[Allergological diagnostics and current allergens in occupational dermatology]. / Allergologische Diagnostik und aktuelle Allergene in der Berufsdermatologie.

A broad spectrum of various substances may cause occupational allergic contact dermatitis. Often, it is difficult to identify potentially or truly relevant allergens at the workplace. Therefore, the consulting physician must have a comprehensive knowledge of possible allergens in different occupations to perform specific diagnostics and to initiate efficient secondary prevention by allergen avoidance. In this review, we give some practically relevant general comments on patch testing in occupational dermatitis, followed by a discussion of important occupational allergens in those occupational groups most frequently affected by occupational dermatitis. Finally, recommendations on which allergens should be tested in the respective occupational groups are given or reported from the literature.

Cellular in vitro assays in the diagnosis of Hymenoptera venom allergy.

BACKGROUND: The current diagnostic procedures of anaphylactic reactions to hymenoptera stings include intradermal tests, venom-specific IgE (sIgE) and possibly sting challenge tests. Sometimes, the culprit insect remains unidentified. The usefulness of the cellular assays CAST-ELISA and Flow-CAST in the management of hymenoptera venom allergy was investigated. METHODS: 134 patients with systemic reactions after a yellow jacket wasp and/or honey bee sting and 44 healthy controls underwent skin tests, as well as determination of sIgE (CAP-FEIA), leukocyte sulfidoleukotriene release (CAST-ELISA) and basophil CD63 expression (Flow-CAST) upon insect venom stimulation. The clinical diagnosis based on the history alone served as reference. Sensitivity, specificity, and positive and negative predictive value of all methods were compared. Concordance and correlations among methods were calculated. RESULTS: Sensitivity and specificity of all in vitro tests were consistently high. The combination of all tests (skin tests, sIgE, combined cellular assays) yielded a positive predictive value of 100% for both venoms, if all 3 were positive, and a negative predictive value of 100%, if at least 1 test was positive. Relative specificities were considerably higher for the cellular assays (honey bee: CAST 91.1%, Flow-CAST 85.7%; yellow jacket wasp: CAST 98.4%, Flow-CAST 92.1%) and allow the detection of the culprit insect in patients with reactivity to both insects. The concordance between methods was good. There is no correlation between severity of clinical reaction and cellular assays. CONCLUSION: CAST-ELISA and Flow-CAST are valuable additional diagnostic tools for establishing the true culprit insect in patients with unclear clinical history or sensitization to both insects.

Quantitative patch and repeated open application testing in methyldibromo glutaronitrile-sensitive patients.

Contact allergy to methyldibromo glutaronitrile (MDBGN), often combined with phenoxyethanol (PE) (e.g., Euxyl K 400), increased throughout the 1990s in Europe. Consequently, in 2003, the European Commission banned its use in leave-on products, where its use concentration was considered too high and the non-sensitizing use concentration as yet unknown. The 2 objectives of the study are (a) to find a maximum non-eliciting concentration in a leave-on product in MDBGN/PE-sensitized patients, which could possibly also be considered safe regarding induction and (b) to find the best patch test concentration for MDBGN. We, therefore, performed a use-related test (ROAT) in patients sensitized to MDBGN/PE (n = 39) with 3 concentrations of MDBGN/PE (50, 100 and 250 p.p.m. MDBGN, respectively). A subset of these patients (n = 24) was later patch-tested with various concentrations (0.1, 0.2, 0.3 and 0.5% MDBGN, respectively). 15 patients (38%, 95% confidence interval (CI) = 23-55%) had a negative and 24 (62%; 95% CI = 45-77%) a positive overall repeated open application test (ROAT) result. 13 reacted to the lowest (50 p.p.m.), 8 to the middle (100 p.p.m.) and 3 to the highest concentration (250 p.p.m.) only. In those 13 reacting to the lowest ROAT concentration, dermatitis developed within a few days (1-7). The strength of the initial and the confirmatory patch test result, respectively, and the outcome of the ROAT were positively associated. Of the 24 patients with a use and confirmatory patch test, 15 reacted to 0.1% MDBGN, 16 to 0.2%, 17 to 0.3% and 22 to 0.5%. With the patch test concentration of 0.5%, the number of ROAT-negative patients but patch-test-positive patients increases considerably, particularly due to + reactions. A maximum sensitivity of 94% (95% CI = 70-100%) is reached with a patch test concentration of 0.2%, and is not further improved by increasing the concentration. However, the specificity decreases dramatically from 88 (95% CI = 47-100%) with 0.2% to a mere 12.5% (95% CI = 0-53%) with 0.5%. It can be concluded (a) that for MDBGN 0.2% is very likely the best patch test concentration and (b) that 50 p.p.m. in a leave-on product can elicit contact dermatitis in sensitized persons. We were, therefore, unable to find a safe, still microbicidal, concentration for leave-on products. By contrast, with other contact allergens, dose-response use tests may be able to identify a non-eliciting concentration, which could give valuable clues to a non-inducing (i.e., safe) concentration in products.

