Experience of clinical services shapes attitudes to mental health data sharing: findings from a UK-wide survey.

BACKGROUND: Routinely-collected mental health data could deliver novel insights for mental health research. However, patients' willingness to share their mental health data remains largely unknown. We investigated factors influencing likelihood of sharing these data for research purposes amongst people with and without experience of mental illness. METHODS: We collected responses from a diverse sample of UK National Health Service (NHS) users (n = 2187) of which about half (n = 1087) had lifetime experience of mental illness. Ordinal logistic regression was used to examine the influence of demographic factors, clinical service experience, and primary mental illness on willingness to share mental health data, contrasted against physical health data. RESULTS: There was a high level of willingness to share mental (89.7%) and physical (92.8%) health data for research purposes. Higher levels of satisfaction with the NHS were associated with greater willingness to share mental health data. Furthermore, people with personal experience of mental illness were more willing than those without to share mental health data, once the variable of NHS satisfaction had been controlled for. Of the mental illnesses recorded, people with depression, obsessive-compulsive disorder (OCD), personality disorder or bipolar disorder were significantly more likely to share their mental health data than people without mental illness. CONCLUSIONS: These findings suggest that positive experiences of health services and personal experience of mental illness are associated with greater willingness to share mental health data. NHS satisfaction is a potentially modifiable factor that could foster public support for increased use of NHS mental health data in research.

Baroreflex impairment and morbidity after major surgery.

BACKGROUND: Baroreflex dysfunction is a common feature of established cardiometabolic diseases that are most frequently associated with the development of critical illness. Laboratory models show that baroreflex dysfunction impairs cardiac contractility and cardiovascular performance, thereby increasing the risk of morbidity after trauma and sepsis. We hypothesized that baroreflex dysfunction contributes to excess postoperative morbidity after major surgery as a consequence of the inability to achieve adequate perioperative tissue oxygen delivery. METHODS: In a randomized controlled trial of goal-directed haemodynamic therapy (GDT) in higher-risk surgical patients, baroreflex function was assessed using the spontaneous baroreflex sensitivity (BRS) method via an arterial line placed before surgery, using a validated sequence method technique (one beat lag). The BRS was calculated during the 6 h postoperative GDT intervention. Analyses of BRS were done by investigators blinded to clinical outcomes. The primary outcome was the association between postoperative baroreflex dysfunction (BRS <6 mm Hg s(-1), a negative prognostic threshold in cardiovascular pathology) and early postoperative morbidity. The relationship between baroreflex dysfunction and postoperative attainment of preoperative indexed oxygen delivery was also assessed. RESULTS: Patients with postoperative baroreflex dysfunction were more likely to sustain infectious {relative risk (RR) 1.75 [95% confidence interval (CI): 1.07-2.85], P=0.02} and cardiovascular morbidity [RR 2.39 (95% CI: 1.22-4.71), P=0.008]. Prolonged hospital stay was more likely in patients with baroreflex dysfunction [unadjusted hazard ratio 1.62 (95% CI: 1.14-2.32), log-rank P=0.004]. Postoperative O2 delivery was 36% (95% CI: 7-65) lower in patients with baroreflex dysfunction in those not randomly assigned to GDT (P=0.02). CONCLUSIONS: Baroreflex dysfunction is associated with excess morbidity, impaired cardiovascular performance, and delayed hospital discharge, suggesting a mechanistic role for autonomic dysfunction in determining perioperative outcome. CLINICAL TRIAL REGISTRATION: ISCRTN76894700.

Effect of sex on torque, recovery, EMG, and MMG responses to fatigue.

OBJECTIVE: The purpose of the present investigation was to examine the effect of sex on maximal voluntary isometric contraction (MVIC) torque and the EMG and MMG responses as a result of fatiguing, intermittent, submaximal (65% of MVIC), isometric elbow flexion muscle contractions. METHODS: Eighteen men and women performed MVIC trials before (pretest), after (posttest), and 5-min after (5-min recovery) performing 50 intermittent, submaximal isometric muscle contractions. Surface electromyographic (EMG) and mechanomyographic (MMG) signals were simultaneously recorded from the biceps brachii muscle. RESULTS: As a result of the fatiguing workbout torque decreased similarly from pretest to posttest for both the men (24.0%) and women (23.3%). After 5-min of recovery, torque had partially recovered for the men, while torque had returned to pretest levels for the women. For both sexes, from pretest to posttest EMG mean power frequency and MMG amplitude decreased, but returned to pretest levels after 5-min of recovery. CONCLUSIONS: In the present study, there were sex-related differences in muscle fatigue that were not associated with the EMG or MMG responses.

