Alleles that increase risk for type 2 diabetes mellitus are not associated with increased risk for Alzheimer's disease

Although epidemiological studies suggest that type 2 diabetes mellitus (T2DM) increases the risk of late-onset Alzheimer's disease (LOAD), the biological basis of this relationship is not well understood. The aim of this study was to examine the genetic comorbidity between the 2 disorders and to investigate whether genetic liability to T2DM, estimated by a genotype risk scores based on T2DM associated loci, is associated with increased risk of LOAD. This study was performed in 2 stages. In stage 1, we combined genotypes for the top 15 T2DM-associated polymorphisms drawn from approximately 3000 individuals (1349 cases and 1351 control subjects) with extracted and/or imputed data from 6 genome-wide studies (>10,000 individuals; 4507 cases, 2183 controls, 4989 population controls) to form a genotype risk score and examined if this was associated with increased LOAD risk in a combined meta-analysis. In stage 2, we investigated the association of LOAD with an expanded T2DM score made of 45 well-established variants drawn from the 6 genome-wide studies. Results were combined in a meta-analysis. Both stage 1 and stage 2 T2DM risk scores were not associated with LOAD risk (odds ratio = 0.988; 95% confidence interval, 0.972-1.004; p = 0.144 and odds ratio = 0.993; 95% confidence interval, 0.983-1.003; p = 0.149 per allele, respectively). Contrary to expectation, genotype risk scores based on established T2DM candidates were not associated with increased risk of LOAD. The observed epidemiological associations between T2DM and LOAD could therefore be a consequence of secondary disease processes, pleiotropic mechanisms, and/or common environmental risk factors. Future work should focus on well-characterized longitudinal cohorts with extensive phenotypic and genetic data relevant to both LOAD and T2DM.

‘‘An old quarrel between us that will never be at an end": Middleton’s Women Beware Women and Late Jacobean Religious Politics

In this article, I examine Thomas Middleton's Women Beware Women as a response to the particular religio-political context in the years surrounding 1621. The onset of the Thirty Years War in 1618 and the subsequent humiliation of James' son-in-law Frederick, Elector of Palatine, the vexed question of a possible Catholic marriage for Charles, Prince of Wales, the ever present difficulty of Anglo-Catholic relations, particularly with Spain, as well as growing religious factionalism within the Church of England between Calvinists and Arminians: all contributed towards a culturally febrile atmosphere, one to which, as I will argue, Middleton was well placed to respond. Given Middleton's Calvinistic beliefs, I suggest that Women Beware Women offers an acerbic examination of contemporary debates concerning human will, especially women's will, as well as promoting a sceptically apocalyptic anti-Catholic agenda throughout. I also examine the religious language and imagery used to construct Bianca as the whore of Babylon, and argue that her emergence and fall offer a political commentary on the precarious position of the English Church around 1621.

Late Pleistocene climate change and landscape dynamics in the Eastern Alps: the inner-alpine Unterangerberg record (Austria)

Drill cores from the inner-alpine valley terrace of Unterangerberg, located in the Eastern Alps of Austria, offer first insights into a Pleistocene sedimentary record that was not accessible so far. The succession comprises diamict, gravel, sand, lignite and thick, fine grained sediments. Additionally, cataclastic deposits originating from two paleo-landslide events are present. Multi-proxy analyses including sedimentological and palynological investigations as well as radiocarbon and luminescence data record the onset of the last glacial period (Wurmian) at Unterangerberg at similar to 120-110 ka. This first time period, correlated to the MIS 5d, was characterised by strong fluvial aggradation under cold climatic conditions, with only sparse vegetation cover. Furthermore, two large and quasi-synchronous landslide events occurred during this time interval. No record of the first Early Wiirmian interstadial (MIS 5c) is preserved. During the second Early Wiirmian interstadial (MIS 5a), the local vegetation was characterised by a boreal forest dominated by Picea, with few thermophilous elements. The subsequent collapse of the vegetation is recorded by sediments dated to similar to 70-60 ka (i.e. MIS 4), with very low pollen concentrations and the potential presence of permafrost. Climatic conditions improved again between similar to 55 and 45 ka (MIS 3) and cold-adapted trees re-appeared during interstadials, forming an open forest vegetation. MIS 3 stadials were shorter and less severe than the MIS 4 at Unterangerberg, and vegetation during these cold phases was mainly composed of shrubs, herbs and grasses, similar to what is known from today's alpine timberline. The Unterangerberg record ended at similar to 45 ka and/or was truncated by ice during the Last Glacial Maximum. (C) 2013 Elsevier Ltd. All rights reserved.