Chlorhexidine anaphylaxis: case report and review of the literature.

Chlorhexidine is a widely used antiseptic and disinfectant. Compared to its ubiquitous use in medical and non-medical environments, the sensitization rate seems to be low. Multivarious hypersensitivity reactions to the agent have been reported, including delayed hypersensitivity reactions such as contact dermatitis, fixed drug eruptions and photosensitivity reactions. An increasing number of immediate-type allergies such as contact urticaria, occupational asthma and anaphylactic shock have been reported. In the case report, we describe anaphylaxis due to topical skin application of chlorhexidine, confirmed by skin testing and sulfidoleukotriene stimulation test (CAST(R): cellular antigen stimulation test). The potential risk of anaphylactic reactions due to the application of chlorhexidine is well known, especially that application to mucous membranes can cause anaphylactic reactions and was therefore discouraged. The use of chlorhexidine at a 0.05% concentration on wounds and intact skin was so far thought to be safe. Besides our patient, only one other case of severe anaphylactic reaction due to application of chlorhexidine on skin has been reported. Hypersensitivity to chlorhexidine is rare, but its potential to cause anaphylactic shock is probably underestimated. This review should remind all clinicians of an important potential risk of this widely used antiseptic.

Interaction between CCK and a preload on reduction of food intake is mediated by CCK-A receptors in humans.

Cholecystokinin (CCK) interacts with neural signals to induce satiety in several species, but the mechanisms are unclear. We therefore tested the hypothesis that alimentary CCK (CCK-A) receptors mediate the interaction of CCK with an appetizer on food intake in humans. CCK octapeptide (CCK-8, 0.75 microgram infused over 10 min) or saline (placebo) with concomitant infusions of saline (placebo) or loxiglumide, a specific CCK-A antagonist, was infused into 16 healthy men with use of a double-blind, four-period design. All subjects received a standard 400-ml appetizer (amounting to 154 kcal) but were free to eat and drink thereafter as much as they wished. The effect of these infusions on feelings of hunger and satiety and on food intake was quantified. CCK-8 induced a reduction in calorie intake (P < 0.05) compared with saline. Furthermore, a decrease in hunger feelings (P < 0.05, saline-CCK-8 vs. all other treatments) and an increase in fullness were observed. These effects were antagonized for hunger and fullness by loxiglumide. We conclude that CCK-8 interacts with an appetizer to modulate satiety in humans. These effects are mediated by CCK-A receptors.

Michael adducts of ascorbic acid as inhibitors of protein phosphatase 2A and inducers of apoptosis.

Michael adducts of ascorbic acid with alpha,beta-unsaturated carbonyl compounds have been shown to be potent inhibitors of protein phosphatase 1 (PP1) without affecting cell viability at the respective concentrations. Here we were able to show that higher concentrations can partially inhibit PP2A activity and concomitantly induce apoptotic cell death. A nitrostyrene adduct of ascorbic acid proved to be a more potent and effective inhibitor of PP2A as well as a stronger inducer of apoptosis. These adducts only slightly lost their cytotoxic potential in multidrug resistant cells that were 10-fold less sensitive to apoptosis induction by okadaic acid and vinblastine.

