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  • 1
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Extracellular amyloid β-peptide (Aβ) deposition is a pathological feature of Alzheimer's disease and the aging brain. Intracellular Aβ accumulation is observed in the human muscle disease, inclusion body myositis. Aβ has been reported to be toxic to neurons through disruption of normal calcium homeostasis. The pathogenic role of Aβ in inclusion body myositis is not as clear. Elevation of intracellular calcium following application of calcium ionophore increases the generation of Aβ from its precursor protein (βAPP). A receptor-based mechanism for the increase in Aβ production has not been reported to our knowledge. Here, we use caffeine to stimulate ryanodine receptor (RYR)-regulated intracellular calcium release channels and show that internal calcium stores also participate in the genesis of Aβ. In cultured HEK293 cells transfected with βAPP cDNA, caffeine (5–10 mM) significantly increased the release of Aβ fourfold compared with control. These actions of caffeine were saturable, modulated by ryanodine, and inhibited by the RYR antagonists ruthenium red and procaine. The calcium reuptake inhibitors thapsigargin and cyclopiazonic acid potentiated caffeine-stimulated Aβ release. NH4Cl and monensin, agents that alter acidic gradients in intracellular vesicles, abolished both the caffeine and ionophore effects. Immunocytochemical studies showed some correspondence between the distribution patterns of RYR and cellular βAPP immunoreactivities. The relevance of these findings to Alzheimer's disease and inclusion body myositis is discussed.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1365-2958
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Biology , Medicine
    Notes: The yeast Candida glabrata rapidly autoactivates transcription of the AMT1 gene in response to potentially toxic copper levels through the copper-inducible binding of the Amt1 transcription factor to a metal response element (MRE) within a positioned nucleosome. Our previous studies have characterized the role of a 16 bp homopolymeric dA:dT DNA structural element in facilitating rapid Amt1 access to the AMT1 promoter nucleosomal MRE. In this study, we have used the genetically more facile yeast Saccharomyces cerevisiae to identify additional cellular factors that are important for promoting rapid autoactivation of the AMT1 gene in response to toxic copper levels. We demonstrate that the Swi/Snf nucleosome remodelling complex and the histone acetyltransferase Gcn5 are both essential for AMT1 gene autoregulation, and that the requirement for these chromatin remodelling factors is target gene specific. Chromatin accessibility measurements performed in vitro and in vivo indicate that part of the absolute requirement for these factors is derived from their involvement in facilitating nucleosomal access to the AMT1 promoter MRE. Additionally, these data implicate the involvement of Swi/Snf and Gcn5 at multiple levels of AMT1 gene autoregulation.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    USA/Oxford, UK : Blackwell Science Ltd
    Cephalalgia 4 (1984), S. 0 
    ISSN: 1468-2982
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The impetus to study sleep changes in a cluster population arose from a recent hypothesis that predicted the finding of sleep apnea in this disorder. It holds that cluster attacks may occur in response to oxygen desaturation. Proposed mechanisms involve impairment of carotid body activity secondary to hypothalamic-vasomotor regulatory dysfunction. Five chronic and five episodic cluster patients underwent nocturnal polysomnography, utilizing standard equipment for monitoring sleep status, cardiac activity, nasal and buccal air flow change, chest and abdominal breathing, muscle activity and oxygen saturation. All episodic patients and one of five chronic patients were found to have sleep apnea (60%). Mean apneas per hour during NREM sleep were similar to that of REM sleep; 26.7 and 28.2, respectively. Six patients with sleep apnea experienced 14 cluster headache attacks during the study period. Eight attacks (57%) followed episodes of oxygen desaturation ranging from 65% to 85%. In the sleep apnea group, 8 out of 14 attacks (57%) were associated with REM; three without, and five following oxygen desaturation. Of the non-apnea group, all of whom had chronic cluster headache, none of 5 attacks were associated with oxygen desaturation, and only 2/5 attacks occurred in relation to REM. Thus, our study showed that sleep apnea was a common finding in a randomly selected group of episodic cluster patients; and most nocturnal attacks were preceded by oxyhemoglobin desaturation and REM-related. These findings were uncommon in the chronic cluster group.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Mutations in the amyloid precursor protein that result in substitutions of glutamic acid at residue 22 of the amyloid β protein (Aβ) with glutamine (Q22, Dutch) or glycine (G22, Arctic) cause aggressive familial neurological diseases characterized by cerebrovascular haemorrhages or Alzheimer's-type dementia, respectively. The present study compared the ability of these peptides to block long-term potentiation (LTP) of glutamatergic transmission in the hippocampus in vivo. The effects of intracerebroventricular injection of wild-type, Q22 and G22 Aβ(1–40) peptides were examined in the CA1 area of urethane-anaesthetized rats. Both mutant peptides were ≈ 100-fold more potent than wild-type Aβ at inhibiting LTP induced by high-frequency stimulation when solutions of Aβ were freshly prepared. Fibrillar material, as determined by electron microscopy, was obvious in all these peptide solutions and exhibited appreciable Congo Red binding, particularly for Aβ(1–40)G22 and Aβ(1–40)Q22. A soluble fraction of Aβ(1–40)G22, obtained following high-speed centrifugation, retained full activity of the peptide solution to inhibit LTP, providing strong evidence that in the case of the Arctic disease a soluble nonfibrillar form of Aβ may represent the primary mediator of Aβ-related cognitive deficits, particularly early in the disease. In contrast, nonfibrillar soluble Aβ(1–40)Q22 supernatant solution was ≈ 10-fold less potent at inhibiting LTP than Aβ(1–40)G22, a finding consistent with fibrillar Aβ contributing to the inhibition of LTP by the Dutch peptide.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Animal data suggest that the widely abused psychostimulant methamphetamine can damage brain dopamine neurones by causing dopamine-dependent oxidative stress; however, the relevance to human methamphetamine users is unclear. We measured levels of key antioxidant defences [reduced (GSH) and oxidized (GSSG) glutathione, six major GSH system enzymes, copper–zinc superoxide dismutase (CuZnSOD), uric acid] that are often altered after exposure to oxidative stress, in autopsied brain of human methamphetamine users and matched controls. Changes in the total (n = 20) methamphetamine group were limited to the dopamine-rich caudate (the striatal subdivision with the most severe dopamine loss) in which only activity of CuZnSOD (+ 14%) and GSSG levels (+ 58%) were changed. In the six methamphetamine users with severe (− 72 to − 97%) caudate dopamine loss, caudate CuZnSOD activity (+ 20%) and uric acid levels (+ 63%) were increased with a trend for decreased (− 35%) GSH concentration. Our data suggest that brain levels of many antioxidant systems are preserved in methamphetamine users and that GSH depletion, commonly observed during severe oxidative stress, might occur only with severe dopamine loss. Increased CuZnSOD and uric acid might reflect compensatory responses to oxidative stress. Future studies are necessary to establish whether these changes are associated with oxidative brain damage in human methamphetamine users.
    Type of Medium: Electronic Resource
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