Lipid peroxidation biomarkers for evaluating oxidative stress in equine neuroaxonal dystrophy.

BackgroundEquine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM) is a neurodegenerative disorder affecting genetically predisposed foals maintained on an α-tocopherol (α-TOH) deficient diet. Currently no antemortem diagnostic test for eNAD/EDM is available.HypothesisBecause α-TOH deficiency is associated with increased lipid peroxidation, it was hypothesized that F2 -isoprostanes (F2 IsoP), F4 -neuroprostanes (F4 NP) and oxysterols derived from free radical oxidation would be increased in the cerebrospinal fluid (CSF) and neural tissue of eNAD/EDM affected horses and could serve as potential biomarkers for disease.AnimalsIsoprostane Study A: 14 Quarter horse foals (10 healthy foals and 4 eNAD/EDM affected foals) at 1 and 6 months of age. Isoprostane Study B: 17 eNAD/EDM affected and 10 unaffected horses ≥ 1-4 years of age. Oxysterol study: eNAD/EDM affected (n = 14, serum; n = 11, CSF; n = 10, spinal cord [SC]) and unaffected horses 1-4 years of age (n = 12, serum; n = 10, CSF; n = 7, SC).ProceduresCerebrospinal fluid [F2 IsoP] and [F4 NP] were assessed using gas chromatography-negative ion chemical ionization mass spectrometry. Serum, CSF, and cervical SC [oxysterols] were quantified using high performance liquid chromatography mass spectrometry. Results were compared with respective α-TOH concentrations.ResultsSpinal cord [7-ketocholesterol], [7-hydroxycholesterol], and [7-keto-27-hydrocholesterol] were higher in eNAD/EDM horses whereas [24-ketocholesterol] was lower. No significant difference was found in CSF [F2 IsoP] and [F4 NP], serum [oxysterols] and CSF [oxysterols] between eNAD/EDM affected and unaffected horses. No correlation was found between [F2 IsoP], [F4 NP], or [oxysterols] and respective [α-TOH].Conclusions and clinical importanceIn the SC, targeted markers of cholesterol oxidation were significantly increased in horses with eNAD/EDM

A Model-Based Analysis of GC-Biased Gene Conversion in the Human and Chimpanzee Genomes

GC-biased gene conversion (gBGC) is a recombination-associated process that favors the fixation of G/C alleles over A/T alleles. In mammals, gBGC is hypothesized to contribute to variation in GC content, rapidly evolving sequences, and the fixation of deleterious mutations, but its prevalence and general functional consequences remain poorly understood. gBGC is difficult to incorporate into models of molecular evolution and so far has primarily been studied using summary statistics from genomic comparisons. Here, we introduce a new probabilistic model that captures the joint effects of natural selection and gBGC on nucleotide substitution patterns, while allowing for correlations along the genome in these effects. We implemented our model in a computer program, called phastBias, that can accurately detect gBGC tracts about 1 kilobase or longer in simulated sequence alignments. When applied to real primate genome sequences, phastBias predicts gBGC tracts that cover roughly 0.3% of the human and chimpanzee genomes and account for 1.2% of human-chimpanzee nucleotide differences. These tracts fall in clusters, particularly in subtelomeric regions; they are enriched for recombination hotspots and fast-evolving sequences; and they display an ongoing fixation preference for G and C alleles. They are also significantly enriched for disease-associated polymorphisms, suggesting that they contribute to the fixation of deleterious alleles. The gBGC tracts provide a unique window into historical recombination processes along the human and chimpanzee lineages. They supply additional evidence of long-term conservation of megabase-scale recombination rates accompanied by rapid turnover of hotspots. Together, these findings shed new light on the evolutionary, functional, and disease implications of gBGC. The phastBias program and our predicted tracts are freely available. © 2013 Capra et al

The Role of GC-Biased Gene Conversion in Shaping the Fastest Evolving Regions of the Human Genome

