Lupus miliaris disseminatus faciei evoked during pregnancy in a patient with cutaneous lupus erythematosus.
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Adult↗
Biomedical subjects
G Messer
Publications and source records attributed to G Messer.
Dorfman-Chanarin syndrome: morphologic studies and presentation of new cases.
Dorfman-Chanarin syndrome, or neutral lipid storage disease with ichthyosis, is a rare inherited metabolic disorder characterized by accumulation of neutral lipids in different tissues. Variability in dermatologic severity is not understood. We report two new cases, compare their features with other reported cases, and examine the possible relationship between the severity of the dermatologic condition and lipid accumulation in various types of skin cells. The localization of lipid droplets was determined in various dermal and epidermal cells by light microscopy of epoxy resin semithin sections and electron microscopy in four cases of Dorfman-Chanarin syndrome. Lipid droplets in the dermis were detected in fibroblasts, Schwann cells in both myelinated and unmyelinated nerves, smooth muscle cells, and sweat gland cells, but not in endothelial cells of blood capillaries. The droplets were not surrounded by a membrane. Findings indicate that there is no correlation between the clinical severity of the disease and the microscopic findings.
Adolescent↗
Isolation of a hypoxia-induced cDNA with homology to the mammalian growth-related protein p23.
Hypoxia leads to a cellular stress reaction and can induce transcription of immediate early genes, such as c-fos. We have generated a differential cDNA cloning strategy to isolate further hypoxia-induced genes. We report on the identification and characterization of a novel transcript (cDNA clone pSH16), which is inducible 12-fold in HeLa cells after 50 min of exposure to hypoxia. Sequence analysis revealed a hybrid transcript with high homology to the mammalian growth-related protein p23 mRNA fused to mitochondrial 16S rRNA. Complete homology was found for the coding region, whereas the 3'-untranslated part of the hypoxia-induced p23 sequence was elongated and carried an ATTTA box and a second consensus poly(A) signal in addition. The functional integrity of the pSH16 mRNA was verified by cell-free translation. Hypoxia induced the expression of both fusion partners, p23 and 16S rRNA, separately. In contrast to the hypoxia-induced expression in HeLa cells, we found constitutive high-level expression in breast and cervix tissue. No further upregulation of p23 transcripts was detectable in primary tumors of the breast and cervix. These data provide first evidence for a hypoxia-induced upregulation of the mammalian growth-related protein p23, which might be relevant for understanding of the physiology of hypoxic conditions in tumors.
Amino Acid Sequence↗
[MRI of fingers in systemic scleroderma. Initial results with contrast-enhanced studies using a dedicated MRI system].
PURPOSE: To estimate disease activity in patients with systemic sclerosis using contrast-enhanced MRI of the skin. MATERIAL AND METHODS: In a pre-study, sequences of a low-field (0.2 T) scanner (Artoscan, Esaote, Genova, Italy) were optimized for detection of intravenous contrast (0.1 mmol/l Gd-DTPA) in six patients with the autoimmune disease systemic scleroderma. Based on the results of the pre-study, 17 patients with scleroderma (7 sclerotic/10 active inflammatory disease) were scanned using gradient-spoiled 3D GRE sequences (FA 90 degrees, TR 100 ms, TE 18 ms), which had been established as most sensitive for intravenous contrast. Contrast enhancement of the skin was determined quantitatively by contrast-to-noise ratios (CNR), comparing post- to pre-contrast and dynamic scans (for 6 min, 1 acquisition/min). Patients in the chronic state with sclerodactylia and active inflammation of the hands were considered separately and compared to a control group (n = 10) matched according to age. RESULTS: CNR increase after intravenous contrast was significantly higher in patients with active disease (86 +/- 16% increase) than sclerosing disease (29 +/- 3%, p < 0.05) and the control group (4 +/- 2%, p < 0.05). The dynamic examination showed a significantly slower decrease after the peak rise in the first minute in patients with active disease (CNR 15.4 +/- 0.7 to 14.2 +/- 1.4) than in those with chronic disease (14.1 +/- 0.5 to 11.3 +/- 0.9, p < 0.05). DISCUSSION: Capillary leakage is the most likely explanation for the increased enhancement in patients with active scleroderma. Using sequences optimized for contrast detection, disease activity in the course of scleroderma and response to therapy can be determined by MRI in the future.
