6 research outputs found
mGlu1 Receptor-Induced LTD of NMDA Receptor Transmission Selectively at Schaffer Collateral-CA1 Synapses Mediates Metaplasticity
No full textHippocampal CA1 pyramidal neurons receive inputs from entorhinal cortex directly via the temporoammonic (TA) pathway and indirectly via the Schaffer collateral (SC) pathway from CA3. NMDARs at synapses of both pathways are critical for the induction of synaptic plasticity, information processing, and learning and memory. We now demonstrate that, in the rat hippocampus, activity-dependent mGlu1 receptor-mediated LTD (mGlu1-LTD) of NMDAR-mediated transmission (EPSCNMDA) at the SC-CA1 input prevents subsequent LTP of AMPAR-mediated transmission. In contrast, there was no activity-dependent mGlu1-LTD of EPSCNMDA at the TA-CA1 pathway, or effects on subsequent plasticity of AMPAR-mediated transmission. Therefore, the two major pathways delivering information to CA1 pyramidal neurons are subject to very different plasticity rules.</p
Microcirculatory Impairment Is Associated With Multiple Organ Dysfunction Following Traumatic Hemorrhagic Shock: The MICROSHOCK Study.
No full textOBJECTIVES
To assess the relationship between microcirculatory perfusion and multiple organ dysfunction syndrome in patients following traumatic hemorrhagic shock.
DESIGN
Multicenter prospective longitudinal observational study.
SETTING
Three U.K. major trauma centers.
PATIENTS
Fifty-eight intubated and ventilated patients with traumatic hemorrhagic shock.
INTERVENTIONS
Sublingual incident dark field microscopy was performed within 12 hours of ICU admission (D0) and repeated 24 and 48 hours later. Cardiac output was assessed using oesophageal Doppler. Multiple organ dysfunction syndrome was defined as Serial Organ Failure Assessment score greater than or equal to 6 at day 7 post injury.
MEASUREMENTS AND MAIN RESULTS
Data from 58 patients were analyzed. Patients had a mean age of 43 ± 19 years, Injury Severity Score of 29 ± 14, and initial lactate of 7.3 ± 6.1 mmol/L and received 6 U (interquartile range, 4-11 U) of packed RBCs during initial resuscitation. Compared with patients without multiple organ dysfunction syndrome at day 7, patients with multiple organ dysfunction syndrome had lower D0 perfused vessel density (11.2 ± 1.8 and 8.6 ± 1.8 mm/mm; p < 0.01) and microcirculatory flow index (2.8 [2.6-2.9] and 2.6 [2.2-2.8]; p < 0.01) but similar cardiac index (2.5 [± 0.6] and 2.1 [± 0.7] L/min//m; p = 0.11). Perfused vessel density demonstrated the best discrimination for predicting subsequent multiple organ dysfunction syndrome (area under curve 0.87 [0.76-0.99]) compared with highest recorded lactate (area under curve 0.69 [0.53-0.84]), cardiac index (area under curve 0.66 [0.49-0.83]) and lowest recorded systolic blood pressure (area under curve 0.54 [0.39-0.70]).
CONCLUSIONS
Microcirculatory hypoperfusion immediately following traumatic hemorrhagic shock and resuscitation is associated with increased multiple organ dysfunction syndrome. Microcirculatory variables are better prognostic indicators for the development of multiple organ dysfunction syndrome than more traditional indices. Microcirculatory perfusion is a potential endpoint of resuscitation following traumatic hemorrhagic shock
Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial
No full textBackground Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the UK; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of paediatric convulsive status epilepticus.Methods This open-label, randomised clinical trial was undertaken at 30 UK emergency departments at secondary and tertiary care centres. Participants aged 6 months to under 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomisation schedule to receive levetiracetam (40 mg/kg over 5 min) or phenytoin (20 mg/kg over at least 20 min), stratified by centre. The primary outcome was time from randomisation to cessation of convulsive status epilepticus, analysed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomisation and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894.Findings Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomised participants were treated and had available data: 152 allocated to levetiracetam, and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomisation to cessation of convulsive status epilepticus was 35 min (IQR 20 to not assessable) in the levetiracetam group and 45 min (24 to not assessable) in the phenytoin group (hazard ratio 1·20, 95% CI 0·91–1·60; p=0·20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral oedema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]). Interpretation Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of paediatric convulsive status epilepticus
Effect of Amoxicillin Dose and Treatment Duration on the Need for Antibiotic Re-treatment in Children With Community-Acquired Pneumonia: The CAP-IT Randomized Clinical Trial.
