Genome-wide scan of copy number variation in late-onset Alzheimer's disease.

Alzheimer's disease is a complex and progressive neurodegenerative disease leading to loss of memory, cognitive impairment, and ultimately death. To date, six large-scale genome-wide association studies have been conducted to identify SNPs that influence disease predisposition. These studies have confirmed the well-known APOE epsilon4 risk allele, identified a novel variant that influences disease risk within the APOE epsilon4 population, found a SNP that modifies the age of disease onset, as well as reported the first sex-linked susceptibility variant. Here we report a genome-wide scan of Alzheimer's disease in a set of 331 cases and 368 controls, extending analyses for the first time to include assessments of copy number variation. In this analysis, no new SNPs show genome-wide significance. We also screened for effects of copy number variation, and while nothing was significant, a duplication in CHRNA7 appears interesting enough to warrant further investigation.

A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins.

The Na+/H+ exchanger regulatory factor (NHERF) binds to the tail of the beta2-adrenergic receptor and plays a role in adrenergic regulation of Na+/H+ exchange. NHERF contains two PDZ domains, the first of which is required for its interaction with the beta2 receptor. Mutagenesis studies of the beta2 receptor tail revealed that the optimal C-terminal motif for binding to the first PDZ domain of NHERF is D-S/T-x-L, a motif distinct from those recognized by other PDZ domains. The first PDZ domain of NHERF-2, a protein that is 52% identical to NHERF and also known as E3KARP, SIP-1, and TKA-1, exhibits binding preferences very similar to those of the first PDZ domain of NHERF. The delineation of the preferred binding motif for the first PDZ domain of the NHERF family of proteins allows for predictions for other proteins that may interact with NHERF or NHERF-2. For example, as would be predicted from the beta2 receptor tail mutagenesis studies, NHERF binds to the tail of the purinergic P2Y1 receptor, a seven-transmembrane receptor with an intracellular C-terminal tail ending in D-T-S-L. NHERF also binds to the tail of the cystic fibrosis transmembrane conductance regulator, which ends in D-T-R-L. Because the preferred binding motif of the first PDZ domain of the NHERF family of proteins is found at the C termini of a variety of intracellular proteins, NHERF and NHERF-2 may be multifunctional adaptor proteins involved in many previously unsuspected aspects of intracellular signaling.

The neural basis of naming impairments in Alzheimer's disease revealed through positron emission tomography.

The naming impairments in Alzheimer's disease (AD) have been attributed to a variety of cognitive processing deficits, including impairments in semantic memory, visual perception, and lexical access. To further understand the underlying biological basis of the naming failures in AD, the present investigation examined the relationship of various classes of naming errors to regional brain measures of cerebral glucose metabolism as measured with 18 F-Fluoro-2-deoxyglucose (FDG) and positron emission tomography (PET). Errors committed on a visual naming test were categorized according to a cognitive processing schema and then examined in relationship to metabolism within specific brain regions. The results revealed an association of semantic errors with glucose metabolism in the frontal and temporal regions. Language access errors, such as circumlocutions, and word blocking nonresponses were associated with decreased metabolism in areas within the left hemisphere. Visuoperceptive errors were related to right inferior parietal metabolic function. The findings suggest that specific brain areas mediate the perceptual, semantic, and lexical processing demands of visual naming and that visual naming problems in dementia are related to dysfunction in specific neural circuits.

Systematic review and metasummary of attitudes toward research in emergency medical conditions

Emergency departments are challenging research settings, where truly informed consent can be difficult to obtain. A deeper understanding of emergency medical patients' opinions about research is needed. We conducted a systematic review and meta-summary of quantitative and qualitative studies on which values, attitudes, or beliefs of emergent medical research participants influence research participation. We included studies of adults that investigated opinions toward emergency medicine research participation. We excluded studies focused on the association between demographics or consent document features and participation and those focused on non-emergency research. In August 2011, we searched the following databases: MEDLINE, EMBASE, Google Scholar, Scirus, PsycINFO, AgeLine and Global Health. Titles, abstracts and then full manuscripts were independently evaluated by two reviewers. Disagreements were resolved by consensus and adjudicated by a third author. Studies were evaluated for bias using standardised scores. We report themes associated with participation or refusal. Our initial search produced over 1800 articles. A total of 44 articles were extracted for full-manuscript analysis, and 14 were retained based on our eligibility criteria. Among factors favouring participation, altruism and personal health benefit had the highest frequency. Mistrust of researchers, feeling like a 'guinea pig' and risk were leading factors favouring refusal. Many studies noted limitations of informed consent processes in emergent conditions. We conclude that highlighting the benefits to the participant and society, mitigating risk and increasing public trust may increase research participation in emergency medical research. New methods for conducting informed consent in such studies are needed.

