Feeding-elicited cataplexy in orexin knockout mice

Mice lacking orexin/hypocretin signaling have sudden episodes of atonia and paralysis during active wakefulness. These events strongly resemble cataplexy, episodes of sudden muscle weakness triggered by strong positive emotions in people with narcolepsy, but it remains unknown whether murine cataplexy is triggered by positive emotions. To determine whether positive emotions elicit murine cataplexy, we placed orexin knockout (KO) mice on a scheduled feeding protocol with regular or highly palatable food. Baseline sleep/wake behavior was recorded with ad libitum regular chow. Mice were then placed on a scheduled feeding protocol in which they received 60% of their normal amount of chow 3 h after dark onset for the next 10 days. Wild-type and KO mice rapidly entrained to scheduled feeding with regular chow, with more wake and locomotor activity prior to the feeding time. On day 10 of scheduled feeding, orexin KO mice had slightly more cataplexy during the food-anticipation period and more cataplexy in the second half of the dark period, when they may have been foraging for residual food. To test whether more palatable food increases cataplexy, mice were then switched to scheduled feeding with an isocaloric amount of Froot Loops, a food often used as a reward in behavioral studies. With this highly palatable food, orexin KO mice had much more cataplexy during the food-anticipation period and throughout the dark period. The increase in cataplexy with scheduled feeding, especially with highly palatable food, suggests that positive emotions may trigger cataplexy in mice, just as in people with narcolepsy. Establishing this connection helps validate orexin KO mice as an excellent model of human narcolepsy and provides an opportunity to better understand the mechanisms that trigger cataplexy

Short-Term Evaluation of Cellular Fate in an Ovine Bone Formation Model.

The ovine critical-sized defect model provides a robust preclinical model for testing tissue-engineered constructs for use in the treatment of non-union bone fractures and severe trauma. A critical question in cell-based therapies is understanding the optimal therapeutic cell dose. Key to defining the dose and ensuring successful outcomes is understanding the fate of implanted cells, e.g., viability, bio-distribution and exogenous infiltration post-implantation. This study evaluates such parameters in an ovine critical-sized defect model 2 and 7 days post-implantation. The fate of cell dose and behaviour post-implantation when combined with nanomedicine approaches for multi-model tracking and remote control using external magnetic fields is also addressed. Autologous STRO-4 selected mesenchymal stromal cells (MSCs) were labelled with a fluorescent lipophilic dye (CM-Dil), functionalised magnetic nanoparticles (MNPs) and delivered to the site within a naturally derived bone extracellular matrix (ECM) gel. Encapsulated cells were implanted within a critical-sized defect in an ovine medial femoral condyle and exposed to dynamic gradients of external magnetic fields for 1 h per day. Sheep were sacrificed at 2 and 7 days post-initial surgery where ECM was harvested. STRO-4-positive (STRO-4+) stromal cells expressed osteocalcin and survived within the harvested gels at day 2 and day 7 with a 50% loss at day 2 and a further 45% loss at 7 days. CD45-positive leucocytes were also observed in addition to endogenous stromal cells. No elevation in serum C-reactive protein (CRP) or non-haem iron levels was observed following implantation in groups containing MNPs with or without magnetic field gradients. The current study demonstrates how numbers of therapeutic cells reduce substantially after implantation in the repair site. Cell death is accompanied by enhanced leucocyte invasion, but not by inflammatory blood marker levels. Crucially, a proportion of implanted STRO-4+ stromal cells expressed osteocalcin, which is indicative of osteogenic differentiation. Furthermore, MNP labelling did not alter cell number or result in a further deleterious impact on stromal cells following implantation

Functional outcome and complications following surgery for Dupuytren’s disease: a multi-centre cross-sectional study

Variables associated with recurrent Dupuytren’s disease, or a ‘diathesis’, have been investigated, but those associated with functional outcome and complications are less well studied. Outcomes 1 or 5 years after an aponeurotomy, fasciectomy or dermofasciectomy were assessed by patient interview and examination at five UK centres. A total of 432 procedures were studied. The reoperation rate did not differ at 1 year (p = 0.396, Chi-square test with Monte Carlo simulation), but was higher after aponeurotomy in the 5-year group (30%, versus 6% after fasciectomy and 0% after dermofasciectomy, p = 0.003, Chi square test with Monte Carlo simulation). Loss of function (DASH>15) did not differ between procedures at 5 years, even when reoperation and other variables were controlled. Diabetes, female gender and previous ipsilateral surgery were associated with poorer function in logistic regression analysis. The variables associated with poor function after treatments differ from diathesis variables. Aponeurotomy had lower complication rates than fasciectomy and dermofasciectomy. This may counterbalance the former’s higher recurrence rate and explain why aponeurotomy demonstrated similar long-term functional outcome compared with excisional surgery in this study

