Alzheimer's disease and age-related macular degeneration have different genetic models for complement gene variation

Alzheimer's disease (AD) and age-related macular degeneration (AMD) are both neurodegenerative disorders which share common pathological and biochemical features of the complement pathway. The aim of this study was to investigate whether there is an association between well replicated AMD genetic risk factors and AD. A large cohort of AD (n = 3898) patients and controls were genotyped for single nucleotide polymorphisms (SNPs) in the complement factor H (CFH), the Age-related maculopathy susceptibility protein 2 (ARMS2) the complement component 2 (C2), the complement factor B (CFB), and the complement component 3 (C3) genes. While significant but modest associations were identified between the complement factor H, the age-related maculopathy susceptibility protein 2, and the complement component 3 single nucleotide polymorphisms and AD, these were different in direction or genetic model to that observed in AMD. In addition the multilocus genetic model that predicts around a half of the sibling risk for AMD does not predict risk for AD. Our study provides further support to the hypothesis that while activation of the alternative complement pathway is central to AMD pathogenesis, it is less involved in AD.

The role of ECE1 variants in cognitive ability in old age and Alzheimer's disease risk

The ß-amyloid peptide may play a central role in Alzheimer's disease (AD) pathogenesis. We have evaluated variants in seven Aß-degrading genes (ACE, ECE1, ECE2, IDE, MME, PLAU, and TF) for association with AD risk in the Genetic and Environmental Risk in Alzheimer's Disease Consortium 1 (GERAD1) cohort, and with three cognitive phenotypes in the Lothian Birth Cohort 1936 (LBC1936), using 128 and 121 SNPs, respectively. In GERAD1, we identified a significant association between a four-SNP intragenic ECE1 haplotype and risk of AD in individuals that carried at least one APOE e4 allele (P = 0.00035, odds ratio = 1.61). In LBC1936, we identified a significant association between a different two-SNP ECE1 intragenic haplotype and non-verbal reasoning in individuals lacking the APOE e4 allele (P = 0.00036, ß = -0.19). Both results showed a trend towards significance after permutation (0.05 <P <0.10). A follow-up cognitive genetic study evaluated the association of ECE1 SNPs in three additional cohorts of non-demented older people. Meta-analysis of the four cohorts identified the significant association (Z <0.05) of SNPs in the ECE-1b promoter with non-verbal reasoning scores, particularly in individuals lacking the APOE e4 allele. Our genetic findings are not wholly consistent. Nonetheless, the AD associated intronic haplotype is linked to the 338A variant of known ECE1b promoter variant, 338C>A (rs213045). We observed significantly less expression from the 338A variant in two human neuroblastoma cell lines and speculate that this promoter may be subject to tissue-specific regulation.

ARMS2 Increases the Risk of Early and Late Age-Related Macular Degeneration in the European Eye Study

OBJECTIVE:
To study associations between severity stages of early and late age-related macular degeneration (AMD) and genetic variations in age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH) and to investigate potential interactions between smoking and ARMS2.
DESIGN:
Population-based, cross-sectional European Eye Study in 7 countries in Europe.
PARTICIPANTS:
Four thousand seven hundred fifty participants, 65 years of age and older, recruited through random sampling.
METHODS:
Participants were classified on the basis of the more severely affected eye into 5 mutually exclusive AMD severity stages ranging from no AMD, 3 categories of early AMD, and late AMD. History of cigarette smoking was available and allowed classification into never, former, and current smokers, with the latter 2 groups combined into a single category of ever smokers for analysis. Genotyping was performed for single nucleotide polymorphisms rs10490924 and rs4146894 in ARMS2 and rs1061170 in CFH. Associations were analyzed by logistic regression.
MAIN OUTCOME MEASURES:
Odds ratios (ORs) for stage of AMD associated with genetic variations in ARMS2 and CFH and interactions between ARMS2 and smoking status.
RESULTS:
Early AMD was present in 36.4% and late AMD was present in 3.3% of participants. Data on both genotype and AMD were available for 4276 people. The ORs for associations between AMD stage and ARMS2 increased monotonically with more severe stages of early AMD and were altered little by adjustment for potential confounders. Compared with persons with no AMD, carriers of the TT genotype for rs10490924 in ARMS2 had a 10-fold increase in risk of late AMD (P<3 × 10(-20)). The ORs for associations with CFH were similar for stage 3 early AMD and late AMD. Interactions between rs10490924 in ARMS2 and smoking status were significant in both unadjusted and adjusted models (P = 0.001). The highest risk was observed in those doubly homozygous for rs10490924 and rs1061170 in CFH (OR, 62.3; 95% confidence interval, 16-242), with P values for trend ranging from 0.03 (early AMD, stage 1) to 1 × 10(-26) (late AMD).
CONCLUSIONS:
A strong association was demonstrated between all stages of AMD and genetic variation in ARMS2, and a significant gene-environment interaction with cigarette smoking was confirmed.

