Biomedical subjects
G Goerz
Publications and source records attributed to G Goerz.
[Drug therapy in gynecology and obstetrics in inducible porphyria].
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Porphyrinogenic effects of atracurium, vecuronium, and pancuronium in a primed rat model.
Steroidal muscle relaxants might theoretically be contraindicated in acute hepatic porphyrias. Atracurium, on the other hand, has been proposed as the muscle relaxant of choice because of its extrahepatic degradation. To further investigate this problem, equipotent doses of atracurium, vecuronium, and pancuronium were determined in male Sprague Dawley rats, using evoked electromyography. After this pilot study, 64 rats were anesthetized, mechanically ventilated, and randomly allocated to eight groups. Animals in groups 1 through 4 received an intraperitoneal injection of arachis-oil 20 h before the experiments. For groups 5 through 8, an experimental porphyria was induced by use of the chemical substance 3,5-dicarbethoxy-1,4-dihydrocollidine (DDC), which was dissolved in arachis-oil and given 20 h prior to the beginning of the study. Rats of groups 1 and 5 served as controls; they received saline and were not given muscle relaxants throughout the experiment. For groups 2 and 6, atracurium was administered at a dosage of 4 mg/kg of body weight, followed by a continuous infusion of 15 mg/kg/h. Animals of groups 3 and 7 received vecuronium at a dosage of 1.5 mg/kg, followed by 7.5 mg/kg/h. For groups 4 and 8, pancuronium was given (0.75 mg/kg and 2.5 mg/kg/h, respectively). At the end of the 3-h study period, the liver was perfused and excised, and urine was obtained. Activity of the hepatic enzyme delta-aminolevulinic acid synthase (ALAS) and urinary concentrations of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) were determined.(ABSTRACT TRUNCATED AT 250 WORDS)
[Chloroquine retinopathy: avoidable by individualized daily dosing].
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UVA-induced autocrine stimulation of fibroblast-derived-collagenase by IL-6: a possible mechanism in dermal photodamage?
Like other cytokines, IL-6 has been reported to stimulate collagenase. In this study we were interested in whether IL-6 is involved in the ultraviolet (UV) mediated up-regulation of fibroblast-derived collagenase. Confluent fibroblast monolayers were irradiated under standardized conditions. Following UVA irradiation the bioactivity of IL-6 increased up to fiftyfold in the supernatants of irradiated compared to mock-irradiated fibroblasts. As determined by Northern blot analysis this was also reflected on the pre-translational level by a tenfold increase of IL-6-specific mRNA following UVA irradiation. Induction of IL-6-specific mRNA was maximal at 6 h post-irradiation, thus clearly preceding the maximal induction of collagenase mRNA at 24 h post-irradiation. To elucidate the regulatory role of IL-6 in the UVA induction of fibroblast-derived collagenase, monospecific polyclonal neutralizing antibodies directed against recombinant human IL-6 and antisense oligonucleotides specifically inhibiting the translation of IL-6 mRNA were used at various concentrations. The amount of UVA-induced collagenase mRNA was reduced in a dose-dependent manner when antibodies or specific antisense oligonucleotides were present during and after irradiation. Taken together our data provide first evidence that UVA enhances IL-6 synthesis and secretion in fibroblasts. IL-6 induces via an autocrine mechanism collagenase and may thus contribute to the actinic damage of the dermis.
Contact dermatitis from UV-A and UV-B filters in a patient with erythropoietic protoporphyria.
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UVA irradiation stimulates the synthesis of various matrix-metalloproteinases (MMPs) in cultured human fibroblasts.
UVA irradiation leads to photoaging including clinical features such as wrinkle formation, reduced recoil capacity and blister formation of the skin. Besides synthesis of the extracellular matrix, its regulated degradation by various matrix-metalloproteinases (MMPs) determines the amount and the composition of the extracellular matrix within the dermis and the basement membrane of the dermo-epidermal junction. In this study we therefore ascertained whether UV irradiation could modulate the synthesis of MMPs with substrate specificities for dermal (collagen I, III, V) and basement membrane compounds (collagen IV, VII, proteoglycans, laminin) and whether synthesis of the counteracting tissue inhibitor of metalloproteinases (TIMP-1) was also affected. Following UVA irradiation specific mRNAs of MMPs 1, 2 and 3 were induced concomitantly up to 5-fold compared to mock irradiated controls. In contrast, TIMP-1 mRNA levels remained unaltered. Immunoprecipitation indicated that after UVA irradiation synthesis and secretion of MMPs 1, 2 and 3 into the supernatant increased. Taken together, our data show that UVA irradiation coordinately induced MMPs 1, 2 and 3 implying similar mechanisms in their regulatory pathways, while TIMP-1 synthesis was not altered. Hence, unbalanced synthesis of MMPs potentially contributes to the dissolution of dermal and basement membrane compounds finally leading to blister formation and cutaneous photoaging.
Lipid composition and synthesis of HaCaT cells, an immortalized human keratinocyte line, in comparison with normal human adult keratinocytes.