Impact of tumor board recommendations on treatment outcome for locally advanced head and neck cancer

Background/Aims: To identify physician selection factors in the treatment of locally advanced head and neck cancer and how treatment outcome is affected by Tumor Board recommendations. Methods: A retrospective analysis of 213 patients treated for locally advanced head and neck cancer in a single institution was performed. All treatments followed Tumor Board recommendations: 115 patients had chemotherapy and radiation, and 98 patients received postoperative radiation. Patient characteristics, treatment toxicity, locoregional control and survival between these two treat- ment groups were compared. Patient survival was compared with survival data reported in randomized studies of locally advanced head and neck cancer. Results: There were no differences in comorbidity factors, and T or N stages between the two groups. A statistically significant number of patients with oropharyngeal and oral cavity tumors had chemoradiation and postoperative radiation, respectively (p < 0.0001). Grade 3-4 toxicities during treatment were 48 and 87% for the postoperative radiation and chemoradiation groups, respectively (p = 0.0001). There were no differences in survival, locoregional recurrences and distant metastases between the two groups. Patient survival was comparable to survival rates reported by randomized studies of locally advanced head and neck cancer. Conclusion: Disease sites remained the key determining factor for treatment selection. Multidisciplinary approaches provided optimal treatment outcome for locally advanced head and neck cancer, with overall survival in these patients being comparable to that reported in randomized clinical trials. Copyright © 2008 S. Karger AG.

Assessment of the potential impacts of coasteering on rocky intertidal habitats in Wales

The relatively new recreational pursuit of coasteering, which has developed in the St David's area of Pembrokeshire, appears to be expanding rapidly. The majority of local commercial recreation providers (outdoor pursuit centers etc.) now appear to offer this pursuit. The majority of the rocky coastlines where it takes place lie within Pembrokeshire Marine Special Area of Conservation (SAC), and are also Sites of Special Scientific Interest (SSSI). No assessment has yet been undertaken of coasteering's potential impact on the intertidal habitats. Therefore the Countryside Council for Wales (CCW) commissioned the Marine Life Information Network (MarLIN) to undertake a desk study of the likely environmental effects of coasteering on rocky intertidal habitats within the Pembrokeshire marine SAC. The desk study was based on a review of the available literature, and in particular the effects of trampling on rocky intertidal communities. Communities (as biotopes) within the Pembrokeshire marine SAC likely to be exposed to coasteering activities were identified from Phase I biotope data for the area, provided by CCW. Where possible, existing research by MarLIN into the intolerance, recoverability and sensitivity of the biotopes identified, was used to identify their potential vulnerability to trampling. The literature review revealed that: - foliose canopy forming algae (e.g. fucoids) were particularly intolerant and sensitive to trampling impacts; - trampling damaged erect coralline turfs, barnacles, and resulted in an increase in bare space; in some cases paths across the shore were visible; - on brown algae dominated shores, understorey algae could suffer due to increased desiccation but algal turf species, opportunists and gastropod grazers (e.g. limpets) could increase in abundance as an indirect effect of trampling, and that - trampling impacts resulted from physical contact and wear and were dependant on the intensity, duration, and frequency of trampling, and even the type of footwear used. A total of 19 intolerant rocky intertidal biotopes were identified as potentially vulnerable to trampling and hence coasteering within the Pembrokeshire marine SAC, of which six are of Welsh importance and eight are nationally rare or scarce. Trampling is a highly localized impact and it was not possible to identify biotopes, and hence communities, actually impacted by coasteering activities in the Pembrokeshire marine SAC. In addition, the majority of the literature addresses the impacts of trampling on wave sheltered or moderately exposed brown algal dominated shores, while coasteering occurs on more wave exposed, steeply inclined shores. Therefore, direct survey of the routes used by coasteering groups within the Pembrokeshire marine SAC is required to identify the intensity, duration and frequency of trampling impact, together with the communities impacted. Given the paucity of data concerning trampling effects in the rocky intertidal in the UK, a survey of the impacts of coasteering would provide an opportunity to examine the effects of trampling and visitor use in steep rocky, wave exposed shores. The report recognizes the potential to engage coasteerers in contributing to the development of strategies for minimizing adverse impacts, recording impacts and collecting information of use in identifying climate change and the occurrence of non-native species.

Depressed mood and dietary fish intake: Direct relationship or indirect relationship as a result of diet and lifestyle?

Previous studies have suggested an association between depressed mood and the dietary intake of fish. In all cases, however, dietary fish intake has been considered at the exclusion of all other aspects of the diet. This analysis investigates associations between depressed mood and dietary fish intake, while also concurrently investigating intake of a number of other dietary components. The analysis is conducted on data from 10,602 men from Northern Ireland and France screened for inclusion into the PRIME cohort study. Depressed mood was assessed using a self-report questionnaire based on the Welsh Pure Depression sub-scale of the Minnesota Multiphasic Personality Inventory, diet was assessed using a Food Frequency Questionnaire, and limited demographics were also measured. Using regression, depressed mood is initially inversely associated with dietary fish intake. On inclusion of all other dietary variables, the strength of this relationship reduces but remains, and significant associations with a number of other foods are also found. On additional inclusion of all demographic variables, the strength of the above relationships again reduces, and associations with various measures of socio-economic status and education are also significant. These findings suggest that depressed mood is associated with fish intake both directly, and indirectly as part of a diet that is associated with depression and as part of a lifestyle that is associated with depression. Additional support for these conclusions is also provided in the pattern of associations between depressed mood and diet in the two countries. The relative contributions of fish intake to depressed mood both directly and indirectly are yet to be determined. However, while diet is not measured and until lifestyle can be adequately measured, the potential roles of diet and lifestyle in the association between depressed mood and dietary fish intake should not be ignored.