Capitalism, the state and health care in the age of austerity:A Marxist analysis

The capacity to provide satisfactory nursing care is being increasingly compromised by current trajectories of healthcare funding and governance. The purpose of this paper is to examine how well Marxist theories of the state and its relationship with capital can explain these trajectories in this period of ever-increasing austerity. Following a brief history of the current crisis, it examines empirically the effects of the crisis, and of the current trajectory of capitalism in general, upon the funding and organization of the UK and US healthcare systems. The deleterious effect of growing income inequalities to the health of the population are also addressed. Marx’s writings on the state and its relation to the capitalist class were fragmentary, and historically and geographically specific. From them, we can extract three theoretical variants: the instrumentalist theory of the state, where the state has no autonomy from capital; the abdication theory, whereby capital abstains from direct political power and relies on the state to serve its interests; and the class-balance theory of the state, whereby the struggle between two opposed classes allows the state to assert itself. Discussion of modern Marxist interpretations include Poulantzas’s structuralist abdication theory and Miliband’s instrumentalist theory. It is concluded that, despite the pluralism of electoral democracies, the bourgeoisie do have an overweening influence upon the state. The bourgeoisie’s ownership of the means of production provides the foundation for its influence because the state is obliged to rely on it to manage the supply of goods and services and the creation of wealth. That power is further reinforced by the infiltration of the bourgeoisie into the organs of state. The level of influence has accelerated rapidly over recent decades. One of the consequences of this has been that healthcare systems have become rich pickings for the evermore confident bourgeoisie.

Impact of Age on the Importance of Systolic and Diastolic Blood Pressures for Stroke Risk:The MOnica, Risk, Genetics, Archiving, and Monograph (MORGAM) Project

This study investigates age-related shifts in the relative importance of systolic (SBP) and diastolic (DBP) blood pressures as predictors of stroke and whether these relations are influenced by other cardiovascular risk factors. Using 34 European cohorts from the MOnica, Risk, Genetics, Archiving, and Monograph (MORGAM) Project with baseline between 1982 and 1997, 68 551 subjects aged 19 to 78 years, without cardiovascular disease and not receiving antihypertensive treatment, were included. During a mean of 13.2 years of follow-up, stroke incidence was 2.8%. Stroke risk was analyzed using hazard ratios per 10-mm Hg/5-mm Hg increase in SBP/DBP by multivariate-adjusted Cox regressions, including SBP and DBP simultaneously. Because of nonlinearity, DBP was analyzed separately for DBP =71 mm Hg and DBP

Neuro developmental status at 1 year predicts neuropsychiatric outcome at 14-15 years of age in very preterm infants

