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.

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.

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.

Fundus autofluorescence in exudative age-related macular degeneration

Aim: To evaluate the distribution of fundus autofluorescence in patients with age-related macular degeneration and choroidal neovascularisation (CNV). Methods: Colour fundus photographs, fundus fluorescein angiograms (FFA) and fundus autofluorescence images were obtained from a group of 40 patients (43 eyes) with age-related macular degeneration and purely classic or occult CNV. Only patients with newly diagnosed CNV and in whom autofluorescence images were obtained within 2 weeks from FFA were included. The distribution of autofluorescence was qualitatively evaluated, and the findings compared with those from colour fundus photographs and FFA. Results: 29 (67%) eyes had classic CNV and 14 (33%) had occult CNV. In 26 (90%) eyes with classic CNV, a low autofluorescence signal was detected at the site of the CNV; in 7 (50%) eyes with occult CNV, multiple foci of low autofluorescence signal were detected. Outside the area affected by the lesion, homogeneous autofluorescence was observed in most of the cases (n = 33, 77%). Similarly, homogeneous autofluorescence was commonly observed in fellow eyes (62%). A pattern of focal increased autofluorescence was rarely seen in eyes with CNV (n = 4, 9%) or in fellow eyes (n = 4, 15%). In 11 of 43 (25%) eyes, areas of increased autofluorescence, other than a pattern of focal increased autofluorescence, were detected. In four patients, autofluorescence images had been obtained before the development of CNV; in none was any increased autofluorescence detected before the formation of CNV. Conclusions: Distinct patterns of autofluorescence were observed in eyes with pure classic and occult CNV. Increased autofluorescence was rarely seen in eyes with CNV and in fellow eyes, suggesting that increased autofluorescence, and thus, retinal pigment epithelium lipofuscin, may not play an essential part in the formation of CNV.

Socio-economic deprivation and visual acuity at presentation in exudative age-related macular degeneration

Aim: To evaluate the influence of socio-economic factors on visual acuity (VA) at presentation in exudative age- related macular degeneration (AMD). Methods: The medical records of all consecutive patients with newly diagnosed exudative AMD examined at the Ophthalmology Departments of Grampian University Hospitals-NHS Trust, Aberdeen, and Gartnavel General Hospital, Glasgow, between July 2004 and June 2005, were reviewed. Demographics, duration of symptoms, VA in study and fellow eye, exudative AMD characteristics, status of fellow eye and patient home address, used to determine the Scottish Index of Multiple Deprivation (SIMD) score, were recorded. The effect of these parameters on VA at presentation was investigated using general linear modelling. Results: Two-hundred and forty patients (median age 79 years) were included in this study; 44 (18.3%) belonged to the lowest 20% SIMD score (most deprived). Age and location and type of the choroidal neovascular- isation were statistically significantly associated with VA at presentation (p = 0.003, p

Classification of fundus autofluorescence patterns in early age-related macular disease

PURPOSE. To describe and classify patterns of abnormal fundus autofluorescence (FAF) in eyes with early nonexudative age-related macular disease (AMD). METHODS. FAF images were recorded in eyes with early AMD by confocal scanning laser ophthalmoscopy (cSLO) with excitation at 488 nm (argon or OPSL laser) and emission above 500 or 521 nm (barrier filter). A standardized protocol for image acquisition and generation of mean images after automated alignment was applied, and routine fundus photographs were obtained. FAF images were classified by two independent observers. The ? statistic was applied to assess intra- and interobserver variability. RESULTS. Alterations in FAF were classified into eight phenotypic patterns including normal, minimal change, focal increased, patchy, linear, lacelike, reticular, and speckled. Areas with abnormal increased or decreased FAF signals may or may not have corresponded to funduscopically visible alterations. For intraobserver variability, ? of observer I was 0.80 (95% confidence interval [CI]0.71-0.89) and of observer II, 0.74. (95% CI, 0.64-0.84). For interobserver variability, ? was 0.77 (95% CI, 0.67-0.87). CONCLUSIONS. Various phenotypic patterns of abnormal FAF can be identified with cSLO imaging. Distinct patterns may reflect heterogeneity at a cellular and molecular level in contrast to a nonspecific aging process. The results indicate that the classification system yields a relatively high degree of intra- and interobserver agreement. It may be applicable for determination of novel prognostic determinants in longitudinal natural history studies, for identification of genetic risk factors, and for monitoring of future therapeutic interventions to slow the progression of early AMD. Copyright © Association for Research in Vision and Ophthalmology.

External beam radiotherapy in exudative age-related macular degeneration: a pooled analysis of phase I data

In recent years external beam radiotherapy (EBRT) has been proposed as a treatment for the wet form of age-related macular degeneration (AMD) where choroidal neovascularization (CNV) is the hallmark. While the majority of pilot (Phase I) studies have reported encouraging results, a few have found no benefit, i.e. EBRT was not found to result in either improvement or stabilization of visual acuity of the treated eye. The natural history of visual loss in untreated CNV of AMD is highly variable. Loss of vision is influenced mainly by the presenting acuity, and size and composition of the lesion, and to a lesser extent by a variety of other factors. Thus the variable outcome reported by the small Phase I studies of EBRT published to date may simply reflect the variation in baseline factors. We therefore obtained information on 409 patients treated with EBRT from eight independent centres, which included details of visual acuity at baseline and at subsequent follow-up visits. Analysis of the data showed that 22.5% and 14.9% of EBRT-treated eyes developed moderate and severe loss of vision, respectively, during an average follow-up of 13 months. Initial visual acuity, which explained 20.5% of the variation in visual loss, was the most important baseline factor studied. Statistically significant differences in loss of vision were observed between centres, after considering the effects of case mix factors. Comparisons with historical data suggested that while moderate visual loss was similar to that of the natural history of the disease, the likelihood of suffering severe visual loss was halved. However, the benefit in terms of maintained/improved vision in the treated eye was modest.

Will VEGF Trap-Eye reduce the treatment burden in neovascular age-related macular degeneration?

Evaluation of: Brown DM, Heier JS, Ciulla T et al. Primary end point results of a Phase II study of vascular endothelial growth factor trap-eye in wet age-related macular degeneration. Ophthalmology 118(6), 1089-1097 (2011); Heier JS, Boyer D, Nguyen QD et al. The 1-year results of CLEAR-IT 2, a Phase 2 study of vascular endothelial growth factor trap-eye dosed as-needed after 12-week fixed dosing. Ophthalmology 118(6), 1098-1106 (2011). Age-related macular degeneration is the most common cause of blindness in older adults in western countries, and is likely to become the largest cause of irreversible sight loss in the developing world. Treatments such as ranibizumab and bevacizumab that inhibit VEGF have improved visual outcomes markedly. Controlled trials and clinical experience have shown that the best outcomes are achieved when monthly treatment has been administered over 2 years. This poses a significant burden on health providers and patients. A novel inhibitor of VEGF, VEGF Trap-Eye, which allows less frequent dosing without loss of efficacy, has emerged as a potential treatment. CLEAR-IT 2 was a prospective randomized Phase II trial designed to assess the safety, tolerability and the anatomic and visual effects of repeated treatments with a range of doses of VEGF Trap-Eye. Impressive anatomic and visual improvements were noted with no safety concerns. © 2011 Expert Reviews Ltd.

The executive committee of the Greek Professional Association of Social Work in an age of austerity: examining its response

This paper explores the response by the Greek Association of Social Workers (SKLE) to Greece's current economic crisis. Socioeconomic conditions in Greece have deteriorated rapidly since the imposition of a Structural Adjustment Programme as a condition of the loan Troika provided to Greece to address its class-based public debt crisis. Interviews were conducted with SKLE Executive Committee members to examine SKLE's response in the context of newly raised inequalities. Research results show that SKLE recognised the negative consequences to both service users and its members. However, SKLE continues to reformulate its strategy mostly as a social partner. SKLE's previous strategy entailed amongst other things the analysis of policy proposals and participation in welfare related government committees. This strategy is no longer relevant because decision-making powers have been transferred to transnational bodies. This paper elaborates on these findings and discusses the barriers that prohibit SKLE from differentiation of its strategy. Although the research is country specific, it has implications for the broader global debate because professional associations must reformulate their strategies for better serving of both their constituents and the collective good based on the social justice mandate of the profession.