in vitro and challenge tests. RESULTS: In four patients (suffering from anaphylaxis grades 2 and 3) out of the 96 (4.2%), skin tests and basophil activation tests strongly suggested IgE-mediated allergy to the contrast materials iopromide (two patients), iomeprol, and iopentol. In two patients with allergies to iopromide and iomeprol, alternative nonionic monomer contrast materials were tolerated, as identified in controlled challenge tests with iopamidol and iopromide, respectively. CONCLUSION: The evaluation of patients with contrast material-induced anaphylaxis (at least those with anaphylaxis > or = grade 2) should always include appropriate skin tests ensuring that patients with an IgE-mediated allergy are not missed. Moreover, allergologic testing may identify a contrast material of the group of nonionic monomers that will be tolerated in future radiologic interventions.

Aminopenicillin-induced exanthema allows treatment with certain cephalosporins or phenoxymethyl penicillin.

OBJECTIVES: Aminopenicillin-induced exanthema poses a problem in the management of infectious diseases. Due to theoretically possible immunological cross-reactivity, all beta-lactam drugs, i.e. penicillins, penicillin derivatives and cephalosporins, are usually avoided. The available alternative antibiotics (macrolides, quinolones and glycopeptides) may be less effective, have more side effects, and their use increases medical costs. Moreover, their use contributes to the increasing bacterial resistance to antibiotics. The aim of the study is to demonstrate that patients with aminopenicillin-induced exanthema may receive specific beta-lactams for future antibiotic therapy. METHODS: Skin testing followed by oral challenges to identify beta-lactams that are tolerated by patients despite confirmed delayed-type non-immunoglobulin E (IgE)-mediated allergic hypersensitivity to aminopenicillins. RESULTS: Sixty-nine out of 71 patients (97.2%) with non-IgE-mediated allergic hypersensitivity to aminopenicillins tolerate cephalosporins without an aminobenzyl side chain such as cefpodoxime or cefixime and 51 patients (71.8%) also tolerate phenoxymethyl penicillin. CONCLUSIONS: The majority of patients with non-IgE-mediated allergic hypersensitivity to aminopenicillins do not cross-react to certain cephalosporins or phenoxymethyl penicillin. Skin and drug challenge tests can be helpful to determine individual cross-reactivity.

Early onset pauciarticular arthritis is the major risk factor for naproxen-induced pseudoporphyria in juvenile idiopathic arthritis.

Pseudoporphyria (PP) is characterized by skin fragility, blistering and scarring in sun-exposed skin areas without abnormalities in porphyrin metabolism. The phenylpropionic acid derivative group of nonsteroidal anti-inflammatory drugs, especially naproxen, is known to cause PP. Naproxen is currently one of the most prescribed drugs in the therapy of juvenile idiopathic arthritis (JIA). The prevalence of PP was determined in a 9-year retrospective study of children with JIA and associated diseases. In addition, we prospectively studied the incidence of PP in 196 patients (127 girls and 69 boys) with JIA and associated diseases treated with naproxen from July 2001 to March 2002. We compared these data with those from a matched control group with JIA and associated diseases not treated with naproxen in order to identify risk factors for development of PP. The incidence of PP in the group of children taking naproxen was 11.4%. PP was particularly frequent in children with the early-onset pauciarticular subtype of JIA (mean age 4.5 years). PP was associated with signs of disease activity, such as reduced haemoglobin (<11.75 g/dl), and increased leucocyte counts (>10,400/microl) and erythocyte sedimentation rate (>26 mm/hour). Comedications, especially chloroquine intake, appeared to be additional risk factors. The mean duration of naproxen therapy before the onset of PP was 18.1 months, and most children with PP developed their lesions within the first 2 years of naproxen treatment. JIA disease activity seems to be a confounding factor for PP. In particular, patients with early-onset pauciarticular JIA patients who have significant inflammation appear to be prone to developing PP upon treatment with naproxen.

Wine anaphylaxis in a German patient: IgE-mediated allergy against a lipid transfer protein of grapes.

BACKGROUND: IgE-mediated allergy to grapes has very rarely been reported in patients from the Mediterranean area. Recently, endochitinase 4 and a lipid transfer protein (LTP) have been identified as major allergens in grape-allergic patients who do not have an associated pollinosis. The purpose of this case study was to identify the allergens responsible for severe anaphylactic reactions after consumption of wine, fresh grapes and raisins in a German patient. METHODS: Prick-to-prick tests and the basophil activation test (BAT) were performed to confirm allergy. Specific IgE was further analyzed by immunoblotting and inhibition tests for the determination of crossreactivity. The IgE-binding protein was subjected to N-terminal microsequencing. RESULTS: Prick-to-prick tests were positive to fresh and cooked white and blue grapes, to raisins, to white and red wine, and to grape extract. Specific IgE against grapes (f259) was 2.43 kU/l (class 2). The BAT showed specific IgE-mediated activation of basophils after stimulation with grape extract. IgE binding to a 15-kDa protein was completely inhibited by pre-incubation with recombinant cherry LTP Pru av 3. N-terminal sequencing identified this 15-kDa protein as grape LTP Vit v 1. CONCLUSION: Our data show that sensitization to LTP can occur outside the Mediterranean area causing severe fruit allergy without association to pollinosis.

The role of lipopolysaccharide in T-cell responses following DNA vaccination.

Bacterial products, including lipopolysaccharide (LPS), are potential impurities in plasmid DNA vaccines. LPS has immunostimulatory properties even at exceedingly low concentrations through activation of Toll-like receptor 4 (TLR4). The potency of T-cell responses after vaccination was tested with DNA containing high LPS or depleted of LPS in TLR4-competent and TLR4-deficient mice. CD8(+) T-cell responses were readily induced in TLR4-deficient mice immunized with DNA depleted of LPS. LPS in DNA vaccines is not required for CD8(+) T-cell responses.

Redundant and alternative roles for activating Fc receptors and complement in an antibody-dependent model of autoimmune vitiligo.

Complement and Fc receptor (FcR)-positive cells mediate effector functions of antibodies. Antibody-dependent immunity against the melanosome membrane glycoprotein gp75/tyrosinase-related protein-1 (TYRP-1) of melanocytes leads to autoimmune hypopigmentation (vitiligo) in mice. Hypopigmentation occurred in mice deficient in activating FcR containing the common gamma subunit (Fc gamma R gamma(-/-)) and in mice deficient in the C3 complement component. Mice doubly deficient in both Fc gamma R gamma and C3 did not develop hypopigmentation, suggesting that complement and Fc gamma R formed redundant mechanisms. Following passive immunization with antibody, no further adaptive immune responses were required. Chimeric Fc gamma R gamma(-/-),C3(-/-) mice reconstituted with bone marrow from either Fc gamma R gamma(-/-) or C3(-/-) mice or adoptively transferred with Fc gamma R gamma(+/-) macrophages did develop antibody-mediated hypopigmentation. Thus, either complement or macrophages expressing activating Fc gamma R can independently and alternatively mediate disease in a model of autoimmune vitiligo.