Cultured keratinocytes are frequently employed for studies of epidermal lipid metabolism. Interpretation of experimental data may be complicated by donor to donor variability, the relatively short culture lifetime and variations between passages, problems that are not encountered to the same extent with immortalized cell lines. The present study was undertaken to compare the lipid composition and synthesis of normal human adult keratinocytes (NHAK) with HaCaT cells, a long-lived, spontaneously immortalized human keratinocyte line, in relation to proliferation and differentiation. No differences between the two cell types were observed: a) in total lipid content; b) in the distribution of major lipid classes during growth at 50%, 75% and 100% confluence; c) in cultures grown at 0.6 mM calcium, at which differentiation is retarded, or at 1.6 mM calcium, at which some differentiation takes place; d) in the incorporation of [14C] acetate into cellular lipids at confluence, or e) in the fatty acid composition of major cellular lipid classes. At 100% confluence NHAK and HaCaT cells differ in their cholesterol metabolism. At all stages of growth, cholesterol synthesis in HaCaT cells is more LDL-dependent than in NHAK. Furthermore, NHAK become less LDL-dependent at confluence whereas HaCaT cells do not. HaCaT cells also revealed a significantly larger fraction of phosphatidyl-ethanolamine, -serine and -inositol at 0.6 mM calcium concentration than NHAK. These findings suggest that HaCaT cells do not differentiate as well as NHAK in vitro and may therefore serve as a model for the study of lipid metabolism in cells defective in terminal differentiation.
Inhibition of hepatic microsomal drug metabolism by atracurium administration in the rat.
The muscle relaxant atracurium is known to undergo extrahepatic degradation via Hofmann elimination and ester hydrolysis. The purpose of the present study was to evaluate the effects of atracurium on hepatic P450-dependent enzyme activities. Thirty-two male Sprague-Dawley rats were anaesthetized, mechanically ventilated, and randomly allocated to one of four study groups: group 1 received saline, group 2 atracurium, group 3 vecuronium, and group 4 pancuronium intravenously for a period of 3 hr. Equipotent doses of the muscle relaxants were applied; the doses had been obtained in a pilot study using evoked electromyography. At the end of the study period, the livers were removed and analyzed. All three muscle relaxants may lead to inhibition of hepatic drug metabolism. Atracurium influences hepatic P450, although it is predominantly degraded in extrahepatic tissues. Further studies are needed to evaluate the contribution of the major metabolite laudanosine to this inhibitory action.
Adverse immune reactions to gold in rheumatoid arthritis: lack of skin reactivity.
Adverse immune reactions develop in up to 30% of patients treated with gold compounds. However, sensitization to gold(I) drugs is rarely demonstrated by in vivo or in vitro testing. Recent data from a mouse model provides evidence that gold(I) is oxidized to gold(III) before T cells are sensitized. To study the diagnostic value of skin tests, patch testing with various gold compounds - including gold(I) and gold(III) - was performed in 50 patients with rheumatoid arthritis treated with gold(I) drugs. Positive patch test reactions to either gold(I) or gold(III) compounds were not detected. In contrast, the lymphocyte transformation test (LTT) revealed a gold(III)-induced response in one of the 7 patients being tested. We conclude that patch testing fails to indicate T cell sensitization to gold(I) drugs in rheumatoid arthritis patients. The in vitro response to gold(III) obtained by LTT supports the hypothesis that biooxidation of gold(I) compounds may play a crucial role for sensitization.
Influence of clonidine on the porphyrin metabolism in female rats.
Effects of different doses of clonidine (CAS 4205-90-7) (15, 150, or 300 micrograms/kg body weight) over a period of 3, 14, or 64 days on the activities of delta-aminolevulinic acid synthase (ALA-S) and the P450 dependent isoenzymes aminopyrine-N-demethylase (ADM), 7-ethoxycoumarin-O-deethylase (7-ECO-D), and 7-ethoxyresorufin-O-deethylase (7-ERO-D) as well as on the hepatic porphyrin and P450 content were studied in female rats. Additionally, the urinary excretion of total porphyrins, and porphyrin precursors delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) and the plasma clonidine level were measured. No changes in the activity of ALA-S and in the hepatic and urinary porphyrin, ALA and PBG contents were observed. An increase in the activities of ADM in the short and median term application of clonidine and of 7-ERO-D in the long term application was detected. It is concluded from these findings that clonidine has no effect on the porphyrin biosynthesis, but has an influence on the activities of P450 dependent isoenzymes ADM or 7-ERO-D.
[Lymphomatoid papulosis in a child].
We report a case of a 3-year-old boy who developed crops of papules and ulcerating nodules on the limbs in April 1992. Periodically, new lesions continue to erupt, while others resolve spontaneously. This course is characteristic for rhythmic paradoxical eruptions. This course and the clinical picture, supported by the histopathological and immunohistochemical findings, led to the diagnosis of lymphomatoid papulosis. Lymphomatoid papulosis is extremely rare in childhood. All published cases of lymphomatoid papulosis in children under 10 years of age are reviewed. The differential diagnosis of lymphomatoid papulosis in childhood includes arthropod assaults, pityriasis lichenoides et varioliformis acuta, primary cutaneous Hodgkin's disease, Ki-1 large cell anaplastic lymphoma and other lymphomas and pseudolymphomas in children.
