Radiological evaluation of colorectal anastomoses

Background and aims: The purpose of this study was to determine the accuracy, interobserver variability, timing and discordance with relaparotomy of postoperative radiological examination of colorectal anastomoses. Patient/methods: From 2000 to 2005, 429 patients underwent an

Prophylactic evaluation of verubecestat on disease- and symptom-modifying effects in 5XFAD mice.

Introduction: Alzheimer\u27s disease (AD) is the most common form of dementia. Beta-secretase (BACE) inhibitors have been proposed as potential therapeutic interventions; however, initiating treatment once disease has significantly progressed has failed to effectively stop or treat disease. Whether BACE inhibition may have efficacy when administered prophylactically in the early stages of AD has been under-investigated. The present studies aimed to evaluate prophylactic treatment of the BACE inhibitor verubecestat in an AD mouse model using the National Institute on Aging (NIA) resources of the Model Organism Development for Late-Onset Alzheimer\u27s Disease (MODEL-AD) Preclinical Testing Core (PTC) Drug Screening Pipeline. Methods: 5XFAD mice were administered verubecestat ad libitum in chow from 3 to 6 months of age, prior to the onset of significant disease pathology. Following treatment (6 months of age), in vivo imaging was conducted with 18F-florbetapir (AV-45/Amyvid) (18F-AV45) and 18-FDG (fluorodeoxyglucose)-PET (positron emission tomography)/MRI (magnetic resonance imaging), brain and plasma amyloid beta (Aβ) were measured, and the clinical and behavioral characteristics of the mice were assessed and correlated with the pharmacokinetic data. Results: Prophylactic verubecestat treatment resulted in dose- and region-dependent attenuations of 18F-AV45 uptake in male and female 5XFAD mice. Plasma Aβ40 and Aβ42 were also dose-dependently attenuated with treatment. Across the dose range evaluated, side effects including coat color changes and motor alterations were reported, in the absence of cognitive improvement or changes in 18F-FDG uptake. Discussion: Prophylactic treatment with verubecestat resulted in attenuated amyloid plaque deposition when treatment was initiated prior to significant pathology in 5XFAD mice. At the same dose range effective at attenuating Aβ levels, verubecestat produced side effects in the absence of improvements in cognitive function. Taken together these data demonstrate the rigorous translational approaches of the MODEL-AD PTC for interrogating potential therapeutics and provide insight into the limitations of verubecestat as a prophylactic intervention for early-stage AD

