Biomedical subjects
M Kerscher
Publications and source records attributed to M Kerscher.
Discrimination of the toxic potential of chemically differing topical glucocorticoids using a neutral red release assay with human keratinocytes and fibroblasts.
In inflammatory skin disease, hydrocortisone and prednisolone double esters are about equipotent to conventional medium potency topical glucocorticoids, such as betamethasone valerate. Local adverse effects, in particular skin atrophy, are a potential problem with topical glucocorticoids. Recently, cell cultures have shown promise as a means of assessing local tolerance. To investigate the toxic potential of hydrocortisone, hydrocortisone-17-butyrate, hydrocortisone aceponate, prednicarbate, triamcinolone acetonide, betamethasone valerate and desoximethasone, human keratinocytes and fibroblasts were exposed to these agents in vitro, using a modified neutral red release assay. In addition, the morphology of these cells was assessed by light microscopy. Although all the topical glucocorticoids tested proved toxic to both cell types, there were major differences between glucocorticoids in their effect on fibroblasts. Hydrocortisone and the non-halogenated double-ester-type glucocorticoids were less toxic than the conventional medium potency topical glucocorticoids tested (betamethasone valerate and desoximethasone). In particular, hydrocortisone aceponate was less toxic than betamethasone valerate (P < or = 0.05). In general, the effect of topical glucocorticoids on the cells, based on neutral red release, was more marked with keratinocytes than with fibroblasts. Although the ranking order with respect to the toxic potential was similar, a clear-cut difference was not observed between non-halogenated double-ester-type glucocorticoids and betamethasone valerate. Morphological changes due to glucocorticoid exposure followed the same pattern with both keratinocytes and fibroblasts. The neutral red release assay is able to discriminate between the cytotoxic effects of chemically differing topical glucocorticoids on human keratinocytes and fibroblasts.(ABSTRACT TRUNCATED AT 250 WORDS)
PUVA-bath photochemotherapy of lichen planus.
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PUVA-bath photochemotherapy resulting in rapid clearance of lymphomatoid papulosis in a child.
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Treatment of localised scleroderma with PUVA bath photochemotherapy.
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The genomic structure of the human AP-2 transcription factor.
The transcription factor AP-2 is encoded by a gene located on chromosome 6 near the HLA locus. Here we describe the genomic organization of the AP-2 gene including an initial characterization of the promoter. We have mapped two mRNA initiation sites, the entire exon-intron structure and located two polyadenylation sites. The mature AP-2 mRNA is spliced from 7 exons distributed over a region of 18 kb genomic DNA. A recently cloned inhibitory AP-2 protein is generated by alternative usage of a C-terminal exon. The proline-rich transactivation motif is encoded by a single exon within the N-terminal region in contrast to the complex DNA binding and dimerization motif which involves amino acid residues located on four different exons. The sites of mRNA initiation are located 220 and 271 bases upstream from the ATG translation start site. Although the promoter contains no canonical sequence motifs for basal transcription factors, such as TATA-, CCAAT- or SP-1 boxes, it mediates cell-type-specific expression of a CAT reporter gene in PA-1 human teratocarcinoma cells and is inactive in murine F9 teratocarcinoma cells. We demonstrate that the promoter of the AP-2 gene is subject to positive autoregulation by its own gene product. A consensus AP-2 binding site is located at position -622 with respect to the ATG. This site binds specifically to bacterially expressed AP-2 as well as to multiple proteins, including AP-2, present in PA-1 and HeLa cell nuclear extracts. A partial AP-2 promoter fragment including the AP-2 consensus binding site is approximately 5-fold transactivated by cotransfection of an AP-2 expression plasmid.
[PUVA bath therapy. Indications and practical implementation].
Systemic PUVA photochemotherapy is widely used for a variety of skin diseases. Administration of 8-methoxypsoralen in a dilute bathwater solution may be an effective alternative therapy with no systemic side-effects and requiring smaller amounts of UVA to induce the required phototoxic response. PUVA baths of the palms and soles are an interesting alternative for dermatoses confined to these sites. This article reviews the authors' experience with PUVA bath therapy. Indications for and applications of this technique are discussed.
MTT-assay and neutral red release (NRR)-assay: relative role in the prediction of the irritancy potential of surfactants.
A comparative study on the in vitro and in vivo irritancy of anionic, amphoteric and non-ionic surfactants was performed. In vitro ED50 values of the surfactants were determined by two cytotoxicity assays, the dimethylthiazoldiphenyltetrazoliumbromide (MTT) assay and the neutral red release (NRR) assay on serum-free cultured human foreskin keratinocytes. In vivo human irritancy data were obtained by a 24 hour occlusive patch test in volunteers and the irritant skin response quantified by visual scoring, evaporimetry and colorimetry. A close relationship between the evaluation methods of the patch test was observed (r = 0.92 to r = 0.96), confirming that the 'bioengineering' methods, such as evaporimetry and colorimetry are suitable for measuring skin irritation. For six surfactants evaluated we found a good correlation (r = 0.91) between the ED50 values of the MTT assay and the in vivo irritancy data. The NRR assay yielded less satisfactory correlation coefficients with regard to MTT assay (r = 0.42) and in vivo irritancy data (r = 0.46). This can be mainly attributed to a misinterpretation of the amphoteric and non-ionic surfactants by the NRR assay. While the NRR assay may better evaluate the anionic surfactants, the MTT assay seems to be more suitable when testing a broader range of chemically diverse surfactants. Limitations of cell culture systems are noted, although the potential usefulness of cultured human skin cells for skin irritancy testing has been clearly demonstrated.
