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G Messer

Publications and source records attributed to G Messer.

At least 19 recordsLinked to original sources
PubMed1997

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↗
PubMed1997

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↗
PubMed1996

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↗
PubMed1996

[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↗
PubMed1996

[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↗
PubMed1996

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↗
PubMed1995

Photodynamic therapy induces expression of interleukin 6 by activation of AP-1 but not NF-kappa B DNA binding.

Inducibility and regulation of the pleiotropic cytokine interleukin 6 (IL-6) upon photodynamic therapy (PDT) was studied in the epithelial cell line HeLa. Photofrin-mediated photosensitization resulted in a rapid and dose-dependent induction of IL-6 mRNA production. Maximal levels were reached after 4 h and had decreased to baseline levels after 24 h. This photochemical induction of IL-6 transcription was followed by a strong secretion of IL-6 protein. In comparison to stimulation by 12-O-tetradecanoylphorbol-13-acetate, the kinetics of IL-6 mRNA and protein synthesis after PDT were delayed, although the maximal amounts of secreted IL-6 protein were comparable. As compared to UV irradiation, on the other hand, PDT-induced IL-6 protein levels were 2- to 10-fold higher and were detectable 4 h earlier. Several potentially relevant regulatory DNA elements of the IL-6 promoter were analyzed by gel retardation assays for PDT-induced protein binding. Interestingly, increased AP-1 DNA binding was detected only at the distal AP-1-specific motif and not at the proximal site, differing in 1 bp. Binding of c-Fos-containing AP-1 heterodimers to the specific motif was up-regulated 30 min after PDT, reaching maximal activity at 4 h. This PDT-induced AP-1 activation was independent from protein kinase C activity. Photosensitization did not induce increased binding at the well-characterized NF-kappa B element, nor at the multiple cytokine- and second messenger-responsive element of the IL-6 promoter. By analyzing the molecular mechanisms of IL-6 up-regulation upon PDT, we provide evidence for regulatory differences compared to UV light, ionizing irradiation, or stimulation by phorbol ester. Furthermore, this study suggests that the "proinflammatory" cytokine IL-6 might be involved in the inflammatory reaction and subsequent immunological antitumor responses.

Base Sequence↗
PubMed1995

Cloning and genomic characterization of LST1: a new gene in the human TNF region.

The leucocyte specific transcript - 1 (LST1) represents the human homolog of the mouse B144 transcript, encoded within the tumor necrosis factor (TNF) region of the human major histocompatibility complex class III interval. The gene is localized about 4 kilobases upstream of the lymphotoxin beta gene. It spans a polymorphic genomic region encompassing the microsatellites TNFd and TNFe in intron 3 and a polymorphic Pvu II restriction site 260 base pairs downstream of the polyadenylation signal. Isolation of a full-length cDNA clone revealed that LST1 codes for IFN-gamma-inducible 800 nt transcripts, which are present in lymphoid tissues, T cells, macrophages, and histiocyte cell lines. The cDNA contains three long open reading frames (ORF) with the most likely ORF encoding a transmembrane protein. Its close linkage to the TNF genes and pattern of expression point toward a possible role for LST1 in the immune response.

Amino Acid Sequence↗
PubMed1995

[Skin ulcers in rheumatoid arthritis].

The appearance of severe ulceration of the skin in patients with rheumatoid arthritis is often associated with a tendency to progression of the underlying disease, involvement of internal organs and increased mortality. In the pathogenesis of such ulceration there are multiple causes for their development, persistence and tendency to poor healing. They include localized or generalized immune complex vasculitis, treatment with anti-inflammatory drugs and their side effects following the treatment, arterial and venous insufficiency, and mechanical factors. The management of severe ulceration requires stabilization of the underlying autoimmune disease, e.g. with high doses of glucocorticosteroids or other immunosuppressive drugs or plasmapheresis. Adjuvant treatment of pain with analgesics, improvement of blood perfusion and anti-inflammatory drugs should accompany the topical therapy of ulcers. After suppression of the local inflammatory reaction surgical intervention becomes necessary in most of the patients, and vascularized muscle flaps should be used in preference to meshgrafts or split skin grafts for extensive ulceration in rheumatoid arthritis. A hopeful perspective in the treatment of severe rheumatoid arthritis might be opened up with immunotherapy using monoclonal antibodies.