Incidence and risk factors for poor ankle functional recovery, and the development and progression of posttraumatic ankle osteoarthritis after significant ankle ligament injury (SALI) : the SALI cohort study protocol

Background: Ankle sprains are one of the most common musculoskeletal injuries, accounting for up to 5% of all Emergency Department visits in the United Kingdom. Ankle injury may be associated with future ankle osteoarthritis. Up to 70% of ankle osteoarthritis cases may be associated with previous ankle injury. There is limited research regarding the association between ankle sprain and ankle osteoarthritis development. The current study aims to phenotype those who suffer significant ankle ligament injuries, identify potential risk factors for ankle injuries and subsequent poor recovery, examine why individuals may develop osteoarthritis, and what factors influence this chance. Methods: In this multicentre cohort study participants were recruited from nine Emergency Departments and two Urgent Care Centres in the United Kingdom. Participants (aged 18–70 years old) were defined as those who had suffered an isolated acute ankle sprain, which was Ottawa Ankle Rules positive, but negative for a significant ankle fracture on x-ray. Age and sex matched controls were also recruited. The controls were individuals who had not suffered a significant ankle injury, including ankle pain, function affected for more than 7 days, or the ankle caused them to report to an Emergency Department. Data is collected through a series of seven questionnaires (at baseline, 3 months, 1 year, 3 years, 5 years, 10 years, and 15 years later). The questionnaires include four sections (demographic questions; index injury, and injury history questions; functional assessment questions; and quality of life questions) and are designed to collect detailed information about the individual, their injury, potential risk factors for ankle sprains and ankle osteoarthritis, plus their medical history and any medication consumed. Discussion: The Significant Ankle Ligament Injury (SALI) study aims to add to the limited knowledge regarding which factors can predict ankle sprains, complaints, and osteoarthritis. This is important because despite ankle sprains being regarded as a benign injury that resolves quickly, residual symptoms are not uncommon months and years after the injury

Compassionate care in the community: reflections of a student nurse.

Reflecting on practice and analysing situations when compassionate care has been delivered can be a valuable way of helping student nurses develop their understanding of humanising care. This exemplar showcases a scenario when a second-year student nurse studying for a BSc (Honours) in adult nursing explored an experience while working in the community. She critically reflected on an incident highlighting a simple yet powerful example of how she helped an older couple manage an aspect of their care. This exercise helped the student to explore and understand what compassionate care means and highlighted how the value of reflection can be used to gain new insights to enhance the care of older people in her future practice in the community

TTF-1 Action on the Transcriptional Regulation of Cyclooxygenase-2 Gene in the Rat Brain

We have recently found that thyroid transcription factor-1 (TTF-1), a homeodomain-containing transcription factor, is postnatally expressed in discrete areas of the hypothalamus and closely involved in neuroendocrine functions. We now report that transcription of cyclooxygenase-2 (COX-2), the rate limiting enzyme in prostaglandin biosynthesis, was inhibited by TTF-1. Double immunohistochemistry demonstrated that TTF-1 was expressed in the astrocytes and endothelial cells of blood vessel in the hypothalamus. Promoter assays and electrophoretic mobility shift assays showed that TTF-1 inhibited COX-2 transcription by binding to specific binding domains in the COX-2 promoter. Furthermore, blocking TTF-1 synthesis by intracerebroventricular injection of an antisense oligomer induced an increase of COX-2 synthesis in non-neuronal cells of the rat hypothalamus, and resulted in animals' hyperthermia. These results suggest that TTF-1 is physiologically involved in the control of thermogenesis by regulating COX-2 transcription in the brain

Validity of the disabilities of the Arm, Shoulder and Hand patient-reported outcome measure (DASH) and the Quickdash when used in Dupuytren’s disease

This study investigated aspects of the validity and reliability of the 30-item Disabilities of the Arm, Shoulder and Hand patient-reported outcome measure (DASH) and its relationship with the shorter 11-item QuickDASH in patients with Dupuytren’s disease. Seven hundred and fifty-nine DASH questionnaires were studied, covering pre- and postoperative patients undergoing different treatments for Dupuytren’s disease. Items related to pain rose early after treatment before returning to baseline, suggesting that studying pain is relevant during postoperative recovery. Across all 759 sets of responses, the QuickDASH agreed closely with the DASH. In exploratory factor analysis, the DASH was not unidimensional, questioning the validity of the DASH summary score in Dupuytren’s disease. Further validation of existing PROMs for use in Dupuytren’s disease is needed. These data suggest that pain is a relevant symptom to study during postoperative recovery following treatment for Dupuytren’s disease

Narcolepsy patients have antibodies that stain distinct cell populations in rat brain and influence sleep patterns.

