Granulomatous skin infection caused by Scopulariopsis brevicaulis.

A 14-year-old girl with a granulomatous infection of the cheek caused by Scopulariopsis brevicaulis is described. Treatment successively consisted of itraconazole and/or terbinafine for 19 months, after which clinical and mycologic cure seemed to be obtained. However, a relapse occurred 10 months later.

Pentoxifylline and skin inflammation.

Cyclic nucleotide phosphodiesterase inhibitors, such as pentoxifylline, have been shown to beneficially influence a large number of inflammatory skin diseases. The biological effects of pentoxifylline on the production of proinflammatory cytokines, leukocyte-endothelial cell adhesion, chemokines and leukocyte-keratinocyte adhesion in skin inflammation are discussed.

Pentoxifylline inhibits human T-cell adhesion to dermal endothelial cells.

Pentoxifylline (PTX), a methyl xanthine derivative with phosphodiesterase inhibitory activity, has been shown to have antiinflammatory effects. Previous studies have demonstrated that PTX can suppress TNF alpha production and function, and can inhibit the adhesion of neutrophils and monocytes to endothelial cells. In the present study, we sought to determine whether PTX also interferes with the adhesion of human peripheral blood T lymphocytes to cells of the human dermal endothelial cell line HMEC-1. Using a cell adhesion immunoassay, the effect of different doses of PTX (10(-5)-10(-2) M) on the binding of unactivated or PMA-activated T cells to unstimulated or TNF alpha-stimulated endothelial cells was investigated. In addition, blocking experiments with monoclonal antibodies against pairs of adhesion molecules known to be involved in endothelial cell/T-cell adhesion were performed. Unactivated T cells showed minimal adhesion to unstimulated endothelial cells. PMA-activated T cells showed an eightfold increased binding to TNF alpha-stimulated endothelial cells, which was found to be mediated largely by LFA-1/ICAM-1. PTX inhibited the binding of PMA-activated T cells to TNF alpha-stimulated endothelial cells in a dose-dependent manner. This inhibition was only found when PTX was present during the adhesion assay. A similar inhibition was found when PTX was replaced by isobutylmethylxanthine, another methyl xanthine derivative, or by a combination of two cAMP analogues. The results suggest that interference with T-cell/endothelial cell adhesion, which forms an essential step in the migration of T cells from the peripheral blood into sites of inflammation, may be another explanation for the beneficial effect of PTX in several inflammatory dermatoses.

Pentoxifylline inhibits T-cell adherence to keratinocytes.

In many inflammatory dermatoses leukocyte function-associated antigen-1/intercellular adhesion molecule-1 mediated T-cell/keratinocyte adhesion is considered to play an important role. Pentoxifylline (PTX), a methylxanthine derivative widely used for the symptomatic treatment of various vascular disorders, was recently found to have anti-inflammatory effects. PTX can suppress tumor necrosis factor-alpha production and function, and inhibits leukocyte-endothelial cell adherence. The aim of the present study was to investigate whether PTX also interferes with T-cell/keratinocyte binding. Peripheral blood T cells were activated with phorbol myristate acetate and co-incubated with interferon-gamma- or tumor necrosis factor-alpha-stimulated keratinocytes (SVK 14 cells) in the presence or absence of PTX. Using an enzyme-linked immuno cell adhesion assay PTX was found to inhibit T-cell/keratinocyte adhesion in a dose-dependent manner. A similar inhibition was found when PTX was replaced by isobutylmethylxanthine, another methylxanthine derivative, or by a combination of two cyclic adenosine monophosphate analogues. No major effect on T-cell/keratinocyte adherence was observed when PTX was present during the pre-incubation of keratinocyte monolayers with tumor necrosis factor-alpha or interferon-gamma prior to the adhesion assay. In keratinocyte monolayers the interferon-gamma or tumor necrosis factor-alpha induced intercellular adhesion molecule-1 expression could not be inhibited by PTX. However, when PTX was added to short-term organ cultures of normal human skin biopsies, the lipopolysaccharide- and tumor necrosis factor-alpha-induced keratinocyte intercellular adhesion molecule-1 expression was blocked completely. The interferon-gamma-induced ICAM-1 expression was not blocked by PTX. The results presented herein suggest that impaired T-cell/keratinocyte binding may be one of the mechanisms by which PTX exerts a beneficial effect in certain inflammatory dermatoses.

