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.

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.

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.

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.

[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.

Bone scan and red blood cell scan in a patient with epidermal naevus syndrome.

A bone scan and red blood cell scan in the rare epidermal naevus syndrome, associated with multiple haemangiomas of the bone and hypophosphataemic osteomalacia in a 20-year-old man are reported. The typical pattern of osteomalacia on the bone scan was associated with lesions of increased bone metabolism in the peripheral bones. The haemangiomas did not pool labelled red blood cells. Thus, the bone scan seems to be suitable for diagnosing the complete extent of haemangiomas in bone, but they could not be specifically proven by red blood cell pooling.

Cross-reaction of a monoclonal anti-filaggrin antibody with glycogen.

A mouse monoclonal anti human filaggrin antibody was found to bind keratohyaline granules of normal epidermis as well as of premalignant and malignant lesions in formalin-fixed tissue sections. In addition, an unexpected binding of this antibody with cells containing glycogen and other PAS positive substances was found, which could be abolished by adsorption of the anti-filaggrin antibody with glycogen or pretreatment of the sections with diastase.

Peanut agglutinin immunohistochemistry of basal cell carcinoma.

103 biopsies of basal cell carcinomas (BCCs) were studied using peanut agglutinin (PNA), PNA antibody and the peroxidase-antiperoxidase technique; 53 specimens of various skin tumors were examined as controls; 96% of the BCCs showed a band-like peritumorous reaction not seen in any other tumor except for the Pinkus' fibroepithelioma. The peritumorous PNA-binding was continuous in 51% of the BCCs studied and discontinuous in 45%; only 4% were completely negative. Both fibroepitheliomas revealed a discontinuous PNA-positive band. A narrow basement membrane-like positivity was seen around some small hair follicles situated within 2 neurofibromas and under one seborrhoeic keratosis. The PNA-binding band is apparently neither fibronectin, laminin, Type IV or Type V collagen and is not a constituent of normal epidermal, adnexal and vascular basement membranes.

[Type IV allergy to components of ophthalmologic drugs]. / Typ-IV-Allergie gegen Inhaltsstoffe von Augentherapeutika.

A review is given on allergens in topical ophthalmological drugs, which are of importance as to allergic type IV-skin reactions. The diagnostic proceedings are demonstrated and the special importance of patch testing and chamber scarification test is outlined by a case report.

Frequency, spectrum and occupational relevance of type IV allergies to rubber chemicals.

3851 consecutive patients patch tested between January 1985 and March 1990 have been analysed for rubber allergies. The incidence of rubber allergy was 3.8% (n = 145). In 80/145 patients (55%), the source of rubber sensitization was occupational, 67 of whom (84%) had acquired allergy from wearing rubber gloves at work. Most of them (36%) were employed in the health services. The most commonly positive rubber-mix in this group was thiuram-mix (72%) followed by carba-mix (25%). 13/80 patients (16%) had occupational rubber allergy from industrial rubber products other than gloves. Patch tests revealed thiuram-mix (62%) as the most commonly positive rubber-mix but, in contrast to the group with glove-induced rubber allergy, black-rubber-mix came second (38%). In 47/145 patients (32%), the source of rubber sensitization was non-occupational; in 18/145 (13%) the origin remained unknown.

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.

Monoclonal antibody Ki-M4 specifically recognizes human dendritic reticulum cells (follicular dendritic cells) and their possible precursor in blood.

Ki-M4, a new IgG3 monoclonal antibody, selectively recognizes dendritic reticulum cells (DRC; follicular dendritic cells) in all human lymphatic organs, as tested by the immunoperoxidase method on the light and electron microscopic level. This antibody was raised against separated lysosomes of the 12-0-tetradecanoyl phorbol-13-acetate (TPA) stimulated permanent cell line, U-937, derived from a human histiocytic lymphoma. No cross-reactivity was encountered in epithelial and mesenchymal cells, including macrophages and other cells detectable in bronchial and peritoneal lavages. In the nonadherent fraction of the mononuclear blood cells collected from the interphase of a Ficoll-Urografin gradient (density = 1.077 g/ml), 0.1 per million of the cells hitherto not classified as monocytes or lymphocytes showed a strong reaction. All other separated blood cell types were devoid of any reactivity. The observation that DRC share a highly restricted, and thus specific, antigen with a small but distinct subpopulation of mononuclear leukocytes implies their blood derivation.

[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.

[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.

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.

Alteration of cell surface carbohydrates associated with ordered and disordered proliferation of oral epithelia: a lectin histochemical study in oral leukoplakias, papillomas and carcinomas.

Cell surface carbohydrates in healthy oral mucosa (n = 15), leukoplakias without (n = 48) and with (n = 62) dysplasia, oral papillomas (n = 6) and squamous cell carcinomas (SCCs) (n = 40) were examined using the lectins peanut agglutinin (PNA), Ulex europaeus agglutinin I (UEA I), soybean agglutinin (SBA), Helix pomatia agglutinin (HPA), and Griffonia simplicifolia agglutinin I (GS I-B4). Binding of these lectins in formalin-fixed, paraffin-embedded tissues was demonstrated using either the peroxidase-anti-peroxidase (PAP) method or the avidin-biotin method. Healthy oral epithelia revealed binding sites for these lectins mostly in the suprabasal keratinocytes with occasional PNA binding also in their basal cells. Unlike healthy mucosa, a number of leukoplakias without and with dysplasia revealed receptor sites for UEA I also in their basal layer. Only those keratinocytes undergoing squamoidal differentiation exhibited SBA binding. Staining patterns of UEA I and SBA did not vary significantly between either leukoplakias without and with dysplasia or papillomas and SCCs. Conversely, a reduction or lack of binding sites for PNA (Gal beta 1-3GalNAc), HPA (D-GalNAc alpha) and GS I-B4 (alpha D-Gal) was observed more frequently in leukoplakias with dysplasia and SCCs contrasting their counterparts lacking epithelial dysplasia. Cell surface glycosyl residues play an important role in the regulation of cell proliferation and epithelial growth. Aberrant glycosylation in oral dysplastic leukoplakias and carcinomas leading to the lack of the relevant terminal sugar residues from their cell surface carbohydrates is probably a major reason for the hyper-/disordered proliferation.

Comparison of cytokeratin, filaggrin and involucrin profiles in oral leukoplakias and squamous carcinomas.

As the distribution pattern of cytokeratin (CK), filaggrin and involucrin has recently been suggested to discriminate between benign and malignant epithelial growths, biopsies of healthy oral mucosa, leukoplakias without and with dysplasia and squamous cell carcinomas were examined immunohistochemically using a panel of 4 monoclonal antibodies (AB) against different cytokeratin polypeptides (34 beta E12, KL1 and Pkk1) and filaggrin as well as a polyclonal AB to involucrin. Major and statistically significant differences were observed in the profiles of CKs (except Pkk1), filaggrin and involucrin between leukoplakias without and with epithelial dysplasia. However, the alteration in the expression of CKs, filaggrin and involucrin proved to be not a constant feature in leukoplakias with dysplasia as a considerable portion (20-25%) of them revealed the profiles of CKs, filaggrin and involucrin similar to those of benign leukoplakias, and vice versa. Immunostaining of these antigens did not define the diagnosis of dysplasia in leukoplakias more precisely than grading in conventional histology can do so far. However, immunohistochemical sensitivity in detecting a broad range of variation in the abnormal maturation patterns of keratinocytes in leukoplakias with dysplasia can be used to divide these lesions into subgroups to elucidate their prognosis in follow-up studies.