Mutation Carriers with Reduced C-Afferent Density Reveal Cortical Dynamics of Pain-Action Relationship during Acute Pain.

The evidence that action shapes perception has become widely accepted, for example, in the domain of vision. However, the manner in which action-relevant factors might influence the neural dynamics of acute pain processing has remained underexplored, particularly the functional roles of anterior insula (AI) and midanterior cingulate cortex (mid-ACC), which are frequently implicated in acute pain. To address this, we examined a unique group of heterozygous carriers of the rare R221W mutation on the nerve growth factor (NGF) gene. R221W carriers show a congenitally reduced density of C-nociceptor afferent nerves in the periphery, but can nonetheless distinguish between painful and nonpainful stimulations. Despite this, carriers display a tendency to underreact to acute pain behaviorally, thus exposing a potential functional gap in the pain-action relationship and allowing closer investigation of how the brain integrates pain and action information. Heterozygous R221W carriers and matched controls performed a functional magnetic resonance imaging (fMRI) task designed to dissociate stimulus type (painful or innocuous) from current behavioral relevance (relevant or irrelevant), by instructing participants to either press or refrain from pressing a button during thermal stimulation. Carriers' subjective pain thresholds did not differ from controls', but the carrier group showed decreased task accuracy. Hemodynamic activation in AI covaried with task performance, revealing a functional role in pain-action integration with increased responses for task-relevant painful stimulation ("signal," requiring button-press execution) over task-irrelevant stimulation ("noise," requiring button-press suppression). As predicted, mid-ACC activation was associated with action execution regardless of pain. Functional connectivity between AI and mid-ACC increased as a function of reported urge to withdraw from the stimulus, suggesting a joint role for these regions in motivated action during pain. The carrier group showed greater activation of primary sensorimotor cortices-but not the AI and mid-ACC regions-during pain and action, suggesting compensatory processing. These findings indicate a critical role for the AI-mid-ACC axis in supporting a flexible, adaptive action selection during pain, alongside the accompanying subjective experience of an urge to escape the pain.

Transition from Gas-like to Liquid-like Behavior in Supercritical N2.

We have studied in detail the transition from gas-like to rigid liquid-like behavior in supercritical N2 at 300 K (2.4 TC). Our study combines neutron diffraction and Raman spectroscopy with ab initio molecular dynamics simulations. We observe a narrow transition from gas-like to rigid liquid-like behavior at ca. 150 MPa, which we associate with the Frenkel line. Our findings allow us to reliably characterize the Frenkel line using both diffraction and spectroscopy methods, backed up by simulation, for the same substance. We clearly lay out what parameters change, and what parameters do not change, when the Frenkel line is crossed.

Prevalence of obstructive sleep apnoea in REM behaviour disorder: response to continuous positive airway pressure therapy.

OBJECTIVES: Rapid eye movement behaviour disorder (RBD) is a parasomnia in which there is loss of muscle atonia during rapid eye movement (REM) sleep, resulting in dream enactment. The aims of this study were to determine the prevalence of obstructive sleep apnoea (OSA) in RBD patients and determine whether continuous positive airway pressure (CPAP) therapy improved RBD symptoms in patients with concomitant RBD and OSA. METHODS: A questionnaire was mailed to 120 patients identified from a tertiary sleep centre with RBD meeting full International Classification for Sleep Disorders-3 (ICSD-3) criteria. Patients were diagnosed as having OSA if they had an apnoea-hypopnea index (AHI) ≥ 5. The questionnaire focused on CPAP-use, compliance and complications. Standard statistical analysis was undertaken using SPSS (v.21, IBM). RESULTS: One hundred and seven of the potential participants (89.2%) had an OSA diagnosis. Out of 72 who responded to the questionnaire, (60%) 27 patients were using CPAP therapy. CPAP therapy improved RBD symptoms in 45.8% of this group. Despite this positive response to treatment in nearly half of CPAP-users, there was no significant difference in subjective or objective CPAP compliance between those who reported RBD improvement and those who did not. Subjective compliance with CPAP was over-reported, with mean usage being 7.17 ± 1.7 h per night compared to objective mean compliance of 5.71 ± 1.7. CONCLUSIONS: OSA is a very common co-morbidity of RBD. CPAP therapy might improve self-reported RBD symptoms further, in addition to standard RBD treatment. However, further research into its topic is necessary.

