Progranulin in frontotemporal lobar degeneration and neuroinflammation

Progranulin (PGRN) is a pleiotropic protein that has gained the attention of the neuroscience community with recent discoveries of mutations in the gene for PGRN that cause frontotemporal lobar degeneration (FTLD). Pathogenic mutations in PGRN result in null alleles, and the disease is likely the result of haploinsufficiency. Little is known about the normal function of PGRN in the central nervous system apart from a role in brain development. It is expressed by microglia and neurons. In the periphery, PGRN is involved in wound repair and inflammation. High PGRN expression has been associated with more aggressive growth of various tumors. The properties of full length PGRN are distinct from those of proteolytically derived peptides, referred to as granulins (GRNs). While PGRN has trophic properties, GRNs are more akin to inflammatory mediators such as cytokines. Loss of the neurotrophic properties of PGRN may play a role in selective neuronal degeneration in FTLD, but neuroinflammation may also be important. Gene expression studies suggest that PGRN is up-regulated in a variety of neuroinflammatory conditions, and increased PGRN expression by microglia may play a pivotal role in the response to brain injury, neuroinflammation and neurodegeneration

A newly designed virtual tour of a Radiotherapy Department for improving patient experience initial staff qualitative evaluation

Abstract: Introduction More informed patients are likely to be more relaxed and less anxious on their cancer journey; evidence suggests knowing practical aspects of attending for radiotherapy and what to expect are very important(1-4). Departmental open evenings providing greater information support, help reduce anxiety and distress levels(5-6). More recently, virtual methods have been used – which is our approach here; by developing a digital virtual tour by local level 3 computer science students, as part of the Innovation Project for Clatterbridge Cancer Centre Liverpool (CCCL). Initial design and evaluation with patients have been undertaken(7). Knowing that Therapeutic Radiographers (TRs) are the natural eyes and ears for capturing the patient voice, we here report the initial evaluation from TR focus groups conducted at CCCL. Method Evaluation by patients used a mixed-methods survey(7). Control (n=9) and intervention (n=14) groups were established – the latter completing the survey after watching the virtual tour. Simultaneously, TR focus groups were conducted (n=17) using open-ended questions for evaluation. Results Qualitative results from TRs covered a wide range of evaluative comments and suggestions for improvement and development. All (100%) felt the virtual tour was a positive addition to the patient’s journey. Some commented it provided a good alternative to in-person open evenings, with enough information delivered at a good pace. The radiographer avatar was in uniform and spoke with a regional accent – both aspects were commented as being usefully informative, with a style and approach considered highly personable. Highlighting available facilities (like the beverage bar) and the inside of the treatment room were particularly noted in allowing patients to know exactly what to expect and help remove fear of the unknown. Improvements were suggested, to further expand the ‘reach’ of the virtual tour – e.g. to highlight transport, phlebotomy and pharmacy services; or link to Macmillan and Chemotherapy suites; and extend into further aspects such as pre-treatment and even how radiotherapy works. Conclusion The responses from this initial evaluation with TRs, who are at the frontline of providing care for radiotherapy patients, has been highly positive – complementing patient responses which, for example, showed reductions in anxiety and improvements in confidence and knowledge in practical matters (such as queue and changing room systems), together with knowing better what to expect through to the treatment room. Its introduction can now be the foundation for providing further key information prior to treatment start, alleviating anxiety and improving the patient experience still further

Synthesis, Molecular Structure, and 1H NMR Analysis of Bis(tetraphenylcyclopentadienyl)ruthenium(II)

Reaction of [Ru(p-cymene)Cl2]2 with K(η5-C5HPh4) in refluxing diglyme yields (η5-C5Ph4)2Ru in ca 50% yield. The complex was not susceptible to oxidation or reduction. (C5HPH4)2Ru crystallizes in the triclinic P1 space group with a = 8.549(4), b = 10.793(4), c = 12.842(5) Å, α = 65.98(3), β = 73.10(3), γ = 83.49(3)° and Z = 1. The least-squares data refined to R(F) = 3.53% and R(wF = 3.82% for the 3952 independent observed reflections with Fo ≥ 5σ(Fo). The metal-centroid distance is 1.832(2) Å and all other bond lengths and angles are similar to other octaphenylmetallocenes. 1H NMR analysis employing 2D J-resolved, COSY and low temperature techniques allowed assignment of all protons in the molecule. The motional processes of the phenyl groups are discussed