Cutaneous hypersensitivity reactions to vitamin K: 2 case reports and a review of the literature.

Between 1964 and 1994, at least 52 patients with cutaneous adverse effects of vitamin K have been described in the European and North American literature. A review of the details of these patients is given and 2 new cases reported. Adverse effects are seen not only in patients with liver-function disturbances but also in patients without liver diseases, and occur mostly after intramuscular or subcutaneous administration of vitamin K1, independent of the total dose. Patch and intracutaneous tests often give positive reactions. The mechanism of action is probably in many patients a delayed-type hypersensitivity reaction.

Effect of calcitriol on growth, differentiation, chemokine mRNA expression of cultured keratinocytes and on keratinocyte-T cell binding.

Calcitriol has recently been shown to be effective against psoriasis. However, its mode of action is not exactly known. The present study focused on the influence of calcitriol on growth, differentiation, chemokine mRNA and ICAM-1 mRNA expression of keratinocytes (KC) and on the binding of T-cells to keratinocytes. In vitro studies showed that calcitriol has a strong anti-proliferative effect and induces terminal differentiation. gamma-IP-10 and ICAM-1 mRNA were induced by gamma-IFN, an induction not influenced by calcitriol. Moreover, the functional expression of ICAM-1 on the KC cell surface as measured by a cell adhesion assay, was not influenced either. IL-8 and huGRO mRNAs were constitutively produced in KC, as was demonstrated after incubation with cycloheximide. Up-regulation of both IL-8 and huGRO mRNA by IL-1 alpha was also not affected by calcitriol. It is concluded that calcitriol has a strong antiproliferative activity and does not interfere with KC responsiveness to gamma-IFN and IL-alpha induced chemokine expression or with the adhesion of T-cells to keratinocytes.

Increased adherence to keratinocytes of peripheral blood mononuclear leucocytes of a patient with drug-induced erythema multiforme.

The pathogenetic mechanisms involved in the development of drug-induced erythema multiforme (EM) are still largely unknown. The observation that epidermal keratinocytes (KC) in EM express intercellular adhesion molecule-1 (ICAM-1) points to a putative role for T-cell/KC adhesion in the pathogenesis of EM. In this study, the binding of peripheral blood mononuclear leucocytes (PBML) from a patient with carbamazepine-induced EM and of normal control PBML to autologous and heterologous KC was investigated, using two different binding assays. Patient PBML obtained at the time of disease (t0) showed an increased binding to ICAM-1-positive heterologous KC, which could be inhibited completely by anti-LFA-1. Adhesion of patient PBML-t0 to autologous KC, and to carbamazepine-pretreated heterologous KC in sections of skin biopsies, was also increased, but was found to be only partially LFA-1-dependent. These findings support the view that PBML/KC adherence plays an important role in the pathogenesis of this drug-induced EM.

CD44 antibody stimulates adhesion of peripheral blood T cells to keratinocytes through the leukocyte function-associated antigen-1/intercellular adhesion molecule-1 pathway.

