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  • Blackwell Science Ltd  (5)
  • 2005-2009  (5)
  • 1
    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.
    Type of Medium: Electronic Resource
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  • 2
    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.
    Type of Medium: Electronic Resource
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  • 3
    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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  • 4
    ISSN: 1365-2222
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background A significant proportion of children with food allergy and more severe forms of atopic dermatis (AD) go on to develop persistent forms of allergic disease such asthma. Defining immune dysregulation in these children will be of great value in understanding disease pathogenesis.Objective In this study we characterized the immune responses of young infants (6–18 months of age) with moderate-to-severe AD (a modified SCORAD〈inlineGraphic alt="geqslant R: gt-or-equal, slanted" extraInfo="nonStandardEntity" href="urn:x-wiley:09547894:CEA2348:ges" location="ges.gif"/〉25) and compared these (n=53) with responses of non-allergic children with no history of dermatitis or sensitization of the same age (n=20).Methods Mononuclear cell cytokine responses to allergens (egg ovalbumin (OVA), β-lactoglobulin (BLG), house dust mite (HDM)), vaccines (tetanus toxoid (TT), diphtheria toxoid (DT)), intestinal flora (heat-killed Lactobacillus species (HKLB)), heat-killed Staphylococcus aureus (HKSA), S. aureus enterotoxin B (SEB) and mitogen (phytohaemaglutinin (PHA)) were compared in children with AD with unaffected children.Results Children with AD had significantly lower spontaneous (unstimulated) production of regulatory cytokine IL-10 (P〈0.001), as well as IFN-γ (P〈0.001) and TNF-α (P〈0.001) compared with the unaffected children. After allowing for differences in baseline levels IL-10 responses to virtually all stimuli (food allergens (P=0.003), vaccines P=0.01, intestinal flora (heat-killed Lactobacillus species (HKLB), P=0.005) and skin flora (heat-killed Staphylococcus aureus (HKSA), P=0.003)) were also significantly attenuated in children with AD. The only exception was HDM, to which responses were stronger in children with AD [P=0.05]. Although there were no significant correlations between HDM IgE and HDM cytokine responses at this age, T-helper type 2 (Th2) IL-5 (P=0.014) and IL-13 (P=0.004) responses to HDM were significantly more frequent in the children with AD. However, while children with AD showed significantly attenuated Th1 IFN-γ responses to food allergens (OVA, P=0.007 and BLG, P〈0.001) and vaccines (DT, P=0.008 and TT, P〈0.001), these children showed no difference in Th1 IFN-γ responses to HDM or microbial agents (HKSA and HKLB).Conclusion A increase in propensity for Th2 responses to aeroallergens in children with AD is associated with early impaired production of IL-10 regulatory cytokine to a broad range of environmental stimuli including foods, intestinal flora, S. aureus, and vaccines.
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  • 5
    ISSN: 1365-2222
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background We recently demonstrated that administration of probiotics resulted in significant clinical improvement in very young children with moderate-to-severe atopic dermatitis (AD). The purpose of this study was to determine the underlying immunological effects that are associated with these apparent clinical benefits.Methods Peripheral blood mononuclear cells (PBMC) were isolated from children (n=53) at baseline and at the end of an 8-week supplementation period during which they received a probiotic (Lactobacillus fermentum PCC™) (n=26) or a placebo (n=27). A further sample was collected at 16 weeks (8 weeks after ceasing the supplement). Cytokine (IL-5, IL-6, IL-10, IL-13, IFN-γ and TNF-α) responses to allergens (egg ovalbumin (OVA), beta lactoglobulin (BLG), house dust mite (HDM)), vaccines (tetanus toxoid (TT)), diphtheria toxoid (DT)), intestinal flora (heat-killed Lactobacillus (HKLB)), heat-killed Staphylococcus aureus (HKSA), Staphylococcus aureus enterotoxin B (SEB) and mitogen (phytohaemaglutinin (PHA)) were compared.Results The administration of probiotics was associated with a significant increase in T-helper type 1(Th1-type) cytokine IFN-γ responses to PHA and SEB at the end of the supplementation period (week 8: P=0.004 and 0.046) as well as 8 weeks after ceasing supplementation (week 16: P=0.005 and 0.021) relative to baseline levels of response. No significant changes were seen in the placebo group. The increase in IFN-γ responses to SEB was directly proportional to the decrease in the severity of AD (r=−0.445, P=0.026) over the intervention period. At the end of the supplementation period (week 8) children receiving probiotics showed significantly higher TNF-α responses to HKLB (P=0.018) and HKSA (P=0.011) but this was no longer evident when supplementation ceased (week 16). Although IL-13 responses to OVA were significantly reduced in children receiving probiotics after 8 weeks (P=0.008), there were no other effects on allergen-specific responses, and this effect was not sustained after ceasing supplementation (week 16). There were no effects on vaccine-specific responses, or on responses to any of the stimuli assessed.Conclusion The improvement in AD severity with probiotic treatment was associated with significant increases in the capacity for Th1 IFN-γ responses and altered responses to skin and enteric flora. This effect was still evident 2 months after the supplementation was ceased. The lack of consistent effects on allergen-specific responses suggests that the effects of probiotics may be mediated through other independent pathways, which need to be explored further.
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