Soluble amyloid oligomers are potent neurotoxins that are involved in a wide range of human degenerative diseases, including Alzheimer disease. In Alzheimer disease, amyloid  (A) oligomers bind to neuronal synapses, inhibit long term potentiation, and induce cell death. Recent evidence indicates that several immunologically distinct structural variants exist as follows: prefibrillar oligomers (PFOs), fibrillar oligomers (FOs), and annular protofibrils. Despite widespread interest, amyloid oligomers are poorly characterized in terms of structural differences and pathological significance. FOs are immunologically related to fibrils because they react with OC, a conformation-dependent, fibril-specific antibody and do not react with antibodies specific for other types of oligomers. However, fibrillar oligomers are much smaller than fibrils. FOs are soluble at 100,000 ؋ g, rich in -sheet structures, but yet bind weakly to thioflavin T. EPR spectroscopy indicates that FOs display significantly more spin-spin interaction at multiple labeled sites than PFOs and are more structurally similar to fibrils. Atomic force microscopy indicates that FOs are approximately one-half to onethird the height of mature fibrils. We found that A FOs do not seed the formation of thioflavin T-positive fibrils from A monomers but instead seed the formation of FOs from A monomers that are positive for the OC anti-fibril antibody. These results indicate that the lattice of FOs is distinct from the fibril lattice even though the polypeptide chains are organized in an immunologically identical conformation. The FOs resulting from seeded reactions have the same dimensions and morphology as the initial seeds, suggesting that the seeds replicate by growing to a limiting size and then splitting, indicating that their lattice is less stable than fibrils. We suggest that FOs may represent small pieces of single fibril protofilament and that the addition of monomers to the ends of FOs is kinetically more favorable than the assembly of the oligomers into fibrils via sheet stacking interaction. These studies provide novel structural insight into the relationship between fibrils and FOs and suggest that the increased toxicity of FOs may be due to their ability to replicate and the exposure of hydrophobic sheet surfaces that are otherwise obscured by sheet-sheet interactions between protofilaments in a fibril.The accumulation of aggregated amyloid proteins is a characteristic hallmark of a wide range of human degenerative diseases, including Alzheimer (AD), 2 type II diabetes, Huntington, Parkinson, and spongiform encephalopathy (1, 2). Although familial mutations that result in increased production of A42 support a causal role of A peptide, the mechanism of A pathogenesis remains unknown and controversial. A plaques composed of A fibrils are evident in both patients with AD and a significant number of healthy individuals who are cognitively normal (3). Emerging evidence implicate soluble oligomers formed during protein aggregation are the prim...
Background Concerns associated with blended enteral feeds include the risk of blocked tubes and microbial contamination, although the available evidence is limited. The present laboratory‐based investigation aimed to examine these risks in a blended feed providing a nutritionally adequate intake for a hypothetical patient. Methods A one‐blended feed recipe was made using three different methods (professional, jug and stick blenders) and three storage procedures. Feed samples were syringed via 10‐, 12‐ and 14‐French (Fr) enteral feeding tubes and both blockages and the time taken were recorded. Feed samples were diluted, plated on agars, incubated and bacterial colony‐forming units (CFU) counted. After storage at −80 °C, identification was undertaken using 16S rRNA polymerase chain reaction sequencing. Results Two blockages occurred during 27 administrations of feed made using a professional blender, although they were resolved with a water flush. No blockages occurred with the 14‐Fr tube and administration was quicker with wider tubes (P < 0.00001). There was no significant difference between the total bacterial CFU of feeds prepared using different methods (P = 0.771) or stored differently. The genus of bacteria identified included Enterococcus, Bacillus, lactose‐fermenting Enterobacteriaceae, Pseudomonas and Staphylococcus. Pathogens, such as Clostridium spp., Salmonella spp. and Vibrio spp., were not identified by phenotypic tests used. Sequencing identified Escherichia coli, Shigella spp., Streptococcus lutetiensis and Staphylococcus epidermidis. Conclusions The present study found no risk of tube blockages when one blended feed recipe made using three methods was delivered via a 14‐Fr tube. There is concern about bacterial contamination, although this was not influenced by the methods of preparation or storage used in the present study.
Hospice-based clinical pharmacists influenced patient outcomes positively by identifying DRPs and recommending appropriate drug therapy.
This research was prompted by the developing political discourse proposing the teaching of Britishness and British values in the context of the United Kingdom. This discourse will be reviewed in the first part of the article, in the context of previous work which has sought to assess how Britishness and related concepts might be promoted through education. The second part will be based on questionnaire responses from a sample of students following post-graduate initial teacher training programmes in a number of higher education partnerships. It indicates that, while political discourse and educational policy have sensitised trainee teachers to the agenda, there remains a deep uncertainty and misgiving about this as an educational objective.
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