[Cyclosporin A therapy in pyoderma gangraenosum].
A 33-year-old woman with pyoderma gangrenosum was treated with cyclosporine A. Cyclosporine A is a valuable drug for the treatment of recalcitrant pyoderma gangrenosum. Its mechanism of action is discussed. The numerous side-effects require close monitoring of cyclosporine A blood levels and several other parameters.
[Hyperpigmentation in primary adrenal cortex insufficiency: Addison disease].
Diffuse hyperpigmentation of the skin may develop without preceding inflammatory skin disease or be associated with various inflammatory disorders. The differential diagnosis of the diffuse hyperpigmentation is complex and difficult. We present a 36-year-old woman with diffuse hyperpigmentation caused by adrenal insufficiency, with special reference to the diagnosis and differential diagnosis of hyperpigmentation associated with endocrine disorders. In addition, metabolic, toxic, nutritional and internal factors and the skin-associated diseases leading to hyperpigmentation are categorized. A classification of diffuse hyperpigmentation is presented.
[Skin diseases of the vulva].
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[Acne necrotica (varioliformis). Necrotizing lymphocytic folliculitis].
We report on a 32-year-old woman with chronic relapsing papular and papulopustular lesions in the area of the hairlines and on the scalp. The diagnosis of acne necrotica (varioliformis) was made on the basis of the typical clinical picture and the histopathology, which showed necrotizing lymphocytic folliculitis. This rare disease must be differentiated from other pustular diseases of the scalp. Acne necrotica has been known as an entity since the beginning of the last century. In recent literature, however, it has received little attention.
[Canthaxanthin retinopathy. Follow-up of over 6 years].
After long-term treatment with high dosages, canthaxanthin causes a characteristic retinopathy with circular, macula surrounding crystals. As changes in retinal functionning disappear relatively easily after withdrawal of the drug, the crystals dissolve rather slowly--over about several years. Five patients showing a profound crystalline retinopathy were re-examined with an average of 69.7 months after withdrawal of the canthaxanthin-containing drug. Three of the patients were treated for erythropoetic protoporphyria (EPP) with Phenoro (2/5 beta-carotene, 3/5 canthaxanthin), two sisters took a canthaxanthin-containing formulation (1/8 beta-carotene, 7/8 canthaxanthin) for cosmetic reasons. Two female patients complained about an increased glare sensitivity, which was explainable for one of them with a subcapsular cataract. The retinal crystals decreased quite differently. Minor deffects of the retinal pigment epithelium remained unchanged in two patients. They increased slightly in the female patient with the smallest crystal formation but highest plasma cholesterol. Shortly after withdrawal of the drugs usually an increase of a-wave amplituded of the electroretinograms was found. The a-waves returned to normal and the b-wave amplitudes showed an increase up to the final control paralleling the reduction of the retinal crystals. A- and b-wave peak latencies which were prolonged under treatment returned to normal.
Migration of a human keratinocyte cell line (HACAT) to interstitial collagen type I is mediated by the alpha 2 beta 1-integrin receptor.
The migratory response of the human keratinocyte cell line HaCaT to collagen type I and the molecular mechanism underlying collagen-mediated migration have been analyzed. The migratory response of HaCaT cells to collagen type I consisted of a dose-dependent migration to insoluble step gradients of substratum-bound collagen (haptotaxis) and to gradients of soluble collagen (chemotaxis). Checkerboard analysis demonstrated a minor chemokinetic component. Denatured collagen type I was less chemoattractive than the native triple-helical form. Pre-treatment of cells with 25-250 micrograms/ml of synthetic peptides containing the fibronectin cell-recognition sequence RGD (Arg-Gly-Asp) resulted in a concentration-dependent inhibition of fibronectin-mediated chemotaxis, whereas chemotaxis to collagen was not affected. We then investigated the role of VLA/collagen-receptors for collagen type I-induced chemotaxis. Monoclonal antibody (MoAb) 5E8, which selectively blocks function of the alpha 2 subunit of the VLA-2/collagen receptor, dose-dependently inhibited the chemotactic response of HaCaT cells to collagen. This effect was specific for collagen-mediated chemotaxis because the chemotactic response to fibronectin remained unaffected. In contrast, a function blocking MoAb directed to the alpha 3 subunit of the coexpressed VLA-3 receptor, which is also capable of binding collagen, had no effect. However, function blocking MoAb directed to the beta 1-chain of integrins completely inhibited chemotaxis to collagen type I. Based on our results, we propose that the chemotactic migration of the human keratinocyte cell line (HaCaT) to collagen type I is specifically mediated by the RGD independent VLA-2/collagen receptor (alpha 2 beta 1) of the integrin family.