Different epigenetic states define syncytiotrophoblast and cytotrophoblast nuclei in the trophoblast of the human placenta.

INTRODUCTION: The syncytiotrophoblast (STB) epithelial covering of the villous tree in the human placenta is a multi-nucleated syncytium that is sustained by continuous incorporation of differentiating cytotrophoblast (CTB) cells. STB nuclei display a variety of morphologies, but are generally more condensed in comparison to CTB nuclei. Here, we consider whether this condensation is a feature of epigenetic regulation of chromatin structure. METHODS: Semi-quantitative immunohistochemical investigations of a panel of histone modifications were performed to determine the relative proportions in CTB and STB nuclear populations. We also investigated the patterns of DNA methylation and distribution of DNA methyltransferases enzymes in these populations. RESULTS: Unexpectedly DNA methylation, and H3K9me3 and H3K27me3, which are modifications associated with heterochromatin, are present at lower levels in STB nuclei compared to CTB, despite the intensive condensation in the former nuclear population and the progenitor state of the latter. By contrast, STB nuclei are enriched for H4K20me3, which is also associated with repressive states. 5'hydroxymethylcytosine immunoreactivity is higher in STB, with intense staining observed in the highly condensed nuclei within syncytial knots. DISCUSSION: Cell-type specific epigenetic states exist within the trophoblast populations potentially regulating their different functions and developmental properties and suggesting non-canonical epigenetic states associated with the properties of these cells.This work was funded by a studentship from the Anatomical Society of Great Britain and Ireland. The study was also supported by the Centre for Trophoblast Research.This is the accepted manuscript. The final version is available at http://www.sciencedirect.com/science/article/pii/S0143400415009248

Pulse-Administered Toceranib Phosphate Plus Lomustine for Treatment of Unresectable Mast Cell Tumors in Dogs.

BackgroundNonresectable mast cell tumors (MCT) in dogs remain a therapeutic challenge, and investigation of novel combination therapies is warranted. Intermittent administration of tyrosine kinase inhibitors (TKI) combined with cytotoxic chemotherapy may effectively chemosensitize canine MCT while decreasing cost and adverse effects associated with either agent administered as monotherapy.Hypothesis/objectivesThe primary study objectives were to (1) identify the maximally tolerated dose (MTD), (2) determine the objective response rate (ORR) and (3) describe the adverse event profile of pulse-administered toceranib phosphate (TOC) combined with lomustine.AnimalsForty-seven client-owned dogs with measurable MCT.MethodsToceranib phosphate was given PO on days 1, 3 and 5 of a 21-day cycle at a target dosage of 2.75 mg/kg. Lomustine was given PO on day 3 of each cycle at a starting dosage of 50 mg/m(2) . All dogs were concurrently treated with diphenhydramine, omeprazole, and prednisone.ResultsThe MTD of lomustine was established at 50 mg/m(2) when combined with pulse-administered TOC; the dose-limiting toxicity was neutropenia. Forty-one dogs treated at the MTD were evaluable for outcome assessment. The ORR was 46% (4 complete response, 15 partial response) and the overall median progression-free survival (PFS) was 53 days (1 to >752 days). On multivariate analysis, variables significantly associated with improved PFS included response to treatment, absence of metastasis, and no previous chemotherapy.Conclusions and clinical importanceCombined treatment with pulse-administered TOC and lomustine generally is well tolerated and may be a reasonable treatment option for dogs with unresectable or metastatic MCT

Flow cytometric characterization and clinical outcome of CD4+ T-cell lymphoma in dogs: 67 cases.

BackgroundCanine T-cell lymphoma (TCL) is conventionally considered an aggressive disease, but some forms are histologically and clinically indolent. CD4 TCL is reported to be the most common subtype of TCL. We assessed flow cytometric characteristics, histologic features when available, and clinical outcomes of CD4+ TCL to determine if flow cytometry can be used to subclassify this group of lymphomas.ObjectiveTo test the hypothesis that canine CD4+ T-cell lymphoma (TCL) is a homogeneous group of lymphomas with an aggressive clinical course.AnimalsSixty-seven dogs diagnosed with CD4+ TCL by flow cytometry and treated at 1 of 3 oncology referral clinics.MethodsRetrospective multivariable analysis of outcome in canine CD4+ TCL including patient characteristics, treatment, and flow cytometric features.ResultsThe majority of CD4+ TCL were CD45+, expressed low class II MHC, and exhibited an aggressive clinical course independent of treatment regimen (median survival, 159 days). Histologically, CD4+ TCL were classified as lymphoblastic or peripheral T cell. Size of the neoplastic lymphocytes had a modest effect on both PFI and survival in this group. A small number of CD4+ TCL were CD45- and class II MHC high, and exhibited an apparently more indolent clinical course (median survival not yet reached).Conclusions and clinical importanceAlthough the majority of CD4+ TCL in dogs had uniform clinical and flow cytometric features and an aggressive clinical course, a subset had a unique immunophenotype that predicts significantly longer survival. This finding strengthens the utility of flow cytometry to aid in the stratification of canine lymphoma