GC-biased gene conversion (gBGC) is a recombination-associated evolutionary process that accelerates the fixation of guanine or cytosine alleles, regardless of their effects on fitness. gBGC can increase the overall rate of substitutions, a hallmark of positive selection. Many fast-evolving genes and noncoding sequences in the human genome have GC-biased substitution patterns, suggesting that gBGC—in contrast to adaptive processes—may have driven the human changes in these sequences. To investigate this hypothesis, we developed a substitution model for DNA sequence evolution that quantifies the nonlinear interacting effects of selection and gBGC on substitution rates and patterns. Based on this model, we used a series of lineage-specific likelihood ratio tests to evaluate sequence alignments for evidence of changes in mode of selection, action of gBGC, or both. With a false positive rate of less than 5% for individual tests, we found that the majority (76%) of previously identified human accelerated regions are best explained without gBGC, whereas a substantial minority (19%) are best explained by the action of gBGC alone. Further, more than half (55%) have substitution rates that significantly exceed local estimates of the neutral rate, suggesting that these regions may have been shaped by positive selection rather than by relaxation of constraint. By distinguishing the effects of gBGC, relaxation of constraint, and positive selection we provide an integrated analysis of the evolutionary forces that shaped the fastest evolving regions of the human genome, which facilitates the design of targeted functional studies of adaptation in humans

General Practitioners’ perceptions of the stigma of dementia and the role of reciprocity

YesA qualitative exploration of the stigma of dementia reported that GPs described lack of reciprocity as one way in which people with dementia are perceived within society. This was closely linked to their perception of dementia as a stigma. In this paper, we explore whether GPs perceive people with dementia as lacking reciprocity and, so, if this is linked with societal opinions about dementia as a stigma. The implications of both perceptions of people with dementia failing to reciprocate and of stigma for timely diagnosis are explored. GPs’ perceptions of societal views of people with dementia included a perception of a lack of reciprocity. Specifically, an absence of reciprocity was linked with; failing to respond to human contact, the absence of an appropriate return on social investment and failing to contribute to, or being a burden to, society. GPs reported a link between societal perceptions of lack of reciprocity and stereotypes about advanced dementia, difficulties communicating with people with dementia and lack of opportunities for people with dementia to reciprocate. GPs occupy a key position, they can challenge stereotypes and, with support and targeted training about communicating with people living with dementia, can emphasise the ways in which people with dementia can communicate, thereby enhancing their potential to reciprocate. Such changes have implications for improved care and quality of life through the continued maintenance of social inclusion and perceptions of personhood.non

A diagnostic dilemma between psychosis and post-traumatic stress disorder: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Post-traumatic stress disorder is defined as a mental disorder that arises from the experience of traumatic life events. Research has shown a high incidence of co-morbidity between post-traumatic stress disorder and psychosis.</p> <p>Case presentation</p> <p>We report the case of a 32-year-old black African woman with a history of both post-traumatic stress disorder and psychosis. Two years ago she presented to mental health services with auditory and visual hallucinations, persecutory delusions, suicidal ideation, recurring nightmares, hyper-arousal, and initial and middle insomnia. She was prescribed trifluoperazine (5 mg/day) and began cognitive-behavioral therapy for psychosis. Her psychotic symptoms gradually resolved over a period of three weeks; however, she continues to experience ongoing symptoms of post-traumatic stress disorder. In our case report, we review both the diagnostic and treatment issues regarding post-traumatic stress disorder with psychotic symptoms.</p> <p>Conclusions</p> <p>There are many factors responsible for the symptoms that occur in response to a traumatic event, including cognitive, affective and environmental factors. These factors may predispose both to the development of post-traumatic stress disorder and/or psychotic disorders. The independent diagnosis of post-traumatic stress disorder with psychotic features remains an open issue. A psychological formulation is essential regarding the appropriate treatment in a clinical setting.</p

