Diagnostic dilemmas in a patient with multivascular embolic stroke.

We describe a patient admitted to the intensive care unit with aphasia, which was due to an embolic ischaemic cerebral stroke associated with a previously unknown patent foramen ovale. Eventually, this finding during echocardiography led us to the diagnosis of pancreatic cancer. The thrombotic complications of pancreatic cancer, in combination with a large, patent foramen ovale, support the mechanism of a paradoxical embolism through the patent foramen ovale as the cause of cerebral ischaemic stroke.

The effect of alefacept on T-cell subsets and cells expressing NK receptors in lesional psoriatic skin: the effects of monotherapy and combination treatment with calcipotriol.

OBJECTIVES: To investigate the effect of weekly alefacept monotherapy 15 mg i.m. on epidermal hyperproliferation, keratinization, T-cell subsets and cells expressing NK receptors during 12 weeks of treatment. Furthermore, the addition of calcipotriol cream to alefacept treatment was studied and compared with alefacept monotherapy. METHODS: Five patients participated in this study, and used weekly alefacept 15 mg i.m. combined with calcipotriol cream up to a maximum of 100 g per week. Biopsies from two lesions (one treated and another lesion not treated with calcipotriol cream) were taken at week 0 and week 12. We investigated the number of T-cell subsets (CD4, CD8, CD45RO, CD45RA, CD2, CD25), cells expressing NK receptors (CD94 and CD161), the proliferation marker Ki-67 and the keratinization marker keratin-10. RESULTS: Alefacept monotherapy induced a statistically significant reduction of CD4+, CD45RO+ and CD2+ cells in dermis and epidermis and CD8+ cells in epidermis at week 12. Furthermore, the keratin-10 positive epidermal surface was significantly increased at week 12. The combination of alefacept and calcipotriol cream induced a statistically significant reduction of only CD4+ and CD45RO+ cells at week 12. CONCLUSIONS: The number of memory effector T-cells in the psoriatic lesion is significantly decreased by alefacept, and calcipotriol cream does not seem to have an additional effect on this reduction. Cells expressing NK receptors are virtually not targeted by alefacept monotherapy or the combination.

Assessment of epidermal subpopulations and proliferation in healthy skin, symptomless and lesional skin of spreading psoriasis.

BACKGROUND: The margin zone in spreading psoriatic lesions has frequently been used as a model to study the changes in epidermal proliferation, keratinization and inflammation during the transition from symptomless to lesional skin. However, the dynamics of the changes in the epidermal subpopulations-basal cells, transit amplifying cells and differentiated cells-have not been studied in the transition between symptomless and lesional skin. OBJECTIVES: To quantify in a dynamic model of the margin zone in psoriasis the characteristics of these subpopulations with respect to epidermal proliferation and differentiation. METHODS: From seven patients with active psoriasis, biopsies were taken from the distant uninvolved skin, outer margin, inner margin and centre of a spreading psoriatic plaque. Frozen sections were labelled immunofluorescently using direct immunofluorescence for Ki-67 and beta1 integrin and the Zenon labelling technique for keratin 6, 10 and 15. Digital photographs of the stained sections were quantitatively analysed. RESULTS: In the distant uninvolved skin the expression of beta1 integrin was decreased and keratin 15 expression was lost. In this area suprabasal cells expressed beta1 integrin and in the outer margin suprabasal cells expressed Ki-67. From the outer to the inner margin of the psoriasis plaque, which coincided with the appearance of the clinical lesion, there was a significant change in the various markers. The patchy expression of keratin 6 in the inner margin became homogeneous in the centre of the psoriasis plaque and here was also coexpression of keratin 6 and keratin 10 in a single cell. CONCLUSIONS: The present study provides additional evidence that the distant uninvolved skin has a prepsoriatic phenotype, which is the first step in a psoriatic cascade. The cascade between symptomless and lesional skin comprises first an abnormality in inflammation with involvement of beta1 integrin-dim cells (transit amplifying cells) subsequently eliciting an enlarged germinative compartment with increased recruitment of cycling epidermal cells and focal expression of proliferation-associated keratins, ultimately culminating in a more-or-less homogeneous epidermis with massive recruitment of cycling epidermal cells and proliferation-associated keratinization.

Effect of calcipotriol on epidermal cell populations in alefacept-treated psoriatic lesions.