Narcolepsy is a chronic sleep disorder, likely with an autoimmune component. During 2009 and 2010, a link between A(H1N1)pdm09 Pandemrix vaccination and onset of narcolepsy was suggested in Scandinavia. In this study, we searched for autoantibodies related to narcolepsy using a neuroanatomical array: rat brain sections were processed for immunohistochemistry/double labeling using patient sera/cerebrospinal fluid as primary antibodies. Sera from 89 narcoleptic patients, 52 patients with other sleep-related disorders (OSRDs), and 137 healthy controls were examined. Three distinct patterns of immunoreactivity were of particular interest: pattern A, hypothalamic melanin-concentrating hormone and proopiomelanocortin but not hypocretin/orexin neurons; pattern B, GABAergic cortical interneurons; and pattern C, mainly globus pallidus neurons. Altogether, 24 of 89 (27%) narcoleptics exhibited pattern A or B or C. None of the patterns were exclusive for narcolepsy but were also detected in the OSRD group at significantly lower numbers. Also, some healthy controls exhibited these patterns. The antigen of pattern A autoantibodies was identified as the common C-terminal epitope of neuropeptide glutamic acid-isoleucine/alpha-melanocyte-stimulating hormone (NEI/alphaMSH) peptides. Passive transfer experiments on rat showed significant effects of pattern A human IgGs on rapid eye movement and slow-wave sleep time parameters in the inactive phase and EEG theta-power in the active phase. We suggest that NEI/alphaMSH autoantibodies may interfere with the fine regulation of sleep, contributing to the complex pathogenesis of narcolepsy and OSRDs. Also, patterns B and C are potentially interesting, because recent data suggest a relevance of those brain regions/neuron populations in the regulation of sleep/arousal

Cholinergic Modulation of Narcoleptic Attacks in Double Orexin Receptor Knockout Mice

To investigate how cholinergic systems regulate aspects of the sleep disorder narcolepsy, we video-monitored mice lacking both orexin (hypocretin) receptors (double knockout; DKO mice) while pharmacologically altering cholinergic transmission. Spontaneous behavioral arrests in DKO mice were highly similar to those reported in orexin-deficient mice and were never observed in wild-type (WT) mice. A survival analysis revealed that arrest lifetimes were exponentially distributed indicating that random, Markovian processes determine arrest lifetime. Low doses (0.01, 0.03 mg/kg, IP), but not a high dose (0.08 mg/kg, IP) of the cholinesterase inhibitor physostigmine increased the number of arrests but did not alter arrest lifetimes. The muscarinic antagonist atropine (0.5 mg/kg, IP) decreased the number of arrests, also without altering arrest lifetimes. To determine if muscarinic transmission in pontine areas linked to REM sleep control also influences behavioral arrests, we microinjected neostigmine (50 nl, 62.5 µM) or neostigmine + atropine (62.5 µM and 111 µM respectively) into the nucleus pontis oralis and caudalis. Neostigmine increased the number of arrests in DKO mice without altering arrest lifetimes but did not provoke arrests in WT mice. Co-injection of atropine abolished this effect. Collectively, our findings establish that behavioral arrests in DKO mice are similar to those in orexin deficient mice and that arrests have exponentially distributed lifetimes. We also show, for the first time in a rodent narcolepsy model, that cholinergic systems can regulate arrest dynamics. Since perturbations of muscarinic transmission altered arrest frequency but not lifetime, our findings suggest cholinergic systems influence arrest initiation without influencing circuits that determine arrest duration

“Making voices heard…”: Index on Censorship as Advocacy Journalism

The magazine Index on Censorship has sought, since its launch in 1972, to provide a space where censorship and abuses against freedom of expression have been identified, highlighted and challenged. Originally set up by a collection of writers and intellectuals who were concerned at the levels of state censorship and repression of artists in and under the influence of the Soviet Union and elsewhere, ‘Index’ has provided those championing the values of freedom of expression with a platform for highlighting human rights abuses, curtailment of civil liberties and formal and informal censorship globally. Charting its inception and development between 1971 and 1974, the paper is the first to situate the journal within the specific academic literature on activist media (Janowitz, 1975; Waisbord, 2009; Fisher, 2016). In doing so the paper advances an argument which draws on the drivers and motivations behind the publication’s launch to signal the development of a particular justification or ‘advocacy’ of a left-libertarian civic model of freedom of speech