[Effectiveness of a micronized purified flavonoid fraction (MPFF) in the healing process of lower limb ulcers. An open multicentre study, controlled and randomized]. / Efficacia della frazione flavonoica purificata micronizzata (FFPM) nell'aumentare la guarigione della ulcere agli arti inferiori. Studio multicentrico in aperto, controllato e randomizato.

OBJECTIVE: To determine the increase in healing rate of venous ulcer in patients receiving a micronised purified flavonoid fraction (MPFF) as supplementation to standard local care. DESIGN: A randomised, open, controlled, multicentre study. SETTING: Departments of Dermatology and University Outpatients Clinics. PATIENTS: One hundred and forty patients with chronic venous insufficiency and venous ulcers. INTERVENTION: PATIENTS received standard compressive therapy plus external treatment alone or 2 tablets of MPFF daily in addition to the above treatment for 24 weeks. MAIN OUTCOME MEASURE: Healing of ulcers and their reduction in size after 24 weeks of treatment. RESULTS: The percentage of patients whose ulcers healed completely was found to be markedly higher in those receiving MPFF in addition to standard external and compressive treatment than in those treated with conventional therapy alone (46.5% vs 27.5%; p<0.05. OR=2.3, 95% CI 1.1-4.6). Ulcers with diameters <3 cm were cured in 71% of patients in the MPFF group and in 50% of patients in the control group, whereas ulcers between 3 and 6 cm in diameter were cured in 60% and 32% of patients (p<0.05), respectively. The mean reduction in ulcer size was also found to be greater in patients treated with MPFF (80%) than in the control group (65%) (p<0.05). The cost-effectiveness ratio (cost per healed ulcer) in the MPFF group was 1026.2 compared with 1871.8 in the control group. CONCLUSIONS: These results indicate that MPFF significantly improves the cure rate in patients with chronic venous insufficiency.

Acrogeria of the Gottron type in a mother and son.

We report a familial case of acrogeria in a mother and son, with characteristic cutaneous involvement and no clinical signs of vascular Ehlers-Danlos syndrome (former EDS type IV) in spite of some tendency to bruising. The biochemical and molecular studies did not disclose any abnormality of collagen type III, which favours the diagnosis of acrogeria. It appears that recognition of acrogeria as an entity is of clinical significance since these cases are not associated with systemic involvement, and specifically with rupture of vessels and internal organs, occasionnally occurring in EDS.

Modulation of CD3-dependent lymphocyte proliferation by extracellular matrix proteins in atopic dermatitis.

Patients with atopic dermatitis were found to have an about 7-fold increased spontaneous proliferative response of peripheral blood lymphocytes and an about 4-fold elevation of CD3-dependent lymphocyte transformation as compared to normal controls. The CD3-dependent lymphocyte response in patients with severe atopic dermatitis lesions was increased to a lower degree than in those with mild skin lesions. Despite a highly increased CD3-dependent lymphocyte response, the extracellular matrix proteins could induce further co-stimulation of lymphocytes in patients with atopic dermatitis, similar to that in normal controls. However, co-activation by type IV collagen was markedly increased in patients with severe lesions, whereas co-stimulations by both type I collagen and fibronectin were decreased in patients with mild lesions. This finding reflects presumably the changes in lymphocyte subpopulations and their activities related to the recirculation of these cells through the active skin lesions and to the contact of T cells with extracellular matrix proteins. The percentage of CD26-positive lymphocytes was also significantly (p < 0.05) increased in patients with severe atopic dermatitis. These data indicate that helper T cells are excessively activated in atopic dermatitis and that the function of beta-1-integrin receptors underlying the extracellular matrix protein-mediated co-activation of CD3-dependent lymphocyte responses is modified by disease severity.

Excessive costimulation of CD3-dependent lymphocyte response by extracellular matrix proteins in severe widespread psoriasis.

Costimulation of anti-CD3-triggered proliferative T-cell responses by type I and type IV collagen and fibronectin was studied in 25 patients with psoriasis and 12 healthy subjects. The stimulation index of anti-CD3-mediated responses in the presence of type I collagen was about half that in the controls. Although the CD3-dependent proliferative response of psoriatic lymphocytes in patients with active widespread plaque psoriasis was reduced by about 50%, costimulatory responses induced by type IV collagen and fibronectin were found to be enhanced in relation to the controls. The degree of costimulation by type IV collagen and fibronectin was related to disease severity. The highest values of the stimulation index were found in patients with a PASI greater than 24, skin involvement of more than 40% of body surface area, and a duration of psoriatic lesions of more than 3 months. The results indicated that in active widespread plaque psoriasis subpopulations of T cells bearing receptors for some extracellular matrix proteins were increased in the peripheral blood. A factor responsible for this phenomenon may be trafficking of T cells through the basement membrane zone of psoriatic lesions, which presumably causes modification of T cell immunological responsiveness after recirculation.

Increased concentration of beta-endorphin in the sera of patients with severe atopic dermatitis.