BACKGROUND AND OBJECTIVES: The effect of the established antipsoriatic treatment with topical calcipotriol (with a maximum of 100 g per week) in addition to systemic treatment with alefacept, a new biological agent for psoriasis, on epidermal cell populations in the psoriatic lesion was investigated using a combination of the Zenon labelling technique and microscopic image analysis. Epidermal cell populations were measured quantitatively with this sensitive method. PATIENTS/METHODS: Frozen sections of non-treated psoriatic epidermis and psoriatic epidermis treated with either alefacept intramuscular or alefacept intramuscular in combination with topical calcipotriol for 12 weeks were compared immunohistochemically. Antibodies against keratin 6, 10 and 15 were labelled with the Zenon technique, whereas antibodies against the Ki-67 antigen and beta-1 integrin were covalently Fluorescein Isothiocyanate (FITC)-labelled. Using image analysis, these markers were measured in the epidermis in a standardized manner. RESULTS AND CONCLUSIONS: Treatment of psoriasis with alefacept resulted in a good clinical response in several patients and in a normalization of epidermal expression of the immunohistochemical parameters for differentiation and proliferation. The addition of topical calcipotriol resulted in a faster clinical improvement with a similar overall clinical response and a similar response of epidermal cell populations as compared to treatment with alefacept monotherapy after 12 weeks of treatment. This study also suggests that the appearance of keratin 15 has a predictive value for the duration of remission. It can be concluded that the addition of a low-dose calcipotriol treatment does not contribute to the clinical efficacy of alefacept, both at the clinical level and with respect to markers for epidermal proliferation and differentiation.

Alefacept modifies long-term disease severity and improves the response to other treatments.

Alefacept treatment has been shown in several multicentre studies to result in prolonged post-treatment remission periods (median duration 241 days). This communication describes the clinical responses of 10 patients to multiple courses of 12 weekly intramuscular injections with alefacept given in combination with available antipsoriatic treatments. It was shown that in this group of 10 patients with moderate-severe psoriasis, 8 were no longer candidates for any more long-term continuous systemic treatment with methotrexate or acitretin, 7 had no options for UVB/PUVA courses and 8 were not suitable for treatment with cyclosporine. In 5 out of these 10 patients alefacept had resulted in a considerable long-term improvement with only mild disease expression, which lasted one year or longer. Patients indicated that these responses were outstanding as compared to the troublesome years before. Another patient reported a major improvement in the quality of life by reduction of itch. In two patients alefacept vastly enhanced the efficacy of dithranol treatment, as compared to previous treatments. Another patient was able to discontinue methotrexate without relapsing during alefacept, in contrast to severe rebound episodes following discontinuation of methotrexate in the past. The long-term responses of 8 out of the 10 patients described in this report indicate that alefacept, in the context of individualised care of patients with moderate to severe psoriasis, can have an important contribution. In particular, the long-term response after stopping alefacept makes this treatment a valuable tool, achieving prolonged disease control in at least some patients with moderate to severe psoriasis.

Aggravation of psoriasis by infections: a constitutional trait or a variable expression?

Focal infections are a well known triggering factor in patients with psoriasis. A question which remains to be answered is whether relapsing of psoriasis after infections is a constitutional trait of a restricted population or whether it is a feature of all patients in some phase of their disease. A questionnaire was mailed to patients with psoriasis comprising general questions, psoriasis related questions and questions on the relationship between focal infections and aggravation of psoriasis. The questionnaire was mailed to 126 patients and 45 questionnaires which were returned, were evaluable. From the 45 questionnaires the following preliminary conclusion can be drawn. Aggravation of psoriasis following infections appeared to be a consistent trait throughout the duration of psoriasis in 18% of patients as opposed to 71% of the patients who did not experience this association at all and 11% who experienced the association sometimes. Patients who experienced aggravation of psoriasis by infections as a consistent feature have an age of onset 9 years earlier as opposed to patients without this association and express guttate psoriasis in the vast majority as first manifestation at initiation of psoriasis. These patients had an average of 4.6 relapses per year in contrast to 1.1 per year in the patients without an association between infection and aggravation of psoriasis. In these patients infections proved to be responsible for 67% of the exacerbations. Stress was indicated in this subpopulation as a triggering factor as well in 88% of the patients. Although this conclusion only can be very preliminary based on the small group of patients, we may conclude that patients with a strong association between aggravation of psoriasis and infections belong to a restricted population of patients tending to an unstable course of the disease.

Occurrence, regulation, and significance of progesterone receptors in human meningioma.

The abundant expression of progesterone receptors (PR) in human meningiomas is well established. It is unknown, however, how PR expression is regulated, especially since estrogen receptors (ER) are virtually absent in these tumors. At the mRNA level, ER splice variants occur in meningioma but these appear not to be involved in the apparently autonomous PR expression. In an earlier study, because other ER-inducible proteins were either not expressed at all (pS2) or were expressed at a very low level compared to their expression in breast cancer (Cathepsin-D), the authors have postulated that the autonomous PR expression in meningioma is PR promoter-related rather than ER-related and have studied PR expression in cultured meningioma cells. PR levels appeared to decrease rapidly in vitro in monolayer as well as in three dimensional spheroid cultures. Culture conditions thus are not yet sufficient for the quantitative evaluation of PR expression. To evaluate whether PR deterioration is associated with cell turnover (meningiomas grow much faster in vitro than in vivo), the relationship between expression of the apoptotic proteins Bcl-2 and Bax and PR expression was investigated. Bcl-2 expression was found to be highest in meningioma with low PR levels, and in breast cancer tissue with high PR levels. Bax expression was not related to PR expression in any of the two tissues. Given the potential benefit of antiprogestin treatment and the occurrence in meningiomas of a protein capable of binding to the estrogen-responsive element, the expression of PR in meningioma remains a fascinating phenomenon which requires further investigation.