Background: Neurodevelopmental and behavioural problems have been repeatedly reported in very preterm. survivors, often showing themselves later in childhood as poor school performance. Early identification of problems would mean that appropriate remedial therapy can be implemented. We have previously shown that neurodevelopmental status at 1 year was predictive of outcome at 8 years in a cohort of preterm. infants. The aim of this paper was to see if neurodevelopmental outcome in adolescence could be predicted by assessment by 1 year in the same cohort of pretem infants. Study design: Prospective cohort study. Subjects: 150 adolescents, born before 33 weeks gestation. Outcome measures: Neurological examination, developmental quotient, vision and hearing by 1 year. At 14-15 years, neurological examination, school performance questionnaire, Schonnell test of reading age, a premorbid adjustment score, Rutter behavioural score and for those born from 1981, cognitive tests (WISC-R). Results: A highly significant relationship existed between neurological status by 1 year and the need for extra educational provision, overall neurodevelopmental status, cognitive function in those that had their IQs measured and premorbid adjustment score of prepsychotic symptoms in adolescence. However, status at 1 year was not predictive of adolescent reading age or behavioural score. Conclusions: Neurodevelopmental assessment at 1 year ispredictive of school performance and outcome in the adolescent period. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

Secondary Outcomes in a Clinical Trial of Carotenoids with Coantioxidants versus Placebo in Early Age-Related Macular Degeneration

Purpose: To report the secondary outcomes in the Carotenoids with Coantioxidants in Age-Related Maculopathy trial.

Design: Randomized double-masked placebo-controlled clinical trial (registered as ISRCTN 94557601).

Participants: Participants included 433 adults 55 years of age or older with early age-related macular degeneration (AMD) in 1 eye and late-stage disease in the fellow eye (group 1) or early AMD in both eyes (group 2).

Intervention: An oral preparation containing lutein (L), zeaxanthin (Z), vitamin C, vitamin E, copper, and zinc or placebo. Best-corrected visual acuity (BCVA), contrast sensitivity (CS), Raman spectroscopy, stereoscopic colour fundus photography, and serum sampling were performed every 6 months with a minimum follow-up time of 12 months.

Main Outcome Measures: Secondary outcomes included differences in BCVA (at 24 and 36 months), CS, Raman counts, serum antioxidant levels, and progression along the AMD severity scale (at 12, 24, and 36 months).

Results: The differential between active and placebo groups increased steadily, with average BCVA in the former being approximately 4.8 letters better than the latter for those who had 36 months of follow-up, and this difference was statistically significant (P = 0.04). In the longitudinal analysis, for a 1-log-unit increase in serum L, visual acuity was better by 1.4 letters (95% confidence interval, 0.3-2.5; P = 0.01), and a slower progression along a morphologic severity scale (P = 0.014) was observed.

Conclusions: Functional and morphologic benefits were observed in key secondary outcomes after supplementation with L, Z, and coantioxidants in persons with early AMD.

Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. © 2012 American Academy of Ophthalmology.

Managing state-owned enterprises in an age of crisis:An analysis of irish experience

As with all aspects of public management, the control, financing, and regulation of state-owned enterprises (SOEs) are matters subject to changing international trends and domestic political imperatives. The effects of the global financial crisis (GFC) on the ownership, financing, and role of SOEs are still unfolding, but undoubtedly will be heavily influenced by a new era of public sector reforms principally designed to reassert central political controls, as well as by fiscal pressures to balance state budgets. In this regard, the Irish experience is instructive, with the findings from two datasets being used here to examine various modes of state enterprise control and their corresponding autonomy. Significantly, there has been considerable variety within and across the SOE sector, demonstrating the need for more detailed understanding of how SOEs are managed. © 2011 Taylor & Francis.

Age-related reference intervals for lymphocyte subsets in whole blood of healthy individuals

Enumeration of various lymphocyte subsets is used widely in the diagnosis and monitoring of various disease states. With the development of flow cytometric technology and whole blood analysis, methodologies have become more sensitive. It is therefore important to establish reference intervals in normal, healthy individuals using these techniques to give a better indication of the border between health and disease. Since some lymphocyte subpopulations are known to change with age, we have enumerated common subsets in healthy individuals from all decades of adult life, including nonagenarian subjects. We report reference intervals for these subsets in each age group, which will be of use in diagnosis and disease monitoring, particularly in elderly subjects, the most rapidly expanding group within the population today.