Prevalence and correlates of physical activity across kidney disease stages: an observational multicentre study

Background: People with chronic kidney disease (CKD) report high levels of physical inactivity, a major modifiable risk factor for morbidity and mortality. Understanding the biological, psychosocial and demographic causes of physical activity behaviour is essential for the development and improvement of potential health interventions and promotional initiatives. This study investigated the prevalence of physical inactivity and determined individual correlates of this behaviour in a large sample of patients across the spectrum of kidney disease. / Methods: A total of 5656 people across all stages of CKD (1–2, 3, 4–5, haemodialysis, peritoneal dialysis and renal transplant recipients) were recruited from 17 sites in England from July 2012 to October 2018. Physical activity was evaluated using the General Practice Physical Activity Questionnaire. Self-reported cardiorespiratory fitness, self-efficacy and stage of change were also assessed. Binominal generalized linear mutually adjusted models were conducted to explore the associations between physical activity and correlate variables. This cross-sectional observational multi-centre study was registered retrospectively as ISRCTN87066351 (October 2015). / Results: The prevalence of physical activity (6–34%) was low and worsened with disease progression. Being older, female and having a greater number of comorbidities were associated with greater odds of being physically inactive. Higher haemoglobin, cardiorespiratory fitness and self-efficacy levels were associated with increased odds of being active. Neither ethnicity nor smoking history had any effect on physical activity. / Conclusions: Levels of physical inactivity are high across all stages of CKD. The identification of stage-specific correlates of physical activity may help to prioritize factors in target groups of kidney patients and improve the development and improvement of public health interventions

Living with frailty and haemodialysis: a qualitative study

Background: Frailty is highly prevalent in people receiving haemodialysis (HD) and is associated with poor outcomes. Understanding the lived experiences of this group is essential to inform holistic care delivery. / Methods: Semi-structured interviews with N = 25 prevalent adults receiving HD from 3 HD units in the UK. Eligibility criteria included a Clinical Frailty Scale (CFS) score of 4–7 and a history of at least one fall in the last 6 months. Sampling began guided by maximum variation sampling to ensure diversity in frailty status; subsequently theoretical sampling enabled exploration of preliminary themes. Analysis was informed by constructivist grounded theory; later we drew upon the socioecological model. / Results: Participants had a mean age of 69 ± 10 years, 13 were female, and 13 were White British. 14 participants were vulnerable or mildly frail (CFS 4–5), and 11 moderately or severely frail (CFS 6–7). Participants characterised frailty as weight loss, weakness, exhaustion, pain and sleep disturbance arising from multiple long-term conditions. Participants’ accounts revealed: the consequences of frailty (variable function and psychological ill-health at the individual level; increasing reliance upon family at the interpersonal level; burdensome health and social care interactions at the organisational level; reduced participation at the community level; challenges with financial support at the societal level); coping strategies (avoidance, vigilance, and resignation); and unmet needs (overprotection from family and healthcare professionals, transactional health and social care exchanges). / Conclusions: The implementation of a holistic needs assessment, person-centred health and social care systems, greater family support and enhancing opportunities for community participation may all improve outcomes and experience. An approach which encompasses all these strategies, together with wider public health interventions, may have a greater sustained impact. Trial registration: ISRCTN12840463

A review of camera trapping for conservation behaviour research

An understanding of animal behaviour is important if conservation initiatives are to be effective. However, quantifying the behaviour of wild animals presents significant challenges. Remote-sensing camera traps are becoming increasingly popular survey instruments that have been used to non-invasively study a variety of animal behaviours, yielding key insights into behavioural repertoires. They are well suited to ethological studies and provide considerable opportunities for generating conservation-relevant behavioural data if novel and robust methodological and analytical solutions can be developed. This paper reviews the current state of camera-trap-based ethological studies, describes new and emerging directions in camera-based conservation behaviour, and highlights a number of limitations and considerations of particular relevance for camera-based studies. Three promising areas of study are discussed: (1) documenting anthropogenic impacts on behaviour; (2) incorporating behavioural responses into management planning and (3) using behavioural indicators such as giving up densities and daily activity patterns. We emphasize the importance of reporting methodological details, utilizing emerging camera trap metadata standards and central data repositories for facilitating reproducibility, comparison and synthesis across studies. Behavioural studies using camera traps are in their infancy; the full potential of the technology is as yet unrealized. Researchers are encouraged to embrace conservation-driven hypotheses in order to meet future challenges and improve the efficacy of conservation and management processes

