The protein kinase C inhibitor AEB071 (sotrastaurin) modulates migration and superoxide anion production by human neutrophils in vitro.

We examined the effect of the protein kinase C-selective inhibitor AEB071 (sotrastaurin) on neutrophil functions in vitro. Pre-incubation with AEB071 at concentrations similar to those reached during in vivo therapy significantly reduced cell capacity to migrate toward three different chemo-attractants and to produce superoxide anions (O2⁻) in response to phorbol myristate acetate (PMA) or to N-formyl-methionyl-leucyl-phenylalanine (fMLP). AEB071 also significantly inhibited the O2⁻ overproduction induced by fMLP in neutrophils primed with tumor necrosis factor alpha (TNF-α) or granulocyte/macrophage-colony stimulating factor (GM-CSF). This inhibition was not linked to fMLP-receptor down-regulation since the drug had no effect on either fMLP-receptors or fMLP-induced CD11b membrane expression. When the activity of AEB071 was compared to that of the conventional protein kinase C (PKC) inhibitor Gö6850 (which, like sotrastaurin, inhibits classical and novel PKC isoforms), Gö6976 (an inhibitor of α and α PKC isoforms) and rottlerin (a prevailing δ PKC isoform inhibitor), AEB071 at an equimolar concentration of 3 µM (close to the maximum drug concentration reached in patients treated with AEB071) caused significantly more inhibition on both chemotactic response and superoxide production. These in vitro findings suggest that neutrophils may offer a cellular target for AEB071 activity in vivo.

Disseminated granuloma annulare: efficacy of cyclosporine therapy.

Granuloma annulare is an anatomo-clinical entity that is frequently encountered in everyday dermatological practice. We report our experience regarding 4 patients with disseminated granuloma annulare. Each patient was treated with a cycle of cyclosporine therapy for six weeks. A cycle of systemic cyclosporine therapy was started at a dose of 4 mg/kg/day for four weeks, subsequently reduced by 0.5 mg/kg/day every two weeks. The clinical picture more or less completely resolved within three weeks in all of the patients, and there were no relapses during the dose-tapering period or the following 12 months. Cyclosporine was optimally tolerated by all four patients, none of whom experienced any therapy-related side effects. Cyclosporine is a valid therapeutic option for the treatment of disseminated granuloma annulare, although we recommend its use in a protected hospital environment that facilitates patient monitoring.

Association of cyclosporine and 311 nM UVB in the treatment of moderate to severe forms of psoriasis: a new strategic approach.

Psoriasis is a T-lymphocyte mediated autoimmune disease. The response to therapies targeting T-lymphocytes suggest that the latter is a key cell in the pathogenesis of the disease. Cyclosporine (CsA) inhibits the proliferation and the IL-2 dependent expansion of T-lymphocytes. Ultraviolet radiation is an effective treatment for psoriasis. Several studies have demonstrated a significant improvement of the therapeutic response when narrow-band radiation is issued by TL-01 fluorescent lamp compared to broad- band UVB issued by other fluorescent sources. The effects of UVB on the immune system appear to be limited to the cell-mediated compartment of the immune response. In order to reduce the cumulative dose of UVB and limit the toxicity of drugs in the therapy of psoriasis, phototherapy with UVB has been used as treatment in association with other standard therapies. The purpose of the study is to evaluate, in patients with moderate to severe psoriasis a combined therapy with Cyclosporine A and 311 nm UVB phototherapy.

Mycosis on mycosis fungoides: zoophilic dermatophytosis selectively superimposed on pre-existing cutaneous T-cell lymphoma (mycosis fungoides) plaques.

