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Find video protocols related to scientific articles indexed in Pubmed.
The human ubiquitin conjugating enzyme UBE2J2 (Ubc6) is a substrate for proteasomal degradation.
Biochem. Biophys. Res. Commun.
PUBLISHED: 07-18-2014
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The human Ube2J2 enzyme functions in the ubiquitination of proteins at the ER. Here we demonstrate that it, and a second ubiquitin conjugating (Ubc) enzyme Ube2G2, are unstable, and incubation of transfected cells with proteasome inhibitors increased steady-state protein levels. For Ube2J2, pharmacological induction of the unfolded protein response (UPR) did not significantly alter ectopic protein levels, however the effect of proteasomal inhibition was abolished if the enzyme was inactivated or truncated to disrupt its ER-localization. These results suggest for the first time that the steady state expression of Ubcs' may be important in regulating the degradation of ER proteins in mammalian cells.
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Single-case effect size calculation: comparing regression and non-parametric approaches across previously published reading intervention data sets.
J Sch Psychol
PUBLISHED: 07-16-2014
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Growing from demands for accountability and research-based practice in the field of education, there is recent focus on developing standards for the implementation and analysis of single-case designs. Effect size methods for single-case designs provide a useful way to discuss treatment magnitude in the context of individual intervention. Although a standard effect size methodology does not yet exist within single-case research, panel experts recently recommended pairing regression and non-parametric approaches when analyzing effect size data. This study compared two single-case effect size methods: the regression-based, Allison-MT method and the newer, non-parametric, Tau-U method. Using previously published research that measured the Words read Correct per Minute (WCPM) variable, these two methods were examined by comparing differences in overall effect size scores and rankings of intervention effect. Results indicated that the regression method produced significantly larger effect sizes than the non-parametric method, but the rankings of the effect size scores had a strong, positive relation. Implications of these findings for research and practice are discussed.
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Emerging approaches to target tumor metabolism.
Curr Opin Pharmacol
PUBLISHED: 04-28-2014
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Therapeutic exploitation of the next generation of drugs targeting the genetic basis of cancer will require an understanding of how cancer genes regulate tumor biology. Reprogramming of tumor metabolism has been linked with activation of oncogenes and inactivation of tumor suppressors. Well established and emerging cancer genes such as MYC, IDH1/2 and KEAP1 regulate tumor metabolism opening up opportunities to evaluate metabolic pathway inhibition as a therapeutic strategy in these tumors.
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Cerebellar mutism after posterior fossa tumor resection: case discussion and recommendations for psychoeducational intervention.
J Pediatr Oncol Nurs
PUBLISHED: 03-11-2014
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Cerebellar mutism (also known as posterior fossa syndrome) is a relatively common complication of posterior fossa surgery for primary brain tumors in children. Many children with cerebellar mutism experience long-term adverse neurological, cognitive, and psychological sequelae and require extensive interdisciplinary support. This study illustrates a typical case of cerebellar mutism in a child after resection of medulloblastoma, followed by a review of associated symptoms, clinical course, and modulating factors. Additionally, recommendations for providing educational support to children with cerebellar mutism are explored.
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Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord.
Neuron
PUBLISHED: 02-25-2014
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Menthol and other counterstimuli relieve itch, resulting in an antipruritic state that persists for minutes to hours. However, the neural basis for this effect is unclear, and the underlying neuromodulatory mechanisms are unknown. Previous studies revealed that Bhlhb5(-/-) mice, which lack a specific population of spinal inhibitory interneurons (B5-I neurons), develop pathological itch. Here we characterize B5-I neurons and show that they belong to a neurochemically distinct subset. We provide cause-and-effect evidence that B5-I neurons inhibit itch and show that dynorphin, which is released from B5-I neurons, is a key neuromodulator of pruritus. Finally, we show that B5-I neurons are innervated by menthol-, capsaicin-, and mustard oil-responsive sensory neurons and are required for the inhibition of itch by menthol. These findings provide a cellular basis for the inhibition of itch by chemical counterstimuli and suggest that kappa opioids may be a broadly effective therapy for pathological itch.
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The head start tobacco cessation initiative: using systems change to support staff identification and intervention for tobacco use in low-income families.