Discrimination of the irritancy potential of surfactants in vitro by two cytotoxicity assays using normal human keratinocytes, HaCaT cells and 3T3 mouse fibroblasts: correlation with in vivo data from a soap chamber assay.
Cell cultures have been proposed as a promising model for local tolerance testing. This study evaluated the cytotoxic effects of surfactants on early passage normal human keratinocytes, transformed human keratinocytes (HaCaT cells) and Swiss 3T3 embryonic mouse fibroblasts. Cell membrane integrity, as assessed by the release of the vital dye neutral red, and cell proliferation, as assessed by measurement of the total protein content, were both affected in a dose-dependent manner in response to surfactant exposure. There was a close correlation between the dose-response characteristics for the three cell types. Two surfactants exhibited differential effects on membrane integrity and proliferation, and thus no significant correlation was found between the two endpoints. The irritation potential of the surfactants to human forearm skin in vivo was assessed in a soap chamber test using transepidermal water loss and skin redness as quantitative endpoints. A comparison between the responses in vivo and in vitro yielded the highest correlation for the neutral red release test on normal keratinocytes. The total protein test did not significantly correlate with the soap chamber assay for keratinocytes and HaCaT cells. These results suggest that cultured normal human keratinocytes may be predictive for the irritancy of various surfactants in man. Definite judgement, however, has still to be based on confirmation in human volunteers of larger groups of compounds with diverse physico-chemical properties.
Chronic cutaneous damage after accidental exposure to ionizing radiation: the Chernobyl experience.
BACKGROUND: The hazards of acute radiation exposure are well known. Bone marrow failure from total body gamma or neutron irradiation is the most clinically relevant aspect of acute radiation disease. With nonhomogeneous exposure, as is characteristic in accidents, other organ systems, such as the skin, may be more important in determining clinical prognosis. This became obvious in the two worst radiation accidents since 1945, the Chernobyl accident in April 1986 and the Goiania accident in September 1987. OBJECTIVE: Our purpose was to describe the characteristic chronic sequelae of accidental cutaneous radiation in a group of patients who survived the Chernobyl nuclear power plant accident. METHODS: Fifteen patients with the delayed type of the cutaneous radiation syndrome were examined between September 1991 and January 1992. All patients had a history of acute radiation disease. The exposure pattern was characterized by partial body exposure with high doses of beta and gamma irradiation from radioactive water, steam, or dust. RESULTS: Radiation-induced lesions were confined primarily to the legs and distal arms, but sometimes involved up to 50% of the total body surface. In addition to telangiectases, radiation keratoses, and radiation ulcers, hemangiomas, hematolymphangiomas, splinter hemorrhages in the distal nail bed, lentiginous hyperpigmentation, and severe subcutaneous fibrosis were noted. No malignant transformation could be detected. Associated diseases included cataracts, chronic hepatitis, and recalcitrant bacterial and herpesvirus infections. CONCLUSION: After accidental partial body exposure to high doses of beta and gamma irradiation, the predominant involvement of the skin, described as the cutaneous radiation syndrome, can become the characteristic feature. This causes longlasting, serious diagnostic and therapeutic problems.
The complete murine cDNA sequence of the transcription factor AP-2.
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Combination phototherapy of psoriasis with calcipotriol and narrow-band UVB.
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Influence of topical erythromycin preparations for acne vulgaris on skin surface pH.
Topical erythromycin is a standard regimen for inflammatory acne vulgaris because of its action against Propionibacterium acnes. Changes in P. acnes colonization are inducible by long-lasting changes of skin surface pH. Therefore, the influence of six erythromycin preparations with approximative pH values of 7.5 (preparation A) to 10.2 (C) on the skin surface pH was evaluated in healthy volunteers using a cross-over design. Following a 14-day run-in period, a constant skin surface pH (5.0) was found. Ten subjects received single doses 2-3 days apart; 20 volunteers applied preparations A and C for 28 days. Single doses of preparations A and E (pH 8.0) increased skin pH to 6.99 and 8.61, respectively, at 15 min; it then gradually declined. The other preparations induced only a minor rise of short duration. At the end of the long-term application, the skin surface pH amounted to 5.73 (A) and 5.39 (C). There was no correlation between the effect on skin surface pH and the approximative pH of the preparations. A close relation of single-dose and long term-effects was observed, however. The skin surface pH during the application of preparation A is high enough to increase P. acnes growth about fourfold as compared with normal skin and thus may counteract the antibacterial effect. Clinical relevance should be evaluated in a controlled clinical trial comparing the efficacy of preparation A with that of preparation C.
