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  • 1
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Transmissible spongiform encephalopathies form a group of fatal neurodegenerative disorders that have the unique property of being infectious, sporadic, or genetic in origin. Although some doubts remain on the nature of the responsible agent of these diseases, it is clear that a protein called PrPSc (which stands for the scrapie isoform of the prion protein) has a central role in their pathology. PrPSc represents a conformational variant of a normal protein of the host: the cellular isoform of the prion protein, or PrPC. Compounds such as glycosaminoglycans and Congo red (CR) have been shown to interfere with both in vitro and in vivo PrPSc formation. It was hypothesized that CR acts by overstabilizing the conformation of PrPSc molecules or by modifying trafficking of PrPC. Using transfected cells expressing 3F4-tagged mouse PrPs, we show here that CR does not interfere with conversion of PrP molecules carrying pathogenic mutations. On the contrary, after incubation with the drug, some of their properties, such as insolubility and protease resistance, are enhanced and are even acquired by the wild-type molecule. This last observation suggests an alternative mechanism of action of CR and leads us to reconsider the relationship between the biochemical properties of PrP and conformational alteration of the protein.
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  • 2
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Transmissible prion diseases are fatal neurodegenerative diseases associated with the conversion of the normal host prion protein (PrPc) into an abnormal isoform (PrPSc) that accumulates in brain. This pathology affects neurons of the central nervous system whereas no clear toxic effect has been reported for peripheral neurons. We examined the subcellular distribution of PrPc and PrPSc in the scrapie-infected mouse neuronal cell lines GT1-7 and N2a, derived, respectively, from the central and peripheral nervous system. We observed that in both cell types, PrPc is present in the endocytic compartment, mainly in LAMP-1-positive late endosomes, but excluded from LYAAT-1-lysosomes. In contrast, PrPSc was distributed differently in the two cell lines. In infected N2a, PrPSc and PrPc had comparable distribution patterns. In infected GT1-7, PrPSc is present in an additional vesicular compartment which is flotillin-1-positive. The level of expression of flotillin-1 is higher in GT1-7 than in N2a cells, but no difference is observed between infected and noninfected cells. In Alzheimer's disease patients, it has been reported that flotillin-1 is abundant in brain areas containing the β-amyloid protein, which accumulates in endosomal vesicles in primary neurons. We propose that the flotillin compartment could store aggregated proteins and play a role in these neurodegenerative pathologies.
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  • 3
    Electronic Resource
    Electronic Resource
    Oxford BSL : Blackwell Science Ltd
    British journal of dermatology 141 (1999), S. 0 
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The clinical efficacy and tolerability of the topical receptor-selective retinoid tazarotene in the treatment of congenital ichthyoses was investigated. Twelve consecutive patients with different forms of congenital ichthyosis were enrolled in an open, non-randomized, intraindividually controlled, half-side pilot study. Diagnoses were X-linked recessive ichthyosis, non-erythrodermic autosomal recessive lamellar ichthyosis, autosomal dominant ichthyosis vulgaris and ichthyosis bullosa of Siemens (IBS). Tazarotene 0.05% gel was applied unilaterally daily on a defined body area measuring 10% of the body surface area. The contralateral side was treated with an ointment containing 10% urea. After 14 days, application frequency was reduced to three times a week, and stopped after another 2 weeks. The follow-up period was 3 months. Reduction in scaling and roughness was used to assess the clinical response in the tazarotene-treated area compared with the control area. Clinical and laboratory assessments were performed every 14 days during the trial. Unilateral improvement in favour of the tazarotene-treated side was observed in nine of 12 patients (75%). Four patients (33%) achieved an excellent response and four (33%) achieved a good response. No therapeutic effect was seen in patients with IBS. The remission persisted during the reduction phase and after discontinuation for up to 2 months. Local irritation in three patients was the only side-effect detectable. Short-term topical application of tazarotene 0.05% gel is a very effective and well-tolerated treatment modality in different forms of congenital ichthyoses and may be an alternative to systemic retinoid therapy.
