A Sustained Dietary Change Increases Epigenetic Variation in Isogenic Mice

Epigenetic changes can be induced by adverse environmental exposures, such as nutritional imbalance, but little is known about the nature or extent of these changes. Here we have explored the epigenomic effects of a sustained nutritional change, excess dietary methyl donors, by assessing genomic CpG methylation patterns in isogenic mice exposed for one or six generations. We find stochastic variation in methylation levels at many loci; exposure to methyl donors increases the magnitude of this variation and the number of variable loci. Several gene ontology categories are significantly overrepresented in genes proximal to these methylation-variable loci, suggesting that certain pathways are susceptible to environmental influence on their epigenetic states. Long-term exposure to the diet (six generations) results in a larger number of loci exhibiting epigenetic variability, suggesting that some of the induced changes are heritable. This finding presents the possibility that epigenetic variation within populations can be induced by environmental change, providing a vehicle for disease predisposition and possibly a substrate for natural selection.This work was supported by the Australian Research Council (DP0771859) and the National Health and Medical Research Council (#459412, #635510)

An association between pulmonary Mycobacterium avium-intracellulare complex infections and biomarkers of Th2-type inflammation

Background: The rising incidence of pulmonary Mycobacterium avium-intracellulare complex (MAI) infection is unexplained but parallels the growing world-wide epidemic of allergic disease. We hypothesized an association between pulmonary MAI infection and Th2-type immune responses as seen in allergy. / Methods: Biomarkers of patient Th2-type immune responses (peripheral blood eosinophil counts and serum IgE levels) were compared between patients with positive pulmonary samples for tuberculosis and non-tuberculous mycobacterial (NTM) infection. A further comparison of clinical characteristics, including respiratory co-morbidities, and biomarkers, was conducted between patients culturing MAI NTM and those culturing NTM other than MAI. / Results: Patients culturing NTM from pulmonary samples had significantly higher peripheral blood eosinophil levels than those culturing Mycobacterium tuberculosis. Furthermore, patients culturing MAI compared to those culturing NTM other than MAI had higher eosinophil counts (mean 0.29x109/L vs 0.15x109/L, p=0.010) and IgE levels (geometric mean 138kU/L vs 47kU/L, p=0.021). However there was no significant difference in the frequency of asthma between the two NTM groups. / Conclusions: There is an association between biomarkers of Th2-type immune responses and pulmonary MAI. Prospective and translational research could identify the direction of causation; and so determine whether our finding may be utilized within future management strategies for MAI

The association between work-related rumination and heart rate variability: A field study

This is the final version. Available on open access from Frontiers Media via the DOI in this recordThe objective of this study was to examine the association between perseverative cognition in the form of work-related rumination, and heart rate variability (HRV). We tested the hypothesis that high ruminators would show lower vagally mediated HRV relative to low ruminators during their leisure time. Individuals were classified as being low (n = 17) or high ruminators (n = 19), using the affective scale on the work-related rumination measure. HRV was assessed using a wrist sensor band (Microsoft Band 2). HRV was sampled between 8 pm and 10 pm over three workday evenings (Monday to Wednesday) while individuals carried out their normal evening routines. Compared to the low ruminators, high affective ruminators demonstrated lower HRV in the form of root mean square successive differences (RMSSDs), relative to the low ruminators, indicating lower parasympathetic activity. There was no significant difference in heart rate, or activity levels between the two groups during the recording periods. The current findings of this study may have implications for the design and delivery of interventions to help individuals unwind post work and to manage stress more effectively. Limitations and implications for future research are discussed

CpG Methylation of a Silent Controlling Element in the Murine Avy Allele Is Incomplete and Unresponsive to Methyl Donor Supplementation

Background: The viable yellow allele of agouti (A vy) is remarkable for its unstable and partially heritable epigenetic state, which produces wide variation in phenotypes of isogenic mice. In the A vy allele an inserted intracisternal A particle (IAP) acts as a controlling element which deregulates expression of agouti by transcription from the LTR of the IAP; the phenotypic state has been linked to CpG methylation of the LTR. Phenotypic variation between A vy mice indicates that the epigenetic state of the IAP is unstable in the germline. Principal Findings: We have made a detailed examination of somatic methylation of the IAP using bisulphite allelic sequencing, and find that the promoter is incompletely methylated even when it is transcriptionally silent. In utero exposure to supplementary methyl donors, which alters the spectrum of A vy phenotypes, does not increase the density of CpG methylation in the silent LTR. Conclusions: Our findings suggest that, contrary to previous supposition, methyl donor supplementation acts through an indirect mechanism to silence A vy. The incomplete cytosine methylation we observe at the somatically silent A vy allele ma