Should sleepy patients see general neurologists?

This paper is based on Dr Morrison's presentation at the St Andrews Day Festival Symposium held at the Royal College of Physicians on 29 November 2014. In this case, as discussed at the Symposium, the patient has presented with 'tired all the time', one of the most common complaints seen by GPs and one which can be linked to a number of physical and psychological causes. Dr Morrison assesses whether Neurology is the most appropriate place for this patient.

Neurology liaison services in the acute medical receiving unit.

INTRODUCTION: Guidelines from the Association of British Neurologists and National Health Service Quality Improvement Scotland suggest that neurologists should be involved in the early management of patients presenting to hospital with acute neurological illness. AIM: We chose to evaluate whether regular neurology review in an acute medical receiving unit in a busy city hospital was feasible, and whether it would have an impact on patient care. METHODS: Over a 5-week period from Monday to Friday, all neurology patients admitted to an acute medical receiving unit were identified and all headaches and blackouts were reviewed. RESULTS: Fourteen (24%) were headache patients, 37 (63%) presumed seizure and 8 (13%) had another neurological illness. Diagnosis was made by the admitting physician in six headache patients (43%). The remaining eight headache patients were diagnosed by the visiting neurologist and two physician diagnoses were revised. The diagnosis made by the admitting physician was clarified by the visiting neurologist in 13 blackout patients (35%) and nine other diagnoses were revised (24%). Appropriate outpatient follow-up or transfer was arranged. CONCLUSION: These results suggest that a daily neurology review service is useful in medical receiving units by clarifying diagnoses, directing tests and limiting inappropriate follow-up.

Working the night shift: a necessary time for training or a risk to health and safety?

The European Working Time Directive (EWTD) limits excessive night shifts and restricts the working week to no more than 48 hours. The underlying rationale is to minimise the health risks to all workers. Here we debate the impact of night rotas for doctors-in-training on patient safety and medical education; when the EWTD was agreed these topics may not have been considered, either systematically or objectively. The impacts of diurnal rhythms on human functions affect all night workers, but the nature of rostered medical and surgical work has little precedent in other industries or even in the contracts of other healthcare staff. For example, rostered night duties need to be distinguished from permanent night shift work. On-call medical night work from training doctors is generally required for short periods and usually involves fewer patients. It is an important time in training, where clinical responsibility and decision-making can be matured in a supervised setting. To comply with the EWTD most hospitals have adopted rota patterns that aim to cover the clinical needs, while ensuring no doctor works for more than 48 hours in an average working week. To monitor this process longterm studies are necessary to evaluate effects on a doctor's health and on patient care generally. The EWTD has also led to a loss of continuity of patient care; does this really matter?

Visualization and characterization of engineered nanoparticles in complex environmental and food matrices using atmospheric scanning electron microscopy.

Imaging and characterization of engineered nanoparticles (ENPs) in water, soils, sediment and food matrices is very important for research into the risks of ENPs to consumers and the environment. However, these analyses pose a significant challenge as most existing techniques require some form of sample manipulation prior to imaging and characterization, which can result in changes in the ENPs in a sample and in the introduction of analytical artefacts. This study therefore explored the application of a newly designed instrument, the atmospheric scanning electron microscope (ASEM), which allows the direct characterization of ENPs in liquid matrices and which therefore overcomes some of the limitations associated with existing imaging methods. ASEM was used to characterize the size distribution of a range of ENPs in a selection of environmental and food matrices, including supernatant of natural sediment, test medium used in ecotoxicology studies, bovine serum albumin and tomato soup under atmospheric conditions. The obtained imaging results were compared to results obtained using conventional imaging by transmission electron microscope (TEM) and SEM as well as to size distribution data derived from nanoparticle tracking analysis (NTA). ASEM analysis was found to be a complementary technique to existing methods that is able to visualize ENPs in complex liquid matrices and to provide ENP size information without extensive sample preparation. ASEM images can detect ENPs in liquids down to 30 nm and to a level of 1 mg L(-1) (9×10(8) particles mL(-1) , 50 nm Au ENPs). The results indicate ASEM is a highly complementary method to existing approaches for analyzing ENPs in complex media and that its use will allow those studying to study ENP behavior in situ, something that is currently extremely challenging to do.

