24 research outputs found
Differential effects of NMDA and AMPA glutamate receptors on functional magnetic resonance imaging signals and evoked neuronal activity during forepaw stimulation of the rat
No full textInternational audienceMost of the currently used methods for functional brain imaging do not visualize neuronal activity directly but rather rely on the elicited hemodynamic and/or metabolic responses. Glutamate, the major excitatory neurotransmitter, plays an important role in the neurovascular/neurometabolic coupling, but the specific mechanisms are still poorly understood. To investigate the role of the two major ionotropic glutamate receptors [NMDA receptors (NMDA-Rs) and AMPA receptors (AMPA-Rs)] for the generation of functional magnetic resonance imaging (fMRI) signals, we used fMRI [measurements of blood oxygenation level-dependent (BOLD), perfusion-weighted imaging (PWI), and cerebral blood volume (CBV)] together with recordings of somatosensory evoked potentials (SEPs) during electrical forepaw stimulation in the alpha-chloralose anesthetized rat. Intravenous injection of the NMDA-R antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate] (0.06 mg/kg plus 3.6 microg x kg(-1) x h(-1)) significantly decreased BOLD (-51 +/- 19%; n = 5) and PWI (-57 +/- 26%; n = 5) responses but reduced the SEPs only mildly (approximately -10%). Systemic application of the AMPA-R antagonist GYKI-53655 [1-(4-aminophenyl)-3-methylcarbamyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine] significantly decreased both the hemodynamic response (BOLD, -49 +/- 13 and -65 +/- 15%; PWI, -22 +/- 48 and -68 +/- 4% for 5 and 7 mg/kg, i.v., respectively; CBV, -80 +/- 7% for 7 mg/kg; n = 4) and the SEPs (up to -60%). These data indicate that the interaction of glutamate with its postsynaptic and/or glial receptors is necessary for the generation of blood flow and BOLD responses and illustrate the differential role of NMDA-Rs and AMPA-Rs in the signaling chain leading from increased neuronal activity to the hemodynamic response in the somatosensory cortex
Ciliary neurotrophic factor activates astrocytes, redistributes their glutamate transporters GLAST and GLT-1 to raft microdomains, and improves glutamate handling in vivo.
No full textNon-directed bronchial lavage is a safe method for sampling the respiratory tract in critically ill patient
No full textVentilated patients are at risk of acquiring ventilator-associated pneumonia. Various techniques are available for diagnosing ventilator-associated pneumonia including bronchoalveolar lavage, protected specimen brush and non-directed bronchoalveolar lavage. There is a paucity of evidence regarding the safety profile of these techniques, particularly non-directed bronchoalveolar lavage. This service evaluation aimed to establish whether non-directed bronchoalveolar lavage is a safe procedure. A prospective service evaluation of non-directed bronchoalveolar lavage on our adult intensive care unit was undertaken by a senior physiotherapist trained into carrying out the procedure, measuring pre- and post-procedure vital signs including heart rate (HR), tidal volume (VT), systolic blood pressure (SBP) and pulse oximetry (SpO2). Eighty-five episodes in 41 patients were included in the evaluation. There was a statistically significant difference between pre- and immediately post-procedure recordings for all vital signs measure. HR (min-1), means (SD) 87.1 (16.4), 91.5 (16.5), 87.5 (15.9), 87.7 (15.7) respectively pre, immediately, 5 min after and 30 min after procedure (P < 0.01). SBP mmHg, means (SD) 133.9 (26.1), 142.1 (25.6), 136.9 (25.3), 134.8 (23.4) pre, immediately, 5 min and 30 min after procedure (P < 0.01). VT mL, median (range) 0.523 (0.118–1.180), 0.512 (0.131–1.05), 0.519 (0.104–0.95), 0.534 (0.110–1.080) each pre, immediately, 5 min and 30 min post procedure (P < 0.05). SpO2 %, median (range) 98 (89–100), 100 (96–100), 98 (92–100), 97 (90–100) again each pre-, immediately post, 5 and 30 min post-procedure time-points (P < 0.0001). The statistically significant difference was not detected between pre-, 5 or 30 min post-procedure time-points. None of the changes observed were clinically significant and no untoward events happened to any of the subjects included. Non-directed bronchoalveolar lavage is a safe and inexpensive procedure that can be carried out easily in an intensive care setting by a trained physiotherapist, avoiding the need for invasive bronchoscopy.</p
The BOLD signal and neurovascular coupling in autism
