Biomedical subjects
Publications and source records attributed to B Kalis.
Medicinal photoprotection is indicated in photosensitive skin diseases and photodermatoses. Vitamin PP and para-aminobenzoic acid can be tried in benign estival polymorphous light eruptions. Carotinoids are efficient in erythropoietic protoporphyria and useful in idiopathic polymorphous light eruptions and in remanent photosensitization. Immunodepressants may be used against remanent photosensitization.
A role for the cytokines produced by tissue-infiltrated inflammatory cells (mainly T-lymphocytes and mast cells) in the pathophysiology of fibrosis has been suggested by several groups. Among the products of these cells, interleukin-4 (IL-4) might be one of the factors involved in the initiation of the fibrotic process. We studied the effects of recombinant human IL-4 on human fibroblast monolayer cultures. IL-4 (10 and 100 U/ml) induced a dose-dependent increase of collagen production. Non-collagen protein synthesis was not significantly altered. A concomitant increase of pro-alpha 1(I) collagen mRNAs was observed, showing that IL-4 acts at a pre-translational level.
BACKGROUND: The biologically active form of vitamin D3, calcitriol, may offer a new therapeutic approach to psoriasis. Calcipotriol, a new vitamin D3 analogue, is at least 100 times less calcemic than calcitriol. OBJECTIVE: Our purpose was to study the efficacy and safety of calcipotriol in the treatment of psoriasis vulgaris. METHODS: In a right/left comparative, double-blind study, treatment with calcipotriol ointment (50 micrograms/gm) twice daily and placebo was given for 4 weeks. The preferred treatment was continued, without opening the code, for another 4 weeks. Efficacy, as measured by the Psoriasis Area and Severity Index and by the investigator's and patient's global assessment, and safety were assessed every 2 weeks. RESULTS: The mean Psoriasis Area and Severity Index fell in 4 weeks from 14.2 to 6.3 with calcipotriol and from 14.1 to 9.2 with placebo (p < 0.001; 95% confidence interval for difference: 1.78-->3.94). Local side effects were equally common with calcipotriol and placebo. The mean serum calcium remained unchanged. CONCLUSION: Topical application of up to 50 gm of calcipotriol ointment per week was found to be an effective and safe treatment of psoriasis vulgaris.
119 patients with metastatic melanoma received fotemustine 100 mg/m2 on days 1 and 8 and dacarbazine 250 mg/m2 on days 15-18. After a 5-week rest, fotemustine 100 mg/m2 on day 1 and dacarbazine 250 mg/m2 on days 2-5 was given every 3-4 weeks. 12 complete responses (11.6%) and 16 partial responses were observed in 103 evaluable patients (response rate 27.2%). The median duration of response was 21.5+ weeks (8+ to 53+). The response rate was 26.3% in CNS, 18.2% in visceral sites and 37.5% in non-visceral sites. The toxicity was mainly haematological: grade III-IV leukopenia in 27.4% and thrombocytopenia in 23.4%. The response rate was lower than that in 63 patients previously reported. The present series had a higher median age (54 vs. 40 years) without any differences in other population variables. However, activity on CNS metastases and on non-visceral sites was confirmed. Haematological toxicity was about 50% lower than that with fotemustine alone. Hence, this is an active outpatient regimen for metastatic melanoma, especially against cerebral and non-visceral metastases.
Recent studies have shown inhibition of collagen synthesis by interferon gamma (IFN-gamma) in monolayer human fibroblast cultures on a plastic solid phase. However, the existence of this effect in vivo has not yet been demonstrated. Three-dimensional fibroblast cultures in collagen matrices (collagen lattices or dermal equivalents) provide a more physiological model than conventional cultures and fairly closely simulate in vivo conditions. This model was used for studying effects of IFN-gamma on normal and scleroderma fibroblasts. IFN-gamma induced a dose-dependent inhibition of fibroblast-mediated retraction of collagen lattices. IFN-gamma also inhibited total protein and collagen synthesis. Scleroderma fibroblasts were especially susceptible to the inhibitory effects of IFN-gamma. Since fibrotic scleroderma lesions are associated with tissue retraction and increased production of extracellular matrix macromolecules, these data confirm the potential value of IFN-gamma for the treatment of scleroderma and other fibrotic diseases.
Explore the source record for details and available documents.