We report a case of tinea corporis caused by a cattle-derived strain of Trichophyton mentagrophytes in a 44-year-old male affected by cutaneous T-cell lymphoma (CTCL, so-called mycosis fungoides). Fungal colonization of glabrous skin was strictly confined within pre-existing lymphomatous plaques. Either oral itraconazole or griseofulvin, or topical terbinafine were ineffective until the patient, who was treated with systemic retinoids and interferon-alpha for his CTCL, was shifted from leucocyte to lymphoblastoid interferon. The hypothesis that a local immunodisturbance could be responsible for the selective superimposition of tinea on CTCL lesions ('mycosis on mycosis'), and that such an immunodisturbance could be partially corrected by the interferon switch is discussed.

Sarcoidosis presenting as erythema annulare centrifugum.

Erythema annulare centrifugum (EAC), a disease belonging to the poorly characterized category of 'figurate erythemas', has been associated with a variety of conditions, such as connective tissue diseases, infections, neoplasms and drug reactions. Here we report a case of EAC associated with sarcoidosis, the first case in the literature to our knowledge. EAC was the sole sign of the granulomatous disease process, which was diagnosed by means of appropriate investigations only after the patient reported the sudden resolution of a long-standing sensitization to perfumes and parabens. Steroid treatment for sarcoidosis improved the patient's condition, and restored the allergic response to these substances.

Intramuscular low dose alpha-2B interferon and etretinate for treatment of mycosis fungoides.

BACKGROUND: Mycosis fungoides is a lymphoma of cutaneous origin characterized by a proliferation of cells with a T phenotype. METHODS: In this pilot study, 13 men with mycosis fungoides in various stages were treated with alpha-2b interferon and etretinate. RESULTS: In ten of them, such a therapy proved to be effective (7 complete responses, 3 partial responses), sometimes with prolonged remissions (up to 20 months, and still persistent) after suspension of the drugs. CONCLUSIONS: We chose low-dose interferon administration in order to prevent side effects, which are said to be dose-dependent. In our experience this is not true, but this drawback seems to be overcome by the very good, sometimes spectacular, response to this combination therapy, particularly in low stage forms of the disease. This fact, compared with results provided by other groups, prompts us to plan new research protocols based on associations of retinoids with different interferon types (or even associations of different interferons), because we believe they will have an important place in treatment of cutaneous T-cell lymphoma in future.

[Laser flow cytofluorimetry in the study of papilloma virus-induced lesions]. / La laser-citofluorimetria a flusso nello studio delle lesioni indotte da papillomavirus.

HPV insertion into the genome can cause permanent changes in cellular DNA that disturb the regulation of cell proliferation. Most HPV-induced epithelial proliferative disease are benign, but not all. We have studied both types of lesion by automated laser flow cytometry to see if there were any permanent changes in the DNA that might serve as reliable prognostic indicators. There were 101 lesions of interest to the dermatologist, stomatologist and gynecologist. Although fluctuations in yields of cells make it difficult to formulate definite conclusions, since many results are heterogeneous and hard to summarize, we found dysplastic and metaplastic lesions always to be hyper- or hypodiploid and to our surprise two cases of common wart were hyperdisploid and another hypodiploid. This present study shows that laser flow cytometry can detect changes in the genome of lesions known to become malignant when the histological degree of transformation still indicates only a preneoplastic condition. This raises the problem of how we should label lesions like common warts, since laser flow cytometry clearly shows that they have net changes, though slight, in DNA content.

Disodium cromoglycate versus diet in the treatment and prevention of nickel-positive pompholyx.

In some cases that have been diagnosed as contact allergy to nickel, there are repeated cutaneous eruptions of pompholyx, even in areas with no direct contact with the metal. The possible alimentary origin of dyshidrotic eczema should be considered when deciding on therapy. We have collected the clinical data for 24 patients with dyshidrotic eczema caused by nickel, to evaluate the benefit of a low-nickel diet versus treatment with oral disodium cromoglycate, comparing both objective and subjective symptoms. A low-nickel diet does not improve these patients but those treated with DSCG reacted better, from both objective and subjective point of view, than either the controls or the patients treated by diet. We next did intestinal permeability tests before therapy and after 15 days of treatment. We found that nickel uptake diminishes simultaneously with the reduction of absorption through the smaller aqueous "pores". This phenomenon was greatest after DSCG. We suggest that DSCG can help selected cases of pompholyx.

