The role of poly(ADP-ribose) polymerase-1 in CNS disease.

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that contributes to both neuronal death and survival under stress conditions. PARP-1 is the most abundant of several PARP family members, accounting for more than 85% of nuclear PARP activity, and is present in all nucleated cells of multicellular animals. When activated by DNA damage, PARP-1 consumes nicotinamide adenine dinucleotide (NAD+) to form branched polymers of ADP-ribose on target proteins. This process can have at least three important consequences in the CNS, depending on the cell type and the extent of DNA damage: 1) Poly(ADP-ribose) formation on histones and on enzymes involved in DNA repair can prevent sister chromatid exchange and facilitate base-excision repair; 2) poly(ADP-ribose) formation can influence the action of transcription factors, notably nuclear factor kappaB, and thereby promote inflammation; and 3) extensive PARP-1 activation can promote neuronal death through mechanisms involving NAD+ depletion and release of apoptosis inducing factor from the mitochondria. PARP-1 activation is thereby a key mediator of neuronal death during excitotoxicity, ischemia, and oxidative stress, and PARP-1 gene deletion or pharmacological inhibition can markedly improve neuronal survival in these settings. PARP-1 activation has also been identified in Alzheimer's disease and in experimental allergic encephalitis, but the role of PARP-1 in these disorders remains to be established.

Neighbourhood unemployment and all cause mortality: a comparison of six countries.

STUDY OBJECTIVE: Studies have shown that living in more deprived neighbourhoods is related to higher mortality rates, independent of individual socioeconomic characteristics. One approach that contributes to understanding the processes underlying this association is to examine whether the relation is modified by the country context. In this study, the size of the association between neighbourhood unemployment rates and all cause mortality was compared across samples from six countries (United States, Netherlands, England, Finland, Italy, and Spain). DESIGN: Data from three prospective cohort studies (ARIC (US), GLOBE (Netherlands), and Whitehall II (England)) and three population based register studies (Helsinki, Turin, Madrid) were analysed. In each study, neighbourhood unemployment rates were derived from census, register based data. Cox proportional hazard models, taking into account the possible correlation of outcomes among people of the same neighbourhood, were used to assess the associations between neighbourhood unemployment and all cause mortality, adjusted for education and occupation at the individual level. RESULTS: In men, after adjustment for age, education, and occupation, living in the quartile of neighbourhoods with the highest compared with the lowest unemployment rates was associated with increased hazards of mortality (14%-46%), although for the Whitehall II study associations were not statistically significant. Similar patterns were found in women, but associations were not statistically significant in two of the five studies that included women. CONCLUSIONS: Living in more deprived neighbourhoods is associated with increased all cause mortality in the US and five European countries, independent of individual socioeconomic characteristics. There is no evidence that country substantially modified this association.

Effects of the characteristics of neighbourhoods and the characteristics of people on cause specific mortality: a register based follow up study of 252,000 men.

STUDY OBJECTIVE: To assess the strength of the associations between neighbourhood characteristics and mortality, after adjusting for individual characteristics. DESIGN AND SETTING: 1990 census records of over 25 year old men in the Helsinki Metropolitan area linked to death records in 1991-1995; almost 1.22 million person years and 15 000 deaths. Individual characteristics were education, occupation based social class, housing tenure, housing density, and living arrangements. Proportion of manual workers, proportion of over 60 year olds, and social cohesion were measured for 55 small areas, and SAS Glimmix was used to fit multilevel models. MAIN RESULTS: Men in areas with high proportion of manual workers and low social cohesion have high mortality, particularly among 25-64 year olds. About 70% of this excess mortality is explained by compositional differences of people living in these areas. Accidents and violence, circulatory diseases, and alcohol related causes contribute most to these area effects. Area characteristics do not consistently modify or mediate the effects of individual socioeconomic characteristics on mortality. CONCLUSIONS: As compared with individual characteristics neighbourhood characteristics have modest independent effects on male mortality. Furthermore, individual socioeconomic characteristics are associated with mortality independently of area characteristics. Rather than the characteristics of areas, other social contexts, such as peer groups and family settings may be more fruitful targets for further research and policy on contextual effects on mortality.