Adult↗
Monitoring cholesterol crystallization from lithogenic model bile by time-lapse density gradient ultracentrifugation.
BACKGROUND/AIMS: Cholesterol crystallization in a dilute, bile salt-rich model bile is a multiphase process in which early filamentous crystals gradually transform to classical cholesterol monohydrate plates. The pertinence of similar transformations in more complex model systems or native bile is, however, unclear. The aim of the present study was to characterize and monitor cholesterol crystallization in a model bile of physiological relevance. METHODS: A supersaturated model bile was prepared with a lipid composition (18 mM cholesterol, 37 mM lecithin, 120 mM taurocholate) that was derived from analyzing 10 gallbladder biles from cholesterol gallstone patients. Cholesterol crystallization was followed by light and electron microscopy, and sequential density gradient analysis of cholesterol-containing precipitates. RESULTS: During cholesterol crystallization a reproducible sequence of events was recorded. First (T<18 h), cholesterol-rich vesicular and multilamellar structures (density 1.005-1.015 g/ml) were observed. Later, (T>60 h) filamentous, helical, tubular (density 1.015-1.04 g/ml) and plate-like (density 1.04-1.06 g/ml) cholesterol crystals appeared. The concentration of crystals increased gradually, while bilayer structures became desaturated with cholesterol and disappeared, and early crystal forms were replaced by plates. Eventually (T>25 days) only classical plate-like cholesterol monohydrate crystals were present. Exposure of cholesterol-containing precipitates to micellar (100 mM) deoxycholate dissolved the bilayer structures but not the crystals. CONCLUSIONS: These data demonstrate that cholesterol crystallization in a physiologically relevant model bile is a multiphase process consisting of a sequence of transitions from vesicular and multilamellar structures to early crystal forms and to classical plate-like cholesterol monohydrate crystals. These transitions are associated with increasing density and decreasing phospholipid content of cholesterol precipitates. We suggest that time-lapse density gradient ultracentrifugation is a useful method for investigating and quantitating the process of cholesterol crystallization and factors that influence this process in bile.
Animals↗
Polymorphism of the tumour necrosis factor-alpha and lymphotoxin-alpha genes in hairy cell leukaemia.
Hairy cell leukaemia (HCL) is a rare chronic B lymphoproliferative disorder which can lead to severe pancytopenia and several immunologic abnormalities. The pathogenetic role of tumour necrosis factor (TNF)-alpha in HCL prompted us to study the potential contribution of functionally important genetic polymorphisms of the TNF gene cluster in a large group of patients with HCL. The TNF-alpha (-308 bp) promoter/enhancer point mutation and two polymorphisms located within the first intron of the lymphotoxin (LT)-alpha gene showed neither significant allelic deviation for the patient group nor, after analysis of clinical characteristics such as blood counts, stable or progressive disease or response to therapy.
Adult↗
Polymorphism of the tumour necrosis factor-alpha and lymphotoxin-alpha genes in chronic lymphocytic leukaemia.
The neoplastic cells of CLL are able to produce TNF which is known to stimulate the proliferation of CLL cells in an autocrine and paracrine manner. Genetic polymorphism of molecules of the TNF ligand superfamily has been described and certain alleles were suspected to predispose to variant biological responses. Previously, the rare allele TNFB*1 of the TNF-beta/lymphotoxin (LT)-alpha gene (NcoI, asparagine at amino acid position 26) was found to be associated with a stronger LT-alpha response of PBMC in vitro. We now report on a significant increase of the allele TNF1 (TNFA -308 G) of the TNF-alpha promoter/enhancer polymorphism in a group of 73 CLL patients when compared to healthy individuals (RR = 3.18, 95% confidence interval 1.57-8.3; P = 0.006). The allelic distribution of the TNF-beta/LT-alpha NcoI polymorphism did not differ significantly from randomized healthy controls. On the other hand, the frequency of the allele TNFB*2 was increased in CLL patients with advanced clinical stage (P = 0.004). These findings indicate immunogenetic associations involving polymorphisms of cytokine genes serving as paracrine and autocrine growth factors, which thus can contribute to the pathogenesis of the TNF/LT-sensitive haematological malignancy CLL.