Effects of fatiguing constant versus alternating intensity intermittent isometric muscle actions on maximal torque and neuromuscular responses.

OBJECTIVE: To determine the effects of constant versus alternating applications of torque during fatiguing, intermittent isometric muscle actions of the leg extensors on maximal voluntary isometric contraction (MVIC) torque and neuromuscular responses. METHODS: Sixteen subjects performed two protocols, each consisting of 50 intermittent isometric muscle actions of the leg extensors with equal average load at a constant 60% MVIC or alternating 40 then 80% (40/80%) MVIC with a work-to-rest ratio of 6-s on and 2-s off. MVIC torque as well as electromyographic signals from the vastus lateralis (VL), vastus medialis (VM), and rectus femoris (RF) and mechanomyographic signals from the VL were recorded pretest, immediately posttest, and 5-min posttest. RESULTS: The results indicated that there were no time-related differences between the 60% MVIC and 40/80% MVIC protocols. The MVIC torque decreased posttest (22 to 26%) and remained depressed 5-min posttest (9%). There were decreases in electromyographic frequency (14 to 19%) and mechanomyographic frequency (23 to 24%) posttest that returned to pretest levels 5-min posttest. There were no changes in electromyographic amplitude and mechanomyogrpahic amplitude. CONCLUSIONS: These findings suggested that these neuromuscular parameters did not track the fatigue-induced changes in MVIC torque after 5-min of recovery.

Four weeks of high- versus low-load resistance training to failure on the rate of torque development, electromechanical delay, and contractile twitch properties.

The purpose of this study was to investigate the effects of 4-weeks of high- versus low-load resistance training to failure on rate of torque development (RTD), electromechanical delay (EMD), and contractile twitch characteristics. Fifteen men (mean±SD; age=21.7±2.4 yrs) were randomly assigned to either a high- (80% 1RM; n=7) or low-load (30% 1RM; n=8) training group and completed elbow flexion resistance training to failure 3 times per week for 4 weeks. The participants were tested at baseline, 2-, and 4-weeks of training. Peak RTD (pRTDV) and RTD at 0-30 (RTD30V), 0-50 (RTD50V), 0-100 (RTD100V), and 0-200 (RTD200V) ms, integrated EMG amplitude (iEMG) at 0-30, 0-50, and 0-100 ms, and EMD were quantified during maximal voluntary isometric muscle actions. Peak twitch torque, peak RTD, time to peak twitch, 1/2 relaxation time and the peak relaxation rate were quantified during evoked twitches. Four weeks of high-load, but not low-load resistance training, increased RTD200V. There were also increases in iEMG during the first 30 ms of muscle activation for the high- and low-load groups, which may have indirectly indicated increases in early phase motor unit recruitment and/or firing frequency. There were no significant training-induced adaptations in EMD or contractile twitch properties.

Electromyographic Responses from the Vastus Medialis during Isometric Muscle Actions.

This study examined the electromyographic (EMG) responses from the vastus medialis (VM) for electrodes placed over and away from the innervation zone (IZ) during a maximal voluntary isometric contraction (MVIC) and sustained, submaximal isometric muscle action. A linear electrode array was placed on the VM to identify the IZ and muscle fiber pennation angle during an MVIC and sustained isometric muscle action at 50% MVIC. EMG amplitude and frequency parameters were determined from 7 bipolar channels of the electrode array, including over the IZ, as well as 10 mm, 20 mm and 30 mm proximal and distal to the IZ. There were no differences between the channels for the patterns of responses for EMG amplitude or mean power frequency during the sustained, submaximal isometric muscle action; however, there were differences between channels during the MVIC. The results of the present study supported the need to standardize the placement of electrodes on the VM for the assessment of EMG amplitude and mean power frequency. Based on the current findings, it is recommended that electrode placements be distal to the IZ and aligned with the muscle fiber pennation angle during MVICs, as well as sustained, submaximal isometric muscle actions.

Randomized controlled trial of vagal modulation by sham feeding in elective non-gastrointestinal (orthopaedic) surgery.

