The genetic basis for most patients with pustular skin disease remains elusive.

BACKGROUND: Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP). OBJECTIVES: To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN. METHODS: Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients - 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype-phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort. RESULTS: The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers. CONCLUSIONS: The identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease-causing genetic factors outside IL36RN.

[Histamine intolerance mimics anorexia nervosa]. / Histaminintoleranz imitiert Anorexia nervosa.

Histamine intolerance is a clinically heterogeneous disease. We present a woman who suffered from weight loss, diarrhea, abdominal pain, headache, flushing and bronchial asthma for several years. When placed on a histamine-poor diet, she experienced weight gain and improvement of other all signs and symptoms, supporting the diagnosis of histamine intolerance. Therefore, this disease should be included in the differential diagnosis of anorexia nervosa.

Structural diversity of lithium neopentoxide compounds.

The reaction of LiN(SiMe(3))(2) with 1 equiv of HOCH(2)CMe(3) (HONep) in toluene led to the formation of [Li(mu3-ONep)](8) (1). The complex adopts a novel dual-edge fused hexagon-square prismatic structure with a C(2v) axis of rotation that relates the top and bottom eight-membered rings. Substituting the noncoordinating solvent toluene for a Lewis basic solvent (THF or py) led to the isolation of compounds of the general formula [Li(mu3)-ONep)](4)(solv)(3), where solv = THF (2) or py (3). The cube structures of 2 and 3 have one Li which is not solvated because of steric crowding of the ONep ligands. Multinuclear solid-state ((6)Li, (7)Li, and (13)C) MAS and solution-state ((1)H, (7)Li, and (13)C) NMR studies were undertaken to verify the identity of the bulk powder and to determine the solution behavior of these compounds.

Allergologically relevant rubber accelerators in single-use medical gloves.

To prevent contact with specific rubber accelerators, sensitized patients have to know in which glove brands these accelerators are present. Additionally, quantitative measurements of the bioavailable amounts of accelerators are needed to assist consumers in selecting gloves with the lowest possible amount of residual rubber accelerators. The aim of the study was to develop an analytical method by which residuals of rubber accelerators in single-use medical gloves could be determined qualitatively and quantitatively. 19 different glove brands were analysed for content of accelerators, and the results were compared to manufacturers' ingredient claims of the identical gloves. ZDEC, ZDBC, ZMBT and ZPC were the most frequently detected chemicals. In 9 of 15 gloves discrepancies were found, usually minor, between content of accelerators declared by manufacturers to be present and accelerators detected by analysis. Both phosphate buffer and acetone were tested as extraction media. No accelerators were detectable with the described chemical analysis in phosphate extracts, whereas acetone was demonstrated to be a technically suitable medium for extraction. However, more kinetic studies of the extraction procedure and studies of skin penetration are needed to document that the extraction procedure simulates the clinical situation.

Graft-versus-host-like mucocutaneous eruptions with serological features of paraneoplastic pemphigus and systemic lupus erythematosus in a patient with non-Hodgkin's lymphoma.

A 63-year-old male patient spontaneously developed severe erosive orogenital mucositis, palmoplantar and gluteal inflammatory lesions resistant to therapy. The skin lesions clinically and histologically resembled lichen-planus-like graft-versus-host disease. Investigation for an underlying autoimmune or malignant disorder revealed a centrocytic-centroblastic low-grade non-Hodgkin's lymphoma (according to the Kiel classification) in the bone marrow, mesenterial and iliacal lymphoma. Serological titers were intermittently positive for ANA, anti-Sm/U1RNP, anti-Ro and anti-dsDNA. Immunoprecipitation of lysates from radiolabeled human keratinocytes with the patient's serum revealed circulating antibodies against 210-kD (desmoplakin II), 190- and 170-kD antigens but none against the 230-kD antigen or 250-kD desmoplakin I. Under cytostatic chemotherapy the lymphomas showed complete and long-lasting remission, whereas the mucocutaneous lesions persisted. Six years after diagnosis, the mucocutaneous lesions are sufficiently controlled by immunosuppressive therapy. In the presented case, several features of lymphoma-associated dysimmunoreactivity are assumed that bring about the intrinsic production of various autoantibodies typical of paraneoplastic pemphigus and systemic lupus erythematosus.

Type I allergies to latex and the aeroallergenic problem.

Between 1989 and 1995, a 12-fold increase in latex allergy was documented amongst our patients. Similar findings have been noted elsewhere. Increase in type I allergies to latex has become an international problem. The issues associated with latex allergy are described, including those posed by the ubiquitous nature of latex in medical equipment, and in commonplace domestic objects. The potential for allergic patients to cross react to a variety of fruits or plants is an added problem for sensitized patients. This paper concludes that the universal introduction of powder-free surgical gloves with low protein content would be a very important measure in the prevention of acquired latex allergy.

