Recent Decisions

Commentaries on recent decisions by Robert W. Cox, Peter O. Kelly, Louis N. Roberts, James K. Stucko, Thomas J. Kelly, Joseph P. Albright, Daniel J. Manelli, and James E. Gould

Optimization and Validation of a Modified Radial-Arm Water Maze Protocol Using a Murine Model of Mild Closed Head Traumatic Brain Injury

Cognitive impairments can be a significant problem after a traumatic brain injury (TBI), which affects millions worldwide each year. There is a need for establish reproducible cognitive assays in rodents to better understand disease mechanisms and to develop therapeutic interventions towards treating TBI-induced impairments. Our goal was to validate and standardize the radial arm water maze (RAWM) test as an assay to screen for cognitive impairments caused by TBI. RAWM is a visuo-spatial learning test, originally designed for use with rats, and later adapted for mice. The present study investigates whether test procedures, such us the presence of extra-maze cues influences learning and memory performance. C57BL/6 mice were tested in an 8-arm RAWM using a four-day protocol. We demonstrated that two days of training, exposing the mice to extra-maze cues and a visible platform, influenced learning and memory performance. Mice that did not receive training performed poorer compared to mice trained. To further validate our RAWM protocol, we used scopolamine. We, also, demonstrated that a single mild closed head injury (CHI) caused deficits in this task at two weeks post-CHI. Our data supported the use of 7 trials per day and a spaced training protocol as key factor to unmask memory impairment following CHI. Here, we provide a detailed standard operating procedure for RAWM test, which can be applied to a variety of mouse models including neurodegenerative diseases and pathology, as well as when pharmacological approaches are used

New graduate doctors' preparedness for practice: A multistakeholder, multicentre narrative study

This is the final version. Available on open access from BMJ Publishing Group via the link in this recordData sharing statement The raw data for this research consist of audio-recordings of narrative interviews and audio diaries. The principal investigator (Professor Lynn V Monrouxe) has access to this specific data set, including audio-recordings of interviews and interview transcripts, in addition to participant contact details and signed consent forms. All authors have access to anonymised data from this set. All data are stored securely on password-protected and encrypted computers. Participants have not given their permission for data sharing outside the research group. Thus, no additional data are available.Objective While previous studies have begun to explore newly graduated junior doctors' preparedness for practice, findings are largely based on simplistic survey data or perceptions of newly graduated junior doctors and their clinical supervisors alone. This study explores, in a deeper manner, multiple stakeholders' conceptualisations of what it means to be prepared for practice and their perceptions about newly graduated junior doctors' preparedness (or unpreparedness) using innovative qualitative methods. Design A multistakeholder, multicentre qualitative study including narrative interviews and longitudinal audio diaries. Setting Four UK settings: England, Northern Ireland, Scotland and Wales. Participants Eight stakeholder groups comprising n=185 participants engaged in 101 narrative interviews (27 group and 84 individual). Twenty-six junior doctors in their first year postgraduation also provided audio diaries over a 3-month period. Results We identified 2186 narratives across all participants (506 classified as 'prepared', 663 as 'unprepared', 951 as 'general'). Seven themes were identified; this paper focuses on two themes pertinent to our research questions: (1) explicit conceptualisations of preparedness for practice; and (2) newly graduated junior doctors' preparedness for the General Medical Council's (GMC) outcomes for graduates. Stakeholders' conceptualisations of preparedness for practice included short-term (hitting the ground running) and long-term preparedness, alongside being prepared for practical and emotional aspects. Stakeholders' perceptions of medical graduates' preparedness for practice varied across different GMC outcomes for graduates (eg, Doctor as Scholar and Scientist, as Practitioner, as Professional) and across stakeholders (eg, newly graduated doctors sometimes perceived themselves as prepared but others did not). Conclusion Our narrative findings highlight the complexities and nuances surrounding new medical graduates' preparedness for practice. We encourage stakeholders to develop a shared understanding (and realistic expectations) of new medical graduates' preparedness. We invite medical school leaders to increase the proportion of time that medical students spend participating meaningfully in multiprofessional teams during workplace learning.General Medical Counci

