Is the association between late-life morbidity and disability attenuated over time? : Exploring the dynamic equilibrium of morbidity hypothesis

Context: There is evidence suggesting that the prevalence of disability in late life has declined over time while the prevalence of disabling chronic diseases has increased. The dynamic equilibrium of morbidity hypothesis suggests that these seemingly contradictory trends are due to the attenuation of the morbidity-disability link over time. The aim of this study was to empirically test this assumption.Methods: Data were drawn from three repeated cross-sections of SWEOLD, a population-based survey among the Swedish men and women ages 77 and older. Logistic regression models were fitted to assess the trends in the prevalence of Activities of Daily Living (ADL) disability, Instrumental ADL (IADL) disability, and selected groups of chronic conditions. The changes in the associations between chronic conditions and disabilities were examined in both multiplicative and additive models.Results: Between 1992 and 2011, the odds of ADL disability significantly declined among women whereas the odds of IADL disability significantly declined among men. During the same period, the prevalence of most chronic morbidities including multimorbidity went up. Significant attenuations of the morbidity-disability associations were found for cardiovascular diseases, metabolic disorders, poor lung function, psychological distress, and multimorbidity.Conclusion: In agreement with the dynamic equilibrium hypothesis, this study concludes that the associations between chronic conditions and disability among the Swedish older adults have largely waned over time.

Gene therapy tools: oligonucleotides and peptides

Genetic mutations can cause a wide range of diseases, e.g. cancer. Gene therapy has the potential to alleviate or even cure these diseases. One of the many gene therapies developed so far is RNA-cleaving deoxyribozymes, short DNA oligonucleotides that specifically bind to and cleave RNA. Since the development of these synthetic catalytic oligonucleotides, the main way of determining their cleavage kinetics has been through the use of a laborious and error prone gel assay to quantify substrate and product at different time-points. We have developed two new methods for this purpose. The first one includes a fluorescent intercalating dye, PicoGreen, which has an increased fluorescence upon binding double-stranded oligonucleotides; during the course of the reaction the fluorescence intensity will decrease as the RNA is cleaved and dissociates from the deoxyribozyme. A second method was developed based on the common denominator of all nucleases, each cleavage event exposes a single phosphate of the oligonucleotide phosphate backbone; the exposed phosphate can simultaneously be released by a phosphatase and directly quantified by a fluorescent phosphate sensor. This method allows for multiple turnover kinetics of diverse types of nucleases, including deoxyribozymes and protein nucleases. The main challenge of gene therapy is often the delivery into the cell. To bypass cellular defenses researchers have used a vast number of methods; one of these are cell-penetrating peptides which can be either covalently coupled to or non-covalently complexed with a cargo to deliver it into a cell. To further evolve cell-penetrating peptides and understand how they work we developed an assay to be able to quickly screen different conditions in a high-throughput manner. A luciferase up- and downregulation experiment was used together with a reduction of the experimental time by 1 day, upscaling from 24- to 96-well plates and the cost was reduced by 95% compared to commercially available assays. In the last paper we evaluated if cell-penetrating peptides could be used to improve the uptake of an LNA oligonucleotide mimic of GRN163L, a telomerase-inhibiting oligonucleotide. The combination of cell-penetrating peptides and our mimic oligonucleotide lead to an IC50 more than 20 times lower than that of GRN163L.