[Update on the latex allergy topic]. / Aktuelles zum Thema Latex-Allergie.

Type I allergies to latex have become an increasing problem in occupational dermatology during the past few years, especially since at least 10% of health care workers are affected. In the Department of Dermatology, University Erlangen-Nuremberg, a 12-fold increase in latex-allergic patients has been documented between 1989 and 1995 with a clear trend to more severe systemic manifestations (from 10.7% in 1989/ 1990 to 44% in 1994/1995). Among the water soluble proteins (molecular weights 2 to 200 kD) which may induce latex allergy, at least 5 are considered as main proteins with known primary structure. In addition some "marker' proteins seem to induce specific IgE antibodies in special risk groups (e.g. 46 kD-protein in medical professions, 14.6 kD- and 27 kD-proteins in children with spina bifida). Cross reactions between latex and several fruits (especially avocado, kiwi, banana and chestnut) in 60 to 70% of latex-allergic patients have to be taken into account when evaluating and counselling affected patients. Most important in prophylaxis is the complete change to powder-free latex gloves in medical institutions, since these gloves usually have a low protein content. Our listing of surgical and examination gloves according to their protein content (as measured by the modified Lowry- and High Pressure Liquid Chromatography method) should be a useful guideline for the choice of suitable gloves.

The automatic search for ligand binding sites in proteins of known three-dimensional structure using only geometric criteria.

The biological function of a protein typically depends on the structure of specific binding sites. These sites are located at the surface of the protein molecule and are determined by geometrical arrangements and physico-chemical properties of tens of non-hydrogen atoms. In this paper we describe a new algorithm called APROPOS, based purely on geometric criteria for identifying such binding sites using atomic co-ordinates. For the description of the protein shape we use an alpha-shape algorithm which generates a whole family of shapes with different levels of detail. Comparing shapes of different resolution we find cavities on the surface of the protein responsible for ligand binding. The algorithm correctly locates more than 95% of all binding sites for ligands and prosthetic groups of molecular mass between about 100 and 2000 Da in a representative set of proteins. Only in very few proteins does the method find binding sites of single ions outside the active site of enzymes. With one exception, we observe that interfaces between subunits show different geometric features compared to binding sites of ligands. Our results clearly support the view that protein-protein interactions occur between flat areas of protein surface whereas specific interactions of smaller ligands take place in pockets in the surface.

[Incidence and increase in type I allergies to rubber gloves in dental medicine students]. / Häufigkeit und Zunahme von Typ-I-Allergien gegen Gummihandschuhe bei Zahnmedizinstudenten.

The prevalence of type I allergy against latex was investigated in dental students by questionnaire, prick tests and the determination of specific IgE antibodies. Positive prick tests against different latex fluids were found in 18 (8.7%) of 206 students, with clinical relevance in 11 cases. When the total number of students in each semester was taken into account an increase in the minimal prevalence of clinically relevant latex allergy from 2% in the second semester to 10.4% in the tenth semester was seen. A history of glove intolerance presenting as a wheal-and-flare reaction was associated with a type I allergy against latex in only 50% of the affected subjects. Atopic diseases and hand eczema of different causes proved to be risk factors in 16 and 5 of 18 students with latex allergy, respectively. A high-ammonia accelerator-free latex fluid proved to be a very reliable test medium compared to the less sensitive determination of specific IgE antibodies to latex.

Extensive linear epidermal nevus associated with hemangiomas of bones and vitamin-D-resistant rickets.

The association of connate, left-sided, extensive epidermal verrucous nevus, multiple isolated bone tumors and vitamin-D-resistant rickets since childhood seen in a 20-year-old male patient corresponded to an epidermal nevus syndrome (ENS). However, other organ involvement occasionally associated with ENS could not be found in this patient, and his intraosseous tumors represented histologically benign hemangiomas. Serum analysis revealed hypophosphatemia (together with phosphaturia), decreased levels of 1,25-dihydroxycholecalciferol and elevated levels of alkaline phosphatase indicating hypophosphatemic osteomalacia. Therefore we suppose that vitamin-D-resistant rickets combined with skeletal tumors represents a peculiar type of osteomalacia caused by unilateral mesenchymomas.

[Benzalkonium chloride--a relevant contact allergen or irritant? Results of a multicenter study of the German Contact Allergy Group]. / Benzalkoniumchlorid--relevantes Kontaktallergen oder Irritans? Ergebnisse einer Multicenter-Studie der Deutschen Kontaktallergiegruppe.