Adult↗
Induction of interleukin 6 by ionizing radiation in a human epithelial cell line: control by corticosteroids.
The cutaneous radiation syndrome after therapeutic or accidental exposure of human skin to ionizing radiation (IR) is accompanied by inflammatory processes which are controlled partly by proinflammatory cytokines. Besides tumour necrosis factor (TNF)-alpha and interleukin (IL)1, the pluripotent cytokine IL-6 belongs to the key mediators of inflammation. So far, there are no reports about the regulation of IL-6 by IR in epidermal cells. As an in vitro model to study the effects of IR on IL-6 gene expression, we treated the human epithelial HeLa cell line with different single X-ray doses between 1 and 20 Gy. Twenty-four hours after irradiation the IL-6 secretion was dose-dependently enhanced as measured by ELISA. At the transcriptional level, a slight increase of IL-6 transcripts was already detectable 1 h after irradiation, with maximum levels at 2 h, and a decline to baseline levels between 8 and 24 h. Addition of the transcriptional inhibitor actinomycin D inhibited the inducibility of IL-6 mRNA by TPA and IR. As the IL-6 promoter contains multiple binding sites for activated glucocorticoid receptors within the 5' regulatory region, the potential modulation of IL-6 expression by the corticosteroids hydrocortisone, dexamethasone and mometasone furoate was included in our study to modify the radiation-induced stress response. All corticosteroids applied could efficiently downregulate TPA- or radiation-induced IL-6 expression on both gene expression and protein levels. Mometasone furoate, followed by dexamethasone, was found to be most effective at low concentrations (1 nM), whereas hydrocortisone had to be applied at about 100-fold higher concentrations to achieve comparable inhibition. This experimental model is aimed at understanding the molecular circuits following IR, and thus to provide a basis for the treatment of radiation effects in skin.
Adrenal Cortex Hormones↗
Primary liver gastrinoma.
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Cytoplasmic Granules↗
Phototesting for polymorphic light eruption (PLE) with consecutive UVA1/UVB-irradiation.
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Erythema↗
Phototesting and photoprotection in LE.
Photosensitivity and induction of skin lesions following UV radiation is a common problem of patients with cutaneous and systemic forms of lupus erythematosus. The detrimental effect of UV radiation to patients with lupus erythematosus was already recognized in the last century. Skin lesions can now be provoked under standardized conditions allowing the diagnosis and classification of patients with photosensitive disorders. The aim of this review is to give an overview on the history, test procedure and test results in patients with lupus erythematosus.
History, 19th Century↗
Endogenous retroviral sequences in the pathogenesis of systemic autoimmune disease.
OBJECTIVES: To update information on endogenous retroviral sequences and discuss their role in systemic autoimmune disease. DATA SOURCES: Articles retrieved after MEDLINE search and personal communications and cooperation with the Institute of Virology. DATA SYNTHESIS: There are 2 modes of pathogenetic mechanisms through which endogenous retroviral sequences could cause systemic autoimmune disease: expression of endogenous retroviral gene products sharing antigenic determinants with cellular proteins; and activation or destruction of cellular genes as a consequence of insertional mutagenesis. Both mechanisms have been demonstrated in vitro and in vivo in animal models. CONCLUSION: Investigations on endogenous retroviral sequences in humans may offer new insights into the pathogenesis of autoimmune disease.
Autoimmune Diseases↗
Transcriptional regulation of the human IL5 gene by ionizing radiation in Jurkat T cells: evidence for repression by an NF-AT-like element.