Aged↗
PubMed1994

HLA-G: expression in human keratinocytes in vitro and in human skin in vivo.

Classical, polymorphic major histocompatibility complex class I molecules are expressed on most nucleated cells. They present peptides at the cell surface and, thus, enable the immune system to scan peptides for their antigenicity. The function of the other, nonclassical class I molecules in man is controversial. HLA-G which has been shown by transfection experiments to be expressed at the cell surface, is only transcribed in placental tissue and in the fetal eye. Therefore, a role of HLA-G in the control of rejection of the allogeneic fetus has been discussed. We found that HLA-G expression is induced in keratinocytes by culture in vitro. Three different alternative splicing products of HLA-G can be detected: a full length transcript, an mRNA lacking exon 3 and a transcript devoid of exon 3 and 4. Reverse transcription followed by polymerase chain reaction also revealed the presence of HLA-G mRNA in vivo in biopsies of either diseased or healthy skin.

Alternative Splicing↗
PubMed1994

Polymorphism of the tumor necrosis factor genes in patients with dermatitis herpetiformis.

In 18 patients with dermatitis herpetiformis (DH) of whom 16 were HLA-DR3 positive and 14 had the HLA-B8, -DR3 haplotype, the frequencies of known mutations of the tumor necrosis factor alpha (TNF-alpha) and TNF-beta genes were investigated using restriction fragment length polymorphism analysis and the single-strand conformational polymorphism technique. In DH, the phenotype frequency (28%) and allele frequency (0.58) of the rare TNF-beta allele TNFB*1 were significantly increased (normal control 12.4% and 0.37). For the TNF-alpha promoter/enhancer polymorphism, the rare allele TNF2 was more frequent in DH patients (11%, 0.47) compared to controls (2%, 0.16). Since functional studies have associated the rare TNFB*1 and TNF2 alleles with a higher secretion of TNF upon activation in vitro, the predominance of these two 'high-response' TNF alleles in DH patients may represent a genetic basis for the chronic inflammatory response in the skin and mucosal tissues of patients with DH.

Alleles↗
PubMed1993

Polymorphism of the tumor necrosis factor beta gene in systemic lupus erythematosus: TNFB-MHC haplotypes.

We investigated the Nco I restriction fragment length polymorphism (RFLP) of the tumor necrosis factor beta (TNFB) gene in 173 patients with systemic lupus erythematosus (SLE), 192 unrelated healthy controls, and eleven panel families, all of German origin. The phenotype frequency of the TNFB*1 allele was significantly increased in patients compared to controls (63.6% vs 47.1%, RR = 1.96, p < 0.002). The results of a two-point haplotype statistical analysis between TNFB and HLA alleles show that there is linkage disequilibrium between TNFB*1 and HLA-A1, Cw7, B8, DR3, DQ2, and C4A DE. The frequency of TNFB*1 was compared in SLE patients and controls in the presence or absence of each of these alleles. TNFB*1 is increased in patients over controls only in the presence of the mentioned alleles. Therefore, the whole haplotype A1, Cw7, B8, TNFB*1, C4A DE, DR3, DQ2 is increased in patients and it cannot be determined which of the genes carried by this haplotype is responsible for the susceptibility to SLE. In addition, two-locus associations were analyzed in 192 unrelated healthy controls for TNFB and class I alleles typed by serology, and for TNFB and class II alleles typed by polymerase chain reaction/oligonucleotide probes. We found positive linkage disequilibrium between TNFB*1 and the following alleles: HLA-A24, HLA-B8, DRB1*0301, DRB1*1104, DRB1*1302, DQA1*0501, DQB1*0201, DQB1*0604, and DPB1*0101. TNFB*2 is associated with HLA-B7, DRB1*1501, and DQB1*0602.