BACKGROUND: Enhanced recovery, in part, aims to reduce postoperative gastrointestinal dysfunction (PGID). Acquired - or established- vagal dysfunction may contribute to PGID, even for surgery not involving the gastrointestinal tract. However, direct evidence for this is lacking. We hypothesized that chewing gum reduces morbidity (including PGID) by preserving efferent vagal neural activity postoperatively after elective orthopaedic surgery. METHODS: In a two-centre randomized controlled trial (n=106), we explored whether patients randomized to prescribed chewing gum for five days postoperatively sustained less morbidity (primary outcome, defined by the Postoperative Morbidity Survey), PGID and faster time to become morbidity free (secondary outcomes). In a subset of patients (n=38), cardiac parasympathetic activity was measured by serial Holter monitoring and assessed using time and frequency domain analyses. RESULTS: Between September 2011 and April 2014, 106 patients were randomized to chewing gum or control. The primary clinical outcome did not differ between groups, with similar morbidity occurring between patients randomized to control (26/30) and chewing gum (21/28; absolute risk reduction (ARR):13% (95%C I:- 6-32); P=0.26). However, chewing gum reduced PGID (ARR:20% (95% CI: 1-38); P=0.049). Chewing gum reduced time to become morbidity-free (relative risk (RR): 1.62 (95% CI: 1.02-2.58); P=0.04) and was associated with a higher proportion of parasympathetic activity contributing to heart rate variability (11% (95% CI: 1-20); P=0.03). CONCLUSIONS: Chewing gum did not alter overall morbidity, but reduced PGID. These data show for the first time that prescription of sham feeding preserves vagal activity in surgery not directly involving the gastrointestinal tract. CLINICAL TRIAL REGISTRATION: ISRCTN20301599.

Physiological Responses during Cycle Ergometry at a Constant Perception of Effort.

13 subjects performed an incremental test to exhaustion, 4, 8-min submaximal rides, and a 1-h ride at the rating of perceived exertion (RPE) that corresponded to the physical working capacity at the OMNI threshold (PWC(OMNI)) to examine: 1) the oxygen consumption (V̇O2), heart rate (HR), minute ventilation (+V̇(E)), respiratory frequency (FR), and power output responses during 1-h work bouts at a constant RPE that corresponded to the PWC(OMNI); and 2) the ability of current models to explain the responses for physiological and perceptual parameters during the 1-h work bouts. The RPE that corresponded to the PWC(OMNI) represented a sustainable exercise intensity (56±5% (V̇O(2Peak)) within the moderate-intensity domain. The mean, normalized slope coefficients for the V̇O2, +V̇(E), and power output vs. time relationships during the 1-h rides were significantly less than zero. The mean, normalized slope coefficient for the FR vs. time relationship during the 1-h rides, however, was not significantly different from zero. Thus, RPE most clearly tracked FR responses during the 1-h rides. It was hypothesized that afferent feedback from respiratory muscles may have mediated the perception of effort during cycle ergometry at a constant RPE in the moderate-intensity domain.

The rate of torque development: a unique, non-invasive indicator of eccentric-induced muscle damage?

This study examined the time courses of recovery for isometric peak torque and rate of torque development (RTD) after eccentric-induced muscle damage. 18 men completed 6 sets of 10 maximal eccentric isokinetic muscle actions at 30° · s(-1). Peak torque, peak RTD and RTD at 10 (RTD10), 50 (RTD50), 100 (RTD100) and 200 ms (RTD200), serum creatine kinase and lactate dehydrogenase were measured before (PRE), immediately after (POST), 24, 48 and 72 h after eccentric exercise. Creatine kinase and lactate dehydrogenase increased from 139 to 6 457 and from 116 to 199 IU · L(-1) from PRE to 72 h, respectively. Peak torque and all RTDs decreased at POST. Peak torque and RTD200 remained lower than PRE through 72 h. Peak RTD remained lower than PRE through 48 h, but was not different from PRE at 72 h. RTD10 and RTD100 were lower than PRE through 24 h, but were not different from PRE at 48 and 72 h. RTD50 decreased at POST, but was not different from PRE at 24 h. Early phase RTDs recovered more quickly than PT and RTD200. Early phase RTDs may reflect neural mechanisms underlying eccentric-induced force decrements, while late RTDs may describe the same physiological mechanisms as PT.

Acute mastoiditis--the role of radiology.

Acute mastoiditis is a commonly occurring condition in children and adults, and one that most radiologists will come across at some point during their on-call duties. Acute mastoiditis is usually clinically apparent. However, the complications, especially the intracranial ones, can be more insidious and may have fatal consequences. Therefore, it is imperative that the radiologist is well versed in identifying these. Local spread of infection from the mastoids and middle ear cleft may occur via four routes: bone erosion, thrombophlebitis, periphlebitis, and via the anatomical pathways. The role of radiology is largely to demonstrate the complications of mastoiditis, which can be clinically occult and are often serious; this article will highlight these complications.