Serum beta-endorphin was measured by radioimmunoassay in 25 patients with atopic dermatitis and 100 healthy subjects. The neuropeptide was found to be markedly (p < 0.001) increased in patients with atopic dermatitis (9.2 +/- 3.4 pg/ml) as compared to normal controls (6.1 +/- 1.5 pg/ml). A correlation between increased serum beta-endorphin concentration and some clinical parameters of the disease has been found. The statistically significant elevation of beta-endorphin was found in patients with widespread atopic dermatitis lesions involving more than 20% of the skin surface (11.1 +/- 3.6 pg/ml), a high disease severity score (10.7 +/- 3.7 pg/ml), and previous bronchial asthma symptoms (11.6 +/- 3.1 pg/ml). A possible explanation of increased beta-endorphin is either its generation in atopic dermatitis lesions by inflammatory cells or activation of pituitary-adrenal axis by psychoneural factors in the mechanism of chronic stress.

Increased concentration of beta-endorphin in sera of patients with psoriasis and other inflammatory dermatoses.

Serum beta-endorphin was quantified by radioimmunoassay in 71 patients with psoriasis vulgaris, other chronic inflammatory skin diseases with T-cell infiltrates [atopic dermatitis (n = 25), and systemic sclerosis (n = 34)], and 100 healthy subjects. The neuropeptide was found to be markedly (P < 0.001) increased in patients with psoriasis (14.4 pg/ml), atopic dermatitis (9.2 pg/ml) and systemic sclerosis (9.8 pg/ml) compared with normal controls (6.1 pg/ml). The highest values of beta-endorphin were found in patients with actively spreading plaque psoriasis (17.3 pg/ml), whereas lesion-free patients showed a reduction in neuropeptide concentration (10.2 pg/ml). The levels were much higher in patients with widespread psoriatic lesions (> 60% body surface; 16.2 pg/ml), which lasted longer than 3 months (15.8 pg/ml), whereas neither the presence of stress nor itching correlated with the serum peptide concentration. Our data suggest that beta-endorphin is produced in psoriatic lesions by inflammatory cells, rather than the increased levels being the result of activation of the pituitary-adrenal axis by chronic stress. The generation of neuropeptide in psoriatic lesions and its antinociceptive effect on the peripheral sensory nerves might explain why pruritus is a relatively rare phenomenon in psoriasis.

Neuropeptides in psoriasis: possible role of beta-endorphin in the pathomechanism of the disease.

BACKGROUND: An increased concentration of neuropeptides in psoriatic lesional skin may be responsible for alterations in the neurogenic erythematous response and transmission of stimuli through sensory nerve fibers (sensation of pruritus). METHODS: Increasing doses of capsaicin from 0.125 to 4 micrograms/cm2 were applied to nonlesional psoriatic skin to establish the minimal dose that induced the substance P-mediated neurogenic response in 30 patients with psoriasis. Plasma beta-endorphin was quantitated in 71 psoriatics by radioimmunoassay using NEN 1251-RIA kit. RESULTS: The mean beta-endorphin concentration was increased about 2-fold compared to normals, whereas doses of capsaicin needed to induce erythema were higher (1-4 micrograms/cm2) in psoriatics (mainly in patients with type II psoriasis) than in healthy subjects (0.125-0.25 microgram/cm2). CONCLUSIONS: The data indicate that increased beta-endorphin in psoriatic skin might affect both substance P-mediated neurogenic inflammation and transmission of sensory stimuli due to local antinociceptive effects of this opioid. The differences in the neurogenic response in type I and II psoriasis may be related to the degradation of substance P and beta-endorphin by neutral proteinases in the lesional skin.

Alterations of T-cell: extracellular matrix proteins interactions in psoriasis.

Recent data indicate that extracellular matrix proteins (collagens, fibronectin) co-stimulate T-cell lymphoproliferative responses in vitro. We have studied the co-stimulatory activities of those proteins in patients with psoriasis, a disease in which T cells infiltrating the skin are continuously exposed to collagen and fibronectin. CD3-triggered T-cell proliferative responses were lower in psoriasis but could be enhanced by collagens I and IV and fibronectin. Interestingly, collagen-I-dependent co-stimulation was markedly decreased in patients with psoriasis, while there was a trend towards the enhancement of collagen-IV-induced responses. Those disturbances were most frequently seen in patients with active and widespread lesions. It appears that abnormalities of extracellular matrix protein-derived signals could play a role in the immunopathology of psoriasis.

Decreased specific anti-elastase activity in the uninvolved skin of patients with psoriasis.

