Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Abeta toxicity

Cells that have evolved to produce large quantities of secreted proteins to serve the integrated functions of complex multicellular organisms are equipped to compensate for protein misfolding. Hepatocytes and plasma cells have well developed chaperone and proteasome systems to ensure that secreted proteins transit the cell efficiently. The number of neurodegenerative disorders associated with protein misfolding suggests that neurons are particularly sensitive to the pathogenic effects of aggregates of misfolded molecules because those systems are less well developed in this lineage. Aggregates of the amyloidogenic (Abeta(1-42)) peptide play a major role in the pathogenesis of Alzheimer's disease (AD), although the precise mechanism is unclear. In genetic studies examining protein-protein interactions that could constitute native mechanisms of neuroprotection in vivo, overexpression of a WT human transthyretin (TTR) transgene was ameliorative in the APP23 transgenic murine model of human AD. Targeted silencing of the endogenous TTR gene accelerated the development of the neuropathologic phenotype. Intraneuronal TTR was seen in the brains of normal humans and mice and in AD patients and APP23 mice. The APP23 brains showed colocalization of extracellular TTR with Abeta in plaques. Using surface plasmon resonance we obtained in vitro evidence of direct protein-protein interaction between TTR and Abeta aggregates. These findings suggest that TTR is protective because of its capacity to bind toxic or pretoxic Abeta aggregates in both the intracellular and extracellular environment in a chaperone-like manner. The interaction may represent a unique normal host defense mechanism, enhancement of which could be therapeutically useful.     

Gaucher disease: molecular screening of the glucocerebrosidase 1601G and 1601A alleles in Victoria, British Columbia, Canada.

Gaucher disease is the most prevalent lysosomal storage disease and it results from inherited deficient glucocerebrosidase activity. The glucocerebrosidase gene from normal people was sequenced by several laboratories and it was noted that a G or A nucleotide may be present at cDNA position 1601, resulting in 495arginine or 495histidine in the glucocerebrosidase polypeptide. In order to rule out the possibility of cloning error and to elucidate the genetic status of the two genotypes and their distribution in the population, we have developed a convenient and reliable method for the molecular screening of the 1601G and 1601A genotypes in the population. This method uses PCR amplification of glucocerebrosidase genomic DNA in blood samples, followed by BsaHI restriction fragment length polymorphism analysis. Out of the 256 subjects without Gaucher disease and 15 Gaucher patients surveyed, the 1601G genotype was present in the homozygous form in all of the asymptomatic subjects and 14 Gaucher patients. In one Gaucher patient who was diagnosed as having type 1 (non-neuropathic) Gaucher disease with the A1226G/T1366G mutations, the heterozygous 1601G/A genotype was detected. These findings indicate that the 1601G genotype which encodes 495arginine of the glucocerebrosidase polypeptide is not a cloning error. Instead, it constitutes the normal as well as predominant genotype in the population in the municipality of Greater Victoria, British Columbia. The 1601A genotype, on the other hand, appears to be quite infrequent in this population. The availability of our restriction enzyme based method has allowed the screening and frequency determination of these two alleles in other populations.     

Impact of fatigue on performance in registered nurses: data mining and implications for practice

Performance of nurses has a direct effect on the quality and safety of care that is delivered. Fatigue has been identified as a factor that leads to performance decrements in healthcare workers, especially nurses. Determining associations between dimensions of fatigue and performance is imperative to better understanding fatigue in nurses and the potential implications for both patient and provider safety. This article identifies associations between ranges of fatigue levels and significant differences in perceived performance, and analyzes interactions between fatigue dimensions in relation to perceived performance scores. Overall, mental fatigue tended to have higher perceived performance decrements than physical and total fatigue in the highest fatigue ranges. As physical fatigue begins to develop in nurses, physical exertion rather than discomfort is more critical to perceived performance. As acute fatigue levels increase, perceived performance levels continue to decrease, whereas the role of chronic fatigue is relatively constant. Minimizing the development of acute fatigue may help in maintaining higher performance levels. The findings from this study provide valuable information in quantifying the changes in perceived performance with regard to specific fatigue levels, as well as an initial understanding of how the individual dimensions and states of fatigue vary in their association with perceived performance decrements.     

Human factors in the development and implementation of telerehabilitation systems

Telemedicine services must be designed and implemented with the users in mind. When conducting telerehabilitation, factors such as age, education and technology experience must be taken into account. In addition, telerehabilitation must also accommodate a range of potential patient impairments, including deficits in language, cognition, motor function, vision and voice. Telerehabilitation technology and treatment environments should adhere to universal design standards so as to be accessible, efficient, usable and understandable to all. This will result in improved access to a wider range of telerehabilitation services that will facilitate and enhance the rehabilitative treatment and recovery of people living with varying levels of injury, impairment and disability.