Midterm Clinical Outcomes of Reimplantation Versus Remodeling Valve-Sparing Aortic Root Replacement in Patients With Connective Tissue Disorders: A Meta-Analysis

This meta-analysis aimed to compare the midterm clinical outcomes of reimplantation versus remodeling techniques for valve-sparing aortic root replacement (VSARR) in patients with connective tissue disorders (CTDs). Studies were screened and identified after the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines from the PubMed, Web of Science, and Embase databases. Forest plots were produced using Review Manager 5.3 (Cochrane, UK). Studies comparing early and midterm clinical outcomes of reimplantation versus remodeling VSARR in patients with CTD with a mean age ≥18 years were included. The sensitivity analysis excluded studies and subgroups of patients that received ring or suture annuloplasty in addition to remodeling surgery. The study selection identified 9 eligible studies. After analysis of the study period and location for patient crossover, 7 retrospective studies consisting of 597 patients (301 reimplantation and 296 remodeling) were pooled. The pooling revealed no significant difference in postoperative mortality (estimated mean follow-up of 10.5 years) (odds ratio [OR] 0.66, 95% confidence interval [CI] 0.30 to 1.48, I2 = 30%, p = 0.32), reoperation (OR 0.35, CI 0.04 to 3.30, I2 = 81%, p = 0.36), or occurrence of postoperative aortic regurgitation of ≥2 (OR 0.56, CI 0.31 to 1.02, I2 = 47%, p = 0.06). The sensitivity analysis excluding annuloplasty demonstrated improved mortality (OR 0.19, CI 0.06 to 0.64, I2 = 0%, p = 0.007) and decreased aortic regurgitation of ≥2 (OR 0.23, CI 0.10 to 0.53, I2 = 47%, p = 0.0005) in reimplantation VSARR. The rates of reoperation remained insignificant in the sensitivity analysis (OR 0.43, CI 0.05 to 3.53, I2 = 71%, p = 0.43). In conclusion, this meta-analysis has demonstrated no significant difference in the midterm clinical outcomes of reimplantation versus remodeling techniques of VSARR. The sensitivity analysis excluding studies and patient subgroups that received remodeling and annuloplasty suggests remodeling alone to be inferior to reimplantation in patients with CTDs. Further research is required to assess remodeling and annuloplasty against reimplantation in patients of this demographic because the current body of knowledge does not allow sufficient analysis

Establishing a Statistical Link between Network Oscillations and Neural Synchrony

Pairs of active neurons frequently fire action potentials or “spikes” nearly synchronously (i.e., within 5 ms of each other). This spike synchrony may occur by chance, based solely on the neurons’ fluctuating firing patterns, or it may occur too frequently to be explicable by chance alone. When spike synchrony above chances levels is present, it may subserve computation for a specific cognitive process, or it could be an irrelevant byproduct of such computation. Either way, spike synchrony is a feature of neural data that should be explained. A point process regression framework has been developed previously for this purpose, using generalized linear models (GLMs). In this framework, the observed number of synchronous spikes is compared to the number predicted by chance under varying assumptions about the factors that affect each of the individual neuron’s firing-rate functions. An important possible source of spike synchrony is network-wide oscillations, which may provide an essential mechanism of network information flow. To establish the statistical link between spike synchrony and network-wide oscillations, we have integrated oscillatory field potentials into our point process regression framework. We first extended a previously-published model of spike-field association and showed that we could recover phase relationships between oscillatory field potentials and firing rates. We then used this new framework to demonstrate the statistical relationship between oscillatory field potentials and spike synchrony in: 1) simulated neurons, 2) in vitro recordings of hippocampal CA1 pyramidal cells, and 3) in vivo recordings of neocortical V4 neurons. Our results provide a rigorous method for establishing a statistical link between network oscillations and neural synchrony

An Opsonophagocytic Killing Assay for the Evaluation of Group A Streptococcus Vaccine Antisera

