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Notes: Background  Combinations of topical treatments and ultraviolet (UV) B phototherapy for plaque psoriasis may be more beneficial than either type of treatment used alone. Objectives  To determine the efficacy of calcitriol 3 µg g−1 ointment in combination with UVB phototherapy in treating plaque psoriasis. Methods  Calcitriol ointment with UVB was compared with vehicle plus UVB in a randomized, double-blind study in 104 patients. Results  Mean global improvement scores for both groups increased over the 8-week study period; there was a statistically significant difference (P 〈 0·05) in favour of the calcitriol/UVB combination from week 1. At end-point, 45% of the calcitriol/UVB group showed considerable improvement or clearing of psoriasis, compared with 21% of the control group. The superiority of calcitriol plus UVB was also reflected in the global severity and Psoriasis Area and Severity Index (PASI) scores; at end-point the mean percentage decrease in PASI score was 65% for the calcitriol/UVB group and 43% for vehicle/UVB (P = 0·0014). The incidence of skin-related adverse events was low (〈 12%) and similar in the two treatment groups. No clinically significant changes in blood chemistry, in particular calcium levels, occurred. The greater efficacy of combined calcitriol and phototherapy allowed a 34% decrease in total UVB exposure. Conclusions  Calcitriol 3 µg g−1 ointment and UVB phototherapy in combination provides a promising therapy for managing chronic plaque psoriasis.

Notes: Previous in vitro studies have shown CD44 isoforms containing the alternatively spliced exon v3 (CD44v3) to be modified with heparan sulphate (HS) and to bind HS-binding basic fibroblast growth factor (bFGF). Here, we demonstrate that exogenously added bFGF is also bound in vivo by CD44v3-positive keratinocytes in normal skin and by tumour cells in basal cell carcinoma and squamous cell carcinoma (SCC), two skin cancers of keratinocyte origin. bFGF binding and CD44v3 expression were colocalized in cultured human normal keratinocytes (HNK) and on the SCC cell line A431. By contrast, benign or malignant tumours of melanocyte origin failed to express CD44v3 and bound no bFGF. The bFGF binding to normal or transformed keratinocytes in vivo and in vitro was dependent on HS modification, as it was completely eliminated by pretreatment with heparitinase or by blocking with free heparin, whereas chondroitinase had no effect. In addition, specific removal of CD44v3 by antibody-induced shedding also diminished bFGF binding to keratinocytes. Furthermore, bFGF stimulated the proliferation of CD44v3-positive HNK and A431 in a dose-dependent fashion. This bFGF effect was again completely abolished by heparitinase or free heparin, but not by chondroitinase. In aggregate, our results suggest that a function of HS-modified CD44 isoforms such as CD44v3 in skin is to present the HS-binding growth factor bFGF, thereby stimulating the proliferation of normal or transformed keratinocytes.

Notes: Background Venous leg ulceration results from chronic venous insufficiency of the lower extremities. We recently showed that matrix metalloproteinase (MMP) -2 plays a major part in the pathogenesis of venous leg ulcers. In vitro activation of recombinant MMP-2 is controlled by the activity of the urokinase-type plasminogen activator (uPA), which acts as a fibrin-independent plasminogen activator. The activity of MMP-2 is potentiated by binding of uPA to the uPA receptor (uPAR). Objectives We aimed to clarify the role of plasminogen activation in venous leg ulcers. Methods The expression of uPA, uPAR, the tissue-type plasminogen activator, and plasminogen activator inhibitor (PAI) -1 and PAI-2 was investigated using reverse transcription followed by polymerase chain reaction and Western blotting. Results These provided direct evidence of elevated expression of uPA and uPAR at the mRNA and protein levels in venous leg ulcers, in comparison with healthy skin. By immunohistochemistry, elevated expression of uPA and uPAR was detected. Fibrin zymography showed significantly elevated endogenous uPA activity in venous leg ulcers in comparison with healthy controls. Conclusions Our findings indicate venous leg ulcers to be characterized by elevated plasminogen activation, suggesting that this enzyme cascade plays a crucial part in maintaining proteolytic activity in venous leg ulcers.