Occupational dermatitis in bakers: a clue for atopic contact dermatitis.

6 patients are described who developed contact dermatitis after cereal contact on atopic skin for periods of 2 to 20 years. 2 patients were wheat flour patch-test-positive. They had punch biopsies taken for standard histological and immunohistochemical investigation by labeling with monoclonal antibodies, anti-DR and anti-IgE. Sections showed features of contact dermatitis. There were many dendritic cells located perivascularly in the papilla and in the epidermidis, intensely positive for monoclonal anti-IgE antibody. In control atopic subjects, there were a few perivascular IgE positive cells, probably mastocytes. This study shows that there may be a relationship between some allergens and atopic eczema in patients exposed to them in the course of their work. In some cases, there was a true allergic contact dermatitis, seen through the clinical and histological characteristics, and the results of immunohistochemical study.

Isotretinoin versus minocycline in cystic acne: a study of lipid metabolism.

We have recently reported that patients with severe nodular cystic acne have much lower levels of HDL-cholesterol, apolipoprotein A and hepatic lipoprotein lipase than healthy controls or subjects with acne vulgaris. Since isotretinoin is very effective in the treatment of the nodular cystic acne but has been shown to increase blood lipid levels, we decided to compare its clinical effectiveness and its effects on lipid metabolism with those of minocycline in patients with nodular cystic acne. After 20 weeks, the number and mean diameter of the cysts were definitely decreased in both groups, but the improvement was more striking in the isotretinoin-treated group. At the end of the treatment, the HDL-C and hepatic lipoprotein lipase levels in this group were increased toward normal, but not in the minocycline-treated group. Our study showed a significant remission in the acne of patients treated with isotretinoin but not in that of the minocycline-treated patients. Furthermore isotretinoin can also correct the altered lipid metabolism in these patients.

Lipoprotein metabolism and lipoprotein lipase in severe cystic acne.

In severe cystic acne we found low levels of high density lipoprotein-cholesterol (HDL-C) and apolipoprotein A (Apo-A) in the presence of normal total lipids. In a larger number of patients, we always observed significantly lower levels of HDL-C and Apo-A than in either age-matched controls or subjects with acne vulgaris. Since lipoprotein lipase is one major determinant of HDL concentration, we assayed the lipase activity in liver and extra-hepatic tissues by the method of Krauss et al. There was highly significant less total and hepatic lipase activity than in age-matched controls. HDL distribution was examined by zonal ultracentrifugation and a decrease in the HDL2 subclass was discovered. Since HDL are inversely correlated to atherosclerosis, cystic acne is one risk factor for atherosclerosis. The linkage between low HDL levels and severe cystic acne should be further investigated.

Unusual cases of Meleda keratoderma treated with aromatic retinoid etretinate.

We studied a brother and sister of South Italian origin with palmoplantar keratoderma which, because of the clinical aspects (transgrediens et progrediens), mode of inheritance (autosomal recessive) and evolution, we diagnosed as Meleda keratoderma with particular clinical features (presence of ainhum-like narrowings and concomitant lesions at other sites). Appropriate classical histologic and familial investigations, as well as HLA typing were done, and retinol-binding protein values were determined. The patients were treated with the aromatic retinoid etretinate, and the clinical and histological results after 9 months' treatment are reported.

Effects of isotretinoin on the neutrophil chemotaxis in cystic acne.

The authors show that the use of Isotretinoin (Ro 4-3740) in cystic acne brings a reduction of chemotactic activity of the neutrophil granulocytes, like another retinoid, Etretinate, in pustular and vulgar psoriasis. This effect of retinoids, with a direct action on the polymorphonuclear leukocytes plays an important role in the recovery of the disease.