Variation in C - reactive protein response according to host and mycobacterial characteristics in active tuberculosis

BACKGROUND: The C - reactive protein (CRP) response is often measured in patients with active tuberculosis (TB) yet little is known about its relationship to clinical features in TB, or whether responses differ between ethnic groups or with different Mycobacterium tuberculosis (M.tb) strain types. We report the relationship between baseline serum CRP prior to treatment and disease characteristics in a metropolitan population with TB resident in a low TB incidence region. METHODS: People treated for TB at four London, UK sites between 2003 and 2014 were assessed and data collected on the following characteristics: baseline CRP level; demographics (ethnicity, gender and age); HIV status; site of TB disease; sputum smear (in pulmonary cases) and culture results. The effect of TB strain-type was also assessed in culture-positive pulmonary cases using VNTR typing data. RESULTS: Three thousands two hundred twenty-two patients were included in the analysis of which 72 % had a baseline CRP at or within 4 weeks prior to starting TB treatment. CRP results were significantly higher in culture positive cases compared to culture negative cases: median 49 mg/L (16-103 mg/L) vs 19 mg/L (IQR 5-72 mg/L), p = <0.001. In those with pulmonary disease, smear positive cases had a higher CRP than smear negative cases: 67 mg/L (31-122 mg/L) vs 24 mg/L (7-72 mg/L), p < 0.001. HIV positive cases had higher baseline CRPs than HIV negative cases: 75 mg/L (26-136 mg/L) vs 37 mg/L (10-88 mg/L), p <0.001. Differing sites of disease were associated with differences in baseline CRP: locations that might be expected to have a high mycobacterial load (e.g. pulmonary disease and disseminated disease) had a significantly higher CRP than those such as skin, lymph node or CNS disease, where the mycobacterial load is typically low in HIV negative subjects. In a multivariable log-scale linear regression model adjusting for host characteristics and M.tb strain type, infection with the East African Indian strain was associated with significantly lower baseline-CRP (fold-change in CRP 0.51 (0.34-0.77), p < 0.01). CONCLUSIONS: Host and mycobacterial factors are strongly associated with baseline CRP response in tuberculosis. This analysis suggests that there are important differences in innate immune response according to ethnicity, Mtb strain type and site of disease. This may reflect differing mycobacterial loads or host immune responses

Improved treatment completion for tuberculosis patients: The case for a dedicated social care team

OBJECTIVES: The increasing social needs of people with Tuberculosis (TB), and the poor adherence to anti-TB therapy (ATT) associated with homelessness, drug or alcohol abuse, and prison history, led us to introduce a social care team (SCT) to support patient engagement with care within this low TB incidence setting. METHODS: Using a risk assessment, patients with social risk factors (SRF) for non-adherence to ATT are identified and a referral made to the SCT, who then provide intensive casework support for areas including homelessness, housing, benefits, debt and immigration. Retrospective data analysis of the social care database from 2017 to 2019 was conducted. Patients who were (n = 170) and were not referred to the SCT (n = 734) were compared. RESULTS: Patients referred were significantly more likely to complete treatment for TB than those not (88.2% versus 77.7% respectively, p = 0.0025), irrespective of receipt of Directly/Video Observed Therapy and adjusting for confounders. CONCLUSIONS: This paper demonstrates important evidence for the positive impact of a dedicated SCT within a TB service, and these improved treatment outcomes provide a strong argument for development of similar SCTs within UK TB services and similar healthcare settings

Developmental contexts and features of elite academy football players: Coach and player perspectives

Player profiling can reap many benefits; through reflective coach-athlete dialogue that produces a profile the athlete has a raised awareness of their own development, while the coach has an opportunity to understand the athlete's viewpoint. In this study, we explored how coaches and players perceived the development features of an elite academy footballer and the contexts in which these features are revealed, in order to develop a player profile to be used for mentoring players. Using a Delphi polling technique, coaches and players experienced a number of 'rounds' of expressing their opinions regarding player development contexts and features, ultimately reduced into a consensus. Players and coaches had differing priorities on the key contexts of player development. These contexts, when they reflect the consensus between players and coaches were heavily dominated by ability within the game and training. Personal, social, school, and lifestyle contexts featured less prominently. Although 'discipline' was frequently mentioned as an important player development feature, coaches and players disagreed on the importance of 'training'

