The psychophysiology of dysautonomia

Modern theories of emotion emphasise the role of homeostatic requirements in motivating and shaping behaviour and link emotions with motor and autonomic responses to define physiological, behavioural and neurobiological phenomena initiated by the emotional valence and relevance of a stimulus. Intermittent dysautonomia is a transient but recurrent dysregulation of autonomic nervous system function, such as orthostatic intolerance (postural tachycardia syndrome, vasovagal syncope) or thermoregulatory dysfunction (essential hyperhidrosis). The sympathetic and parasympathetic nervous systems often work antagonistically and with organ specificity, producing definable patterns of activity, yet despite the coupling of emotion with autonomic function, the evidence for robust emotionspecific patterns remains elusive. Although psychiatric patients may report symptoms akin to intermittent dysautonomia, such as sweating, faintness or palpitations, autonomic diagnostic criteria are rarely met. However, comorbid psychological symptoms, such as subclinical anxiety and depression, are often reported in intermittent dysautonomia. Recent neuroimaging techniques have elucidated the interrelationship of autonomic and neurobiological pathophysiology and the perturbation of autonomic neuroanatomy by peripheral autonomic function and dysfunction. This thesis will investigate the complex interplay between brain and body in intermittent dysautonomia and healthy controls in order to improve our understanding of the common cognitive-affective symptomatology in vasovagal syncope (VVS), the postural tachycardia syndrome (PoTS) and essential hyperhidrosis (EH) that can complicate diagnosis and treatment. Moreover, organic conditions that provide such an overrepresentation of comorbid psychological symptoms may provide insight into cognitive-affective processes beyond autonomic medicine

Orthostatic intolerance and autonomic dysfunction following bariatric surgery: A retrospective study and review of the literature

The prevalence and costs of the obesity epidemic and obesity-related conditions, including diabetes mellitus, is consistently increasing worldwide. Bariatric medicine is attempting to address this with weight loss and exercise programmes, and with increasing frequency, various forms of bariatric surgery. There has been considerable success reported after bariatric surgery but not without. We describe 14 patients with orthostatic intolerance (OI) post bariatric surgery. We report on OI (postural dizziness, palpitations and fainting), the results of cardiovascular autonomic testing and the associated and/or causative findings as well as reviewing the literature to consider the possible mechanisms. Comprehensive autonomic testing revealed that 35.7% (Buchwald et al., 2004) of these patients fulfilled the criteria for the Postural Tachycardia Syndrome (PoTS), 57.1% (Cremieux et al., 2008) had low levels of basal BP and 42.9% (Cammisotto & Bendayan, 2007) patients were presyncopal and 14.3% (Billakanty et al., 2008) experienced syncope. We propose that the incidence of OI post-bariatric surgery is higher than considered, that certain cohorts may be more susceptible to complications, and that further research is needed to identify the prevalence and, ideally anticipate occurrence. With the increasing prevalence of obesity and required clinical interventions, further understanding of the pathophysiological processes causing autonomic dysfunction after bariatric interventions will aid management, which may differ in those with an underlying disposition to autonomic involvement, such as diabetics, in whom such procedures are increasingly used

Orthostatic intolerance and autonomic dysfunction following bariatric surgery: A retrospective study and review of the literature

The prevalence and costs of the obesity epidemic and obesity-related conditions, including diabetes mellitus, is consistently increasing worldwide. Bariatric medicine is attempting to address this with weight loss and exercise programmes, and with increasing frequency, various forms of bariatric surgery. There has been considerable success reported after bariatric surgery but not without. We describe 14 patients with orthostatic intolerance (OI) post bariatric surgery. We report on OI (postural dizziness, palpitations and fainting), the results of cardiovascular autonomic testing and the associated and/or causative findings as well as reviewing the literature to consider the possible mechanisms. Comprehensive autonomic testing revealed that 35.7% (Buchwald et al., 2004) of these patients fulfilled the criteria for the Postural Tachycardia Syndrome (PoTS), 57.1% (Cremieux et al., 2008) had low levels of basal BP and 42.9% (Cammisotto & Bendayan, 2007) patients were presyncopal and 14.3% (Billakanty et al., 2008) experienced syncope. We propose that the incidence of OI post-bariatric surgery is higher than considered, that certain cohorts may be more susceptible to complications, and that further research is needed to identify the prevalence and, ideally anticipate occurrence. With the increasing prevalence of obesity and required clinical interventions, further understanding of the pathophysiological processes causing autonomic dysfunction after bariatric interventions will aid management, which may differ in those with an underlying disposition to autonomic involvement, such as diabetics, in whom such procedures are increasingly used

Skeletal muscle cells possess a 'memory' of acute early life TNF-α exposure: role of epigenetic adaptation.