J Community Health
PUBLISHED: 02-18-2014
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Tobacco use continues to be the leading cause of preventable illness and death in the United States. Remarkably, more than nine million preschool-aged children are exposed to secondhand smoke, resulting in increased rates of morbidity and mortality. Even more disturbing is that tobacco use is highest among people with the lowest levels of income and education. Thus, reaching these populations is a challenge facing tobacco control programs. This report describes an innovative pilot project implementing a systems change model that involves multiple stakeholders in integrating evidence-based cessation strategies into federal Head Start programs, which serve low-income adults and their children. The Tobacco Cessation Initiative was developed through a partnership between the American Legacy Foundation, the Mailman School of Public Health at Columbia University, and the Louisiana State University Health Sciences Center School of Public Health. The partnership developed guidelines to fit into the overall mission of Head Start by enabling participating sites to incorporate tobacco cessation identification and referral protocols into their existing infrastructures. This program allowed Head Start sites to incorporate, into their existing family services, protocols for user identification and referral; build partnerships with groups supporting tobacco cessation; link families to cessation services; and educate families about risks associated with exposure to secondhand smoke. Applying system strategies in non-clinical settings such as Head Start offers a way to improve the health and quality of life of preschool children at the highest risk for exposure to secondhand smoke.
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The DiReCT study - improving recruitment into clinical trials: a mixed methods study investigating the ethical acceptability, feasibility and recruitment yield of the cohort multiple randomised controlled trials design.
Trials
PUBLISHED: 02-13-2014
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The 'cohort multiple Randomised Controlled Trial' (cmRCT) design has been proposed as a potential solution to poor recruitment into clinical trials. The design randomly selects participants eligible for experimental treatments from a pre-enrolled cohort of patients, recruiting participants to multiple trials from a single cohort. Controls remain unaware of their participation in specific trials.
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Transplant restoration of spinal cord inhibitory controls ameliorates neuropathic itch.
J. Clin. Invest.
PUBLISHED: 01-14-2014
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The transmission of pruritoceptive (itch) messages involves specific neural circuits within the spinal cord that are distinct from those that transmit pain messages. These itch-specific circuits are tonically regulated by inhibitory interneurons in the dorsal horn. Consistent with these findings, it has previously been reported that loss of GABAergic interneurons in mice harboring a deletion of the transcription factor Bhlhb5 generates a severe, nonremitting condition of chronic itch. Here, we tested the hypothesis that the neuropathic itch in BHLHB5-deficient animals can be treated by restoring inhibitory controls through spinal cord transplantation and integration of precursors of cortical inhibitory interneurons derived from the embryonic medial ganglionic eminence. We specifically targeted the transplants to segments of the spinal cord innervated by areas of the body that were most severely affected. BHLHB5-deficient mice that received transplants demonstrated a substantial reduction of excessive scratching and dramatic resolution of skin lesions. In contrast, the scratching persisted and skin lesions worsened over time in sham-treated mice. Together, these results indicate that cell-mediated restoration of inhibitory controls has potential as a powerful, cell-based therapy for neuropathic itch that not only ameliorates symptoms of chronic itch, but also may modify disease.
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Prevalence and causes of prescribing errors: the PRescribing Outcomes for Trainee Doctors Engaged in Clinical Training (PROTECT) study.
PLoS ONE
PUBLISHED: 01-01-2014
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Study objectives were to investigate the prevalence and causes of prescribing errors amongst foundation doctors (i.e. junior doctors in their first (F1) or second (F2) year of post-graduate training), describe their knowledge and experience of prescribing errors, and explore their self-efficacy (i.e. confidence) in prescribing.
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AZD3514: a small molecule that modulates androgen receptor signaling and function in vitro and in vivo.
Mol. Cancer Ther.
PUBLISHED: 07-16-2013
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Continued androgen receptor (AR) expression and signaling is a key driver in castration-resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed, and therefore remains a target for the treatment of progressive disease. Here, we describe the biological characterization of AZD3514, an orally bioavailable drug that inhibits androgen-dependent and -independent AR signaling. AZD3514 modulates AR signaling through two distinct mechanisms, an inhibition of ligand-driven nuclear translocation of AR and a downregulation of receptor levels, both of which were observed in vitro and in vivo. AZD3514 inhibited testosterone-driven seminal vesicle development in juvenile male rats and the growth of androgen-dependent Dunning R3327H prostate tumors in adult rats. Furthermore, this class of compound showed antitumor activity in the HID28 mouse model of CRPC in vivo. AZD3514 is currently in phase I clinical evaluation.