0.25% prednicarbate cream and the corresponding vehicle induce less skin atrophy than 0.1% betamethasone-17-valerate cream and 0.05% clobetasol-17-propionate cream.
The atrophogenic potential of medium-potent topical glucocorticoids is still controversial. In a double-blind controlled trial 24 healthy volunteers either applied 0.25% prednicarbate cream or the corresponding vehicle to one and 0.1% betamethasone-17-valerate cream or 0.05% clobetasol-17-propionate cream to the other forearm twice daily. Skin thickness was regularly assessed during the six week period of application and for further three weeks thereafter, using both the B- and A-mode of a 20 MHz ultrasound scanner. Both betamethasone-17-valerate and clobetasol-17-propionate cream significantly reduced skin thickness as compared to cream base while prednicarbate cream did not. Given that 0.1% betamethasone-17-valerate- and 0.25% prednicarbate cream are reported to be about equipotent in the treatment of atopic eczema the latter preparation shows an increased ratio between its desired anti-inflammatory and its unwanted atrophogenic effect.
Commercial glucocorticoid formulations and skin dryness. Could it be caused by the vehicle?
Eczema craquelé can be induced by repeated open application of a topical glucocorticoid, viz. 0.05% clobetasole 17-propionate cream. This might not be invariably due to the active component. Comparison of the skin surface roughness as assessed by profilometry and as expressed by RZDIN showed a decrease after repeated open application of 0.1% betamethasone 17-valerate cream and 0.25% prednicarbate cream, but an increase following the vehicle of the latter preparation. Thus commercial oil-in-water emulsion preparations seem to be potentially injurious to human skin, though this may be masked when a glucocorticoid is added.
[Acute reduction of increased atrial natriuretic peptide level and cyclic guanosine monophosphate in patients with chronic heart failure caused by beta-adrenergic stimulation with dopexamine hydrochloride. Correlation with hemodynamic parameters].
In eight patients (63 +/- 8 years) with dilated cardiomyopathy, the acute effects of positive inotropic stimulation with dopexamine hydrochloride, a beta-2-agonistic and DA1-dopaminergic catecholamine, on the plasma levels of ANP and cGMP were tested. A four-point dose-response curve was prepared for dopexamine from 1 microgram/kg/min to 4 micrograms/kg/min. Each infusion stage lasted 15 min; ANP and cGMP were taken from the mixed venous blood. Hemodynamic parameters were determined by a Swan-Ganz catheter; cardiac output was determined by thermodilution. ANP dropped by 40% from 348 +/- 124 pg/ml to 208 +/- 70 pg/ml (p less than or equal to 0.01), while cGMP dropped by 25% from 4.8 +/- 1.6 pmol to 3.6 +/- 1.3 pmol/ml at the time of maximum hemodynamic effect after 1 h. Linear regression analyses revealed a significant relationship (p less than or equal to 0.01) between ANP as the independent variable and cGMP as the dependent variable. The hemodynamic determinants of the ANP concentration proved to be--independently of each other--the pulmonary capillary wedge pressure (p less than or equal to 0.01) and the mean right atrial pressure (p less than or equal to 0.01). The results show that chronically elevated ANP and cGMP levels can be strikingly reduced within a short time, whereby ANP and cGMP show similar kinetics. The results suggest a use of ANP and cGMP as humoral parameters in the therapy control of chronic heart failure.
[Detoxication of juvenile addicts in a general hospital (author's transl)].
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Time course of 8-methoxypsoralen-induced skin photosensitization in PUVA-bath photochemotherapy.
In recent years PUVA-bath photochemotherapy has been shown to be an effective treatment modality for several dermatoses. A limitation of PUVA-bath photochemotherapy has been the lack of guidelines for optimal performance, including the time course of photosensitization of the skin exposed to the 8-methoxypsoralen (8-MOP) bath water solution. In the present study 12 healthy volunteers were exposed to a 20 min bath in 150 l of an 8-MOP water solution (0.5 mg/l, 37 degrees C). Immediately, as well as 1, 2, 3 and 5 h after the 8-MOP bath, irradiation was performed with increasing doses of UVA (0.5, 1, 2, 3, 5 J/cm2) on 2 cm2 test areas. The minimal phototoxic dose (MPD) was determined 72 h after the UVA exposure. In all volunteers, photosensitization was highest immediately after the bath, with a MPD significantly below 5 J/cm2 (0.5-2 J/cm2). One hour after the bath, erythema could be induced by 2 to 5 J/cm2 UVA. Two hours after the bath, erythema could be induced using irradiation of 5 J/cm2 only in two volunteers. Three and five hours after the 8-MOP bath, no erythema could be induced in any volunteer by UVA doses up to 5 J/cm2. Our results indicate that optimal bath-PUVA requires UVA irradiation immediately after the 8-MOP bath. Further, these results imply that no restrictions on further sun exposure are mandatory 3 h after the 8-MOP bath, thus allowing the patient to pursue normal life activities.