No full textImportance: The optimal dose and duration of oral amoxicillin for children with community-acquired pneumonia (CAP) are unclear. Objective: To determine whether lower-dose amoxicillin is noninferior to higher dose and whether 3-day treatment is noninferior to 7 days. Design, Setting, and Participants: Multicenter, randomized, 2 × 2 factorial noninferiority trial enrolling 824 children, aged 6 months and older, with clinically diagnosed CAP, treated with amoxicillin on discharge from emergency departments and inpatient wards of 28 hospitals in the UK and 1 in Ireland between February 2017 and April 2019, with last trial visit on May 21, 2019. Interventions: Children were randomized 1:1 to receive oral amoxicillin at a lower dose (35-50 mg/kg/d; n = 410) or higher dose (70-90 mg/kg/d; n = 404), for a shorter duration (3 days; n = 413) or a longer duration (7 days; n = 401). Main Outcomes and Measures: The primary outcome was clinically indicated antibiotic re-treatment for respiratory infection within 28 days after randomization. The noninferiority margin was 8%. Secondary outcomes included severity/duration of 9 parent-reported CAP symptoms, 3 antibiotic-related adverse events, and phenotypic resistance in colonizing Streptococcus pneumoniae isolates. Results: Of 824 participants randomized into 1 of the 4 groups, 814 received at least 1 dose of trial medication (median [IQR] age, 2.5 years [1.6-2.7]; 421 [52%] males and 393 [48%] females), and the primary outcome was available for 789 (97%). For lower vs higher dose, the primary outcome occurred in 12.6% with lower dose vs 12.4% with higher dose (difference, 0.2% [1-sided 95% CI -∞ to 4.0%]), and in 12.5% with 3-day treatment vs 12.5% with 7-day treatment (difference, 0.1% [1-sided 95% CI -∞ to 3.9]). Both groups demonstrated noninferiority with no significant interaction between dose and duration (P = .63). Of the 14 prespecified secondary end points, the only significant differences were 3-day vs 7-day treatment for cough duration (median 12 days vs 10 days; hazard ratio [HR], 1.2 [95% CI, 1.0 to 1.4]; P = .04) and sleep disturbed by cough (median, 4 days vs 4 days; HR, 1.2 [95% CI, 1.0 to 1.4]; P = .03). Among the subgroup of children with severe CAP, the primary end point occurred in 17.3% of lower-dose recipients vs 13.5% of higher-dose recipients (difference, 3.8% [1-sided 95% CI, -∞ to10%]; P value for interaction = .18) and in 16.0% with 3-day treatment vs 14.8% with 7-day treatment (difference, 1.2% [1-sided 95% CI, -∞ to 7.4%]; P value for interaction = .73). Conclusions and Relevance: Among children with CAP discharged from an emergency department or hospital ward (within 48 hours), lower-dose outpatient oral amoxicillin was noninferior to higher dose, and 3-day duration was noninferior to 7 days, with regard to need for antibiotic re-treatment. However, disease severity, treatment setting, prior antibiotics received, and acceptability of the noninferiority margin require consideration when interpreting the findings. Trial Registration: ISRCTN Identifier: ISRCTN76888927
Microglial glutathione and glutamate: regulation mechanisms
No full textMicroglia, the immune cells of the central nervous system (CNS), are important in the protection of the CNS, but may be implicated in the pathogenesis of neuroinflammatory disease. Upon activation, microglia produce reactive oxygen and nitrogen species; intracellular antioxidants are therefore likely to be important in their self-defence. Here, it was confirmed that cultured microglia contain high levels of glutathione, the predominant intracellular antioxidant in mammalian cells. The activation of microglia with lipopolysaccharide (LPS) or LPS + interferon-gamma was shown to affect their glutathione levels. GSH levels in primary microglia and those of the BV-2 cell line increased upon activation, whilst levels in N9 microglial cells decreased.
Microglial glutathione synthesis is dependent upon cystine uptake via the xc- transporter, which exchanges cystine and glutamate. Glutamate is an excitatory neurotransmitter whose extracellular concentration is tightly regulated by excitatory amino acid transporters, as high levels cause toxicity to neurones and other CNS cell types through overstimulation of glutamate receptors or by causing reversal of xc- transporters. Following exposure to LPS, increased extracellular glutamate and increased levels of messenger ribonucleic acid (mRNA) for xCT, the specific subunit of xc-, were observed in BV-2 and primary microglial cells, suggesting upregulated GSH synthesis. An activation-induced decrease in N9 GSH levels suggests that this cell line is more susceptible to oxidative damage, and may be less able to upregulate GSH synthesis. Albumin, to which microglia may be exposed following blood-brain barrier damage, increased iNOS expression, glutamate release, xCT mRNA levels and intracellular levels of GSH and ATP in BV-2 and primary microglia. Primary and BV-2 microglial conditioned medium contained low levels of GSH, suggesting that microglia may release GSH.
Modulation of microglial metabotropic glutamate receptors (mGluRs) may alter microglial activation and neurotoxicity. Here, stimulation of the neuroprotective mGluR5 and group III mGluRs caused a decline in GSH levels in BV-2 and N9 microglia, respectively. In contrast mGluR1 stimulation may increase BV-2 GSH levels. The work presented in this thesis therefore extends current knowledge regarding microglial GSH and its regulation, and contributes to the understanding of microglial neurotoxicity and neuroprotection
The surgical safety checklist and patient outcomes after surgery: a prospective observational cohort study, systematic review and meta-analysis
No full textThe ISOS study was funded through an unrestricted research
grant from Nestle Health Sciences. T.E.F.A. is supported by a
Medical Research Council/British Journal of Anaesthesia clinical
research training fellowship. B.B. is funded by a National
Research Foundation rating grant and an MRC (SA) selfinitiated
research grant. M.G. is a Chief Scientist Office (Scotland)
NHS Research Scheme Clinician. R.P. is a UK National
Institute for Health Research Professor