Sufficient quantity and quality of skeletal muscle is required to maintain lifespan and healthspan into older age. The concept of skeletal muscle programming/memory has been suggested to contribute to accelerated muscle decline in the elderly in association with early life stress such as fetal malnutrition. Further, muscle cells in vitro appear to remember the in vivo environments from which they are derived (e.g. cancer, obesity, type II diabetes, physical inactivity and nutrient restriction). Tumour-necrosis factor alpha (TNF-α) is a pleiotropic cytokine that is chronically elevated in sarcopenia and cancer cachexia. Higher TNF-α levels are strongly correlated with muscle loss, reduced strength and therefore morbidity and earlier mortality. We have extensively shown that TNF-α impairs regenerative capacity in mouse and human muscle derived stem cells [Meadows et al. (J Cell Physiol 183(3):330-337, 2000); Foulstone et al. (J Cell Physiol 189(2):207-215, 2001); Foulstone et al. (Exp Cell Res 294(1):223-235, 2004); Stewart et al. (J Cell Physiol 198(2):237-247, 2004); Al-Shanti et al. (Growth factors (Chur, Switzerland) 26(2):61-73, 2008); Saini et al. (Growth factors (Chur, Switzerland) 26(5):239-253, 2008); Sharples et al. (J Cell Physiol 225(1):240-250, 2010)]. We have also recently established an epigenetically mediated mechanism (SIRT1-histone deacetylase) regulating survival of myoblasts in the presence of TNF-α [Saini et al. (Exp Physiol 97(3):400-418, 2012)]. We therefore wished to extend this work in relation to muscle memory of catabolic stimuli and the potential underlying epigenetic modulation of muscle loss. To enable this aim; C2C12 myoblasts were cultured in the absence or presence of early TNF-α (early proliferative lifespan) followed by 30 population doublings in the absence of TNF-α, prior to the induction of differentiation in low serum media (LSM) in the absence or presence of late TNF-α (late proliferative lifespan). The cells that received an early plus late lifespan dose of TNF-α exhibited reduced morphological (myotube number) and biochemical (creatine kinase activity) differentiation vs. control cells that underwent the same number of proliferative divisions but only a later life encounter with TNF-α. This suggested that muscle cells had a morphological memory of the acute early lifespan TNF-α encounter. Importantly, methylation of myoD CpG islands were increased in the early TNF-α cells, 30 population doublings later, suggesting that even after an acute encounter with TNF-α, the cells have the capability of retaining elevated methylation for at least 30 cellular divisions. Despite these fascinating findings, there were no further increases in myoD methylation or changes in its gene expression when these cells were exposed to a later TNF-α dose suggesting that this was not directly responsible for the decline in differentiation observed. In conclusion, data suggest that elevated myoD methylation is retained throughout muscle cells proliferative lifespan as result of early life TNF-α treatment and has implications for the epigenetic control of muscle loss

L-glutamine improves skeletal muscle cell differentiation and prevents myotube atrophy after cytokine (TNF-α) stress via reduced p38 MAPK signal transduction