At eight dermatological clinics, a total of 2146 patients were tested between May 1990 and December 1991 to determine the significance of the preservative benzalkonium chloride in inducing allergic contact dermatitis and to evaluate recommendations for patch testing. In 225 cases an allergic reaction was proven, with 258 irritant reactions in addition. Only 12 cases were clinically relevant. Therefore, benzalkonium chloride is considered a weak allergen. A doubtful (erythema) or an incipient positive (with occasional papules) reaction may be regarded as an irritant reaction. In isolated cases a "repeated open application test" (ROAT) should be applied to determine clinical relevance. Our recommendation for patch testing is 0.1% benzalkonium chloride in vaseline, and also in water for special cases.

[Pityriasis-lichenoides-et-varioliformis-acuta-like drug exanthema caused by astemizole]. / Pityriasis-lichenoides-et-varioliformis-acutaähnliches Arzneiexanthem durch Astemizol.

We report on a 40-year-old male patient who developed an unusual generalized drug eruption taking the form of a histologically confirmed pityriasis lichenoides et varioliformis acuta (PLEVA) after oral intake of the H1-antagonist astemizole. On two occasions, independently repeated medication with astemizole exacerbated the typical rash again. Oral exposure and the specific lymphocyte transformation test confirmed the suspected causal connection between astemizole and PLEVA.

Effects of interferon-alpha-2b on the clinical course, inflammatory skin infiltrates and peripheral blood lymphocytes in patients with severe atopic eczema.

Increased serum IgE and enhanced susceptibility to viral infections, decreased levels of interferons, lymphocytic skin infiltrates and IgE-bearing epidermal Langerhans cells are striking features in patients with atopic eczema (AE). Since the hyper-IgE syndrome is known to improve under alpha-interferon (alpha-IFN) therapy, we treated 7 patients with severe AE and high serum IgE exclusively with 3 x 10(6) units IFN alpha 2b thrice weekly for 3 months. Before treatment the skin infiltrates mainly consisted of CD3+/CD4+/TcR alpha/beta + lymphocytes, whereas the CD3+/CD8+ phenotype was limited to about 10% of cells. After 6 weeks of therapy, epidermal inflammation with CD4+ and CD8+ cells was reduced but dense infiltrates remained in papillary perivascular areas. Expression of TcR gamma/delta, HLA-DR and CD25 showed no significant changes. Initially high serum IgE and soluble CD23 as well as cell-bound IgE dropped under therapy, whereas a short-term elevation in serum IL-2 receptor was observed. On peripheral blood lymphocytes slightly reduced expression of HLA-DR, LFA-1, CD23 and ICAM-1 was seen after 100 days. LFA-3 expression became reduced in 4 patients, the CD4/CD8 ratio decreased in all cases. After an initial therapeutic response of all patients, significant longer-lasting improvement of the skin lesions could only be observed in 2 of 7 patients. The data of our long-term study suggest that systemic IFN alpha 2b treatment leads to a remarkable reduction in epidermal inflammation but does not significantly influence cutaneous cell subsets. Immunomodulatory effects became obvious by reduced peripheral cell subsets expressing TcR alpha/beta, MHC class II and adhesion molecules.

Cutaneous pleomorphic large cell lymphoma.

The case of a primary cutaneous pleomorphic large cell lymphoma occurring in a twenty-one-year-old woman who presented with a blue-reddish nodule on her left cheek of three months' duration is presented. The tumor consisted of pleomorphic blast cells showing high mitotic activity. On immunohistochemical examination, the majority of the tumor cells expressed CD 3 (Leu-4), CD 4 (Leu-3), HLA-DR CD 30 (Ki-1/Ber-H 2), and CD 25 (IL2 receptor). Twenty-two months after excision of the tumor there is no detectable systemic spread of the lymphoma. This case provides further evidence for recent observations that primary cutaneous Ki-1-positive large cell lymphomas without lymph node involvement may have a favorable prognosis after local treatment despite showing histologic pattern of malignancy.

Allergic and irritant reactions to rubber gloves in medical health services. Spectrum, diagnostic approach, and therapy.

Delayed-type allergies account for most reactions to gloves. These have been found in 32 of 39 patients (82%) attending our department with occupationally induced contact dermatitis to gloves. Accelerators, mainly of the thiuram group, antioxidants, vulcanizers, organic pigments, and, presumably, glove powder ingredients are known responsible allergens. In contrast, immediate-type allergies to rubber gloves were less frequent (13 of 39 patients [33%] with occupationally induced glove allergies). They usually present as contact urticaria. Responsible allergens are latex, glove powder, and accelerators. On the basis of the numerous glove-related allergens, a comprehensive schedule of diagnostic tests is proposed. In addition, we introduce a new classification of hypoallergenic gloves according to their basic materials and ingredients and thus provide a guideline for individual therapy.