Base Sequence↗
PubMed1993

[Herpes gestationis: immunologic and immunogenetic aspects].

Herpes gestationis or pemphigoid gestationis (PG) is a bullous disease developing in association with pregnancy. It is believed to be an immunologically mediated disorder. Antibody binding by specific autoantibodies was detected in placental tissue and in the area of the hemidesmosomes and the basal membrane zone of the skin. These autoantibodies react with antigens of 180 kDa and 230 kDa relative molecular mass, which are presumably identical to the bullous pemphigoid antigen BPAG1 and BPAG2. The herpes gestationis factor (HG factor) preferentially binds to the 180-kDa antigen (BPAG2). The involvement of specific autoantibodies against adhesion molecules suggests the involvement of an aberrant immune response. Several groups have reported an association of pemphigoid gestationis to alleles of the human leukocyte antigens; HLA-B8 (class I) and HLA-DR3 and HLA-DR4 (class II), encoded on the short arm of chromosome 6. The unique feature of pemphigoid gestations is compared with other bullous dermatoses the association with the hormonal regulation during pregnancy and the presence of allogenic tissue. The hormonal regulation at the level of gene expression, possibly including gene expression of non-classic HLA class I molecules such as HLA-G, may be a cofactor in the pathogenesis of pemphigoid gestationis. This account, together with a case report, discusses the association of pemphigoid gestationis with HLA and a putative pathophysiological role of the newly described non-classical HLA molecules encoded in the MHC.

Autoantibodies↗
PubMed1993

[Immunogenetic findings in herpes gestationis].

A 27-year-old woman suffered from herpes gestationis in her second pregnancy. The pruricy urticarial and bullous skin lesions were exacerbated immediately after birth, and premenstrually after the onset of menstruation. The diagnosis was confirmed by the determination of anti-basement membrane antibodies of the IgG class both in the serum (herpes gestationis factor) and in lesional skin by immunofluorescence techniques. The newborn had no skin lesions and no basement membrane zone antibodies were detected. The HLA (human leucocyte antigen) typing revealed the HLA-A11/1, B18/w63, C-/-, DR4/w13, DQw3/w1 haplotype in the mother and the HLA-A3/31, B7/35, Cw7/w4, DR2/3, DQw1/w2 haplotype in the father. Comparison with the first child (HLA-A11/31, B18/35, -/Cw4, DR4/3, DQw3/w2) showed that the second child (HLA-A11/3, B18/7, -/Cw7, DR4/2, DQw3/w1) had a different HLA haplotype. The pattern of the HLA haplotype of the mother and the father seems to be important in the immunopathogenesis of herpes gestationis.

Adult↗
PubMed1992

Leishmania infections damage the feeding mechanism of the sandfly vector and implement parasite transmission by bite.

Leishmania parasites are transmitted by the bites of infected female sandflies by a mechanism that has not been clarified. Leishmania infections in the vector develop only in the gut, and the parasites' exit is through the food channel in the proboscis. The problem is how during the bite, when blood flows in, parasites are emitted through the same channel in the opposite direction. It is well documented that infected sandflies maintained on sugar diets are potent vectors, whereas transmission fails after constant feeding on blood. Hence to study the mechanism of transmission, we fed these diets to Phlebotomus papatasi infected with L. major. Histological examination demonstrated that only in the sugar-fed flies did the cuticle lining of the cardiac valve detach and other valve tissues degenerate gradually. The injury of the main valve of the food pumps hindered gorging of most flies when force-fed from capillaries, and they regurgitated the gut contents with fluids from the capillaries. We suggest that infections are caused by parasites regurgitated from the stomach that are deposited in the host tissue. We found that secretion of chitinolytic enzymes by cultured L. major parasites is inhibited by blood or hemoglobin, and hence these enzymes are apparently absent from the blood-fed infected flies, where the cardiac valve appears undamaged. We therefore presume that lysis of the chitin in the cuticle lining of the valve leads to exposure and degeneration of the underlying tissues.

Animals↗