Implications For The Origin Of GRB 051103 From LIGO Observations

We present the results of a LIGO search for gravitational waves (GWs) associated with GRB 051103, a short-duration hard-spectrum gamma-ray burst (GRB) whose electromagnetically determined sky position is coincident with the spiral galaxy M81, which is 3.6 Mpc from Earth. Possible progenitors for short-hard GRBs include compact object mergers and soft gamma repeater (SGR) giant flares. A merger progenitor would produce a characteristic GW signal that should be detectable at the distance of M81, while GW emission from an SGR is not expected to be detectable at that distance. We found no evidence of a GW signal associated with GRB 051103. Assuming weakly beamed gamma-ray emission with a jet semi-angle of 30 deg we exclude a binary neutron star merger in M81 as the progenitor with a confidence of 98%. Neutron star-black hole mergers are excluded with > 99% confidence. If the event occurred in M81 our findings support the the hypothesis that GRB 051103 was due to an SGR giant flare, making it the most distant extragalactic magnetar observed to date.Comment: 8 pages, 3 figures. For a repository of data used in the publication, go to: https://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=15166 . Also see the announcement for this paper on ligo.org at: http://www.ligo.org/science/Publication-GRB051103/index.ph

Gravitational Waves From Known Pulsars: Results From The Initial Detector Era

We present the results of searches for gravitational waves from a large selection of pulsars using data from the most recent science runs (S6, VSR2 and VSR4) of the initial generation of interferometric gravitational wave detectors LIGO (Laser Interferometric Gravitational-wave Observatory) and Virgo. We do not see evidence for gravitational wave emission from any of the targeted sources but produce upper limits on the emission amplitude. We highlight the results from seven young pulsars with large spin-down luminosities. We reach within a factor of five of the canonical spin-down limit for all seven of these, whilst for the Crab and Vela pulsars we further surpass their spin-down limits. We present new or updated limits for 172 other pulsars (including both young and millisecond pulsars). Now that the detectors are undergoing major upgrades, and, for completeness, we bring together all of the most up-to-date results from all pulsars searched for during the operations of the first-generation LIGO, Virgo and GEO600 detectors. This gives a total of 195 pulsars including the most recent results described in this paper.United States National Science FoundationScience and Technology Facilities Council of the United KingdomMax-Planck-SocietyState of Niedersachsen/GermanyAustralian Research CouncilInternational Science Linkages program of the Commonwealth of AustraliaCouncil of Scientific and Industrial Research of IndiaIstituto Nazionale di Fisica Nucleare of ItalySpanish Ministerio de Economia y CompetitividadConselleria d'Economia Hisenda i Innovacio of the Govern de les Illes BalearsNetherlands Organisation for Scientific ResearchPolish Ministry of Science and Higher EducationFOCUS Programme of Foundation for Polish ScienceRoyal SocietyScottish Funding CouncilScottish Universities Physics AllianceNational Aeronautics and Space AdministrationOTKA of HungaryLyon Institute of Origins (LIO)National Research Foundation of KoreaIndustry CanadaProvince of Ontario through the Ministry of Economic Development and InnovationNational Science and Engineering Research Council CanadaCarnegie TrustLeverhulme TrustDavid and Lucile Packard FoundationResearch CorporationAlfred P. Sloan FoundationAstronom

A Wide and Deep Neural Network for Survival Analysis from Anatomical Shape and Tabular Clinical Data

We introduce a wide and deep neural network for prediction of progression from patients with mild cognitive impairment to Alzheimer's disease. Information from anatomical shape and tabular clinical data (demographics, biomarkers) are fused in a single neural network. The network is invariant to shape transformations and avoids the need to identify point correspondences between shapes. To account for right censored time-to-event data, i.e., when it is only known that a patient did not develop Alzheimer's disease up to a particular time point, we employ a loss commonly used in survival analysis. Our network is trained end-to-end to combine information from a patient's hippocampus shape and clinical biomarkers. Our experiments on data from the Alzheimer's Disease Neuroimaging Initiative demonstrate that our proposed model is able to learn a shape descriptor that augments clinical biomarkers and outperforms a deep neural network on shape alone and a linear model on common clinical biomarkers.Comment: Data and Machine Learning Advances with Multiple Views Workshop, ECML-PKDD 201