Notes: We report four patients with severe erythrodermic, pustular psoriasis, or plaque-type psoriasis, who were treated with a combination of acitretin and bath PUVA, After 4 weeks out-patient treatment, the psoriasis in all patients had improved by ≥90%. No patient had relapsed when reviewed at 3 months. No significant side-effects were seen with the combined retinoid/bath PUVA treatment. Acitretin and bath PUVA may be safely combined for the treatment of severe psoriasis.

Notes: Summary The clinical and histopathological classification of erythema exudativum multiforme major (EEMM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are difficult, due to the lack of clear-cut criteria. Based on a new clinical classification, 149 of 219 (68%) histopathological specimens, from a total of 534 patients with EEMM. SJS and TEN, have been reviewed. A comparison was made with the clinical picture, and any past history of infection or drug intake. All patients had been included in the German Registry of Severe Skin Reactions between April 1990 and December 1993. No differences could be found between the biopsies examined and the total number of histopathological specimens, concerning clinical diagnosis, gender and age. Sections from 28 of 149 specimens were not diagnostic or were too old to be properly evaluated. In nine cases, other diagnoses were proposed. One hundred and eleven of the histological slides with the diagnosis of EEMM (n= 16), SJS (n=34) and TEN (n=61), were classified as epidermal type of erythema multiforme. In these 111 slides, necrotic keratinocytes could be found, ranging from individual cells to confluent epidermal necrosis. The epidermo-dermal junction showed changes ranging from vacuolar alteration up to subepidermal blisters. The dermal infiltrate was superficial and mostly perivascular. It was sparse in SJS and TEN, and more pronounced in EEMM. Oedema in the papillary dermis was evident occasionally in all clinical groups. In 59 of 111 cases (53%), at least one eosinophil was present in the dermis. In 11 of 111 (10%), more than 10 eosinophils per field could be seen. Eosinophils were less common in the patients with the most severe forms of TEN, in whom there was detachment of more than 30% of the skin surface area. No differences in the history for drug intake, or for infection with Mycoplasma pneumoniae, herpes simplex and other organisms, could be detected between patients with or without eosinophils in their skin sections. This dermatopathological study of patients with EEMM. SJS and TEN indicates that the epidermal type of erythema multiforme is the pathological correlate for these diseases.

Notes: The cell adhesion molecule uvomorulin is important in cell recognition processes, both during tissue formation in embryonic development and in the maintenance of adult epithelia. In addition, uvomorulin appears to play a crucial role in carcinogenesis. Therefore, in the present study, the expression of uvomorulin in normal human skin and several benign and malignant proliferative skin lesions was evaluated by immunofluorescence microscopy using affinity purified antibodies. In normal human epidermis, basal and suprabasal keratinocytes showed a strong and homogeneous staining of the cell membrane. In contrast, uvomorulin expression was decreased in squamous cell, as well as in solid basal cell, carcinoma. Interestingly, solid basal cell carcinoma showed a dimorphic staining pattern with a reduced fluorescence of the inner cell layers and normal staining of the peripheral basal cells. In contrast, no such dimorphic staining pattern could be observed in squamous cell carcinoma, in which uvomorulin expression was homogeneously reduced. Decreased expression of uvomorulin was not specific for malignant skin lesions, since it could also be observed in condylomata acuminata. These studies demonstrate that human uvomorulin is differentially expressed in proliferative skin disorders, which may account at least in part for the differences observed in the clinical course between squamous cell and basal cell carcinoma.

Notes: The incidence of pericapillary fibrin cuffs was investigated in 49 biopsies of venous leg ulcers and 67 biopsies of leg ulcers of non-venous etiology. Pericapillary fibrin cuffs were seen in 28 biopsies (57.1%) of venous leg ulcers, but only in 11 biopsies (16.4%) of non-venous leg ulcers. In the venous leg ulcers pericapillary fibrin cuffs occurred predominantly near the ulcer surface and around dilated capillaries. Dilation of the capillaries and inflammation probably contribute more to the pathogenesis of pericapillary fibrin cuffs than venous hypertension.