Three-dimensional collagen lattice cultures of fibroblasts mimic the in vivo situation better than monolayer cultures. Here, skin fibroblasts from scleroderma patients and healthy controls were cultivated in collagen lattices, and the effects of recombinant human gamma-interferon (IFN-gamma) on these cultures investigated. IFN-gamma inhibited collagen lattice retraction in a dose-dependent way at concentrations ranging from 10 to 10,000 U/ml. This effect was independent of any alteration to the cell proliferation within the lattices. The inhibition was of the same order of magnitude in normal and pathological fibroblasts. The synthesis of collagen and non-collagen proteins, particularly fibronectin, was increased in scleroderma cultures. It was inhibited in both normal and scleroderma fibroblasts by IFN-gamma, with a maximal effect at the concentration 1000 U/ml, but the inhibition of protein synthesis was far more intense in scleroderma than in normal cells. In situ hybridization, Northern blot and dot blot analyses showed that mRNA coding for pro alpha 1(I) collagen was decreased in IFN-gamma-treated cells, indicating an effect at the pretranslational level. IFN-gamma also inhibited glycosaminoglycan synthesis, but in scleroderma cells only. This study shows that IFN-gamma regulates cell behavior in three-dimensional collagen matrices: (i) it decreases protein and specifically glycosaminoglycan synthesis in scleroderma fibroblasts, (ii) it modulates the interactions between cells and matrix that lead to the retraction of the lattice. Whereas collagen synthesis is largely decreased in lattice cultures like in vivo, it remains increased in the case of scleroderma compared to normal fibroblasts and may be down-regulated by IFN-gamma. Similar conclusions may be drawn for fibronectin and glycosaminoglycans. The inhibitory effect of IFN-gamma on the retraction capacity of fibroblasts and on their ability to synthesize increased amounts of extracellular matrix macromolecules may be of potential interest for therapeutic use of IFN-gamma in scleroderma patients.
Forty-five patients with cutaneous T-cell lymphomas (CTCL), 32 with mycosis fungoides (MF) and 13 with Sézary syndrome (SS), were treated with interferon-alpha 2a (IFN-alpha 2a) (6-9 x 10(6) IU daily) for 3 months. Those responding to treatment were then treated with interferon-alpha alone (6-9 x 10(6) IU three times weekly), and non-responders received a combination of etretinate (0.5 mg/kg/day) and IFN-alpha 2a in similar concentrations. After 12 months of treatment, 28/45 patients (62.2%) were in complete or partial (greater than 50%) remission. Of these, 17 (60.7%) were receiving IFN-alpha alone and 11 the combined interferon-retinoid therapy. Of the patients with MF stage I and II, 20/25 were responders (12 receiving IFN-alpha alone and eight on combined therapy), whereas only 8/20 with stage IV or SS responded to treatment (five receiving IFN-alpha 2a alone and three combined therapy). These results suggest that the association of etretinate with low-dose recombinant IFN-alpha 2a is an effective means of treating epidermotropic CTCL, particularly in the early stages.
Skin fibroblasts from 18 scleroderma patients were seeded into collagen lattices and their ability to retract their substratum was compared with that of control fibroblasts from healthy donors. When considered as a whole, scleroderma fibroblasts retracted lattices earlier and more intensely than controls. Analysis of individual results demonstrated that morphea and diffuse systemic sclerosis (dSSc) fibroblasts had different kinetics of lattice retraction. Fibroblasts which contracted lattices more intensely than controls were found to produce increased levels of fibronectin. A comparison of the retraction of collagen lattices by fibroblasts from involved (IS) and uninvolved skin (US) of the same patients (n = 4) showed that those from IS retracted the lattices more than fibroblasts from normal donors, whereas a high variability was found with fibroblasts from US. The increased retraction of collagen lattices seems to be a feature of the more severe forms of scleroderma.
Explore the source record for details and available documents.