No full textBOLD (blood oxygen level dependent) fMRI (functional magnetic resonance imaging) is commonly used to study differences in neuronal activity between human populations. As the BOLD response is an indirect measure of neuronal activity, meaningful interpretation of differences in BOLD responses between groups relies upon a stable relationship existing between neuronal activity and the BOLD response across these groups. However, this relationship can be altered by changes in neurovascular coupling or energy consumption, which would lead to problems in identifying differences in neuronal activity. In this review, we focus on fMRI studies of people with autism, and comparisons that are made of their BOLD responses with those of control groups. We examine neurophysiological differences in autism that may alter neurovascular coupling or energy use, discuss recent studies that have used fMRI to identify differences between participants with autism and control participants, and explore experimental approaches that could help attribute between-group differences in BOLD signals to either neuronal or neurovascular factors
Evaluating the quality improvement impact of the Global Tracheostomy Collaborative in four diverse NHS hospitals
No full textTracheostomies are predominantly used in Head & Neck Surgery and the critically ill. The needs of these complex patients frequently cross traditional speciality working boundaries and locations and any resulting airway problems can rapidly lead to significant harm. The Global Tracheostomy Collaborative (GTC) was formed in 2012 with the aim of bringing together international expertise in tracheostomy care in order to bring about rapid adoption of best practices and to improve the quality and safety of care to this vulnerable group. The primary aim of this project was to improve the safety and quality of care delivered to adult patients with new or existing tracheostomies. We implemented changes guided by the GTC using multiple PDSA cycles over a 12-month period. Interventions were across three themes: educational, patient-centred (earlier vocalisation and enteral intake) and organisational. We hypothesised that systematic healthcare improvements would reduce the severity of harm resulting from tracheostomy-related safety incidents and improve surrogate markers of the quality of patient-centred care. Furthermore, we hypothesised that raising the quality and safety of healthcare services would lead to more efficient care, measured by earlier tracheostomy decannulation times and reduced hospital lengths of stay. This Quality Improvement project implemented the GTC into four diverse NHS Trusts in Greater Manchester. Key drivers implemented included multidisciplinary tracheostomy steering groups, ward rounds and bedside teams, standardisation of tracheostomy protocols, staff education and meaningful involvement of patient and family. Surrogates for the quality and safety of care were captured for all patients using a bespoke database. Implementing the GTC into four NHS Trusts rapidly and positively impacted on patient safety metrics and surrogates for the quality of care delivered. It is likely that the comprehensive resources of the GTC will be of benefit to other NHS hospitals and indeed other healthcare systems around the world.</p
Efeitos das injeções de agonistas e antagonistas adrenérgicos no núcleo mediano da rafe sobre comportamentos relacionados à ansiedade e ingestão de alimento em ratos
No full textTese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Neurociências, Florianópolis, 2011Este estudo investigou a participação de receptores adrenérgicos .1, .2 e ß2 do núcleo mediano da rafe (MR) de ratos saciados no controle dos comportamentos relacionados à ansiedade e ingestão de alimento, a fim de estabelecer uma associação funcional entre eles. O agonista adrenérgico-.1 fenilefrina (FEN) (0, 0,2, 2, 6, 20 nmol) foi injetado no MR ou no núcleo pontino (Pn); o agonista adrenérgico-.2 clonidina (CLO) foi injetado no MR (0, 0,2, 2, 6, 20 nmol), no Pn (0,2 e 20 nmol) ou na formação reticular mesencefálica (FRm) (0,2 e 20 nmol); o agonista adrenérgico-ß2 terbutalina (TER) (0, 0,2, 2, 6, 20 nmol) foi injetado no MR ou no Pn. O antagonista adrenérgico-.1 prazosin (PRA, 40 nmol) ou veículo foram injetados no MR 15 min antes do tratamento com FEN (0,2 nmol); o antagonista adrenérgico-.2 ioimbina (YOH, 40 nmol) foi administrado 15 min antes da CLO (0,2 nmol e 20 nmol) ou veículo. Os animais