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Rasip1 mediates Rap1 regulation of Rho in endothelial barrier function through ArhGAP29.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 06-24-2013
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Rap1 is a small GTPase regulating cell-cell adhesion, cell-matrix adhesion, and actin rearrangements, all processes dynamically coordinated during cell spreading and endothelial barrier function. Here, we identify the adaptor protein ras-interacting protein 1 (Rasip1) as a Rap1-effector involved in cell spreading and endothelial barrier function. Using Förster resonance energy transfer, we show that Rasip1 interacts with active Rap1 in a cellular context. Rasip1 mediates Rap1-induced cell spreading through its interaction partner Rho GTPase-activating protein 29 (ArhGAP29), a GTPase activating protein for Rho proteins. Accordingly, the Rap1-Rasip1 complex induces cell spreading by inhibiting Rho signaling. The Rasip1-ArhGAP29 pathway also functions in Rap1-mediated regulation of endothelial junctions, which controls endothelial barrier function. In this process, Rasip1 cooperates with its close relative ras-association and dilute domain-containing protein (Radil) to inhibit Rho-mediated stress fiber formation and induces junctional tightening. These results reveal an effector pathway for Rap1 in the modulation of Rho signaling and actin dynamics, through which Rap1 modulates endothelial barrier function.
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Junior doctors perceptions of their self-efficacy in prescribing, their prescribing errors and the possible causes of errors.
Br J Clin Pharmacol
PUBLISHED: 03-08-2013
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The aim of the study was to explore and compare junior doctors perceptions of their self-efficacy in prescribing, their prescribing errors and the possible causes of those errors.
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Medical students illness-related cognitions.
Med Educ
PUBLISHED: 10-13-2011
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Doctors do not follow guidance when managing their own health and illness. This behaviour may start at medical school. This study aimed to investigate whether inappropriate responses to illness are an issue for medical students and, if so, to identify the determinants of students responses to illness.
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10-year cognition in preterms after random assignment to fatty acid supplementation in infancy.
Pediatrics
PUBLISHED: 09-19-2011
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To test the hypothesis that long-chain polyunsaturated fatty acid (LCPUFA) supplementation in infancy would improve cognition into later childhood (after 9 years) at both general and specific levels.
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Pain and itch: insights into the neural circuits of aversive somatosensation in health and disease.
Curr. Opin. Neurobiol.
PUBLISHED: 09-16-2011
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Although pain and itch are distinct sensations, most noxious chemicals are not very specific to one sensation over the other, and recent discoveries are revealing that Trp channels function as transducers for both. A key difference between these sensations is that itch is initiated by irritation of the skin, whereas pain can be elicited from almost anywhere in the body; thus, itch may be encoded by the selective activation of specific subsets of neurons that are tuned to detect harmful stimuli at the surface and have specialized central connectivity that is specific to itch. Within the spinal cord, cross-modal inhibition between pain and itch may help sharpen the distinction between these sensations. Moreover, this idea that somatosensory modalities inhibit one another may be generalizable to other somatosensory subtypes, such as cold and hot. Importantly, just as there are inhibitory circuits in the dorsal horn that mediate cross-inhibition between modalities, it appears that there are also excitatory connections that can be unmasked upon injury or in disease, leading to abnormally elevated pain states such as allodynia. We are now beginning to understand some of this dorsal horn circuitry, and these discoveries are proving to be relevant for pathological conditions of chronic pain and itch.
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The effects of oxytocin on social cognition and behaviour in frontotemporal dementia.
Brain
PUBLISHED: 08-22-2011
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Patients with behavioural variant frontotemporal dementia demonstrate abnormalities in behaviour and social cognition, including deficits in emotion recognition. Recent studies suggest that the neuropeptide oxytocin is an important mediator of social behaviour, enhancing prosocial behaviours and some aspects of emotion recognition across species. The objective of this study was to assess the effects of a single dose of intranasal oxytocin on neuropsychiatric behaviours and emotion processing in patients with behavioural variant frontotemporal dementia. In a double-blind, placebo-controlled, randomized cross-over design, 20 patients with behavioural variant frontotemporal dementia received one dose of 24 IU of intranasal oxytocin or placebo and then completed emotion recognition tasks known to be affected by frontotemporal dementia and by oxytocin. Caregivers completed validated behavioural ratings at 8?h and 1 week following drug administrations. A significant improvement in scores on the Neuropsychiatric Inventory was observed on the evening of oxytocin administration compared with placebo and compared with baseline ratings. Oxytocin was also associated with reduced recognition of angry facial expressions by patients with behavioural variant frontotemporal dementia. Together these findings suggest that oxytocin is a potentially promising, novel symptomatic treatment candidate for patients with behavioural variant frontotemporal dementia and that further study of this neuropeptide in frontotemporal dementia is warranted.