We report the results of a French multicentre study to evaluate the efficiency of psoralen plus ultraviolet A (PUVA) therapy in the prophylactic treatment of benign summer light eruption (BSLE) and to establish the optimal protocol of radiation. Nine photobiology centres took part in this study; 83 patients (76 of them women) were evaluated. The radiation protocols were as follows: oral psoralen (8-methoxypsoralen; 0.6 mg/kg) was taken at each session; the starting dose of UVA radiation was determined according to skin type, with increments of 0.5 J/cm2 every 2 sessions. The subjects were randomized to receive 10-20 sessions 3 times per week. PUVA therapy was very effective: 68 patients (82%) reported total protection from BSLE. Four patients (5%) showed progress. Only 13% showed no improvement. The satisfactory results were not correlated with either the number of sessions or the J/cm2 of UVA. The intensity of tanning after the PUVA sessions did not appear to predict cure. Thirty-six percent of the patients had adverse reactions to treatment, including erythema, pruritus and triggering of BSLE. However, these effects only required the treatment to be stopped in 2% of the cases (for severe pruritus). The results in the various centres were similar.
Interleukin-4 (IL-4) is one of the products of T-lymphocytes and mast cells, inflammatory cells which accumulate in connective tissues at early stages of fibrosis. We tested the effects of IL-4 on human fibroblasts from normal and scleroderma skin seeded in three dimensional collagen lattices ("dermal equivalents"). IL-4 (10 and 100 U/ml) stimulated collagen synthesis in a dose-dependent manner. No significant alteration of lattice retraction and cell proliferation was observed. At the concentration 100 U/ml, Il-4 was approximately twice more efficient on collagen synthesis than Transforming Growth Factor beta (10 ng/ml). IL-4 secretion in connective tissues might be an important factor for the development of fibrotic processes.
Vitamin A acid has been used for 20 years in the local treatment of acne. In 1986, Kligman published a description of the efficacy of this molecule against skin ageing. In 1987, we began a study which is still in progress. It is intended to confirm the beneficial effects already observed in photosenescence and to demonstrate them by non-invasive methods and by standardized photographs. This study was randomized and carried out under double blind. Each patient acted as her own control. The concentration administered was 0.025 per cent for 6 months and then 0.05 per cent. The patient was followed up every month for 6 months and then every 4 months. The results demonstrated a reduction in the number and depth of the wrinkles and a regression of the pigmented spots. Safety was excellent and all the patients were highly satisfied with the treatment.
Sixteen patients with localized scleroderma (LS) and 11 with progressive systemic sclerosis (PSS) were studied using non-invasive techniques to determine skin thickness, skin extensibility, transcutaneous PO2 and cutaneous blood flow and were compared with normal controls. LS was characterized by a decreased skin extensibility with thickening of the skin in progressive lesions. There was an increase in the cutaneous microcirculation with a decrease in the PO2. In PSS, there was a decrease in the skin extensibility caused by thickening of the skin, but no change in cutaneous microcirculation or PO2 values. These results indicate that skin thickness and extensibility are the most useful parameters in the study of the progression of LS and PSS.
Fifty patients suffering from histologically proven metastatic melanoma were treated with a combination of DTIC (400 mg/m2 i.v. every 28 days) and recombinant alpha 2A interferon (Roferon-A) 10 x 10(6) U/m2 daily, administered intramuscularly or subcutaneously for 2 months followed by 7 x 10(6) U/m2 3 times a week. Treatment was carried out for a period of 12 months unless progressive disease was noted after 3 months. Among the 49 evaluable patients, 6 achieved a complete response (CR) and 4 a partial response (PR) (response rate, 20%) at 2 months, 8 CR and 3 PR (25%) and 8 CR and 2 PR (23%; 95% confidence limits, 13-40%) occurred at month 6 and 12 respectively These responses occurred notably in patients with cutaneous (3 cases) or lymph node metastases (4 cases), but 3 responses included visceral sites: lung (1 CR), liver (1CR and 1PR). Average response duration was 16.5 months (range 4-29 + months). The time required for objective response can be up to 6 months, which suggest that treatment should receive a reasonable trial period (at least 3 months). Clinical toxicity consisted mainly of a flu-like syndrome, anorexia and fever, and occurred in more than 50% of patients; hematologic and hepatic toxicities required a dose reduction in 54% of patients but in only one case did treatment have to be terminated because of this. Seventeen (35%) of the patients are still alive, 4 with metastases (follow-up period: 18-34 + months) and 13 without metastases (follow-up period: 13-32 + months). A combined regimen of r-IFN alpha 2A and dacarbazine is effective in treating patients with metastatic melanoma, with acceptable toxicities and a reasonable quality of life (out-patient treatment or district nurse care). The objective response rate (23% at 12 months) compares favourably with those of earlier trials using the same combination of drugs, and occurred not only in cutaneous and lymph node metastases but also in visceral metastases.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.