Close contact between T lymphocytes and keratinocytes is an important feature of many inflammatory skin diseases. In vitro studies showed that stimulation of keratinocytes with interferon-gamma or tumor necrosis factor-alpha and of T cells with phorbol esters results in a leukocyte function-associated antigen (LFA)-1/intercellular adhesion molecule (ICAM)-1-mediated adhesion. The present study was performed to investigate the role of the CD44 molecule in keratinocyte/T-cell binding. The CD44 class of lymphocyte adhesion receptors is involved in lymphocyte binding to high endothelial venules and to extracellular matrix compounds and is therefore important in lymphocyte recirculation and homing. Moreover, CD44 can act as a co-stimulating signal in T-cell activation and promotes homotypic adhesion of in vitro cultured CD3-stimulated T cells. Using a cell adhesion assay a sixfold increase in T-cell/keratinocyte adhesion was found after pre-incubating the T cells with anti-CD44. This increased adhesion was found to require an intact cytoskeleton, to be energy and magnesium dependent, and could be completely inhibited by anti-LFA-1 and anti-ICAM-1. Pretreatment of T cells with hyaluronic acid, a ligand for CD44 and an extracellular matrix compound in the dermis and epidermis, did not affect T-cell/keratinocyte adhesion.

PUVA keratosis. A clinical and histopathologic entity associated with an increased risk of nonmelanoma skin cancer.

BACKGROUND: Various types of hyperkeratotic lesions can be observed in patients with psoriasis treated with PUVA. Clinically it can be difficult to classify them and to differentiate benign from malignant hyperkeratotic lesions. Recently, we introduced the term PUVA keratosis, which we regard as a distinct entity. OBJECTIVE: The purpose of the study was to describe in more detail the clinical and histopathologic features of PUVA keratoses and to investigate a possible relation with nonmelanoma skin cancer. METHODS: A group of 13 psoriasis patients with PUVA keratoses was studied and compared with 247 psoriasis patients without these keratoses, who had also received long-term therapy with PUVA. RESULTS: The presence of PUVA keratoses was associated with an increased risk of nonmelanoma skin cancer. The estimated relative risk for skin cancer in patients with PUVA keratoses, adjusted for age, sex, and UVA dose, as compared with psoriasis patients without these keratoses, who had also received long-term PUVA treatment, was 6.5 (95% confidence interval, 1.3 to 32.1). Squamous cell carcinomas contributed the most to this increased risk. CONCLUSION: PUVA keratoses are associated with an increased risk of nonmelanoma skin cancer. Therefore careful clinical follow-up of psoriasis patients with PUVA keratoses is necessary, and cessation of PUVA treatment should be considered.

'High single-dose' European PUVA regimen also causes an excess of non-melanoma skin cancer.

We report the results of a long-term (12.8 years) follow-up study of the detection of malignant and benign skin tumours in patients with psoriasis, who were treated with PUVA according to the European, 'high single-dose' regimen. A total of 13 squamous cell carcinomas (SCC) and 24 basal cell carcinomas (BCC) were diagnosed in 11 of 260 patients. The incidence of both SCC and BCC was increased in comparison with the general Dutch population. The ratio of SCC to BCC in the general population was 1:8 but was 1:2.5 in our study group. A positive correlation was observed between the development of SCC and the total UVA dosage, the age of the patient at the start of the PUVA treatment and a history of arsenic use. This dose-related increase in the incidence of SCC, reported in studies from the U.S.A., has not been found in earlier European studies. The average time period between the start of PUVA therapy and the diagnosis of the first malignant skin tumour was 6.0 years for SCC and 4.7 years for BCC. Among the 49 benign skin tumours were actinic keratoses, a keratoacanthoma and 'PUVA keratoses', a newly described hyperkeratotic lesion, especially found in PUVA-treated patients.

Spectophotometric quantification of cell-cell adherence by an enzyme-linked immuno-cell adhesion assay.

In the present study a spectophotometric method was developed to determine the number of T cells binding to human epidermal keratinocytes (KC). In this cell adhesion assay the adherent T cells were detected with a cell-specific monoclonal antibody conjugated to horseradish peroxidase and the coloured substrate quantified in an ELISA reader at 492 nm. A correlation was demonstrated between the number of T cells and the extinction values measured. The enzyme-linked immuno-cell adhesion assay (ELICAA) was used to quantify KC/T lymphocyte adherence in a series of experiments designed to evaluate its reliability and reproducibility. Compared with the 51Cr-labelled adherence assay, the ELICAA was a safe, rapid and accurate method avoiding the use of radioactive material.