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Psychosocial functioning and health-related quality of life in paediatric inflammatory bowel disease.
J. Pediatr. Gastroenterol. Nutr.
PUBLISHED: 08-09-2011
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The present systematic review examined the literature focusing on psychosocial functioning and health-related quality of life (HRQOL) in young people with inflammatory bowel disease (IBD). It aimed to critique the methodological quality of the identified studies, discuss the implications of their findings, and make recommendations for future research.
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Ezrin is required for efficient Rap1-induced cell spreading.
J. Cell. Sci.
PUBLISHED: 05-03-2011
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The Rap family of small GTPases regulate the adhesion of cells to extracellular matrices. Several Rap-binding proteins have been shown to function as effectors that mediate Rap-induced adhesion. However, little is known regarding the relationships between these effectors, or about other proteins that are downstream of or act in parallel to the effectors. To establish whether an array of effectors was required for Rap-induced cell adhesion and spreading, and to find new components involved in Rap-signal transduction, we performed a small-scale siRNA screen in A549 lung epithelial cells. Of the Rap effectors tested, only Radil blocked Rap-induced spreading. Additionally, we identified a novel role for Ezrin downstream of Rap1. Ezrin was necessary for Rap-induced cell spreading, but not Rap-induced cell adhesion or basal adhesion processes. Furthermore, Ezrin depletion inhibited Rap-induced cell spreading in several cell lines, including primary human umbilical vein endothelial cells. Interestingly, Radixin and Moesin, two proteins with high homology to Ezrin, are not required for Rap-induced cell spreading and cannot compensate for loss of Ezrin to rescue Rap-induced cell spreading. Here, we present a novel function for Ezrin in Rap1-induced cell spreading and evidence of a non-redundant role of an ERM family member.
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Examining workgroup diversity effects: does playing by the (group-retention) rules help or hinder?
Behav Res Methods
PUBLISHED: 02-08-2011
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Group diversity researchers are often faced with the problem of calculating diversity indices for groups that are incomplete due to participant nonresponse. Because participant nonresponse may attenuate the correlations that are observed between group diversity scores and outcome variables, some researchers use group-retention rules based on within-group response rates. With this approach, only those groups that have a within-group response rate at, or higher than, the rate prescribed by the group-retention rule are retained for subsequent analyses. We conducted two sets of experiments using computer simulations to determine the usefulness of group-retention rules. We found that group-retention rules are not a substitute for a high response rate and may decrease the accuracy of observed relations, and consequently, we advise against their use in diversity research.
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Levels of acculturation and effect on glycemic control in Mexicans and Mexican Americans with type 2 diabetes.
Postgrad Med
PUBLISHED: 02-05-2011
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Acculturation of Mexican Americans toward the predominant American culture has been shown to influence health outcomes. Little is known about the role of acculturation in diabetes control.
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Developmental origin of preBötzinger complex respiratory neurons.
J. Neurosci.
PUBLISHED: 11-05-2010
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A subset of preBötzinger Complex (preBötC) neurokinin 1 receptor (NK1R) and somatostatin peptide (SST)-expressing neurons are necessary for breathing in adult rats, in vivo. Their developmental origins and relationship to other preBötC glutamatergic neurons are unknown. Here we show, in mice, that the "core" of preBötC SST(+)/NK1R(+)/SST 2a receptor(+) (SST2aR) neurons, are derived from Dbx1-expressing progenitors. We also show that Dbx1-derived neurons heterogeneously coexpress NK1R and SST2aR within and beyond the borders of preBötC. More striking, we find that nearly all non-catecholaminergic glutamatergic neurons of the ventrolateral medulla (VLM) are also Dbx1 derived. PreBötC SST(+) neurons are born between E9.5 and E11.5 in the same proportion as non-SST-expressing neurons. Additionally, preBötC Dbx1 neurons are respiratory modulated and show an early inspiratory phase of firing in rhythmically active slice preparations. Loss of Dbx1 eliminates all glutamatergic neurons from the respiratory VLM including preBötC NK1R(+)/SST(+) neurons. Dbx1 mutant mice do not express any spontaneous respiratory behaviors in vivo. Moreover, they do not generate rhythmic inspiratory activity in isolated en bloc preparations even after acidic or serotonergic stimulation. These data indicate that preBötC core neurons represent a subset of a larger, more heterogeneous population of VLM Dbx1-derived neurons. These data indicate that Dbx1-derived neurons are essential for the expression and, we hypothesize, are responsible for the generation of respiratory behavior both in vitro and in vivo.