The effects of aerobic training and age on plasma sICAM-1.

Chronic low-grade systemic inflammation plays a role in the development of cardiovascular (CV) disease. Habitual endurance exercise training reduces the risk of CV disease in part through anti-inflammatory mechanisms. The purpose of this study was to investigate the effects of age, endurance training status, and their interaction on pro-inflammatory plasma cytokines involved in the pathogenesis of CV disease. Subjects were BMI-matched young (25±3 years; endurance trained: n=9, sedentary: n=11) and older (62±5 years; endurance-trained: n=12, sedentary: n=11) men. Plasma cytokine concentrations were determined by multiplex cytometric bead assay. Soluble intercellular adhesion molecule-1 (sICAM-1) levels were 40% higher in sedentary older men compared to young sedentary subjects (P=0.048), but they were not different between the young and older trained men. Furthermore, sICAM-1 levels were negatively correlated with maximal oxygen uptake (V˙O2max; r= - 0.38, P=0.01) across all subjects. There were no significant differences among the groups in plasma concentrations of monocyte chemoattractant protein-1 (MCP-1), soluble tumor necrosis-α receptor (sTNFR), soluble CD40 ligand (sCD40L), or resistin. We conclude that habitual endurance training is associated with an attenuated age-related increase in plasma sICAM-1.

Nf1 deficiency causes Ras-mediated granulocyte/macrophage colony stimulating factor hypersensitivity and chronic myeloid leukaemia.

The Ras signal transduction pathway is often deregulated in human myeloid leukaemia. For example, activating point mutations in RAS genes are found in some patients with juvenile chronic myelogenous leukaemia (JCML), while other patients with JCML show loss of the neurofibromatosis type 1 (NF1) gene, a Ras GTPase activating protein. By generating mice whose haematopoietic system is reconsituted with Nf1 deficient haematopoietic stem cells we show that Nf1 gene loss, by itself, is sufficient to produce the myeloproliferative symptoms associated with human JCML. We also provide evidence to indicate that Nf1 gene loss induces myeloproliferative disease through a Ras-mediated hypersensitivity to granulocyte/macrophage-colony stimulating factor (GM-CSF). Finally, we describe a genetic screen for identifying genes that cooperate with Nf1 gene loss during progression to acute myeloid leukaemia.

Cooperative activation of Hoxa and Pbx1-related genes in murine myeloid leukaemias.

Retroviruses induce myeloid leukaemia in BXH-2 mice by the insertional mutation of cellular proto-oncogenes or tumour suppressor genes. Disease genes can thus be identified by proviral tagging through the identification of common viral integration sites in BXH-2 leukaemia. Here, we describe a new approach for proviral tagging that greatly facilitates the identification of BXH-2 leukaemia genes. Using this approach, we identify three genes whose expression is activated by proviral integration in BXH-2 leukaemias; Hoxa7, Hoxa9, and a Pbx1-related homeobox gene, Meis1. Proviral activation of Hoxa7 or Hoxa9 is strongly correlated with proviral activation of Meis1 implying that Hoxa7 and Hoxa9 cooperate with Meis1 in leukaemia formation. These studies provide the first genetic evidence that Pbx1-related genes cooperate with Hox genes in leukaemia formation and identify a number of new murine myeloid leukaemia genes.

GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor function.

The growth hormone-releasing hormone receptor (GHRHR) is a member of the family of G protein-coupled receptors that is expressed on pituitary somatotrope cells and mediates the actions of GHRH in stimulating growth hormone (GH) synthesis and secretion. We report that the Ghrhr gene is located in the middle of mouse chromosome 6 in the same region as the little mutation. Mice homozygous for this mutation have reduced GH secretion and a dwarf phenotype. A missense mutation was identified in the extracellular domain of the little GHRHR that disrupts receptor function, suggesting that the growth deficit in these mice results from a defect in the GHRHR. Similar alterations in GHRHR might explain some isolated GH deficiencies in humans.

Anchored reference loci for comparative genome mapping in mammals.

Recent advances in gene mapping technologies have led to increased emphasis in developing representative genetic maps for several species, particularly domestic plants and animals. These maps are being compiled with two distinct goals: to provide a resource for genetic analysis, and to help dissect the evolution of genome organization by comparing linkage relationships of homologous genes. We propose here a list of 321 reference anchor loci suitable for comparative gene mapping in mammals and other vertebrate classes. We selected cloned mouse and human functional genes spaced an average of 5-10 centiMorgans throughout their respective genomes. We also attempted to include loci that are evolutionarily conserved and represented in comparative gene maps in other mammalian orders, particularly cattle and the domestic cat. We believe that the map may provide the basis for a unified approach to comparative analysis of mammalian species genomes.