Genotype x environment interactions in eggplant for fruit phenolic acid content

Eggplant fruit are a rich source of phenolic acids that influence fruit culinary quality and antioxidant content. We evaluated the influence of production environments and stability of diverse genotypes across environments for eggplant fruit phenolic acid content. Ten Solanum melongena accessions consisting of five F-1 hybrid cultivars, three open-pollinated cultivars and two land race accessions, plus one S. macrocarpon and one S. aethiopicum accession, were grown at two locations under greenhouse and open field environments. Twenty phenolic acid conjugates were identified in fruit flesh and assigned to six classes that included hydroxycinnamic acid amides, caffeoylquinic acid esters, hydroxycinnamoylquinic acid esters, malonylcaffeoylquinic acid esters, di-hydroxycinnamoylquinic acid esters, and other hydroxycinnamic acid conjugates. There were significant differences among accessions for total phenolic acid conjugate content and for all six classes. There were no significant differences detected among the environments for any of the variables. However, the environment x accession interaction was highly significant for all phenolic acid classes. Broad-sense heritability estimates for all six phenolic acid classes were high, ranging from 0.64 to 0.96. Stability analysis demonstrated widespread instability for phenolic acid content across environments. Stability of the predominant caffeoylquinic acid esters class positively influenced stability of total phenolic acid content for some but not all genotypes. High heritability, coupled with highly significant genotype x environment interactions suggests that stability estimates may improve the efficiency of breeding new genotypes with predictable performance across environments.Stommel, JR.; Whitaker, B.; Haynes, K.; Prohens Tomás, J. (2015). Genotype x environment interactions in eggplant for fruit phenolic acid content. 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Biol Pharm Bull 29:2236–2240Fernandez GCJ (1991) Analysis of genotype × environment interaction by stability estimates. HortScience 26:947–950García-Salas P, Gómez-Caravaca AM, Morales-Soto A, Segura-Carretero A, Fernández-Gutiérrez A (2014) Identification and quantification of phenolic compounds in diverse cultivars of eggplant grown in different seasons by high-performance liquid chromatography coupled to diode array detector and electrospray-quadrupole-time of flight-mass spectrometry. Food Res Int 57:114–122Hanson PM, Yang RY, Tsou SCS, Ledesma K, Engle L, Lee TC (2006) Diversity in eggplant (Solanum melongena) for superoxide scavenging activity, total phenolics, and ascorbic acid. J Food Compos Anal 19:594–600Kang MS (1989) A new SAS program for calculating stability variance parameters. J Hered 80:415Klein RM (1990) Failure of supplementary ultraviolet radiation to enhance flower color under greenhouse conditions. HortScience 25:307–308Knapp SJ, Stroup WW, Ross WM (1985) Exact confidence intervals for heritability on a progeny mean basis. Crop Sci 25:192–194Luthria D, Singh AP, Wilson T, Vorsa N, Banuelos GS, Vinyard BT (2010) Influence of conventional and organic agricultural practices on the phenolic content in eggplant pulp: plant to plant variation. Food Chem 121:406–411Ma C, Whitaker BD, Kennelly EJ (2010) New 5-O-caffeoylquinic acid derivatives in fruit of wild eggplant relative S. viarum. J Agric Food Chem 58:9645–9651Manach C, Scalbert A, Morand C, Remesy C, Jimenez L (2004) Polyphenols: food sources and bioavailability. Am J Clin Nutr 79:727–747Mennella G, Scalzo R, Fibiani M, D’Alessandro A, Francese G, Toppino L, Acciarri N, Almeida AE, Rotino GL (2012) Chemical and bioactive quality traits during fruit ripening in eggplant (S. melongena L.) and allied species. J Agric Food Chem 60:11821–11831Meyer RS, Karol KG, Little DP, Nee MH, Litt A (2012) Phylogeographic relationships among Asian eggplants and new perspectives on eggplant domestication. Mol Phylogenet Evol 63:685–701Ong KW, Hsu A, Tan BK (2012) Chlorogenic acid stimulates glucose transport in skeletal muscle via AMPK activation: a contributor to the beneficial effects of coffee on diabetes. PLoS One 7:e32718Payyavula RS, Duroy AN, Kuhl JC, Pantoha A, Pillai SS (2012) Differential effects of environment on potato phenylpropanoid and carotenoid expression. BMC Plant Biol 12:39Plazas M, Prohens J, Cuñat AN, Vilanova S, Gramazio P, Herraiz FJ, Andújar I (2014) Reducing capacity, chlorogenic acid content and biological activity in a collection of scarlet (Solanum aethiopicum) and gboma (S. macrocarpon) eggplants. Int J Mol Sci 15:17221–17241Prior RL (2003) Fruits and vegetables in the prevention of cellular oxidative damage. Am J Clin Nutr 78:570S–578SPritts M, Luby J (1990) Stability indices for horticultural crops. HortScience 25:740–745Prohens J, Rodriguez-Burruezo A, Raigon MD, Nuez F (2007) Total phenolic acid concentration and browning susceptibility in a collection of different varietal types and hybrids of eggplant: implications for breeding for higher nutritional quality and reduced browning. J Am Soc Hortic Sci 132:638–646Prohens J, Whitaker BD, Plazas M, Vilanova S, Hurtado M, Blasco M, Gramazio P, Stommel JR (2013) Genetic diversity in morphological characters and phenolic acids content resulting from an interspecific cross between eggplant, Solanum melongena, and its wild ancestor (S. incancum). Ann Appl Biol 162:242–257Raigon MD, Prohens J, Munoz-Falcon JE, Nuez F (2008) Comparison of eggplant landraces and commercial varieties for fruit content of phenolics, minerals, dry matter and protein. J Food Compos Anal 21:370–376Raigon MD, Rodriguez-Burruezo A, Prohens J (2010) Effects of organic and conventional cultivation methods on composition of eggplant fruits. Agric Food Chem 58:6833–6840San Jose R, Sanchez-Mata MC, Camara M, Prohens J (2014) Eggplant fruit composition as affected by the cultivation environment and genetic constitution. J Sci Food Agric 94:2774–2784Sato Y, Itagaki S, Kurokawa T, Ogur J, Kobayashi M, Hirano T, Sugawara M, Iseki K (2011) In vitro and in vivo antioxidant properties of chlorogenic acid and caffeic acid. Int J Pharm 403:136–138Setimela PS, Vivek B, Banziger M, Crossa J, Maideni F (2007) Evaluation of early to medium maturing open pollinated maize varieties in SADC region using GGE biplot based on the SREG model. Field Crop Res 103:161–169Shukla GK (1972) Some statistical aspects of partitioning genotype environment components of variability. 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Just a wind-up? Ethnicity, religion and prejudice in Scottish football-related comedy