foram colocados no labirinto em cruz elevado (LCE) para avaliação de variáveis espaço-temporais e etológicas. Na sequência, os comportamentos ingestivos e não-ingestivos foram registrados durante 30 min e a quantidade de ração e água consumida foram mensuradas. Tanto no LCE quanto na caixa de registro alimentar, todas as doses de FEN injetadas no MR diminuíram a freqüência de exibição da avaliação de risco (AR), um parâmetro etológico indicador de ansiólise; as variáveis espaço-temporais permaneceram inalteradas. Não houve alteração de comportamentos relacionados à ansiedade após o tratamento com FEN no Pn. O tratamento prévio com PRA no MR bloqueou o efeito ansiolítico da FEN. A dose mais alta de CLO injetada no MR aumentou a frequência de AR, um efeito ansiogênico; resultado similar foi observado após a injeção da mesma dose da droga no Pn e na FRm. O tratamento prévio com YOH no MR bloqueou o efeito ansiogênico da CLO. Todas as doses de TER injetadas no MR e no Pn diminuíram a frequência de AR, aumentaram a % do tempo de permanência nos braços abertos e aumentaram o número de entradas nos braços abertos do LCE, indicando efeito ansiolítico. A ingestão de alimento não foi afetada pela injeção de FEN no MR ou no Pn. O tratamento isolado com PRA no MR causou hiperfagia, acompanhada por redução na latência para iniciar a alimentação, aumento na duração, bem como aumento na frequência da resposta de alimentação. A maior dose de CLO também causou hiperfagia acompanhada por redução na latência para iniciar a alimentação e aumento na freqüência desta resposta quando injetada no MR, mas não no Pn ou na FRm. O tratamento prévio com YOH no MR bloqueou o efeito ingestivo da CLO. A ingestão de alimento não foi afetada após a injeção de TER no MR e no Pn. Os resultados indicam que: 1) a ativação de receptores adrenérgicos-a1 do MR têm efeito ansiolítico, enquanto a ativação de receptores adrenérgicos-a2 deste núcleo causa ansiogênese, sendo que estas respostas comportamentais parecem ser mediadas, respectivamente, pelo aumento e diminuição da liberação de 5-HT do MR; 2) no animal saciado há uma influência adrenérgica mediada por receptores adrenérgicos-a1 do MR, que ativa tonicamente um circuito inibitório, possivelmente neurônios serotonérgicos deste núcleo, e impede o comportamento ingestivo; 3) a ativação de receptores adrenérgicos-ß2 do MR têm efeito ansiolítico, sem alterar o comportamento de ingestão de alimento; 4) os comportamentos de ansiedade e ingestivos controlados por circuitos adrenérgicos do MR operam por vias neurais independentes
Improving tracheostomy care in the United Kingdom: results of a guided quality improvement programme in 20 diverse hospitals
No full textBackground
Inconsistent and poorly coordinated systems of tracheostomy care commonly result in frustrations, delays, and harm. Quality improvement strategies described by exemplar hospitals of the Global Tracheostomy Collaborative have potential to mitigate such problems. This 3 yr guided implementation programme investigated interventions designed to improve the quality and safety of tracheostomy care.
Methods
The programme management team guided the implementation of 18 interventions over three phases (baseline/implementation/evaluation). Mixed-methods interviews, focus groups, and Hospital Anxiety and Depression Scale questionnaires defined outcome measures, with patient-level databases tracking and benchmarking process metrics. Appreciative inquiry, interviews, and Normalisation Measure Development questionnaires explored change barriers and enablers.
Results
All sites implemented at least 16/18 interventions, with the magnitude of some improvements linked to staff engagement (1536 questionnaires from 1019 staff), and 2405 admissions (1868 ICU/high-dependency unit; 7.3% children) were prospectively captured. Median stay was 50 hospital days, 23 ICU days, and 28 tracheostomy days. Incident severity score reduced significantly (n=606; P<0.01). There were significant reductions in ICU (−;0.25 days month−1), ventilator (−;0.11 days month−1), tracheostomy (−;0.35 days month−1), and hospital (−;0.78 days month−1) days (all P<0.01). Time to first vocalisation and first oral intake both decreased by 7 days (n=733; P<0.01). Anxiety decreased by 44% (from 35.9% to 20.0%), and depression decreased by 55% (from 38.7% to 18.3%) (n=385; both P<0.01). Independent economic analysis demonstrated £33 251 savings per patient, with projected annual UK National Health Service savings of £275 million.