The mouse Snell's waltzer deafness gene encodes an unconventional myosin required for structural integrity of inner ear hair cells.

The mouse represents an excellent model system for the study of genetic deafness in humans. Many mouse deafness mutants have been identified and the anatomy of the mouse and human ear is similar. Here we report the use of a positional cloning approach to identify the gene encoded by the mouse recessive deafness mutation, Snell's waltzer (sv). We show that sv encodes an unconventional myosin heavy chain, myosin VI, which is expressed within the sensory hair cells of the inner ear, and appears to be required for maintaining their structural integrity. The requirement for myosin VI in hearing makes this gene an excellent candidate for a human deafness disorder.

Maternal imprinting of the mouse Snrpn gene and conserved linkage homology with the human Prader-Willi syndrome region.

Prader-Willi syndrome (PWS) is associated with paternal gene deficiencies in human chromosome 15q11-13, suggesting that PWS is caused by a deficiency in one or more maternally imprinted genes. We have now mapped a gene, Snrpn, encoding a brain-enriched small nuclear ribonucleoprotein (snRNP)-associated polypeptide SmN, to mouse chromosome 7 in a region of homology with human chromosome 15q11-13 and demonstrated that Snrpn is a maternally imprinted gene in mouse. These studies, in combination with the accompanying human mapping studies showing that SNRPN maps in the Prader-Willi critical region, identify SNRPN as a candidate gene involved in PWS and suggest that PWS may be caused, in part, by defects in mRNA processing.

The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice.

Non-agouti-lethal 18H (a18H) mice are dark agouti with black pinna hairs. What makes these mice unique is that they develop a spectrum of immunological diseases not seen in other agouti mutant mice. On the JU/Ct background, a18H mice develop an inflammatory disease of the large intestine. On the C57BL/6J background, they develop a fatal disease characterized by pulmonary chronic interstitial inflammation and alveolar proteinosis, inflammation of the glandular stomach and skin resulting in scarring due to constant itching, and hyperplasia of lymphoid cells, haematopoietic cells and the forestomach epithelium. Previous studies suggested that the a18H mutation results from a paracentric inversion that affects two loci: agouti and another, as yet unidentified locus designated itchy (the provisional gene symbol is Itch), that is responsible for the immunological phenotype of a18H mice. Here we confirm that a18H results from an inversion and show that Itch encodes a novel E3 ubiquitin protein ligase, a protein involved in ubiquitin-mediated protein degradation. Our results indicate that ubiquitin-dependent proteolysis is an important mediator of the immune response in vivo and provide evidence for Itch's role in inflammation and the regulation of epithelial and haematopoietic cell growth.

A mouse model for Prader-Willi syndrome imprinting-centre mutations.

Imprinting in the 15q11-q13 region involves an 'imprinting centre' (IC), mapping in part to the promoter and first exon of SNRPN. Deletion of this IC abolishes local paternally derived gene expression and results in Prader-Willi syndrome (PWS). We have created two deletion mutations in mice to understand PWS and the mechanism of this IC. Mice harbouring an intragenic deletion in Snrpn are phenotypically normal, suggesting that mutations of SNRPN are not sufficient to induce PWS. Mice with a larger deletion involving both Snrpn and the putative PWS-IC lack expression of the imprinted genes Zfp127 (mouse homologue of ZNF127), Ndn and Ipw, and manifest several phenotypes common to PWS infants. These data demonstrate that both the position of the IC and its role in the coordinate expression of genes is conserved between mouse and human, and indicate that the mouse is a suitable model system in which to investigate the molecular mechanisms of imprinting in this region of the genome.

Comparative anchor tagged sequences (CATS) for integrative mapping of mammalian genomes.

Precise comparisons of mammalian gene maps require common anchor loci as landmarks for conserved chromosomal segments. Using a computer script that automates DNA sequence database alignments, we designed 410 evolutionarily conserved primer pair sequences which are specific for anchor locus gene amplification from any mammalian species' DNA. Primer pairs were designed to span introns for polymorphism ascertainment, and to include sufficient exonic sequence (25-400 bp) to allow for gene identification. A total of 318 primer pairs were optimized for domestic cats, and 86% of the sequenced feline PCR products showed homology to the gene of primer origin. A screen of 20 mammals from 11 orders revealed that 35-52% of the 318 primers yielded a single PCR product without further optimization suggesting that nearly 75% can be optimized for any eutherian mammal.