The pressure-temperature phase diagram of MgH2 and isotopic substitution.

Computational thermodynamics using density functional theory ab initio codes is a powerful tool for calculating phase diagrams. The method is usually applied at the standard pressure of p = 1 bar and where the Gibbs energy is assumed to be equal to the Helmholtz energy. In this work, we have calculated the Gibbs energy in order to study the release temperature and phase modifications of MgH(2) at high pressures up to 10 GPa (100 kbar). The isotopic substitution of hydrogen with deuterium (or tritium) does not bring about any strong effects on the phase diagram. These considerations are of extreme importance for (i) the synthesis of novel substitutional magnesium based materials at high pressure and (ii) the determination of the correct reference states for the calculation of phase diagrams at high pressure. The calculated results are compared with experimental data obtained with an in situ neutron diffraction measurement.

Diagnosing narcolepsy with cataplexy on history alone: challenging the International Classification of Sleep Disorders (ICSD-2) criteria.

BACKGROUND AND PURPOSE: The second version of the International Classification of Sleep Disorders suggests narcolepsy with cataplexy can be diagnosed on history alone. PATIENTS: Five patients with a history supportive of narcolepsy/cataplexy. METHOD: Case review following clinical investigation. RESULTS: None of the five patients had a diagnosis of narcolepsy/cataplexy on the basis of objective testing using polysomnography (PSG) and multiple sleep latency testing (MSLT). CONCLUSION: PSG and MSLT should always be used in conjunction with a comprehensive history taken by an experienced sleep physician to support a diagnosis of narcolepsy with cataplexy and to exclude other conditions that may mimic narcolepsy.

Feeling good: on the role of C fiber mediated touch in interoception.

The human skin is innervated by a network of thin, slow-conducting afferent (C and Aδ) fibers, transmitting a diverse range of information. Classically, these fibers are described as thermo-, noci- or chemoreceptive, whereas mechanoreception is attributed exclusively to thick, fast-conducting (Aß) afferents. A growing body of evidence, however, supports the notion that C tactile afferents comprise a second anatomically and functionally distinct system signaling touch in humans. This review discusses established as well as recent findings which highlight fundamental differences in peripheral and central information coding and processing between Aß and C mechanoreception. We conclude that from the skin through the brain, C touch shares more characteristics with interoceptive modalities (e.g. pain, temperature, and itch) than exteroceptive Aß touch, vision or hearing. In this light, we discuss the motivational-affective role of C touch as an integral part of a thin-fiber afferent homeostatic network for the maintenance of physical and social well-being.

Intranasal diamorphine for acute sickle cell pain.

The painful crisis is the commonest acute presentation of sickle cell disease (SCD), yet effective pain control in hospital is often delayed, inadequate and dependent on injected opiates. Intranasal diamorphine (IND) has been used in paediatric emergency departments for management of acute pain associated with fractures, but the analgesic effect is short lived. We evaluated its efficacy and safety when given in combination with intravenous or oral morphine for rapid analgesia for children presenting to our emergency department with painful crisis of SCD. In phase 1, nine patients received IND plus intravenous morphine. In phase 2, 13 received IND plus oral morphine. There was a rapid improvement in pain score; the proportions in severe pain at t = 0, 15, 30 and 120 minutes in phase 1 were 78%, 11%, 0% and 11%, respectively; in phase 2, 77%, 30%, 15% and 0%, respectively. There were no serious side effects and questionnaire scores indicated that children found IND effective and acceptable. IND can be recommended for acute control of sickle pain in children presenting to hospital.

Urological conditions in pregnancy: a diagnostic and therapeutic challenge.

Urological conditions in pregnancy represent a major diagnostic and therapeutic challenge. The potential adverse effects of anaesthesia, radiation and drugs on the fetus often complicate traditional diagnostic and treatment measures. As frontline clinicians, obstetricians need an awareness of symptoms, associated obstetric complications and an appreciation of available current diagnostic and therapeutic modalities and their associated risks. This article describes common urinary problems encountered in pregnancy: infection, hydronephrosis and urolithiasis specifically. The aim of this paper is to review the safety, efficacy and role of different imaging studies available for the diagnosis of urolithiasis in pregnancy. Conservative management as first line treatment and a variety of interventional urological procedures with postoperative management are also discussed. Such a background may facilitate a rational management protocol for urological problems in a pregnant woman.