Synthesis, Characterization, and Crystal Structure of the (η5-C5Ph5)Cr(CO)3 Radical

The reaction between Cr(CO)6 and Na(C5Ph5 ) in refluxing diglyme yields [Na(diglyme)3/2][(C5Ph5)Cr(CO)3], 1. Metathesis of 1 with [Ph3P=N=PPh3 ]Cl in CH2Cl2 yields [Ph3P=N=PPh3][(C5Ph5)Cr(CO)3], 2. Oxidation of 1 by AgBF4 in cold THF under an argon atmosphere produces (C5Ph5)Cr(CO)3, 3. Complexes 2 and 3 form a redox pair connected by a quasireversible one-electron process, E0 = -0.69 V vs ferrocene in CH2Cl2, E0 = -0.50 V in CH3CN, ks = 0.12 cm/s. ESR spectra of (C5Ph5)Cr(CO)3 in toluene at 90 K gave a rhombic g-tensor with components 2.1366, 2.0224, and 1.9953, consistent with the expected low-spin d5 electronic configuration. The largest g-tensor component was significantly temperature dependent, suggesting an equilibrium between conformations with 2A´ and 2A˝ ground states. Crystal structures of [Ph3P=N=PPh3][(C5Ph5)Cr(CO)3] and (C5Ph5)Cr(CO)3 were obtained

Imbalance in the response of pre- and post-synaptic components to amyloidopathy

Alzheimer’s disease (AD)-associated synaptic dysfunction drives the progression of pathology from its earliest stages. Aβ species, both soluble and in plaque deposits, have been causally related to the progressive, structural and functional impairments observed in AD. It is, however, still unclear how Aβ plaques develop over time and how they progressively affect local synapse density and turnover. Here we observed, in a mouse model of AD, that Aβ plaques grow faster in the earlier stages of the disease and if their initial area is > 500 µm2; this may be due to deposition occurring in the cloud part of the plaque. In addition, synaptic turnover is higher in the presence of amyloid pathology and this is paralleled by a reduction in pre- but not post-synaptic densities. Plaque proximity does not appear to have an impact on synaptic dynamics. These observations indicate an imbalance in the response of the pre- and post-synaptic terminals and that therapeutics, alongside targeting the underlying pathology, need to address changes in synapse dynamics

High-risk sexual offenders: an examination of sexual fantasy, sexual paraphilia, psychopathy, and offence characteristics

High-risk sexual offenders are a complex and heterogeneous group of offenders about whom researchers, clinicians, and law enforcement agencies still know relatively little. In response to the paucity of information that is specifically applicable to high-risk offenders, the present study investigated the potential influence of sexual fantasy, sexual paraphilia, and psychopathy on the offending behaviour of 139 of the highest risk sexual offenders in one province of Canada. The sample included 41 child molesters, 42 rapists, 18 rapist/ molesters, 30 mixed offenders, and 6 "other" sexual offenders. Two offenders could not be categorized by type due to insufficient file information. Data analyses revealed significant differences between offender types for a number of criminal history variables including past sexual and nonsexual convictions, number of victims, weapon use, and age of offending onset. Further, there were significant differences between offender types for sexual fantasy themes, paraphilia diagnoses, and levels of psychopathy. For example, results revealed that offenders' sexual fantasies were significantly more likely to correspond with the specific type of index sexual offence that they had committed. Further, offenders scoring high in psychopathy were significantly more likely to have a sadistic paraphilia than offenders with either low or moderate psychopathy scores. Results from the current study provide a refined and informed understanding of sexual offending behaviour with important implications for future research, assessment, and treatment, as well as law enforcement practices when working with high-risk sexual offenders

Understanding the conditions that influence the roles of midwives in Ontario, Canada’s health system: an embedded single-case study