This article probes how media representations of football in Scotland sustain the hegemonic ideologies associated with ethnicity and religion. The paper probes the football-related comedy output of one radio programme; radio output and football comedy are both neglected cultural material in studies of sport in Scotland. It argues that ambiguity and allusive language in comedy construct multiple interpretative possibilities that can demean the social and cultural identity of particular groups in society. The discussion analyses specific sketches from the Scottish radio comedy show Watson's Wind Up. It is concluded that although humorous, these sketches reveal how ideas, myths and stereotypes that coalesce round Celtic FC and the Irish-descended and Catholic communities in Scotland reinforce and sustain anti-Irish and anti-Catholic bigotry

Appeals to evidence for the resolution of wicked problems: the origins and mechanisms of evidentiary bias

Wicked policy problems are often said to be characterized by their ‘intractability’, whereby appeals to evidence are unable to provide policy resolution. Advocates for ‘Evidence Based Policy’ (EBP) often lament these situations as representing the misuse of evidence for strategic ends, while critical policy studies authors counter that policy decisions are fundamentally about competing values, with the (blind) embrace of technical evidence depoliticizing political decisions. This paper aims to help resolve these conflicts and, in doing so, consider how to address this particular feature of problem wickedness. Specifically the paper delineates two forms of evidentiary bias that drive intractability, each of which is reflected by contrasting positions in the EBP debates: ‘technical bias’ - referring to invalid uses of evidence; and ‘issue bias’ - referring to how pieces of evidence direct policy agendas to particular concerns. Drawing on the fields of policy studies and cognitive psychology, the paper explores the ways in which competing interests and values manifest in these forms of bias, and shape evidence utilization through different mechanisms. The paper presents a conceptual framework reflecting on how the nature of policy problems in terms of their complexity, contestation, and polarization can help identify the potential origins and mechanisms of evidentiary bias leading to intractability in some wicked policy debates. The discussion reflects on whether being better informed about such mechanisms permit future work that may lead to strategies to mitigate or overcome such intractability in the future

Polyfunctional Hiv-Specific Antibody Responses Are Associated with Spontaneous Hiv Control

