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.

Studies on Transformations of H-Phosphonates into DNA Analogues Containing P-S or P-C Bonds

In this thesis, mechanistic and synthetic studies on transformations of H-phosphonates into DNA analogues containing P-S or P-C bonds are described. Configurational stability of dinucleoside H-phosphonates and the stereochemical course of their sulfurisation in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were investigated. In light of these studies, the reported stereoselective sulfurisation of dinucleoside H-phosphonates and benzoylphosphonates in the presence of DBU was proved to be incorrect. Efficient protocols for the synthesis of new nucleotide analogues with non-ionic C-phosphonate internucleotide linkages were developed. The synthesis of dinucleoside 2-pyridylphosphonates was successfully performed by a DBU-promoted reaction of H-phosphonate diesters with N-methoxypyridinium salts. The thio analogues, 2-pyridyl- and 4-pyridyl phosphonothioate diesters, could be obtained by modifying the reactions developed for their oxo counterparts. Dinucleoside 3-pyridylphosphonates were prepared via a palladium(0)-catalysed cross coupling strategy that could be extended also to the synthesis of nucleotide analogues with metal-complexing properties, i.e. terpyridyl- and bipyridylphosphonate derivatives. Oligonucleotides modified with pyridylphosphonate internucleotide linkages have been prepared and preliminary studies on their hybridisation properties and resistance towards enzymatic degradation were performed. Finally, nucleotidic units for the incorporation of pyridylphosphonate groups at the 5’-terminus of oligonucleotides were designed. Condensations of such units with a suitably protected nucleoside afforded after oxidation the expected dinucleoside (3’-5’)-phosphates with pyridylphosphonate monoester functions at the 5’-ends.