Age-related changes in non-receptor dependent generation of reactive oxygen species from phagocytes of healthy adults

Several authors have shown that neutrophil generation of reactive oxygen species (ROS) declines with advancing age. Similar changes have also been suggested in monocytes. In both cases alterations in second messenger activity have been implicated as the most likely explanation for these observations. The aim of this study was to investigate the effect of age on phagocyte ROS generation, stimulated by the direct activation of protein kinase C (PKC). Venous blood was drawn from normal healthy subjects, cells were separated on a double density gradient into mononuclear and polymorphonuclear (pmn) cells. Phorbol myristate acetate (PMA) was employed as a cell stimulus. Superoxide generation was measured by cytochrome c reduction and myeloperoxidase (MPO) products by measurement of peak luminol chemiluminescence (CL). Fifty-eight subjects, 25 males and 33 females, were studied, median age 49 years (range 26-88 years). Polymorphonuclear cell superoxide generation was significantly higher in males and there was a trend towards higher pmn MPO product generation in males. Using Spearman's ranked correlation coefficient, monocyte superoxide generation was negatively correlated with age (r = -0.473, P <0.001). No changes in the generation of MPO products was found. There were also trends towards a negative correlation of pmn cytochrome c reduction and peak luminol CL with age in males but not females. Since PMA directly activates protein kinase C, reduced monocyte superoxide generation with increasing age appears to be related to alterations in the ROS generating system downstream of the cell receptor. Impaired monocyte superoxide generation may have implications for non-specific defence against certain infections and early tumour growth in the elderly. Factors underlying these changes in monocyte function therefore require further study.

Anthropometric measurements from a cross-sectional survey of community dwelling subjects aged over 90 years of age

To measure anthropometric variables of weight, height, body mass index (BMI) and triceps skin fold thickness (TSF) and produce local percentiles for > 90 y old subjects. To assess prevalence of conventional measures of under nutrition (BMI at or below 18.5 kg/m2) or over nutrition (BMI values > 30 kg/m2) in this age group.

Changes in lymphocyte subsets, interleukin 2, and soluble interleukin 2 receptor in old and very old age

In this study, the changes in some of the cellular components of the immune system and the activity of the cytokine interleukin 2, important for immune activation and lymphocyte proliferation, were measured in a large cross-sectional study of all age groups including octogenarian and nonagenarian subjects. In 206 apparently well community-living subjects, the absolute lymphocyte count and T and B cell numbers fell a little in old and very old subjects. Within the T cell compartment, helper/inducer CD4+ T cells, together with their subsets identified as 'naive' (CD4+/CD45RA+) and 'memory' (CD4+/CD45RO+) cells, also showed a decline with increased age. The suppressor/cytotoxic CD8+ subset showed no age-related change. The levels of the cytokine interleukin 2 were very low in octogenarian and nonagenarian subjects, while the soluble interleukin 2 receptor levels increased with increasing age. The interleukin 2 levels were associated with number and percentage of the 'memory' (CD4+/CD45RO+) subset of T cells which mediates the host response to previously met antigens. Since the interleukin 2 values were very low in the oldest groups and were associated with a reduced 'memory' (CD4+/CD45RO+) compartment, this suggests a possible mechanism of why the very elderly subject is more susceptible to morbidity and mortality from infectious or other agents.

A revised age for the Kawakawa/Oruanui tephra, a key marker for the Last Glacial Maximum in New Zealand

The Kawakawa/Oruanui tephra (KOT) is a key chronostratigraphic marker in terrestrial and marine deposits of the New Zealand (NZ) sector of the southwest Pacific. Erupted early during the Last Glacial Maximum (LGM), the wide distribution of the KOT enables inter-regional alignment of proxy records and facilitates comparison between NZ climatic variations and those from well-dated records elsewhere. We present 22 new radiocarbon ages for the KOT from sites and materials considered optimal for dating, and apply Bayesian statistical methods via OxCal4.1.7 that incorporate stratigraphic information to develop a new age probability model for KOT. The revised calibrated age, ±2 standard deviations, for the eruption of the KOT is 25,360 ± 160 cal yr BP. The age revision provides a basis for refining marine reservoir ages for the LGM in the southwest Pacific.