The natural history of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality in the USA, and it remains one of the few diseases that continues to increase its numbers. The development and progression of COPD can vary dramatically between individuals. A low level of lung function remains the cornerstone of COPD diagnosis and is a key predictor of prognosis. Lung function, however, is not the only factor in determining morbidity and mortality related to COPD, with factors such as body mass index, exercise capability and comorbid disease being important predictors of poor outcomes. Exacerbations of COPD are additional important indicators of both quality of life and outcomes in COPD patients. Definitions of exacerbations can vary, ranging from an increase in symptoms to COPD-related hospitalisations and death. COPD exacerbations are more common in patients with lower levels of lung function and may lead to more rapid declines in lung function. Better understanding of the natural history of COPD may lead to better definitions of specific COPD phenotypes, better interventions and improved outcomes

The phosphorylation of Hsp20 enhances its association with amyloid-β to increase protection against neuronal cell death

This project was funded by a doctoral training studentship from the Biotechnology and Biological Sciences Research Council Doctoral Training Programme in Biochemistry and Molecular Biology at the University of Glasgow [grant number BB/F016735/1].Up-regulation of Hsp20 protein levels in response to amyloid fibril formation is considered a key protective response against the onset of Alzheimer's disease (AD). Indeed, the physical interaction between Hsp20 and Aβ is known to prevent Aβ oligomerisation and protects neuronal cells from Aβ mediated toxicity, however, details of the molecular mechanism and regulatory cell signalling events behind this process have remained elusive. Using both conventional MTT end-point assays and novel real time measurement of cell impedance, we show that Hsp20 protects human neuroblastoma SH-SY5Y cells from the neurotoxic effects of Aβ. In an attempt to provide a mechanism for the neuroprotection afforded by Hsp20, we used peptide array, co-immunoprecipitation analysis and NMR techniques to map the interaction between Hsp20 and Aβ and report a binding mode where Hsp20 binds adjacent to the oligomerisation domain of Aβ, preventing aggregation. The Hsp20/Aβ interaction is enhanced by Hsp20 phosphorylation, which serves to increase association with low molecular weight Aβ species and decrease the effective concentration of Hsp20 required to disrupt the formation of amyloid oligomers. Finally, using a novel fluorescent assay for the real time evaluation of morphology-specific Aβ aggregation, we show that phospho-dependency of this effect is more pronounced for fibrils than for globular Aβ forms and that 25mers corresponding to the Hsp20 N-terminal can be used as Aβ aggregate inhibitors. Our report is the first to provide a molecular model for the Hsp20/Aβ complex and the first to suggest that modulation of the cAMP/cGMP pathways could be a novel route to enhance Hsp20-mediated attenuation of Aβ fibril neurotoxicity.Publisher PDFPeer reviewe

On the martingale property of certain local martingales

The stochastic exponential Zt=expMt−M0−(12)MMt of a continuous local martingale M is itself a continuous local martingale. We give a necessary and sufficient condition for the process Z to be a true martingale in the case where Mt=0tb(Yu)dWu and Y is a one-dimensional diffusion driven by a Brownian motion W. Furthermore, we provide a necessary and sufficient condition for Z to be a uniformly integrable martingale in the same setting. These conditions are deterministic and expressed only in terms of the function b and the drift and diffusion coefficients of Y. As an application we provide a deterministic criterion for the absence of bubbles in a one-dimensional setting