Notes: The standard form of CD44 (CD44s) and CD44 isoforms, containing sequences encoded by one or several of 10 different variant CD44 exons (v1-v10), are thought to play a crucial role in the growth and metastasis of certain human tumors. Recently, monoclonal antibodies (mAbs) directed against all CD44 isoforms (panCD44), or against epitopes encoded by specific variant exons (CD44v) have been developed, which unfortunately only stain cryopreserved tissues. We wished to develop a technique to unmask chemically CD44s and CD44v epitopes in paraffin-embedded specimens of human skin cancers, so that they would be accessible for these mAbs. To address this issue, CD44s and CD44v expression was compared in cryopreserved and in formalin-fixed, paraffin-embedded biopsies obtained from the same basal cell carcinomas (BCC), squamous cell carcinomas (SCC), primary malignant melanomas (PMM) and metastatic malignant melanomas (MMM). Formalin-fixed tumors were de-paraffinized and treated briefly with an antigen retrieval fluid (TUF™) at 95°C or left untreated. In untreated paraffin-embedded tissues, no CD44s or CD44v staining was detected. In contrast, in antigen retrieval fluid-treated biopsies CD44s and CD44v expression was identical to that in cryopreserved specimens of the same tumor with the exception of mAbs detecting v7/8 and v10. We conclude that antigen retrieval unmasks certain epitopes in formalin-fixed, paraffin-embedded tissues, thus facilitating future research on the relevance of CD44s and CD44v expression for human skin carcinogenesis.

Notes: Abstract Prostaglandins have been shown to be involved in the suppression of contact hypersensitivity (CHS) by so-far ill understood mechanisms. T-cell migration across the lining of cytokine-activated endo-thelial cells (EC) is thought to be a central step in the initiation of CHS. The aim of our investigation was therefore to examine whether prosta-glandin E1 (PGE1) influences cytokine-induced TK-1 mouse T-cell lymphoma adhesion to eEnd.2 mouse endothelioma cells. Here, we report that PGE1 (10−12− 10−8 M) dose-dependently reduced TNFα-induccd T-cell binding, while TNFα-unstimulated adhesion was not affected. To test whether PGE, acted primarily on T-cells or on EC, they were separately pretreated with PGE, prior to the adhesion assay. Selective PGE1 pretreatment of eEnd.2, but not of TK-1 dose-dependenlly inhibited TNFα, stimulated T-cell adhesion. Since binding of TK-1 to TNFα-treated eEnd.2 is mediated by the interaction of ICAM-1 and VCAM-1 (on EC) with their receptors LFA-1 and VLA-4 (on T-cells), we further investigated whether PGE1 would modulate the expression of these molecules. FACS-analysis revealed PGE1 to inhibit TNFα-induced upregulation of ICAM-1, but not of VCAM-I on EC. Furthermore, constitutive LFA-1 and VLA-4 expression on T-cells was not affected by PGE1. We conclude that PGE1 supresses T-cell adhesion to EC by selectively inhibiting TNFα-induced upregulation of ICAM-1 on EC. This may be one mechanism by which prostaglandins suppress immune responses requiring T-cell EC interactions such as contact hypersensitivity in skin.

Notes: Abstract Low constitutive N-acetylating capacity has been implicated as a predisposing factor for the development of adverse reactions to certain drugs. This prompted us to investigate whether the N-acetylating capacity of patients with serious cutaneous adverse reactions, i.e., Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) differed from that of healthy control subjects. N-acctylating activity was measured in hair root cells by preparing a homogenate from freshly extracted hair roots and assessing acetyl-CoA-dependent N-acetylation by RP-HPLC using 2-aminofluorene as a substrate. Samples were obtained from hospitalized patients suffering from acute SJS and TEN or from healthy controls. All patients with SJS and TEN were found to have a low N-acetylating capacity (0.85 nmol/mg/min compared to 2.21 nmol/mg/min in controls, p〈0.05). Based on these findings, a low constitutive N-acetylating capacity may be one of the predisposing factors for the development of serious cutaneous adverse reactions to drugs that require N-acetylation in these patients.