Elite controllers (ECs) represent a unique model of a functional cure for HIV-1 infection as these individuals develop HIV-specific immunity able to persistently suppress viremia. Because accumulating evidence suggests that HIV controllers generate antibodies with enhanced capacity to drive antibody-dependent cellular cytotoxicity (ADCC) that may contribute to viral containment, we profiled an array of extra-neutralizing antibody effector functions across HIV-infected populations with varying degrees of viral control to define the characteristics of antibodies associated with spontaneous control. While neither the overall magnitude of antibody titer nor individual effector functions were increased in ECs, a more functionally coordinated innate immune–recruiting response was observed. Specifically, ECs demonstrated polyfunctional humoral immune responses able to coordinately recruit ADCC, other NK functions, monocyte and neutrophil phagocytosis, and complement. This functionally coordinated response was associated with qualitatively superior IgG3/IgG1 responses, whereas HIV-specific IgG2/IgG4 responses, prevalent among viremic subjects, were associated with poorer overall antibody activity. Rather than linking viral control to any single activity, this study highlights the critical nature of functionally coordinated antibodies in HIV control and associates this polyfunctionality with preferential induction of potent antibody subclasses, supporting coordinated antibody activity as a goal in strategies directed at an HIV-1 functional cure

Fine epitope signature of antibody neutralization breadth at the HIV-1 envelope CD4-binding site

Major advances in donor identification, antigen probe design, and experimental methods to clone pathogen-specific antibodies have led to an exponential growth in the number of newly characterized broadly neutralizing antibodies (bnAbs) that recognize the HIV-1 envelope glycoprotein. Characterization of these bnAbs has defined new epitopes and novel modes of recognition that can result in potent neutralization of HIV-1. However, the translation of envelope recognition profiles in biophysical assays into an understanding of in vivo activity has lagged behind, and identification of subjects and mAbs with potent antiviral activity has remained reliant on empirical evaluation of neutralization potency and breadth. To begin to address this discrepancy between recombinant protein recognition and virus neutralization, we studied the fine epitope specificity of a panel of CD4-binding site (CD4bs) antibodies to define the molecular recognition features of functionally potent humoral responses targeting the HIV-1 envelope site bound by CD4. Whereas previous studies have used neutralization data and machine-learning methods to provide epitope maps, here, this approach was reversed, demonstrating that simple binding assays of fine epitope specificity can prospectively identify broadly neutralizing CD4bs–specific mAbs. Building on this result, we show that epitope mapping and prediction of neutralization breadth can also be accomplished in the assessment of polyclonal serum responses. Thus, this study identifies a set of CD4bs bnAb signature amino acid residues and demonstrates that sensitivity to mutations at signature positions is sufficient to predict neutralization breadth of polyclonal sera with a high degree of accuracy across cohorts and across clades

An intelligent interactive system for delivering individualized information to patients

This paper is a report on the first phase of a long-term, interdisciplinary project whose goal is to increase the overall effectiveness of physicians ’ time, and thus the quality of health care, by improving the information exchange between physicians and patients in clinical settings. We are focusing on patients with long-term and chronic conditions, initially on migraine patients, who require periodic interaction with their physicians for effective management of their condition. We are using medical informatics to focus on the information needs of patients, as well as of physicians, and to address problems of information exchange. This requires understanding patients’ concerns to design an appropriate system, and using state-of-the-art artificial intelligence techniques to build an interactive explanation system. In contrast to many other knowledge-based systems, our system’s design is based on empirical data on actual information needs. We used ethnographic techniques to observe explanations actually given in clinic settings, and to conduct interviews with migraine sufferers and physicians. Our system has an extensive knowledge base that contains both general medical terminology and specific knowledge about migraine, such a

RA-MAP, molecular immunological landscapes in early rheumatoid arthritis and healthy vaccine recipients

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with poorly defined aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the peripheral blood immune cell landscape of early, drug naive RA, we performed comprehensive clinical and molecular profiling of 267 RA patients and 52 healthy vaccine recipients for up to 18 months to establish a high quality sample biobank including plasma, serum, peripheral blood cells, urine, genomic DNA, RNA from whole blood, lymphocyte and monocyte subsets. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and autoantibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource offering insights into immune-mediated disease pathogenesis, progression and therapeutic response, ultimately contributing to the development and application of targeted therapies for RA.</p