Playing safe: Assessing the risk of sexual abuse to elite child athletes

Young athletes frequently suffer from being seen as athletes first and children second. This has consequences for their legal, civil and human rights as children (Kelly et al., 1995) and for the way in which sport organisations choose to intervene on their behalf to protect them from physical, psychological and sexual abuses (Brackenridge, 1994). Sport careers peak at different ages depending on the sport: in some, children as young as 12 or 13 may reach the highest levels of competitive performance; in others, full maturity as an athlete may come late into adulthood or even middle age. Recognition of this variation has given rise to the concept of ‘sport age’ (Kirby, 1986) referring to sport-specific athlete development. This concept is of significance in helping to identify the developmental process in terms of athletic, rather than chronological, maturity. The risk of sexual abuse in sport, formerly ignored or denied, has now been documented in a number of studies, using both quantitative and qualitative methods (Kirby & Greaves, 1996; Brackenridge, 1997; Volkwein, 1996). Drawing on data from these studies and from the previous work on sport age and athletic maturation, this paper proposes a possible means of identifying and assessing relative risk of sexual abuse to elite young athletes in selected sports. The concept of a ‘stage of imminent achievement’ (SIA) is proposed as the period of peak vulnerability of young athletes to sexual abuse

Systematic review and meta-analysis of reduction in all-cause mortality from walking and cycling and shape of dose response relationship

BACKGROUND AND OBJECTIVE: Walking and cycling have shown beneficial effects on population risk of all-cause mortality (ACM). This paper aims to review the evidence and quantify these effects, adjusted for other physical activity (PA). DATA SOURCES: We conducted a systematic review to identify relevant studies. Searches were conducted in November 2013 using the following health databases of publications: Embase (OvidSP); Medline (OvidSP); Web of Knowledge; CINAHL; SCOPUS; SPORTDiscus. We also searched reference lists of relevant texts and reviews. STUDY ELIGIBILITY CRITERIA AND PARTICIPANTS: Eligible studies were prospective cohort design and reporting walking or cycling exposure and mortality as an outcome. Only cohorts of individuals healthy at baseline were considered eligible. STUDY APPRAISAL AND SYNTHESIS METHODS: Extracted data included study population and location, sample size, population characteristics (age and sex), follow-up in years, walking or cycling exposure, mortality outcome, and adjustment for other co-variables. We used random-effects meta-analyses to investigate the beneficial effects of regular walking and cycling. RESULTS: Walking (18 results from 14 studies) and cycling (8 results from 7 studies) were shown to reduce the risk of all-cause mortality, adjusted for other PA. For a standardised dose of 11.25 MET.hours per week (or 675 MET.minutes per week), the reduction in risk for ACM was 11% (95% CI = 4 to 17%) for walking and 10% (95% CI = 6 to 13%) for cycling. The estimates for walking are based on 280,000 participants and 2.6 million person-years and for cycling they are based on 187,000 individuals and 2.1 million person-years. The shape of the dose-response relationship was modelled through meta-analysis of pooled relative risks within three exposure intervals. The dose-response analysis showed that walking or cycling had the greatest effect on risk for ACM in the first (lowest) exposure interval. CONCLUSIONS AND IMPLICATIONS: The analysis shows that walking and cycling have population-level health benefits even after adjustment for other PA. Public health approaches would have the biggest impact if they are able to increase walking and cycling levels in the groups that have the lowest levels of these activities. REVIEW REGISTRATION: The review protocol was registered with PROSPERO (International database of prospectively registered systematic reviews in health and social care) PROSPERO 2013: CRD42013004266

Blockade of Astrocytic Calcineurin/NFAT Signaling Helps to Normalize Hippocampal Synaptic Function and Plasticity in a Rat Model of Traumatic Brain Injury