The Complete Works of John Milton: Volume III: The Shorter Poems (816pp.)

Volume III of the new eleven-volume edition of Milton's Complete Works provides a definitive scholarly edition of all of Milton's shorter poems in English, Latin, Italian, and Greek, as well as his Mask, taken from both published and manuscript sources. It includes his 1645 Poems complete with all prefatory materials, thus illuminating the ways in which author, publisher, and print shop shaped this volume. It then presents all the new poems added in the 1673 edition (with the new Table of Contents), as well as the poems omitted from both editions. A careful collation of textual variants among these sources as well as the 1637 anonymous publication of Milton's Mask is provided. The Bridgewater manuscript of Milton's Mask (probably close to the acting version) and his working copy from the Trinity Manuscript, with its many alterations and additions, are transcribed in their entirety, so that the various versions may be compared and studied. 

A special feature of this edition is a new translation of Milton's many Latin and Greek poems that is both accurate and attentive to their literary qualities. This is augmented by a detailed and comprehensive commentary that highlights classical, vernacular, and neo-Latin parallels. A poetic translation of Milton's six Italian sonnets and Canzone is also supplied. In addition, the Appendices contain all the versions of Milton's shorter poems in all the contemporary manuscript and printed sources, so they may be examined in relation to their specific contexts. The transcription of all the versions of Milton's poems in the Trinity Manuscript allows in several cases, notably 'Lycidas' and 'At a Solemn Music,' for examination of the evolution of these poems as Milton weighed choiced of diction and sound qualities, enabling further understanding of his poetic practices. 

Barbara Lewalski is responsible for text, textual apparatus, and commentary pertaining to the vernacular poems in all sections of this edition including the appendices, and manuscript transcriptions (with the exception of A Maske), as well as the Occasions, Vernacular Poems,and Textual Introductions. Estelle Haan is responsible for text, textual apparatus, and commentary for the Poemata in all sections of this edition,and for the Poemata Introduction. She has also provided all translations from Latin, Italian, and Greek in the Testimonia, Poemata, and associated commentary, and transcriptions of the BL Damon, the Bodleian AdJoannem Rousium, and A Maske from the Trinity and Bridgewater manuscripts. Andrew McNeillie has provided poetic translations for Milton’s Italian sonnets, and Jason Rosenblatt has provided some Hebrew text and commentary pertaining to Milton’s Psalm translations.John Cunningham has transcribed Henry Lawes’ music for Milton’s masque, with commentary (Appendix E). Biblical references are taken from the King James (Authorized) Version.

Visual feedback alters the variations in corticospinal excitability that arise from rhythmic movements of the opposite limb

Augmented visual feedback can have a profound bearing on the stability of bimanual coordination. Indeed, this has been used to render tractable the study of patterns of coordination that cannot otherwise be produced in a stable fashion. In previous investigations (Carson et al. 1999), we have shown that rhythmic movements, brought about by the contraction of muscles on one side of the body, lead to phase-locked changes in the excitability of homologous motor pathways of the opposite limb. The present study was conducted to assess whether these changes are influenced by the presence of visual feedback of the moving limb. Eight participants performed rhythmic flexion-extension movements of the left wrist to the beat of a metronome (1.5 Hz). In 50% of trials, visual feedback of wrist displacement was provided in relation to a target amplitude, defined by the mean movement amplitude generated during the immediately preceding no feedback trial. Motor potentials (MEPs) were evoked in the quiescent muscles of the right limb by magnetic stimulation of the left motor cortex. Consistent with our previous observations, MEP amplitudes were modulated during the movement cycle of the opposite limb. The extent of this modulation was, however, smaller in the presence of visual feedback of the moving limb (FCR omega(2) =0.41; ECR omega(2)=0.29) than in trials in which there was no visual feedback (FCR omega(2)=0.51; ECR omega(2)=0.48). In addition, the relationship between the level of FCR activation and the excitability of the homologous corticospinal pathway of the opposite limb was sensitive to the vision condition; the degree of correlation between the two variables was larger when there was no visual feedback of the moving limb. The results of the present study support the view that increases in the stability of bimanual coordination brought about by augmented feedback may be mediated by changes in the crossed modulation of excitability in homologous motor pathways.

Rubén Darío's new unpublished and unknown documents: on La "Isla de Oro", the "Poema del Otoño" and the years of "Mundial"

This article studies and reproduces a group of documents that includes some hand-written and typed texts most likely authored by Rubén Darío, along with others where Darío’s authorship can be easily contested. These documents seem to have originated during the years of Mundial Magazine (1912-1914), and besides the interest for their probably unpublished nature, they also show the cooperation between Darío and his collaborators in the preparation of his original manuscripts right before being sent to the publishers.