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Development of learning outcomes for an undergraduate prescribing curriculum (British Pharmacological Society prescribing initiative).
Br J Clin Pharmacol
PUBLISHED: 09-16-2010
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The question of whether new medical graduates are adequately prepared for the challenge of prescribing has been raised. Although broad outcomes for prescribing competency have been agreed, clarity is needed on the detailed outcomes expected of new graduates. This study aimed to create a consensus on the required competencies for new graduates in the area of prescribing.
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The 10-year follow-up of a randomised trial of long-chain polyunsaturated fatty acid supplementation in preterm infants: effects on growth and blood pressure.
Arch. Dis. Child.
PUBLISHED: 06-01-2010
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To test the hypothesis that consumption of infant formulas containing long-chain polyunsaturated fatty acids (LCPUFAs) by preterm infants would favourably influence growth, body composition and blood pressure (BP) at age 10 years.
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Neuropsychological and psychiatric functioning in sheep farmers exposed to low levels of organophosphate pesticides.
Neurotoxicol Teratol
PUBLISHED: 03-02-2010
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The study aim was to determine whether low level exposure to organophosphate pesticides (OPs) causes neuropsychological or psychiatric impairment. Methodological weaknesses of earlier studies were addressed by: recruiting participants who had retired on ill health grounds; excluding participants with a history of acute poisoning, medical or psychiatric conditions that might account for ill health; and exploring factors which may render some individuals more vulnerable to the effects of OPs than others. Performance on tests of cognition and mood of 127 exposed sheep farmers (67 working, 60 retired) was compared with 78 unexposed controls (38 working, 40 retired) and published test norms derived from a cross section of several thousand adults in the general population. Over 40% of the exposed cohort reported clinically significant levels of anxiety and depression compared to less than 23% of controls. Exposed subjects performed significantly worse than controls and standardisation samples on tests of memory, response speed, fine motor control, mental flexibility and strategy making, even after controlling for the effects of mood. The pattern was similar for both working and retired groups. The cognitive deficits identified cannot be attributed to mood disorder, malingering, a history of acute exposure or genetic vulnerability in terms of PON1(192) polymorphisms. Results suggest a relationship may exist between low level exposure to organophosphates and impaired neurobehavioural functioning and these findings have implications for working practice and for other occupational groups exposed to OPs such as aviation workers and Gulf War veterans.
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Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice.
Neuron
PUBLISHED: 02-19-2010
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Itch is the least well understood of all the somatic senses, and the neural circuits that underlie this sensation are poorly defined. Here we show that the atonal-related transcription factor Bhlhb5 is transiently expressed in the dorsal horn of the developing spinal cord and appears to play a role in the formation and regulation of pruritic (itch) circuits. Mice lacking Bhlhb5 develop self-inflicted skin lesions and show significantly enhanced scratching responses to pruritic agents. Through genetic fate-mapping and conditional ablation, we provide evidence that the pruritic phenotype in Bhlhb5 mutants is due to selective loss of a subset of inhibitory interneurons in the dorsal horn. Our findings suggest that Bhlhb5 is required for the survival of a specific population of inhibitory interneurons that regulate pruritus, and provide evidence that the loss of inhibitory synaptic input results in abnormal itch.
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Medical students attitudes towards disability and support for disability in medicine.
Med Teach
PUBLISHED: 10-09-2009
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The number of medical students disclosing a disability is lower than the number of disabled doctors.
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What is the scale of prescribing errors committed by junior doctors? A systematic review.
Br J Clin Pharmacol
PUBLISHED: 09-11-2009
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Prescribing errors are an important cause of patient safety incidents, generally considered to be made more frequently by junior doctors, but prevalence and causality are unclear. In order to inform the design of an educational intervention, a systematic review of the literature on prescribing errors made by junior doctors was undertaken.