The correlation between colorectal cancer rates of proliferation and apoptosis and systemic cytokine levels; plus their influence upon survival.

Colorectal cancer development is associated with a shift in host immunity with suppression of the cell-mediated immune system (CMI) and a predominance of humoral immunity (HI). Tumour progression is also associated with increased rates of cell proliferation and apoptosis. The aim of this study was to investigate whether these factors correlate and have an influence upon prognosis. Long-term follow-up was performed on 40 patients with colorectal cancer who had levels of tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma and interleukin (IL)-10 measured from stimulated blood cultures before surgery. Their archived tumour specimens were analysed to determine a Ki-67-derived proliferation index (PI) and a M30-derived apoptosis index (AI). Tumour necrosis factor-alpha levels negatively correlated to tumour proliferation (rho=-0.697, P=0.01). Interleukin-10 levels had a positive correlation with tumour proliferation (rho=0.452, P=0.05) and apoptosis (rho=0.587, P=0.01). Patient survival correlates to tumour pathological stage (P=0.0038) and vascular invasion (P=0.0014). An AI< or =0.6% and TNF-alpha levels > or =8148 pg ml(-1) correlate to improved survival (P=0.032, P=0.021). Tumour proliferation and apoptosis correlate to progressive suppression of the CMI-associated cytokine TNF-alpha and to and higher levels of IL-10. Survival is dependent upon the histological stage of the tumour, vascular invasion, rates of apoptosis and proliferation and systemic immunity which are all interconnected.

Control of corrosion and aggression in drinking water systems.

Corrosion and/or aggression are common problems arising in pipelines transporting terrestrial waters. The kinetics and severity of such events depend on both the quality of the water being transported and the material properties of the pipeline. Irrespective of the nature of the problem, its solution (or at least its minimisation) is strongly linked to control of pH, calcium concentration and carbonate chemistry of the water (stabilisation). However, application of such chemistry to water treatment problems is complex and time consuming. Various numerical, graphical and computer techniques have been developed to address this, but these are either of insufficient accuracy, too time consuming or lacking in generality. In this paper algorithms are presented for solving a broad spectrum of problems related to control of mineral precipitation/aggression, pH and chemical dosing in water treatment. These have been incorporated into a computer software package, STASOFT, which offers the requisite framework for use in water treatment. Various stabilisation problems pertinent to water supply are addressed.

Co-localization of cell surface receptors at high spatial resolution by single-particle fluorescence imaging.

Dual-wavelength single-particle fluorescence imaging has been used to quantify the co-localization of receptors and/or ligands on cells by widefield microscopy. Methods for correction of chromatic aberration and identification of submicroscopic artefacts are presented, with data for the lipopolysaccharide/CD14 and MHC class II/CD74 systems.

Measurements of associations of cell-surface receptors by single-particle fluorescence imaging.

SPFI (single-particle fluorescence imaging) uses the high sensitivity of fluorescence to visualize individual molecules that have been selectively labelled with small fluorescent particles. The images of particles are diffraction-limited spots that are analysed by fitting with a two-dimensional Gaussian function. The spot intensities depend on whether they arise from one or more particles; this provides the basis for determining self-association of cell-surface receptors. We have used this approach to determine dimerization of MHC class II molecules and its disruption by interface peptides. We have also exploited the positional information obtained from SPFI to detect co-localization of cell-surface molecules. This involves labelling two different molecules with different coloured fluorophores and determining their positions separately by dual wavelength imaging. The images are analysed to quantify the overlap of the particle images and hence determine the extent of co-localization of the labelled molecules. The technique provides quantification of the extent of co-localization and can detect whether co-localized molecules occur singly or in clusters. We have obtained preliminary data for co-localization of lipopolysaccharide and CD14 on intact cells. We also show that HLA-DR (human leukocyte antigen-DR) and CD74 are partially co-localized and that interaction between these molecules involves the peptide-binding groove of HLA-DR.