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  • 4
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The proliferation and survival of new cells in the dentate gyrus of mammals is a complex process that is subject to numerous influences, presenting a confusing picture. We suggest regarding these processes on the level of small networks, which can be simulated in silico and which illustrate in a nutshell the influences that proliferating cells exert on plasticity and the conditions they require for survival. Beyond the insights gained by this consideration, we review the available literature on factors that regulate cell proliferation and neurogenesis in the dentate gyrus in vivo. It turns out that the rate of cell proliferation and excitatory afferents via the perforant path interactively determine cell survival, such that the best network stability is achieved when either of the two is increased whereas concurrent activation of the two factors lowers cell survival rates. Consequently, the mitotic activity is regulated by systemic parameters in compliance with the hippocampal network's requirements. The resulting neurogenesis, in contrast, depends on local factors, i.e. the activity flow within the network. In the process of cell differentiation and survival, each cell's spectrum of afferent and efferent connections decides whether it will integrate into the network or undergo apoptosis, and it is the current neuronal activity which determines the synaptic spectrum. We believe that this framework will help explain the biology of dentate cell proliferation and provide a basis for future research hypotheses.
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  • 5
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Adult Long–Evans male rats sustained injections of 5,7-dihydroxytryptamine into the fimbria–fornix (2.5 µg/side) and the cingular bundle (1.5 µg/side) and/or to intraseptal injections of 192 IgG-saporin (0.4 µg/side) in order to deprive the hippocampus of its serotonergic and cholinergic innervations, respectively. Sham-operated rats were used as controls. The rats were tested for locomotor activity (postoperative days 18, 42 and 65), spontaneous T-maze alternation (days 20–29), beam-walking sensorimotor (days 34–38), water maze (days 53–64) and radial maze (days 80–133) performances. The cholinergic lesions, which decreased the hippocampal concentration of ACh by about 65%, induced nocturnal hyperlocomotion, reduced T-maze alternation, impaired reference-memory in the water maze and working-memory in the radial maze, but had no effect on beam-walking scores and working-memory in the water maze. The serotonergic lesions, which decreased the serotonergic innervation of the hippocampus by about 55%, failed to induce any behavioural deficit. In the group of rats given combined lesions, all deficits produced by the cholinergic lesions were observed, but the nocturnal hyperlocomotion and the working-memory deficits in the radial maze were attenuated significantly. These results suggest that attenuation of the serotonergic tone in the hippocampus may compensate for some dysfunctions subsequent to the loss of cholinergic hippocampal inputs. This observation is in close concordance with data showing that a reduction of the serotonergic tone, by pharmacological activation of somatodendritic 5-HT1A receptors on raphe neurons, attenuates the cognitive disturbances produced by the intrahippocampal infusion of the antimuscarinic drug, scopolamine. This work has been presented previously [Serotonin Club/Brain Research Bulletin conference, Serotonin: From Molecule to the Clinic (satellite to the Society for Neuroscience Meeting, New Orleans, USA, November 2–3, 2000)].
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  • 6
    ISSN: 1365-2036
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Clarithromycin and nitroimidazoles such as metronidazole and ornidazole are among the most frequently used antibiotics for curing Helicobacter pylori infection. However, controversial data exist on whether their in vitro resistance has a negative impact on treatment outcome.〈section xml:id="abs1-2"〉〈title type="main"〉Methods:Patients with H. pylori positive active peptic ulcer disease were randomly assigned to receive lansoprazole 30 mg o.d., amoxycillin 1 g b.d. and ornidazole 500 mg b.d. (LAO) or lansoprazole 30 mg o.d., amoxycillin 1 g b.d. and clarithromycin 500 mg b.d. (LAC) for 2 weeks. Pre-treatment resistance to ornidazole and clarithromycin was assessed by Epsilometer (E-) test. Four weeks after completion of treatment, patients underwent a 13C urea breath test to assess H. pylori status.〈section xml:id="abs1-3"〉〈title type="main"〉Results:Data from 80 patients with active peptic ulcer disease and positive H. pylori status were analysed. The prevalence of primary drug resistance was 25% for metronidazole and 7.5% for clarithromycin. In patients treated with LAO, effective treatment was achieved in 87% of metronidazole-susceptible, but only 30% of metronidazole-resistant strains (P 〈 0.01). In the LAC group, therapy was successful in 81% of clarithromycin-susceptible strains, whereas treatment failed in all patients with primary clarithromycin resistance (n = 3).〈section xml:id="abs1-4"〉〈title type="main"〉Conclusion:Resistance against nitroimidazoles significantly affects treatment outcome in H. pylori eradication therapy.