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Do educational interventions improve prescribing by medical students and junior doctors? A systematic review.
Br J Clin Pharmacol
PUBLISHED: 07-15-2009
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Our aim was to review systematically the literature on educational interventions to improve prescribing by medical students and junior doctors. MEDLINE, EMBASE, Educational Resource Information Center, British Education Index, PsycINFO, CINAHL, TIMELIT, Cochrane Trials Database and grey literature were searched. Inclusion criteria were: educational interventions to improve medical student and/or junior doctors prescribing, in primary or secondary care settings, and published after 1990. After screening 3189 records, we retrieved 11 controlled and four before-and-after trials. Ten controlled trials showed improvements in the scores of the intervention group on written scenarios or clinical examination stations, but one study in junior doctors showed no effect on real-life prescription errors. Only one intervention [the World Health Organization (WHO) Good Prescribing Guide, in six randomized trials] had been tested in a variety of international settings and across a range of students at different levels. All four before-and-after trials reported significant improvements in written tests or clinical stations. However, most studies tested only small numbers of participants and were affected by a range of methodological flaws. There is only moderate evidence in the literature to inform medical schools about how to prepare medical students for the challenges of prescribing. The WHO Good Prescribing Guide is the only model that has been widely used and shown to improve prescribing. Although it is based on sound principles, there is a need for further development. Robust methods of assessment are required to show clearly whether particular teaching interventions are successful.
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Students attitudes towards the introduction of a Personal and Professional Development portfolio: potential barriers and facilitators.
BMC Med Educ
PUBLISHED: 06-30-2009
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Portfolios, widely used in undergraduate and postgraduate medicine, have variable purposes, formats and success. A recent systematic review summarised factors necessary for successful portfolio introduction but there are no studies investigating the views of students inexperienced in portfolio use towards portfolio learning. This studys aim was to survey student views about a prospective Professional and Personal Development (PPD) portfolio.
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Sp1 and Sp3 regulate transcription of the cyclin-dependent kinase 5 regulatory subunit 2 (p39) promoter in neuronal cells.
Biochim. Biophys. Acta
PUBLISHED: 05-14-2009
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Cyclin-dependent kinase 5 (cdk5) activity is critical for development and function of the nervous system. Cdk5 activity is dependent on association with the regulators p35 and p39 whose expression is highly regulated in the developing nervous system.We have identified a small 200 bp fragment of the p39 promoter that is sufficient for cell type-specific expression in neuronal cells. Mutational analysis revealed that a cluster of predicted binding sites for Sp1, AP-1/CREB/ATF and E box-binding transcription factors is essential for full activity of the p39 promoter. Electrophoretic mobility shift assays revealed that Sp1 and Sp3 bound to sequences required for p39 promoter function and chromatin immunoprecipitation assays confirmed binding of these proteins to the endogenous p39 promoter. Furthermore, depletion of either Sp1 or Sp3 by siRNA reduced expression from the p39 promoter. Our data suggest that the ubiquitously expressed transcription factors Sp1 and Sp3 regulate transcription of the cdk5 regulator p39 in neuronal cells, possibly in cooperation with tissue-specific transcription factors.
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Rap1 can bypass the FAK-Src-Paxillin cascade to induce cell spreading and focal adhesion formation.
PLoS ONE
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We developed new image analysis tools to analyse quantitatively the extracellular-matrix-dependent cell spreading process imaged by live-cell epifluorescence microscopy. Using these tools, we investigated cell spreading induced by activation of the small GTPase, Rap1. After replating and initial adhesion, unstimulated cells exhibited extensive protrusion and retraction as their spread area increased, and displayed an angular shape that was remodelled over time. In contrast, activation of endogenous Rap1, via 007-mediated stimulation of Epac1, induced protrusion along the entire cell periphery, resulting in a rounder spread surface, an accelerated spreading rate and an increased spread area compared to control cells. Whereas basal, anisotropic, spreading was completely dependent on Src activity, Rap1-induced spreading was refractory to Src inhibition. Under Src inhibited conditions, the characteristic Src-induced tyrosine phosphorylations of FAK and paxillin did not occur, but Rap1 could induce the formation of actomyosin-connected adhesions, which contained vinculin at levels comparable to that found in unperturbed focal adhesions. From these results, we conclude that Rap1 can induce cell adhesion and stimulate an accelerated rate of cell spreading through mechanisms that bypass the canonical FAK-Src-Paxillin signalling cascade.