Eosinophilia is often observed in patients with parasitic infections and atopic diseases like allergic asthma and atopic dermatitis. Additionally, it is a typical feature of the inflammatory reaction after therapeutic and accidental exposure to ionizing radiation. This uniquely specific phenomenon regulated by the cytokine interleukin 5 (IL-5) suggests specific control for IL5 gene expression. In this study, we generated promoter-CAT constructs containing different human IL-5 promoter regions spanning from positions -507 to +43. Transfection experiments in Jurkat T cells revealed that the promoter sequence from -57 to +43 was required for constitutive and inducible IL-5 promoter activity. Low baseline CAT activity could be enhanced by treatment with phenylmercuric acetate (PMA) or the combination of PMA and calcium ionophore. The promoter region between positions -97 and +43 showed responsiveness to low-dose X rays. Electrophoretic mobility shift assays demonstrated that the region from -117 to -97 was responsive to irradiation. Transcription factors specifically bound to this sequence showed a dose-dependent response to single doses of X rays between 1 and 8 Gy. Competition analysis indicated that the protein-DNA complexes at this region were related to the nuclear factor of activated T cells (NF-AT). Further confirmation was obtained by the addition of specific antibodies into protein-DNA reactions. For the first time, we have demonstrated that specific DNA binding of NF-ATp at the promoter region from -117 to -97 is involved in transcriptional regulation of the human IL5 gene in response to ionizing radiation.
DNA↗
Lack of IL-12 signaling in human allergen-specific Th2 cells.
IL-12 is a powerful skewer of CD4+ T cell responses toward the Th1 phenotype by inducing IFN-gamma production in naive Th cells. In the present study we addressed the question of whether IL-12 can reverse established Th2 responses into Th1/Th0 responses by inducing IFN-gamma production in memory Th2 cells. To this aim, allergen-specific CD4+ T cell clones (TCC) were generated from the peripheral blood of three atopic patients, and their cytokine profiles were analyzed. The majority of these TCC exhibited a strongly polarized Th2 cytokine profile, and the production of IFN-gamma could not be induced by exogenous IL-12. Only those TCC with low IFN-gamma levels in the absence of IL-12 responded to IL-12 by additional enhancement of IFN-gamma production. The IL-12 nonresponsiveness of the Th2 clones was further evident by the total lack of IL-12-induced phosphorylation of STAT4 (signal transducer and activator of transcription-4), a transcription factor that is typically involved in IL-12 signaling. Consequently, IL-12 also failed to induce the DNA-binding activity of STAT4-containing complexes in the nuclei of these Th2 clones. All TCC expressed equal levels of the low-affinity IL-12R beta1 subunit. Our results indicate that human allergen-specific Th cells with strongly polarized Th2 cytokine profiles do not respond to IL-12 and, therefore, cannot be induced to produce IFN-gamma. The apparent high frequency of IL-12-nonresponsive Th cells within the allergen-specific populations in atopic patients predicts a limited skewing potential of IL-12 in the case of established Th2 responses, but only affecting newly recruited naive Th cells.
Allergens↗
[Endogenous retroviral sequences as a factor in the pathogenesis of systemic lupus erythematosus].
Endogenous retroviral sequences (ERV) are integrated parts of the human genome. They make up at least 1% of the total genomic DNA. This pool of genetic material might help explain the long discussed role of retroviruses in autoimmune disease. Their proviral features suggest two possible models leading to autoimmune disease: the mobile insertion into a or near a somatic gene, changing its function, and the expression of proteins by ERV, which then might act as autoantigens or superantigens. These mechanisms are supported by prior studies of systemic lupus erythematosus (SLE). In MRL-lpr/lpr mice with SLE-like disease the insertion of a mobile retroviral element, the early transposon (ETn), into the second intron of the fas gene leads to reduced apoptosis, accumulation of lymphocytes and earlier mortality. Investigations of murine and human SLE demonstrate autoantibodies against self-proteins, which crossreact with retroviral proteins. Future investigations may further establish the interrelation between the activation of endogenous retroviral sequences and SLE with its multifactorial genetic determinants.
Animals↗
[Historical development of photodynamic therapy].
