Complete replication of hepatitis C virus in cell culture.

Many aspects of the hepatitis C virus (HCV) life cycle have not been reproduced in cell culture, which has slowed research progress on this important human pathogen. Here, we describe a full-length HCV genome that replicates and produces virus particles that are infectious in cell culture (HCVcc). Replication of HCVcc was robust, producing nearly 10(5) infectious units per milliliter within 48 hours. Virus particles were filterable and neutralized with a monoclonal antibody against the viral glycoprotein E2. Viral entry was dependent on cellular expression of a putative HCV receptor, CD81. HCVcc replication was inhibited by interferon-alpha and by several HCV-specific antiviral compounds, suggesting that this in vitro system will aid in the search for improved antivirals

Public involvement in research: Assessing impact through a realist evaluation

BackgroundThis study was concerned with developing the evidence base for public involvement in research in health and social care. There now is significant support for public involvement within the National Institute for Health Research, and researchers applying for National Institute for Health Research grants are expected to involve the public. Despite this policy commitment, evidence for the benefits of public involvement in research remains limited. This study addressed this need through a realist evaluation.Aim and objectivesThe aim was to identify the contextual factors and mechanisms that are regularly associated with effective public involvement in research. The objectives included identifying a sample of eight research projects and their desired outcomes of public involvement, tracking the impact of public involvement in these case studies, and comparing the associated contextual factors and mechanisms.DesignThe research design was based on the application of realist theory of evaluation, which argues that social programmes are driven by an underlying vision of change – a ‘programme theory’ of how the intervention is supposed to work. The role of the evaluator is to compare theory and practice. Impact can be understood by identifying regularities of context, mechanism and outcome. Thus the key question for the evaluator is ‘What works for whom in what circumstances . . . and why?’ (Pawson R. The Science of Evaluation. London: Sage; 2013). We therefore planned a realist evaluation based on qualitative case studies of public involvement in research.Setting and participantsEight diverse case studies of research projects in health and social care took place over the calendar year 2012 with 88 interviews from 42 participants across the eight studies: researchers, research managers, third-sector partners and research partners (members of the public involved in research).ResultsCase study data supported the importance of some aspects of our theory of public involvement in research and led us to amend other elements. Public involvement was associated with improvements in research design and delivery, particularly recruitment strategies and materials, and data collection tools. This study identified the previously unrecognised importance of principal investigator leadership as a key contextual factor leading to the impact of public involvement; alternatively, public involvement might still be effective without principal investigator leadership where there is a wider culture of involvement. In terms of the mechanisms of involvement, allocating staff time to facilitate involvement appeared more important than formal budgeting. Another important new finding was that many research proposals significantly undercosted public involvement. Nurturing good interpersonal relationships was crucial to effective involvement. Payment for research partner time and formal training appeared more significant for some types of public involvement than others. Feedback to research partners on the value of their contribution was important in maintaining motivation and confidence.ConclusionsA revised theory of public involvement in research was developed and tested, which identifies key regularities of context, mechanism and outcome in how public involvement in research works. Implications for future research include the need to further explore how leadership on public involvement might be facilitated, methodological work on assessing impact and the development of economic analysis of involvement.Funding detailsThe National Institute for Health Research Health Service and Delivery programme

The C677T methylenetetrahydrofolate reductase variant and third trimester obstetrical complications in women with unexplained elevations of maternal serum alpha-fetoprotein

INTRODUCTION: The C677T MTHFR variant has been associated with the same third trimester pregnancy complications as seen in women who have elevations of maternal serum α-fetoprotein (MSAFP). We hypothesized that these women with third trimester pregnancy complications and MSAFP elevations would have an increased frequency of the variant compared to an abnormal study control group (women with MSAFP elevations without pregnancy complications) as well as to normal population controls. METHODS: Women who had unexplained elevations of MSAFP in pregnancy were ascertained retrospectively. The frequency of the C677T MTHFR variant among those women with unexplained elevations of MSAFP who had experienced later pregnancy complications was compared to that of women with unexplained elevations of MSAFP without complications as well as to that of the previously established Manitoba frequency. RESULTS: Women who had complications of pregnancy and an unexplained MSAFP elevation had a higher allele frequency for the C677T MTHFR variant (q = 0.36,) compared to women with MSAFP elevations and normal pregnancy outcomes (q = 0.25, OR 1.73 95% CI 1.25–2.37, p = 0.03). The frequency was also higher than that of the population controls (q= 0.25, OR 1.70 95% CI 1.11–2.60, p = 0.007). The frequency in women with MSAFP elevations without pregnancy complications was not significantly different from that of the population controls (p = 0.41). CONCLUSION: Women with unexplained elevations of MSAFP and who experience complications in later pregnancy are more likely to have one or two alleles of the C677T MTHFR variant

Making Sense of Family Deaths in Urban Senegal: Diversities, Contexts, and Comparisons

Despite calls for cross-cultural research, Minority world perspectives still dominate death and bereavement studies, emphasizing individualized emotions and neglecting contextual diversities. In research concerned with contemporary African societies, on the other hand, death and loss are generally subsumed within concerns about AIDS or poverty, with little attention paid to the emotional and personal significance of a death. Here, we draw on interactionist sociology to present major themes from a qualitative study of family deaths in urban Senegal, theoretically framed through the duality of meanings-in-context. Such themes included family and community as support and motivation; religious beliefs and practices as frameworks for solace and (regulatory) meaning; and material circumstances as these are intrinsically bound up with emotions. Although we identify the experience of (embodied, emotional) pain as a common response across Minority and Majority worlds, we also explore significant divergencies, varying according to localized contexts and broader power dynamics

Sexed up: theorizing the sexualization of culture

This paper reviews and examines emerging academic approaches to the study of ‘sexualized culture’; an examination made necessary by contemporary preoccupations with sexual values, practices and identities, the emergence of new forms of sexual experience and the apparent breakdown of rules, categories and regulations designed to keep the obscene at bay. The paper maps out some key themes and preoccupations in recent academic writing on sex and sexuality, especially those relating to the contemporary or emerging characteristics of sexual discourse. The key issues of pornographication and democratization, taste formations, postmodern sex and intimacy, and sexual citizenship are explored in detail. </p

Identification of an Endogenous Ligand Bound to a Native Orphan Nuclear Receptor

Orphan nuclear receptors have been instrumental in identifying novel signaling pathways and therapeutic targets. However, identification of ligands for these receptors has often been based on random compound screens or other biased approaches. As a result, it remains unclear in many cases if the reported ligands are the true endogenous ligands, – i.e., the ligand that is bound to the receptor in an unperturbed in vivo setting. Technical limitations have limited our ability to identify ligands based on this rigorous definition. The orphan receptor hepatocyte nuclear factor 4 α (HNF4α) is a key regulator of many metabolic pathways and linked to several diseases including diabetes, atherosclerosis, hemophilia and cancer. Here we utilize an affinity isolation/mass-spectrometry (AIMS) approach to demonstrate that HNF4α is selectively occupied by linoleic acid (LA, C18:2ω6) in mammalian cells and in the liver of fed mice. Receptor occupancy is dramatically reduced in the fasted state and in a receptor carrying a mutation derived from patients with Maturity Onset Diabetes of the Young 1 (MODY1). Interestingly, however, ligand occupancy does not appear to have a significant effect on HNF4α transcriptional activity, as evidenced by genome-wide expression profiling in cells derived from human colon. We also use AIMS to show that LA binding is reversible in intact cells, indicating that HNF4α could be a viable drug target. This study establishes a general method to identify true endogenous ligands for nuclear receptors (and other lipid binding proteins), independent of transcriptional function, and to track in vivo receptor occupancy under physiologically relevant conditions

Cavalier King Charles Spaniels with Chiari-like malformation and Syringomyelia have increased variability of spatio-temporal gait characteristics

Abstract Background Chiari-like malformation in the Cavalier King Charles Spaniel is a herniation of the cerebellum and brainstem into or through the foramen magnum. This condition predisposes to Syringomyelia; fluid filled syrinxes within the spinal cord. The resulting pathology in spinal cord and cerebellum create neuropathic pain and changes in gait. This study aims to quantify the changes in gait for Cavalier King Charles Spaniel with Chiari-like malformation and Syringomyelia. Methods We compared Cavalier King Charles Spaniel with Chiari-like malformation with (n = 9) and without (n = 8) Syringomyelia to Border Terriers (n = 8). Two video cameras and manual tracking was used to quantify gait parameters. Results and conclusions We found a significant increase in coefficient of variation for the spatio-temporal characteristics and ipsilateral distance between paws and a wider base of support in the thoracic limbs but not in the pelvic limbs for Cavalier King Charles Spaniels compared with the border terrier

Rapid Identification of Hospitalized Patients at High Risk for MRSA Carriage

Patients who are asymptomatic carriers of methicillin-resistant Staphylococcus aureus (MRSA) are major reservoirs for transmission of MRSA to other patients. Medical personnel are usually not aware when these high-risk patients are hospitalized. We developed and tested an enterprise-wide electronic surveillance system to identify patients at high risk for MRSA carriage at hospital admission and during hospitalization. During a two-month study, nasal swabs from 153 high-risk patients were tested for MRSA carriage using polymerase chain reaction (PCR) of which 31 (20.3%) were positive compared to 12 of 293 (4.1%, p < 0.001) low-risk patients. The mean interval from admission to availability of PCR test results was 19.2 hours. Computer alerts for patients at high-risk of MRSA carriage were found to be reliable, timely and offer the potential to replace testing all patients. Previous MRSA colonization was the best predictor but other risk factors were needed to increase the sensitivity of the algorith

Comments on a class of orthogonality relations relevant to fluid-structure interaction

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Borderline personality traits, rumination and self-injurious behavior: An empirical test of the emotional cascades model in adult male offenders

The aim of the study was to examine whether the emotional cascade model, which suggests that the relationship between emotional and behavioural dysregulation in Borderline Personality Disorder (BPD) is mediated by rumination, applies to a sample of adult male offenders. The study focused on individuals with “BPD traits” and two dysregulated behaviors that are particularly relevant to the prison population: non-suicidal self-injury (NSSI) and suicidality. Participants were 179 adult male offenders detained in a medium-secure prison, all of whom completed a battery of measures and self-reported their actual prison behaviour. The results support the application of the emotional cascade model to adult male offenders, suggesting that emotional cascades may play an important role in NSSI and suicidality in this population, although this relationship needs further exploration. These findings highlight the benefits of targeting rumination to manage risk of NSSI and suicidality within custodial settings