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Neurobehavioral problems following low-level exposure to organophosphate pesticides: a systematic and meta-analytic review.
Crit. Rev. Toxicol.
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Meta-analysis was carried out to determine the neurotoxic effects of long-term exposure to low levels of organophosphates (OPs) in occupational settings. Concern about the effects of OPs on human health has been growing as they are increasingly used throughout the world for a variety of agricultural, industrial and domestic purposes. The neurotoxic effects of acute poisoning are well established but the possibility that low-level exposure causes ill health is controversial. It is important to get a clear answer to this question as more individuals are at risk of low-level exposure than acute poisoning. Although a number of reviews on this topic have been published in the past, authors have come to conflicting conclusions. To date, none of these reviews have attempted quantitative evaluation of study findings using meta-analysis. This paper reviews the available evidence concerning the neurotoxicity of low-level occupational exposure to OPs and goes on to report the results of a meta-analysis of 14 studies which fulfilled criteria for this type of statistical analysis (means and standard deviations of dependant variables reported). Data were assimilated from more than 1600 participants. The majority of well designed studies found a significant association between low-level exposure to OPs and impaired neurobehavioral function which is consistent, small to moderate in magnitude and concerned primarily with cognitive functions such as psychomotor speed, executive function, visuospatial ability, working and visual memory. Unresolved issues in the literature which should become the focus of further studies are highlighted and discussed.
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Perceived causes of prescribing errors by junior doctors in hospital inpatients: a study from the PROTECT programme.
BMJ Qual Saf
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Prescribing errors are a major cause of patient safety incidents. Understanding the underlying factors is essential in developing interventions to address this problem. This study aimed to investigate the perceived causes of prescribing errors among foundation (junior) doctors in Scotland.
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Learning curves, taking instructions, and patient safety: using a theoretical domains framework in an interview study to investigate prescribing errors among trainee doctors.
Implement Sci
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Prescribing errors are a major source of morbidity and mortality and represent a significant patient safety concern. Evidence suggests that trainee doctors are responsible for most prescribing errors. Understanding the factors that influence prescribing behavior may lead to effective interventions to reduce errors. Existing investigations of prescribing errors have been based on Human Error Theory but not on other relevant behavioral theories. The aim of this study was to apply a broad theory-based approach using the Theoretical Domains Framework (TDF) to investigate prescribing in the hospital context among a sample of trainee doctors.
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MEDI0639: a novel therapeutic antibody targeting Dll4 modulates endothelial cell function and angiogenesis in vivo.
Mol. Cancer Ther.
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The Notch signaling pathway has been implicated in cell fate determination and differentiation in many tissues. Accumulating evidence points toward a pivotal role in blood vessel formation, and the importance of the Delta-like ligand (Dll) 4-Notch1 ligand-receptor interaction has been shown in both physiological and tumor angiogenesis. Disruption of this interaction leads to a reduction in tumor growth as a result of an increase in nonfunctional vasculature leading to poor perfusion of the tumor. MEDI0639 is an investigational human therapeutic antibody that targets Dll4 to inhibit the interaction between Dll4 and Notch1. The antibody cross-reacts to cynomolgus monkey but not mouse species orthologues. In vitro MEDI0639 inhibits the binding of Notch1 to Dll4, interacting via a novel epitope that has not been previously described. Binding to this epitope translates into MEDI0639 reversing Notch1-mediated suppression of human umbilical vein endothelial cell growth in vitro. MEDI0639 administration resulted in stimulation of tubule formation in a three-dimensional (3D) endothelial cell outgrowth assay, a phenotype driven by disruption of the Dll4-Notch signaling axis. In contrast, in a two-dimensional endothelial cell-fibroblast coculture model, MEDI0639 is a potent inhibitor of tubule formation. In vivo, MEDI0639 shows activity in a human endothelial cell angiogenesis assay promoting human vessel formation and reducing the number of vessels with smooth muscle actin-positive mural cells coverage. Collectively, the data show that MEDI0639 is a potent modulator of Dll4-Notch signaling pathway.
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Who makes prescribing decisions in hospital inpatients? An observational study.
Postgrad Med J
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Errors involving drug prescriptions are a key target for patient safety initiatives. Recent studies have focused on error rates across different grades of doctors in order to target interventions. However, many prescriptions are not instigated by the doctor who writes them. It is important to clarify how often this occurs in order to interpret these studies and create interventions. This study aimed to provisionally quantify and describe prescriptions where the identity of the decision maker and prescription writer differed.