The late effects of cancer and cancer treatment:a rapid review

This paper aims to synthesize literature about the definition, prevalence, onset and treatments associated with late effects. A rapid review was conducted using Google Scholar to identify reviews related to the late effects of adult-onset cancers. Papers were included if they provided a definition of late effects and/or presented a review of late effects as a result of adult-onset cancers in patients aged 18 years or older. Reviews related to nonmelanoma skin cancer were excluded. Reviews focusing on late effects in survivors of childhood-onset cancers (younger than 18 years) were ineligible for inclusion in the review. A total of 16 reviews were identified. Between 0% and 100% of survivors experienced a range of physical, psychological and social late effects. The onset of physical late effects was defined broadly as 'months or years' after treatment, whereas psychological late effects were defined as occurring at the end of treatment or similarly to physical late effects as 'months or years' after treatment. Few reviews provided an operational definition of late effects, and the onset of late effects was not often reported. Thus, reviews may have included the acute and long-term effects of cancer treatment. Evidence regarding causes, prevalence, and onset was incomplete for many late effects. Understanding the cause and onset of late effects is important in order to provide timely interventions to reduce the risk of late effect development in cancer patients.

The latest LGM culmination of the Garda Glacier (Italian Alps) and the onset of glacial termination. Age of glacial collapse and vegetation chronosequence

In the deglacial sequence of the largest end moraine system of the Italian Alps, we focused on the latest culmination of the Last Glacial Maximum, before a sudden downwasting of the piedmontane lobe occupying the modern lake basin. We obtained a robust chronology for this culmination and for the subsequent deglacial history by cross-radiocarbon dating of a proximal fluvioglacial plain and of a deglacial continuous lake sedimentation. We used reworked dinocysts to locate sources of glacial abrasion and to mark the input of glacial meltwater until depletion. The palynological record from postglacial lake sediments provided the first vegetation chronosequence directly reacting to the early Lateglacial withdrawal so far documented in the Alps.

Glacier collapse occurred soon after 17.46 +/- 0.2 ka cal BP, which is, the Manerba advance culmination. Basin deglaciation of several overdeepened foreland piedmont lakes on southern and northern sides of the Alps appears to be synchronous at millennial scale and near-synchronous with large-scale glacial retreat at global scale. The pioneering succession shows a first afforestation step at a median modeled age of 64 years after deglaciation, while rapid tree growth lagged 7 centuries. Between 16.4 +/- 0.16 and 15.5 +/- 0.16 ka cal BP, a regressive phase interrupted forest growth marking a Lateglacial phase of continental-dry climate predating GI-1. This event, spanning the most advanced phases of North-Atlantic H1, is consistently radiocarbon-framed at three deglacial lake records so far investigated on the Italian side of the Alps. Relationships with the Gschnitz stadial from the Alpine record of Lateglacial advances are discussed

Late effects of cancer and cancer treatment-the perspective of the patient

PURPOSE: Understanding the experience of late effects from the perspective of cancer survivors is essential to inform patient-centred care. This study investigated the nature and onset of late effects experienced by survivors and the manner in which late effects have affected their lives.

METHODS: Sixteen purposively selected cancer survivors participated in a qualitative interview study. The data were analysed inductively using a narrative schema in order to derive the main themes that characterised patients' accounts of late effects.

RESULTS: Individual survivors tended to experience more than one late effect spanning a range of physical and psychological effects. Late effects impacted on relationships, working life, finances and the ability to undertake daily activities. Survivors reported experiencing psychological late effects from around the end of treatment whereas the onset of physical effects occurred later during the post-treatment period. Late effects were managed using formal health services, informal social support and use of 'wellbeing strategies'. Survivors engaged in a process of searching for reasons for experiencing late effects and struggled to make sense of their situation. In particular, a process of 'peer-patient comparison' was used by survivors to help them make sense of, or cope with, their late effects. There appeared to be an association between personal disposition and adaptation and adjustment to the impact of late effects.

CONCLUSIONS: Cancer survivors identified potential components for supported self-management or intervention programmes, as well as important considerations in terms of peer comparisons, personal disposition and making sense of experienced late effects.

Late-Glacial and early Holocene marine 14C reservoir ages off North Iceland (16-9 cal kyr BP)

Tephrochronological age models and 48 14C age determinations on molluscs and foraminifera (planktonic and benthic) are applied for the calculation of marine 14C reservoir age variability during a time period covering the Heinrich event H1 to early Holocene (16–9 cal kyr BP). Our data source consists of four high-resolution marine sediment cores (HM107-04, HM107-05, MD99-2271, MD99-2275) from the North Icelandic shelf. The marine reservoir age (ΔR) is found to be extremely variable, ranging from 385 to 1065 14C years. Extreme ΔR values occur at the end of H1, with values around 1000 14C years (~15 cal kyr BP), probably due to reduced northward flow of well-ventilated subtropical surface waters and a southward expansion of polar waters, as well as an expansion of sea ice limiting air-sea gas exchange. With the onset of the Bølling-Allerød interstadial, the ΔR values decrease towards 0 14C years suggesting a more vigorous North Atlantic Current and an active meridional overturning circulation system. During the Younger Dryas stadial, ΔR values are consistently around 700 14C years suggesting e renewed expansion of polar waters and a weakened meridional overtuning circulation. Interestingly, ΔR values remain high (~200 14C years) at the onset of the Holocene suggesting continued high influence of polar waters. Subsequently, ΔR values rapidly decrease to ~¬ 250 14C years around 11 cal kyr BP, indicating increased air-sea CO2 exchange with the coeval atmosphere. The ΔR values average around 0 14C years from around 10.5 to 9.0 cal kyr BP.

Wide-ranging alterations in the brain fatty acid complement of subjects with late Alzheimer’s disease as detected by GC-MS

Disturbed lipid metabolism is a well-established feature of human Alzheimer’s disease (AD). The present study used gas chromatography-mass spectrometry (GC-MS) analysis of fatty acid methyl esters (FAMES) to profile all detectable fatty acid (FA) species present in post-mortem neocortical tissue (Brodmann 7 region). Quantitative targeted analysis was undertaken from 29 subjects (n=15 age-matched controls; n=14 late-stage AD). GC-MS analysis of FAMES detected a total of 24 FAs and of these, 20 were fully quantifiable. The results showed significant and wide ranging elevations in AD brain FA concentrations. A total of 9 FAs were elevated in AD with cis-13,16-docosenoic acid increased most (170%; P=0.033). Intriguingly, docosahexanoic acid (DHA; C22:6) concentrations were elevated (47%; P=0.018) which conflicts with the findings of others (unaltered or decreased) in some brain regions after the onset of AD. Furthermore, our results appear to indicate that subject gender influences brain FA levels in AD subjects (but not in age-matched control subjects). Among AD subjects 7 FA species were significantly higher in males than in females. These preliminary findings pinpoint FA disturbances as potentially important in the pathology of AD. Further work is required to determine if such changes are influenced by disease severity or different types of dementia.

Wide-ranging alterations in the brain fatty acid complement of subjects with late Alzheimer's disease as detected by GC-MS

Disturbed lipid metabolism is a well-established feature of human Alzheimer's disease (AD). The present study used gas chromatography-mass spectrometry (GC-MS) analysis of fatty acid methyl esters (FAMES) to profile all detectable fatty acid (FA) species present in post-mortem neocortical tissue (Brodmann 7 region). Quantitative targeted analysis was undertaken from 29 subjects (n=15 age-matched controls; n=14 late-stage AD). GC-MS analysis of FAMES detected a total of 24 FAs and of these, 20 were fully quantifiable. The results showed significant and wide ranging elevations in AD brain FA concentrations. A total of 9 FAs were elevated in AD with cis-13,16-docosenoic acid increased most (170%; P=0.033). Intriguingly, docosahexanoic acid (DHA; C22:6) concentrations were elevated (47%; P=0.018) which conflicts with the findings of others (unaltered or decreased) in some brain regions after the onset of AD. Furthermore, our results appear to indicate that subject gender influences brain FA levels in AD subjects (but not in age-matched control subjects). Among AD subjects 7 FA species were significantly higher in males than in females. These preliminary findings pinpoint FA disturbances as potentially important in the pathology of AD. Further work is required to determine if such changes are influenced by disease severity or different types of dementia.

Late referral for assessment of renal failure

It has been recommended that adult patients with a serum creatinine above 150 µmol/l should be referred to a nephrologist for specialist assessment. This study ascertained all patients in Northern Ireland with creatinine above this concentration in 2001 (n?=?19 286 ) to see if this triggered referral within the subsequent year. After exclusion of those who were already known to a nephrologist and those who had acute renal failure, it was found that younger patients and diabetic patients were more likely to be referred. There was no difference in referral rates between male and female patients. However, only 6.5% of all non-diabetic subjects and 19% of diabetic patients were referred within 12 months after a first increased serum creatinine test.