PET imaging of putative microglial activation in individuals at ultra-high risk for psychosis, recently diagnosed and chronically ill with schizophrenia

We examined putative microglial activation as a function of illness course in schizophrenia. Microglial activity was quantified using [11C](R)-(1-[2-chrorophynyl]-N-methyl-N-[1-methylpropyl]-3 isoquinoline carboxamide (11C-(R)-PK11195) positron emission tomography (PET) in: (i) 10 individuals at ultra-high risk (UHR) of psychosis; (ii) 18 patients recently diagnosed with schizophrenia; (iii) 15 patients chronically ill with schizophrenia; and, (iv) 27 age-matched healthy controls. Regional-binding potential (BPND) was calculated using the simplified reference-tissue model with four alternative reference inputs. The UHR, recent-onset and chronic patient groups were compared to age-matched healthy control groups to examine between-group BPND differences in 6 regions: dorsal frontal, orbital frontal, anterior cingulate, medial temporal, thalamus and insula. Correlation analysis tested for BPND associations with gray matter volume, peripheral cytokines and clinical variables. The null hypothesis of equality in BPND between patients (UHR, recent-onset and chronic) and respective healthy control groups (younger and older) was not rejected for any group comparison or region. Across all subjects, BPND was positively correlated to age in the thalamus (r=0.43, P=0.008, false discovery rate). No correlations with regional gray matter, peripheral cytokine levels or clinical symptoms were detected. We therefore found no evidence of microglial activation in groups of individuals at high risk, recently diagnosed or chronically ill with schizophrenia. While the possibility of 11C-(R)-PK11195-binding differences in certain patient subgroups remains, the patient cohorts in our study, who also displayed normal peripheral cytokine profiles, do not substantiate the assumption of microglial activation in schizophrenia as a regular and defining feature, as measured by 11C-(R)-PK11195 BPND.M A Di Biase, A Zalesky, G O'keefe, L Laskaris, B T Baune, C S Weickert, J Olver, P D McGorry, G P Amminger, B Nelson, A M Scott, I Hickie, R Banati, F Turkheimer, M Yaqub, I P Everall, C Pantelis and V Crople

A Sustained Dietary Change Increases Epigenetic Variation in Isogenic Mice

Epigenetic changes can be induced by adverse environmental exposures, such as nutritional imbalance, but little is known about the nature or extent of these changes. Here we have explored the epigenomic effects of a sustained nutritional change, excess dietary methyl donors, by assessing genomic CpG methylation patterns in isogenic mice exposed for one or six generations. We find stochastic variation in methylation levels at many loci; exposure to methyl donors increases the magnitude of this variation and the number of variable loci. Several gene ontology categories are significantly overrepresented in genes proximal to these methylation-variable loci, suggesting that certain pathways are susceptible to environmental influence on their epigenetic states. Long-term exposure to the diet (six generations) results in a larger number of loci exhibiting epigenetic variability, suggesting that some of the induced changes are heritable. This finding presents the possibility that epigenetic variation within populations can be induced by environmental change, providing a vehicle for disease predisposition and possibly a substrate for natural selection

Views on a brief mindfulness intervention among patients with long-term illness.

BACKGROUND: Chronic illness is the leading cause of death in the UK and worldwide. Psychological therapies to support self-management have been shown to play an important role in helping those with chronic illness cope; more recently, the therapeutic benefits of mindfulness approaches have become evident for managing depression and other distressing emotions. Brief guided mindfulness interventions, are more convenient than intensive traditional programmes requiring regular attendance but have been less explored. This study assessed views on a brief (i.e., 10 min) mindfulness intervention for those with specific long-term illnesses. METHODS: Semi-structured interviews and focus groups were conducted with chronic illness patient groups (i.e., chronic obstructive pulmonary disease, chronic pain and cardiovascular disease), designed to capture the acceptability and feasibility of the intervention. The interviews were conducted after use of a mindfulness based audio in clinic and, one week later, after use in the patient's own environment. Interviews were recorded, transcribed and analysed using thematic analysis. RESULTS: In total, a combination of 18 interviews and focus groups were conducted among 14 patients. Recruitment was most successful with chronic pain patients. All patients reported benefits such as feelings of relaxation and improved coping with symptoms. While the wording and content of the audio were generally well received, it was suggested that the length could be increased, as it felt rushed, and that more guidance about the purpose of mindfulness, and when to use it, was needed. CONCLUSIONS: A brief mindfulness intervention was well accepted among patients with long-term illness. The intervention may benefit by being lengthened and by offering further guidance on its use