Conclusions
This guided improvement programme for tracheostomy patients significantly improved the quality and safety of care, contributing rich qualitative improvement data. Patient-centred outcomes were improved along with significant efficiency and cost savings across diverse UK hospitals.
Clinical trial registration
IRAS-ID-206955; REC-Ref-16/LO/1196; NIHR Portfolio CPMS ID 31544
Ciliary neurotrophic factor activates astrocytes, redistributes their glutamate transporters GLAST and GLT-1 to raft microdomains, and improves glutamate handling in vivo.
No full textTo study the functional role of activated astrocytes in glutamate homeostasis in vivo, we used a model of sustained astrocytic activation in the rat striatum through lentiviral-mediated gene delivery of ciliary neurotrophic factor (CNTF). CNTF-activated astrocytes were hypertrophic, expressed immature intermediate filament proteins and highly glycosylated forms of their glutamate transporters GLAST and GLT-1. CNTF overexpression produced a redistribution of GLAST and GLT-1 into raft functional membrane microdomains, which are important for glutamate uptake. In contrast, CNTF had no detectable effect on the expression of a number of neuronal proteins and on the spontaneous glutamatergic transmission recorded from striatal medium spiny neurons. These results were replicated in vitro by application of recombinant CNTF on a mixed neuron/astrocyte striatal culture. Using microdialysis in the rat striatum, we found that the accumulation of extracellular glutamate induced by quinolinate (QA) was reduced threefold with CNTF. In line with this result, CNTF significantly increased QA-induced [(18)F]-fluoro-2-deoxyglucose uptake, an indirect index of glutamate uptake by astrocytes. Together, these data demonstrate that CNTF activation of astrocytes in vivo is associated with marked phenotypic and molecular changes leading to a better handling of increased levels of extracellular glutamate. Activated astrocytes may therefore be important prosurvival agents in pathological conditions involving defects in glutamate homeostasis
Estudo do mecanismo neuroprotetor da guanosina em fatias de hipocampo de ratos submetidas à privação de glicose e oxigêncio
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas. Programa de Pós-Graduação em Neurociências
Regulation of the microglial NADPH oxidase by neurotransmitters: implications for microglial – neuronal interactions
No full textNeurotransmitter dysregulation and reactive oxygen species (ROS) are a hallmark of neurodegenerative disease. Microglia, the immune cells of the CNS, express three NADPH oxidase isoforms (Nox1, Nox2 and Nox4), which produce superoxide that is used as an intracellular signalling molecule, mediating the production of neurotoxic and neurotrophic factors. Microglia also express a range of neurotransmitter receptors, enabling them to respond to physiological and pathological levels of neurotransmitters. As both microglial superoxide production and neurotransmitter dysregulation are common to many neurodegenerative conditions, the interaction between microglial neurotransmitter receptor modulation and NADPH oxidase activation was investigated.
Superoxide production was assessed in primary and BV2 microglia using flow cytometry, HPLC, fluorescence microscopy, and a colorometric assay. Glutamate (1 μM), GABA (100 μM) or BzATP (250 μM) induced NADPH oxidase derived superoxide production. Furthermore, antagonism of the group I mGluRs induced Nox1 and Nox2 dependent superoxide production through PKC / PI3-K pathways and p44/42ERK activation. Activation of mGluR3 induced Nox2 and Nox4 activation in a p44/42ERK and p38MAPK dependent manner, whilst activation of the group III mGluRs induced Nox2 and Nox4 activation dependent on p38MAPK signalling. Microglial NMDA receptor activation promoted superoxide production that was dependent on p38MAPK activation. Modulation of the microglial glutamate receptors mediated protection of cerebellar granule neurons, as deomstrated using microglial conditioned media assays. Activation of the microglial GABAA receptor induced Nox1 activation through PKC and p38MAPK signalling which mediated TNFα release and neurotoxicity, whilst P2Y2/4 receptor activation mediated Nox1 activation through PI3-K and p38MAPK with neurotoxic consequences. The findings in this thesis show that microglial Nox2 and Nox4 activation has neuroprotective consequences, whereas microglial Nox1 activation mediates neurotoxicity. Modulation of the microglial neurotransmitter receptors therefore has ramifications for the survival of neurons in degenerative diseases, which could have important consequences for the production of future therapies for neurodegenerative conditions