Hamster pancreatic beta cell lines with altered sensitivity towards apoptotic signalling by phosphatase inhibitors.

Specific inhibitors of serine/threonine phosphatases like okadaic acid can induce apoptotic cell death in the pancreatic beta cell line HIT. Cultivation in stepwise increased concentrations of okadaic acid enabled the isolation of HIT100R cells which proliferate at 100 nM okadaic acid (8 - 10 times the initially lethal concentration). These two cell lines were used to characterize the events triggered by okadaic acid that led to apoptosis. Biochemical markers, e.g. cytochrome c release from mitochondria and increase of caspase-3-like activity, revealed that induction of apoptosis by 100 nM okadaic acid in parental HIT cells started with the release of cytochrome c. In HIT100R cells 500 nM okadaic acid were necessary to induce alterations comparable to those observed with 100 nM okadaic acid in non-resistant HIT cells. In contrast to okadaic acid, the potency of the structurally different phosphatase inhibitor cantharidic acid to induce cytochrome c release, increase of caspase-3-like activity and DNA fragmentation was comparable in HIT and HIT100R cells. Thus, no cross-resistance between these phosphatase inhibitors seemed to exist. Phosphatase activity in extracts from HIT and HIT100R cells did not differ in its total amount or in its sensitivity for okadaic acid. Since higher concentrations of okadaic acid were needed to induce apoptosis in HIT100R cells, a compromised intracellular accumulation of the toxin appeared likely. Functional and structural analysis revealed that this was achieved by the development of the multidrug resistance phenotype in HIT100R cells. The underlying mechanism appeared to be the enhanced expression of the pgp1 but not the pgp2 gene.

Phosphatase inhibitors induce defective hormone secretion in insulin-secreting cells and entry into apoptosis.

A long-term (> or =24 h) exposure of insulin-secreting HIT T15 cells to the phosphatase inhibitor, okadaic acid (OA), at concentrations inhibiting serine/threonine phosphatases 1 (PP1) and 2A (PP2A) reduced proliferation and insulin secretion. The reduced proliferation was related to the induction of apoptosis as evidenced by morphological criteria and the occurrence of internucleosomal DNA fragmentation after 15 h in 50 nM OA. The compromised insulin secretion was not simply a consequence of a lowered hormone content and cell growth, but comprised also a complete suppression of secretion stimulated by K+ depolarisation and forskolin. K+ depolarisation of HIT cells cultured for 24 h in 50 nM OA resulted in a nearly unimpaired influx of Ca2+, but did not induce secretion. These observations suggest that the secretory defect may be localised distal to Ca2+ influx in stimulus secretion coupling of insulin-secreting cells.

Codon 215 mutations in human immunodeficiency virus-infected pregnant women. Swiss Collaborative 'HIV and Pregnancy' Study.

In 1994, the Pediatric AIDS Clinical Trials Group (PACTG) Protocol 076 demonstrated a two-thirds reduction of perinatal human immunodeficiency virus (HIV) type 1 transmission with zidovudine chemoprophylaxis. However, zidovudine alone does not fully suppress HIV replication, and chemoprophylaxis with zidovudine alone might select for zidovudine-resistant viral variants, decreasing the efficacy of zidovudine prophylaxis and affecting future responses to combined antiretroviral regimens. Sixty-two HIV-infected pregnant women consecutively enrolled in the ongoing Swiss HIV and Pregnancy Study were prospectively evaluated for the presence or development of zidovudine resistance by analysis of codon 215 of the reverse transcriptase gene. Six women (9.6%) harbored a codon T215Y/F mutation, which is associated with high-level resistance to zidovudine. Postnatal evaluation was completed in all children of mothers harboring the mutation. None was HIV-infected. The observed prevalence of codon 215 mutations of 9.6% raises important concerns regarding the future use of the PACTG 076 regimen.