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Examining the convergent validity of shared mental model measures.
Behav Res Methods
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Despite widespread interest in shared mental models (SMMs) within teams and groups and an extensive empirical literature examining SMM-performance links, very little is known about the convergent validity of commonly used measures of SMMs. In this study, two-person teams (n = 96) engaged in a complex flight task and completed three SMM measures: concept mapping, paired ratings, and causal mapping. Task-based sharedness scores were compared across the measures. Analyses were conducted in two ways: using SMMs of actual team members (n = 96 pairs) and using the SMMs of pairs of participants who worked separately but for whom similarity indices were calculated after the study (n = 18,240). The purpose of the latter pairs, coined pseudo-partners, was to create a sample with considerable power to test the convergent validity of the SMM measures. The results call into some question the convergent validity of these task-based SMM measures.
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Results of Duchenne muscular dystrophy family screening in practice: leaks rather than cascades?
Clin. Genet.
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Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by mutations in the gene that encodes the protein dystrophin. Approximately 2 of 3 affected boys inherit their mutation from their carrier mother whereupon other female relatives are at risk of carrying the mutation. Female carriers are also at risk of developing cardiomyopathy and regular cardiac screening is recommended. Clinical genetics services offer genetic counselling and carrier tests for consenting relatives of DMD patients known as cascade screening. We retrospectively analysed data from two genetics centres, West of Scotland and South East Thames where the latter centre operated a computer-held DMD register. Over the period, 1971-2008, a total of 843 potential carriers, in 195 West of Scotland families, were tested: 16% of 1st degree relatives and 48% of 2nd degree and more distant relatives were not tested. In South East Thames, a total of 1223 potential carriers in 349 families were tested: 49% of 1st degree and 65% of 2nd degree and more distant relatives were not tested. These data are similar to Becker muscular dystrophy/DMD carrier screening results recently reported from the Netherlands. Retrospective results from three countries indicate that despite efforts to offer extended cascade screening, significant numbers of potential carriers of DMD remain unaware of their reproductive and health risks.
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Prescribing and the core curriculum for tomorrows doctors: BPS curriculum in clinical pharmacology and prescribing for medical students.
Br J Clin Pharmacol
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Prescribing is one of the commonest tasks expected of new doctors and is a complex process involving a mixture of knowledge, judgement and skills. Preparing graduates to be prescribers is one of the greatest challenges of modern undergraduate medical education and there is some evidence to suggest that training could be improved. The aims of this article are (i) to review some of the challenges of delivering effective prescribing education, (ii) to provide a clear statement of the learning outcomes in clinical pharmacology and prescribing that should be expected of all medical graduates and (iii) to describe a curriculum that might enable students to achieve these outcomes. We build on the previous curriculum recommendations of the British Pharmacological Society and take into account those of other key bodies, notably the General Medical Council. We have also reviewed relevant evidence from the literature and set our work in the context of recent trends in medical education. We divide our recommended learning objectives into four sections: principles of clinical pharmacology, essential drugs, essential therapeutic problems and prescribing skills. Although these will not necessarily be accepted universally we believe that they will help those who design and map undergraduate curricula to explore potential gaps and identify improvements.
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Bhlhb5 and Prdm8 form a repressor complex involved in neuronal circuit assembly.
Neuron
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Although transcription factors that repress gene expression play critical roles in nervous system development, their mechanism of action remains to be understood. Here, we report that the Olig-related transcription factor Bhlhb5 (also known as Bhlhe22) forms a repressor complex with the PR/SET domain protein, Prdm8. We find that Bhlhb5 binds to sequence-specific DNA elements and then recruits Prdm8, which mediates the repression of target genes. This interaction is critical for repressor function since mice lacking either Bhlhb5 or Prdm8 have strikingly similar cellular and behavioral phenotypes, including axonal mistargeting by neurons of the dorsal telencephalon and abnormal itch-like behavior. We provide evidence that Cadherin-11 functions as target of the Prdm8/Bhlhb5 repressor complex that must be repressed for proper neural circuit formation to occur. These findings suggest that Prdm8 is an obligate partner of Bhlhb5, forming a repressor complex that directs neural circuit assembly in part through the precise regulation of Cadherin-11.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.