Increasing evidence suggests that the calcineurin (CN)-dependent transcription factor NFAT (Nuclear Factor of Activated T cells) mediates deleterious effects of astrocytes in progressive neurodegenerative conditions. However, the impact of astrocytic CN/NFAT signaling on neural function/recovery after acute injury has not been investigated extensively. Using a controlled cortical impact (CCI) procedure in rats, we show that traumatic brain injury is associated with an increase in the activities of NFATs 1 and 4 in the hippocampus at 7 d after injury. NFAT4, but not NFAT1, exhibited extensive labeling in astrocytes and was found throughout the axon/dendrite layers of CA1 and the dentate gyrus. Blockade of the astrocytic CN/NFAT pathway in rats using adeno-associated virus (AAV) vectors expressing the astrocyte-specific promoter Gfa2 and the NFAT-inhibitory peptide VIVIT prevented the injury-related loss of basal CA1 synaptic strength and key synaptic proteins and reduced the susceptibility to induction of long-term depression. In conjunction with these seemingly beneficial effects, VIVIT treatment elicited a marked increase in the expression of the prosynaptogenic factor SPARCL1 (hevin), especially in hippocampal tissue ipsilateral to the CCI injury. However, in contrast to previous work on Alzheimer\u27s mouse models, AAV-Gfa2-VIVIT had no effects on the levels of GFAP and Iba1, suggesting that synaptic benefits of VIVIT were not attributable to a reduction in glial activation per se. Together, the results implicate the astrocytic CN/NFAT4 pathway as a key mechanism for disrupting synaptic remodeling and homeostasis in the hippocampus after acute injury

Phantom limb pain, cortical reorganization and the therapeutic effect of mental imagery

Using functional MRI (fMRI) we investigated 13 upper limb amputees with phantom limb pain (PLP) during hand and lip movement, before and after intensive 6-week training in mental imagery. Prior to training, activation elicited during lip purse showed evidence of cortical reorganization of motor (M1) and somatosensory (S1) cortices, expanding from lip area to hand area, which correlated with pain scores. In addition, during imagined movement of the phantom hand, and executed movement of the intact hand, group maps demonstrated activation not only in bilateral M1 and S1 hand area, but also lip area, showing a two-way process of reorganization. In healthy participants, activation during lip purse and imagined and executed movement of the non-dominant hand was confined to the respective cortical representation areas only. Following training, patients reported a significant reduction in intensity and unpleasantness of constant pain and exacerbations, with a corresponding elimination of cortical reorganization. Post hoc analyses showed that intensity of constant pain, but not exacerbations, correlated with reduction in cortical reorganization. The results of this study add to our current understanding of the pathophysiology of PLP, underlining the reversibility of neuroplastic changes in this patient population while offering a novel, simple method of pain relief

Role of Esrrg in the Fibrate-Mediated Regulation of Lipid Metabolism Genes in Human ApoA-I Transgenic Mice

We have used a new ApoA-I transgenic mouse model to identify by global gene expression profiling, candidate genes that affect lipid and lipoprotein metabolism in response to fenofibrate treatment. Multilevel bioinformatical analysis and stringent selection criteria (2-fold change, 0% false discovery rate) identified 267 significantly changed genes involved in several molecular pathways. The fenofibrate-treated group did not have significantly altered levels of hepatic human APOA-I mRNA and plasma ApoA-I compared with the control group. However, the treatment increased cholesterol levels to 1.95-fold mainly due to the increase in high-density lipoprotein (HDL) cholesterol. The observed changes in HDL are associated with the upregulation of genes involved in phospholipid biosynthesis and lipid hydrolysis, as well as phospholipid transfer protein. Significant upregulation was observed in genes involved in fatty acid transport and β-oxidation, but not in those of fatty acid and cholesterol biosynthesis, Krebs cycle and gluconeogenesis. Fenofibrate changed significantly the expression of seven transcription factors. The estrogen receptor-related gamma gene was upregulated 2.36-fold and had a significant positive correlation with genes of lipid and lipoprotein metabolism and mitochondrial functions, indicating an important role of this orphan receptor in mediating the fenofibrate-induced activation of a specific subset of its target genes.National Institutes of Health (HL48739 and HL68216); European Union (LSHM-CT-2006-0376331, LSHG-CT-2006-037277); the Biomedical Research Foundation of the Academy of Athens; the Hellenic Cardiological Society; the John F Kostopoulos Foundatio

Ethanol reversal of tolerance to the respiratory depressant effects of morphine

Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO(2) in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths