The effects of maribavir on the autophosphorylation of ganciclovir resistant mutants of the cytomegalovirus UL97 protein

BACKGROUND: The UL97 protein kinase of human cytomegalovirus phosphorylates the antiviral drug ganciclovir and is the target of maribavir action. A detailed enzyme kinetic analysis of maribavir on the various enzymatic functions of wild type and ganciclovir resistant forms of UL97 is required. METHODS: Wild type and site directed mutant forms of the human cytomegalovirus UL97 gene product were expressed using recombinant baculoviruses and the purified products used to assess the effects of maribavir on the ganciclovir (GCV) kinase and protein kinase (PK) activities. RESULTS: Maribavir was a potent inhibitor of the autophosporylation of the wild type and all the major GCV resistant UL97 mutants analysed (M460I, H520Q, A594V and L595F) with a mean IC50 of 35 nM. The M460I mutation resulted in hypersensitivity to maribavir with an IC50 of 4.8 nM. A maribavir resistant mutant of UL97 (L397R) was functionally compromised as both a GCV kinase and a protein kinase (~ 10% of wild type levels). Enzyme kinetic experiments demonstrated that maribavir was a competitive inhibitor of ATP with a Ki of 10 nM. DISCUSSION: Maribavir is a potent competitive inhibitor of the UL97 protein kinase function and shows increased activity against the M460I GCV-resistant mutant which may impact on the management of GCV drug resistance in patients

Experiences of older people dying in nursing homes : a narrative systematic review of qualitative studies

Objectives To identify and synthesise qualitative research from 2001 investigating older people's (65+ years) experiences of dying in nursing and care homes. Methods and outcomes Eight electronic databases (AMED, ASSIA, CINAHL Plus, Embase, HMIC, Medline, PsychINFO and Scopus) from 2001 to July 2017 were searched. Studies were included if they were qualitative, primary research and described the experiences of dying in nursing or care homes from the perspectives of the older people themselves, their families or staff. Study quality assessment was undertaken to systematically assess methodological quality, but no studies were excluded as a result. Results 1305 articles were identified. Nine met the inclusion criteria. North American studies dominated. Most used a mixture of observations and interviews. All the included studies highlighted the physical discomfort of dying, with many older people experiencing potentially avoidable symptoms if care were to be improved. Negative psychosocial experiences such as loneliness and depression were also often described in addition to limited support with spiritual needs. Conclusions More qualitative research giving a holistic understanding of older people’s experiences of dying in residential care homes is needed. Undertaking research on this topic is challenging and requires great sensitivity, but the dearth of qualitative research from the perspectives of those most closely involved in older people’s deaths hampers service improvement

Superconductivity in Li3Ca2C6 intercalated graphite

In this letter, we report the discovery of superconductivity in Li3Ca2C6. Several graphite intercalation compounds (GICs) with electron donors, are well known as superconductors. It is probably not astonishing, since it is generally admitted that low dimensionality promotes high superconducting transition temperatures. Superconductivity is lacking in pristine graphite, but after charging the graphene planes by intercalation, its electronic properties change considerably and superconducting behaviour can appear. Li3Ca2C6 is a ternary GIC, for which the intercalated sheets are very thick and poly-layered (five lithium layers and two calcium ones). It contains a great amount of metal (five metallic atoms for six carbon ones). Its critical temperature of 11.15 K is very close to that of CaC6 GIC (11.5 K). Both CaC6 and Li3Ca2C6 GICs possess currently the highest transition temperatures among all the GICs.Comment: 5 pages, 3 figure

Estimating Costs and Benefits Associated with Evidence-Based Violence Prevention: Four case studies based on the Fourth R program

Teen violence in dating and peer relationships has huge costs to society in numerous areas including health care, social services, the workforce and the justice system. Physical, psychological, and sexual abuse have long-lasting ramifications for the perpetrators as well as the victims, and for the families involved on both sides of that equation. An effective violence prevention program that is part of a school’s curriculum is beneficial not only for teaching teenagers what is appropriate behaviour in a relationship, but also for helping them break the cycle of violence which may have begun at home with their own maltreatment as children. The Fourth R program is an efficacious violence prevention program that was developed in Ontario and has been implemented in schools throughout Canada and the U.S. Covering relationship dynamics common to dating violence as well as substance abuse, peer violence and unsafe sex, the program can be adapted to different cultures and to same-sex relationships. The program, which gets its name from the traditional 3Rs — reading, ’riting and ’rithmetic — offers schools the opportunity to provide effective programming for teens to reduce the likelihood of them using relationship for violence as they move into adulthood. The federal government has estimated that the societal costs of relationship violence amount to more than $7 billion. These costs can continue to be incurred through the legal and health-care systems as the ripple effects of violence play out over the years, even after a relationship has ended. Other types of violence are also costly to society and not just in terms of dollars, but in young lives diverted into criminal activity. Up to 15 per cent of youth who become involved with the justice system grow into serious adult offenders who develop lengthy criminal careers. Yet, research shows that if prevention programs such as the Fourth R can deter just one 14-year-old high-risk juvenile from a life of crime, up to$5 million can be saved in costs to society

Phonon dispersion and low energy anomaly in CaC6_6

We report measurements of phonon dispersion in CaC$_6$ using inelastic X-ray and neutron scattering. We find good overall agreement, particularly in the 50 meV energy region, between experimental data and first-principles density-functional-theory calculations. However, on the longitudinal dispersion along the $(1 1 1)$ axis of the rhombohedral representation, we find an unexpected anti-crossing with an additional longitudinal mode, at about 11 meV. At a comparable energy, we observe also unexpected intensity on the in-plane direction. These results resolve the previous incorrect assignment of a longitudinal phonon mode to a transverse mode in the same energy range. By calculating the electron susceptibility from first principles we show that this longitudinal excitation is unlikely to be due to a plasmon and consequently can probably be due to defects or vacancies present in the sample.Comment: Accepted for publication in Physical Review

A randomised, controlled study of outcome and cost effectiveness for RA patients attending nurse-led rheumatology clinics: Study protocol of an ongoing nationwide multi-centre study

Background: The rise in the number of patients with arthritis coupled with understaffing of medical services has seen the deployment of Clinical Nurse Specialists in running nurse-led clinics alongside the rheumatologist clinics. There are no systematic reviews of nurse-led care effectiveness in rheumatoid arthritis. Few published RCTs exist and they have shown positive results for nurse-led care but they have several limitations and there has been no economic assessment of rheumatology nurse-led care in the UK. Objective: This paper outlines the study protocol and methodology currently being used to evaluate the outcomes and cost effectiveness for patients attending rheumatology nurse-led clinics. Design and methods: A multi-centred, pragmatic randomised controlled trial with a non-inferiority design; the null hypothesis being that of 'inferiority' of nurse-led clinics compared to physician-led clinics. The primary outcome is rheumatoid arthritis disease activity (measured by DAS28 score) and secondary outcomes are quality of life, self-efficacy, disability, psychological well-being, satisfaction, pain, fatigue and stiffness. Cost effectiveness will be measured using the EQ-5D, DAS28 and cost profile for each centre. Power calculations: In this trial, a DAS28 change of 0.6 is considered to be the threshold for clinical distinction of 'inferiority'. A sample size of 180 participants (90 per treatment arm) is needed to reject the null hypothesis of 'inferiority', given 90% power. Primary analysis will focus on 2-sided 95% confidence interval evaluation of between-group differences in DAS28 change scores averaged over 4 equidistant follow up time points (13, 26, 39 and 52 weeks). Cost effectiveness will be evaluated assessing the joint parameterisation of costs and effects. Results: The study started in July 2007 and the results are expected after July 2011. Trial registration: The International Standard Randomised Controlled Trial Number ISRCTN29803766. © 2011 Elsevier Ltd

Association of rheumatoid factor and anti-cyclic citrullinated peptide positivity, but not carriage of shared epitope or PTPN22 susceptibility variants, with anti-tumour necrosis factor response in rheumatoid arthritis

OBJECTIVE: To determine whether rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP) antibodies, or carriage of shared epitope (SE) and PTPN22 genetic susceptibility variants predict response to therapy in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor (TNF) agents. METHODS: UK-wide multicentre collaborations were established to recruit a large cohort of patients treated with anti-TNF drugs for RA. Serum RF, anti-CCP antibody and SE status were determined using commercially available kits. PTPN22 R620W genotyping was performed by Sequenom MassArray. Linear regression analyses were performed to investigate the role of these four factors in predicting response to treatment by 6 months, defined as the absolute change in 28-joint Disease Activity Score (DAS28). RESULTS: Of the 642 patients analysed, 46% received infliximab, 43% etanercept and 11% adalimumab. In all, 89% and 82% of patients were RF and anti-CCP positive, respectively. Patients that were RF negative had a 0.48 (95% CI 0.08 to 0.87) greater mean improvement in DAS28 compared to patients that were RF positive. A better response was also seen among patients that were anti-CCP negative. No association was demonstrated between drug response and SE or PTPN22 620W carriage. CONCLUSION: The presence of RF or anti-CCP antibodies was associated with a reduced response to anti-TNF drugs. However, these antibodies only account for a small proportion of the variance in treatment response. It is likely that genetic factors will contribute to treatment response, but these do not include the well established RA susceptibility loci, SE and PTPN22

Reduced cellularity of bone marrow in multiple sclerosis with decreased MSC expansion potential and premature ageing in vitro

Background: Autologous bone-marrow-derived cells are currently employed in clinical studies of cell-based therapy in multiple sclerosis (MS) although the bone marrow microenvironment and marrow-derived cells isolated from patients with MS have not been extensively characterised. Objectives: To examine the bone marrow microenvironment and assess the proliferative potential of multipotent mesenchymal stromal cells (MSCs) in progressive MS. Methods: Comparative phenotypic analysis of bone marrow and marrow-derived MSCs isolated from patients with progressive MS and control subjects was undertaken. Results: In MS marrow, there was an interstitial infiltrate of inflammatory cells with lymphoid (predominantly T-cell) nodules although total cellularity was reduced. Controlling for age, MSCs isolated from patients with MS had reduced in vitro expansion potential as determined by population doubling time, colony-forming unit assay, and expression of β-galactosidase. MS MSCs expressed reduced levels of Stro-1 and displayed accelerated shortening of telomere terminal restriction fragments (TRF) in vitro. Conclusion: Our results are consistent with reduced proliferative capacity and ex vivo premature ageing of bone-marrow-derived cells, particularly MSCs, in MS. They have significant implication for MSC-based therapies for MS and suggest that accelerated cellular ageing and senescence may contribute to the pathophysiology of progressive MS. </jats:sec