Abstract: Background: Despite the significant variability in the role and integration of midwifery across provincial and territorial health systems, there has been limited scholarly inquiry into whether, how and under what conditions midwifery has been assigned roles and integrated into Canada’s health systems. Methods: We use Yin’s (2014) embedded single-case study design, which allows for an in-depth exploration to qualitatively assess how, since the regulation of midwives in 1994, the Ontario health system has assigned roles to and integrated midwives as a service delivery option. Kingdon’s agenda setting and 3i + E theoretical frameworks are used to analyze two recent key policy directions (decision to fund freestanding midwifery-led birth centres and the Patients First primary care reform) that presented opportunities for the integration of midwives into the health system. Data were collected from key informant interviews and documents. Results: Nineteen key informant interviews were conducted, and 50 documents were reviewed in addition to field notes taken during the interviews. Our findings suggest that while midwifery was created as a self-regulated profession in 1994, health-system transformation initiatives have restricted the profession’s integration into Ontario’s health system. The policy legacies of how past decisions influence the decisions possible today have the most explanatory power to understand why midwives have had limited integration into interprofessional maternity care. The most important policy legacies to emerge from the analyses were related to payment mechanisms. In the medical model, payment mechanisms privilege physician-provided and hospital-based services, while payment mechanisms in the midwifery model have imposed unintended restrictions on the profession’s ability to practice in interprofessional environments. Conclusions: This is the first study to explain why midwives have not been fully integrated into the Ontario health system, as well as the limitations placed on their roles and scope of practice. The study also builds a theoretical understanding of the integration process of healthcare professions within health systems and how policy legacies shape service delivery options

A critical interpretive synthesis of the roles of midwives in health systems

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Survey of the quality of experimental design, statistical analysis and reporting of research using animals

For scientific, ethical and economic reasons, experiments involving animals should be appropriately designed, correctly analysed and transparently reported. This increases the scientific validity of the results, and maximises the knowledge gained from each experiment. A minimum amount of relevant information must be included in scientific publications to ensure that the methods and results of a study can be reviewed, analysed and repeated. Omitting essential information can raise scientific and ethical concerns. We report the findings of a systematic survey of reporting, experimental design and statistical analysis in published biomedical research using laboratory animals. Medline and EMBASE were searched for studies reporting research on live rats, mice and non-human primates carried out in UK and US publicly funded research establishments. Detailed information was collected from 271 publications, about the objective or hypothesis of the study, the number, sex, age and/or weight of animals used, and experimental and statistical methods. Only 59% of the studies stated the hypothesis or objective of the study and the number and characteristics of the animals used. Appropriate and efficient experimental design is a critical component of high-quality science. Most of the papers surveyed did not use randomisation (87%) or blinding (86%), to reduce bias in animal selection and outcome assessment. Only 70% of the publications that used statistical methods described their methods and presented the results with a measure of error or variability. This survey has identified a number of issues that need to be addressed in order to improve experimental design and reporting in publications describing research using animals. Scientific publication is a powerful and important source of information; the authors of scientific publications therefore have a responsibility to describe their methods and results comprehensively, accurately and transparently, and peer reviewers and journal editors share the responsibility to ensure that published studies fulfil these criteria

Halogen Oxidation Reactions of (C5Ph5)Cr(CO)3 and Lewis Base Addition To [(C5Ph5)Cr(μ-X)X]2: Electrochemical, Magnetic, and Raman Spectroscopic Characterization of [(C5Ph5)CrX2]2 and (C5Ph5)CrX2(THF) (X = Cl, Br, I). X-ray Crystal Structure of [(C5Ph5)Cr(μ-Cl)Cl]2

The 17-electron complex (C5Ph5)Cr(CO)3 reacts with halogens (C6H5I•Cl2, Br2, and I2) in C6H6 to yield the dimeric oxidation products [(C5Ph5)Cr(m-X)X]2 as thermally stable solids. Reactions with other chlorinating agents similarly yield [(C5Ph5)CrCl2]2. An X-ray crystal structure of [(C5Ph5)Cr(m-Cl)Cl]2 was obtained. The magnetic properties of the Cl2 bridged dimer have been determined and modeled using the usual isotropic hamiltonian which yields J/k = –30 K. Low-temperature (77 K) Raman spectra of solid [(C5Ph5)CrX2]2 (X = Cl, I) allow assignments to be made for the metal-ring and metal halogen stretching modes in the low frequency region (\u3c 600 cm-1). Tetrahydrofuran (THF) cleaves these dimers to yield complexes of the form (C5Ph5)CrX2(THF)