Group A Streptococcus (GAS) is a major cause of global mortality, yet there are no licensed GAS vaccines. Vaccine progress has been hampered, in part, by a lack of standardized assays able to quantify antibody function in test antisera. The most widely used assay was developed over 50 years ago by Rebecca Lancefield and relies on human whole blood as a source of complement and neutrophils. Recently, an opsonophagocytic killing (OPK) assay has been developed for GAS by adapting the OPK methods utilized in Streptococcus pneumoniae vaccine testing. This assay uses dimethylformamide (DMF)-differentiated human promyelocytic leukemia cells (HL-60 cells) as a source of neutrophils and baby rabbit complement, thus removing the major sources of variation in the Lancefield assays. This protocol outlines methods for performing a GAS OPK assay including titering test sera to generate an opsonic index. This in vitro assay could aid in selecting vaccine candidates by demonstrating whether candidate-induced antibodies lead to complement deposition and opsonophagocytic killing

Understanding health-care outcomes of older people with cognitive impairment and/or dementia admitted to hospital: a mixed-methods study

BACKGROUND: Cognitive impairment is common in older people admitted to hospital, but previous research has focused on single conditions. OBJECTIVE: This project sits in phase 0/1 of the Medical Research Council Framework for the Development and Evaluation of Complex Interventions. It aims to develop an understanding of current health-care outcomes. This will be used in the future development of a multidomain intervention for people with confusion (dementia and cognitive impairment) in general hospitals. The research was conducted from January 2015 to June 2018 and used data from people admitted between 2012 and 2013. DESIGN: For the review of outcomes, the systematic review identified peer-reviewed quantitative epidemiology measuring prevalence and associations with outcomes. Screening for duplication and relevance was followed by full-text review, quality assessment and a narrative review (141 papers). A survey sought opinion on the key outcomes for people with dementia and/or confusion and their carers in the acute hospital (n = 78). For the analysis of outcomes including cost, the prospective cohort study was in a medical admissions unit in an acute hospital in one Scottish health board covering 10% of the Scottish population. The participants (n = 6724) were older people (aged ≥ 65 years) with or without a cognitive spectrum disorder who were admitted as medical emergencies between January 2012 and December 2013 and who underwent a structured nurse assessment. ‘Cognitive spectrum disorder’ was defined as any combination of delirium, known dementia or an Abbreviated Mental Test score of < 8 out of 10 points. The main outcome measures were living at home 30 days after discharge, mortality within 2 years of admission, length of stay, re-admission within 2 years of admission and cost. DATA SOURCES: Scottish Morbidity Records 01 was linked to the Older Persons Routine Acute Assessment data set. RESULTS: In the systematic review, methodological heterogeneity, especially concerning diagnostic criteria, means that there is significant overlap in conditions of patients presenting to general hospitals with confusion. Patients and their families expect that patients are discharged in the same or a better condition than they were in on admission or, failing that, that they have a satisfactory experience of their admission. Cognitive spectrum disorders were present in more than one-third of patients aged ≥ 65 years, and in over half of those aged ≥ 85 years. Outcomes were worse in those patients with cognitive spectrum disorders than in those without: length of stay 25.0 vs. 11.8 days, 30-day mortality 13.6% vs. 9.0%, 1-year mortality 40.0% vs. 26.0%, 1-year mortality or re-admission 62.4% vs. 51.5%, respectively (all p < 0.01). There was relatively little difference by cognitive spectrum disorder type; for example, the presence of any cognitive spectrum disorder was associated with an increased mortality over the entire period of follow-up, but with different temporal patterns depending on the type of cognitive spectrum disorder. The cost of admission was higher for those with cognitive spectrum disorders, but the average daily cost was lower. LIMITATIONS: A lack of diagnosis and/or standardisation of diagnosis for dementia and/or delirium was a limitation for the systematic review, the quantitative study and the economic study. The economic study was limited to in-hospital costs as data for social or informal care costs were unavailable. The survey was conducted online, limiting its reach to older carers and those people with cognitive spectrum disorders. CONCLUSIONS: Cognitive spectrum disorders are common in older inpatients and are associated with considerably worse health-care outcomes, with significant overlap between individual cognitive spectrum disorders. This suggests the need for health-care systems to systematically identify and develop care pathways for older people with cognitive spectrum disorders, and avoid focusing on only condition-specific pathways. FUTURE WORKS: Development and evaluation of a multidomain intervention for the management of patients with cognitive spectrum disorders in hospital. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015024492. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 9, No. 8. See the NIHR Journals Library website for further project information