Photodynamic therapy is based on the accumulation of photosensitizing drugs in tumours and subsequent activation by visible light, leading to the release of singlet oxygen in photochemical reactions. Besides the treatment of precancerous lesions and malignant tumours in superficial sites, new experimental indications, such as psoriasis, are being investigated. The development of new photosensitizing agents for topical application and appropriate light sources has led to increasing interest in this promising treatment modality among dermatologists. This historical review deals with the scientific investigations of photodynamic therapy and diagnosis that started with the experiments of Oscar Raab at the end of the nineteenth century.
Germany↗
Strong and prolonged induction of c-jun and c-fos proto-oncogenes by photodynamic therapy.
Photodynamic therapy (PDT) is currently under investigation in phase II and III clinical studies for the treatment of tumours in superficial localisations. Thus far, the underlying mechanisms of PDT regarding cellular responses and gene regulation are poorly understood. Photochemically generated singlet oxygen (1O2) is mainly responsible for cytotoxicity induced by PDT. If targeted cells are not disintegrated, photo-oxidative stress leads to transcription and translation of various stress response and cytokine genes. Tumour necrosis factor (TNF) alpha, interleukin (IL) 1 and IL-6 are strongly induced by photodynamic treatment, supporting inflammatory action and immunological anti-tumour responses. To investigate the first steps of gene activation, this study focused on the proto-oncogenes c-jun and c-fos, both coding for the transcription factor activator protein 1 (AP-1), which was found to mediate IL-6 gene expression. We here determine the effects of photodynamic treatment on transcriptional regulation and DNA binding of transcription factor AP-1 in order to understand the modulation of subsequent regulatory steps. Photodynamic treatment of epithelial HeLa cells was performed by incubation with Photofrin and illumination with 630 nm laser light in vitro. Expression of the c-jun and c-fos genes was determined by way of Northern blot analysis, and DNA-binding activity of the transcription factor AP-1 was evaluated by electrophoretic mobility shift assay (EMSA). Photofrin-mediated photosensitisation of HeLa cells resulted in a rapid and dose-dependent induction of both genes but preferential expression of c-jun. Compared with the transient expression of c-jun and c-fos by phorbol ester stimulation, photodynamic treatment led to a prolonged activation pattern of both immediate early genes. Furthermore, mRNA stability studies revealed an increased half-life of c-jun and c-fos transcripts resulting from photosensitisation. Although mRNA accumulation after PDT was stronger and more prolonged compared with phorbol ester stimulation, with regard to AP-1 DNA-binding activity, phorbol ester was more efficient. Surprisingly, in addition to the activation of AP-1 DNA-binding via PDT, photodynamic treatment can decrease AP-1 DNA-binding of other strong inducers, such as the protein kinase C-mediated pathway of phorbol esters and the antioxidant pyrrolidine dithiocarbamate (PDTC). This study demonstrates a strong induction of c-jun and c-fos expression by PDT, with prolonged kinetics and mRNA stabilisation as compared with activation by phorbol esters. Interestingly, this observation is not coincident with an overinduction of AP-1 DNA-binding, hence suggesting that post-translational modifications are dominant regulatory mechanisms after PDT that tightly control AP-1 activity in the nucleus thus limiting the risk of deregulated oncogene expression.
Antioxidants↗
Polymorphism within the second intron of the IL-1 receptor antagonist gene in patients with hematopoietic malignancies.
Alleles of the IL-1 genes are associated with several autoimmune and inflammatory diseases, where they tend to have a role in the severity of the disease rather than in susceptibility to the disease itself. Allele 2 of the variable number tandem repeat (VNTR) polymorphism in the IL-1 receptor antagonist (IL-1ra) gene was the first marker of the IL-1 cluster to be associated in this way with severity of chronic, systemic and local inflammatory diseases. Because of the role that IL-1 also plays in the pathobiology of certain hematopoietic disorders, we aimed at examining the allelic distribution of the IL-1ra VNTR in leukemias, lymphomas and related malignancies. While in patients with chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), multiple myeloma (MM) and related disorders, primary acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and Hodgkin's disease (HD), the allelic distribution of IL-1RN was comparable to that seen in healthy control subjects, in a small group of patients with secondary AML the frequency of the IL-1RN*4 allele appeared to be significantly increased.
Alleles↗