Tumour Necrosis Factor- Alpha (TNF-α) is chronically elevated in conditions where skeletal muscle loss occurs. As L-glutamine can dampen the effects of inflamed environments, we investigated the role of L-glutamine in both differentiating C2C12 myoblasts and existing myotubes in the absence/presence of TNF-α (20 ng.ml−1) ± L-glutamine (20 mM).TNF-α reduced the proportion of cells in G1 phase, as well as biochemical (CK activity) and morphological differentiation (myotube number), with corresponding reductions in transcript expression of: Myogenin, Igf-I and Igfbp5. Furthermore, when administered to mature myotubes, TNF-α induced myotube loss and atrophy underpinned by reductions in Myogenin, Igf-I, Igfbp2 and glutamine synthetase and parallel increases in Fox03, Cfos, p53 and Bid gene expression. Investigation of signaling activity suggested that Akt and ERK1/2 were unchanged, JNK increased (non-significantly) whereas P38 MAPK substantially and significantly increased in both myoblasts and myotubes in the presence of TNF-α. Importantly, 20 mM L-glutamine reduced p38 MAPK activity in TNF-α conditions back to control levels, with a corresponding rescue of myoblast differentiation and a reversal of atrophy in myotubes. L-glutamine resulted in upregulation of genes associated with growth and survival including; Myogenin, Igf-Ir, Myhc2 & 7, Tnfsfr1b, Adra1d and restored atrophic gene expression of Fox03 back to baseline in TNF-α conditions. In conclusion, L-glutamine supplementation rescued suppressed muscle cell differentiation and prevented myotube atrophy in an inflamed environment via regulation of p38 MAPK. L-glutamine administration could represent an important therapeutic strategy for reducing muscle loss in catabolic diseases and inflamed ageing. This article is protected by copyright. All rights reserve

UBR5 is a Novel E3 Ubiquitin Ligase involved in Skeletal Muscle Hypertrophy and Recovery from Atrophy

We have recently identified that a HECT domain E3 ubiquitin ligase, named UBR5, was epigenetically altered (via DNA methylation) after human skeletal muscle hypertrophy, where its gene expression was positively correlated with increased lean leg mass in humans [1]. This was counterintuitive given the well-defined role of other E3 ligase family members, MuRF1 and MAFbx in muscle atrophy. Therefore, in the present study we aimed to investigate this relatively uncharacterised E3 ubiquitin ligase using multiple in-vivo and in-vitro models of skeletal muscle atrophy, injury, recovery from atrophy as well as anabolism and hypertrophy. We report for the first time, that during atrophy evoked by tetrodotoxin (TTX) nerve silencing in rats, the UBR5 promoter was significantly hypomethylated with a concomitant increase in gene expression early (3 & 7 days) after the induction of atrophy. However, at these timepoints larger increases in MuRF1/MAFbx were observed, and UBR5 expression had returned to baseline levels during later atrophy (14 days) where muscle mass loss was greatest. We confirmed an alternate gene expression profile for UBR5 versus MuRF1/MAFbx in a secondary model of atrophy induced by 7 days continuous low frequency electrical stimulation, where UBR5 demonstrated no significant increase, whereas MuRF1/MAFbx were elevated. Further, after partial (52%) recovery of muscle mass following 7 days TTX-cessation, UBR5 was hypomethylated and increased at the gene expression level, while alternately, reductions in gene expression of MuRF1 and MAFbx were observed. To substantiate these gene expression findings, we observed a significant increase in UBR5 protein abundance after full recovery (14 days) of muscle mass from hindlimb unloading (HU) in rats. Aged rats also demonstrated a similar temporal increase in UBR5 protein abundance after recovery from HU. Further, we confirmed significant increases in UBR5 protein during recovery from nerve crush injury in mice at 28 and 45 days, that related to a full recovery of muscle mass between 45-60 days. During anabolism and hypertrophy, UBR5 gene expression increased following an acute bout of mechanical loading in three-dimensional bioengineered mouse muscle in-vitro, and after chronic electrical stimulation-induced hypertrophy in rats in-vivo, without increases in MuRF1/MAFbx. Additionally, increased UBR5 protein abundance was identified following synergist ablation/functional overload (FO)-induced hypertrophy of the plantaris muscle in mice in-vivo, and finally over a 7-day time-course of regeneration in primary human muscle cells in-vitro. Finally, genetic association studies (> 700,000 SNPs) in human cohorts identified that the A alleles of rs10505025 and rs4734621 SNPs were strongly associated with larger cross-sectional area of fast-twitch muscle fibres and favoured strength/power versus endurance/untrained phenotypes. Overall, we suggest that UBR5 is a novel E3 ubiquitin ligase that is alternatively regulated compared to MuRF1/MAFbx, and is elevated during early atrophy (but not later atrophy), recovery, anabolism and hypertrophy in animals in-vivo as well as during human muscle cell regeneration in-vitro. In humans, genetic variations of the UBR5 gene are strongly associated with larger fast-twitch muscle fibres and strength/power performance