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  • 7
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Summary Background Lupus erythematosus tumidus (LET), a photosensitive skin disorder with characteristic clinical and histological features, has not been generally accepted as a subset of cutaneous lupus erythematosus (CLE). Objectives To analyse the expression of epidermal surface molecules in skin biopsy specimens from patients with LET and to relate the results to other variants of CLE, such as discoid lupus erythematosus (DLE) and subacute CLE (SCLE). Methods In total, 45 patients with different subtypes of CLE were included in the study, and cryostat sections from primary and ultraviolet (UV) A- and UVB-induced skin lesions were investigated using immunohistochemical methods. Results In contrast to healthy controls, skin lesions of LET showed upregulation of intercellular adhesion molecule-1 (ICAM-1) and histocompatibility class II molecules (HLA-DR), with an expression pattern resembling that seen in DLE and SCLE. Furthermore, staining with a monoclonal antibody against 27E10, a distinct marker for cell activation and differentiation, revealed intense focal or band-like labelling of all epidermal layers independent of the type of lesion. Conclusions Expression of epidermal surface molecules such as ICAM-1, HLA-DR and 27E10 is equally upregulated in primary and UV-induced lesions of patients with LET, DLE and SCLE. These results support our recent clinical findings that LET represents a distinct subset of CLE with a similar immunopathomechanism rather than a different disease.
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  • 8
    ISSN: 1468-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: A group of interested European Contact Dermatologists/Photobiologists met to produce a consensus statement on methodology, test materials and interpretation of photopatch testing. While it is recognized that a range of local variables operate throughout Europe, the underlying purpose of the work is to act as an essential preamble to a Pan European Photopatch Test Study focusing particularly on sunscreen chemicals.
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  • 9
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: In rheumatoid arthritis (RA), fibroblasts have been shown to be crucial for disease progression as well as joint destruction. In the model of human/murine SCID arthritis, synovial explants as well as fibroblasts from human rheumatoid synovial membrane induce destructive arthritis in immunodeficient mice. Hereby, the underlying cartilage destruction is accomplished by murine fibroblasts. Therefore, murine destructive fibroblasts represent a promising tool to investigate destruction of articular cartilage and bone. In this context, a novel destructive murine fibroblast line (LS48) was examined for morphological, ultrastructural, immunological and functional cellular parameters. These cells were injected into knees of SCID mice. Subsequently, the animals were monitored for joint swelling and serological parameters of arthritis by radiological methods. Finally, cartilage destruction was assessed morphologically. Cultured LS48 cells exhibit characteristic features that resemble those of activated synovial fibroblasts in human RA. Expression levels of inducible nitric oxide synthase, interleukin-6, tumour necrosis factor-α and matrix metalloproteinases were comparable to those detected in invasive human fibroblasts. The instillation of 5 × 105 LS48 cells into the knee joints of SCID mice initiated a rapid progressive process, that caused cartilage destruction within 10 days, and morphological examinations revealed that articular cartilage was infiltrated by the fibroblasts injected previously. In summary, the intra-articular application of LS48 cells represents a rapid and highly reproducible model to investigate the initiation and progression of cartilage destruction in connection with RA therapy and represents an easy-to-handle animal model.
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  • 10
    ISSN: 1365-4632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Objective To characterize the immune response to Propionibacterium acnes in acne patients. Design Comparison of serologic responses in acne and normal patients using counterimmunoelectrophoresis for antibody and an enzyme-linked immunosorbent assay (ELISA) to detect immunoglobulin G (IgG) antibody. Setting The serum of acne and nonacne patients from the Dermatology Clinic at the Medical College of Ohio was utilized for analysis. Results Using counterimmunoelectrophoresis, antibody was detected in 13 of 20 acne patients. The antigen was detectable as an anion in the barbital buffer at pH 8.2, strongly suggesting a carbohydrate component. By ELISA, the antibody proved to be IgG, and the bacteria and its water-soluble fractions were capable of fixing complement. Conclusions The primary instigator of inflammation in acne vulgaris is an immunologic reaction to extracellular products of P. acnes. The immunologic response involves both humoral and cell-mediated pathways. The antibodies to P. acnes have not been characterized fully, although they are largely of the IgG class. We have further characterized the dominant antigen to have a carbohydrate component.
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