Inhibitory activities against elastase, chymotrypsin and trypsin were studied in the fluid from experimentally developed suction blisters in the uninvolved skin of patients with psoriasis. These activities determined by spectrophotometry of specific synthetic low molecular weight substrates were compared with respective antiproteinase activities in sera of 32 patients with psoriatic lesions, ten patients in remission, and ten healthy volunteers. A marked reduction (29.2%) in the specific elastase inhibitory activity of blister fluid was found in patients with psoriasis when compared with normal subjects (p less than 0.05), since neither chymotrypsin nor trypsin inhibitory activities were altered. This reduction was despite about a 30% increase in the elastase inhibitory activity in the sera of these patients, which was related presumably to their increased activity of alpha 1-proteinase inhibitor, the main serum antiserine proteinase inhibitor. A decreased blister fluid:serum elastase inhibition ratio was shown in a large majority of patients with psoriasis, even in symptomless patients. The deficiency in specific elastase inhibitory activity of suction blister fluid was predominantly associated with early onset of psoriasis, guttate lesions and inactive lesions, skin involvement less than 20% of body surface, duration of relapse shorter than 2 months, and frequent relapses. These data indicate that the uninvolved skin of patients with psoriasis contains low concentrations of specific elastase tissue inhibitor, which deficiency might result in an excessive in vivo hydrolytic activity of neutrophil elastase released from migrating cells in the psoriatic skin.

Neurogenic inflammation induced by capsaicin in patients with psoriasis.

Increasing doses of capsaicin were applied topically to the forearm skin of 30 patients with psoriasis, 16 patients with systemic scleroderma and 16 healthy volunteers. Only one-third of the patients with psoriasis responded with neurogenic inflammation to capsaicin doses of 0.125 and 0.25 microgram/cm2 in contrast to 81% of scleroderma patients and all the normal controls, who showed a positive cutaneous reaction. Higher doses of capsaicin (0.5-4 micrograms/cm2) were required to induce erythema and flare in patients with late-onset psoriasis (after 21 years of age) as well as in patients with more than 40% of skin surface involved with psoriatic lesion.

Ultrastructural changes of the skin induced by human leukocyte elastase and cathepsin G.

Human neutrophil elastase and cathepsin G at a concentration of 10(-6) M were found to attack various substrates when normal skin biopsy specimens were incubated at 37 degrees C for 1 h with either of these enzymes. Elastase damaged primarily hemidesmosomes, leading to the epidermal cleavage from the dermis, whereas cathepsin G damaged the membrane structures. Both these neutral proteinases were highly specific to basal lamina of blood vessels. This indicates that neutrophil elastase and neutrophil cathepsin G may play different roles in various skin diseases related to enhanced activity and infiltration of neutrophils.

[Atopic dermatitis: the role of mechanical trauma]. / Atopowe zapalenie skóry: rola urazów mechanicznych.

A case of atopic dermatitis was observed in a patient in whom clinical observation and radioimmunoassays failed to demonstrate any possible role of allergic mechanisms. The lesions were caused exclusively by contact with the irritating substances and mechanical pressure, even, at times, by pressure of clothes.

Basement membrane zone as a target for human neutrophil elastase in psoriasis.

Human neutrophil elastase was found, by indirect immunofluorescence using rabbit anti-elastase anti-serum, to be bound to basement membrane of psoriatic plaques in vivo. The enzyme was also identified inside the migrating neutrophils in the reticular dermis and dermal papillae, as well as outside the cells in micro-abscesses in psoriatic skin. In vitro incubation of normal skin with human neutrophil elastase resulted in the destruction of hemidesmosomes and separation of the epidermis from the dermis above localizations of bullous pemphigoid antigen. These findings are direct evidence that human neutrophil elastase could play a role in psoriasis in in vivo destruction of the epidermal-dermal junction.

Two subpopulations of patients with early and late onset of psoriasis differ regarding alpha 1-proteinase inhibitor activity.

Two subpopulations of patients with psoriasis were identified when activity of alpha 1-proteinase inhibitor was analysed according to the patient's age at onset of the disease. Patients with early onset had more active lesions, high incidence of familial psoriasis, and reduced alpha 1-proteinase inhibitor during flare similar to that activity in remission. In contrast, alpha 1-proteinase activity increased significantly during flare in patients with late onset (above 21 yrs of age) in response to the inflammatory process in the psoriatic skin.

Alpha 1-proteinase inhibitor in psoriasis: reduced activity in symptom-free patients and during flare.

The aim of this study was to quantitate the active fraction of the alpha 1-proteinase inhibitor (alpha 1-PI) in psoriasis. Serum proteinase inhibitory capacity was measured vs porcine pancreatic elastase of a known active fraction against its specific substrate (Suc-Ala3-pNA). The inhibitory capacity was determined in 21 symptom-free patients, 134 patients with skin lesions, and 23 healthy volunteers. Alpha 1-PI was found to be significantly decreased in symptom-free patients and in those with stationary lesions, in a manner similar to the reduced activity of neutrophil proteinases, elastase, and cathepsin G. The synthesis of alpha 1-PI was stimulated during the appearance of active psoriatic lesions, but to a much lesser degree in patients with early onset (less than or equal to 21 years) than in patients with late onset of psoriasis (greater than 21 years). The early onset subgroup differed by a more frequent familial occurrence of psoriasis and a more severe course of the disease. The data indicate that the regulation of the proteinase-alpha 1-PI system in psoriasis is abnormal and this may contribute to the pathogenesis of the disease. The decreased alpha 1-PI during flare may be responsible for the disease activity, at least in patients with early onset of psoriasis.