Appropriate interventions for the prevention and management of self-harm: a qualitative exploration of service-users' views

BACKGROUND: The engagement of service-users in exploring appropriate interventions for self-harm has been relatively neglected in comparison with clinical studies focusing on the management and prevention of self-harm. The purpose of this study was to investigate perceptions of interventions for self-harm (formal and informal, prevention and treatment) among people who have first-hand experience as a result of their own behaviour. METHODS: Semi-structured interviews were undertaken with 14 patients admitted to hospital following a repeat act of self-harm. Data analysis was undertaken thematically, drawing broadly on some of the principles and techniques of grounded theory RESULTS: The patients were a heterogeneous group with respect to their personal characteristics and the nature of their self-harm. Thirteen of the 14 patient accounts could be assigned to one or more of three overlapping experiential themes: the experience of psychiatric illness, the experience of alcohol dependency, and the experience of traumatic life events and chronic life problems. These themes were related to the nature of patients' self-harm and their experiences of, and attitudes towards, interventions for self-harm and their attitudes towards these. There was a clear preference for specialist community-based interventions, which focus on the provision of immediate aftercare and acknowledge that the management of self-harm may not necessarily involve its prevention. The findings generate the preliminary hypothesis that personal circumstances and life history are major influences on the choice of interventions for self-harm. CONCLUSION: This study attests to the importance of recognising differences within the self-harming population, and acknowledging patients' personal circumstances and life history. These may provide clues to the antecedents of their self-harm, and lead to more acceptable and appropriate treatments

DNA methylation across the genome in aged human skeletal muscle tissue and muscle-derived cells: the role of HOX genes and physical activity.

Skeletal muscle tissue demonstrates global hypermethylation with age. However, methylome changes across the time-course of differentiation in aged human muscle derived cells, and larger coverage arrays in aged muscle tissue have not been undertaken. Using 850K DNA methylation arrays we compared the methylomes of young (27 ± 4.4 years) and aged (83 ± 4 years) human skeletal muscle and that of young/aged heterogenous muscle-derived human primary cells (HDMCs) over several time points of differentiation (0, 72 h, 7, 10 days). Aged muscle tissue was hypermethylated compared with young tissue, enriched for; pathways-in-cancer (including; focal adhesion, MAPK signaling, PI3K-Akt-mTOR signaling, p53 signaling, Jak-STAT signaling, TGF-beta and notch signaling), rap1-signaling, axon-guidance and hippo-signalling. Aged cells also demonstrated a hypermethylated profile in pathways; axon-guidance, adherens-junction and calcium-signaling, particularly at later timepoints of myotube formation, corresponding with reduced morphological differentiation and reductions in MyoD/Myogenin gene expression compared with young cells. While young cells showed little alterations in DNA methylation during differentiation, aged cells demonstrated extensive and significantly altered DNA methylation, particularly at 7 days of differentiation and most notably in focal adhesion and PI3K-AKT signalling pathways. While the methylomes were vastly different between muscle tissue and HDMCs, we identified a small number of CpG sites showing a hypermethylated state with age, in both muscle tissue and cells on genes KIF15, DYRK2, FHL2, MRPS33, ABCA17P. Most notably, differential methylation analysis of chromosomal regions identified three locations containing enrichment of 6-8 CpGs in the HOX family of genes altered with age. With HOXD10, HOXD9, HOXD8, HOXA3, HOXC9, HOXB1, HOXB3, HOXC-AS2 and HOXC10 all hypermethylated in aged tissue. In aged cells the same HOX genes (and additionally HOXC-AS3) displayed the most variable methylation at 7 days of differentiation versus young cells, with HOXD8, HOXC9, HOXB1 and HOXC-AS3 hypermethylated and HOXC10 and HOXC-AS2 hypomethylated. We also determined that there was an inverse relationship between DNA methylation and gene expression for HOXB1, HOXA3 and HOXC-AS3. Finally, increased physical activity in young adults was associated with oppositely regulating HOXB1 and HOXA3 methylation compared with age. Overall, we demonstrate that a considerable number of HOX genes are differentially epigenetically regulated in aged human skeletal muscle and HDMCs and increased physical activity may help prevent age-related epigenetic changes in these HOX genes