Summary
Target‐controlled infusion systems are increasingly used to administer intravenous anaesthetic drugs to achieve a user‐specified plasma or effect‐site target concentration. While several ...studies have investigated the ability of the underlying pharmacokinetic‐dynamic models to predict plasma concentrations, there are no data on their performance in predicting drug concentrations in the human brain. We assessed the predictive performance of the Marsh propofol model and Minto remifentanil model for plasma and brain tissue concentrations. Plasma samples were obtained during neurosurgery from 38 patients, and brain tissue samples from nine patients. Propofol and remifentanil concentrations were measured using gas chromatography mass spectrometry and liquid chromatography tandem mass spectrometry. Data were analysed from the nine patients in whom both plasma and brain samples were simultaneously obtained. For the Minto model (five patients), the median performance error was 72% for plasma and −14% for brain tissue concentration predictions. The model tended to underestimate plasma remifentanil concentrations, and to overestimate brain tissue remifentanil concentrations. For the Marsh model (five patients), the median prediction errors for plasma and brain tissue concentrations were 12% and 81%, respectively. However, when the data from all blood propofol assays (36 patients) were analysed, the median prediction error was 11%, with overprediction in 15 (42%) patients and underprediction in 21 (58%). These findings confirm earlier reports demonstrating inaccuracy for commonly used pharmacokinetic‐dynamic models for plasma concentrations and extend these findings to the prediction of effect‐site concentrations.
Damage to the eye from blast exposure can occur as a result of the overpressure air-wave (primary injury), flying debris (secondary injury), blunt force trauma (tertiary injury), and/or ...chemical/thermal burns (quaternary injury). In this study, we investigated damage in the contralateral eye after a blast directed at the ipsilateral eye in the C57Bl/6J and DBA/2J mouse. Assessments of ocular health (gross pathology, electroretinogram recordings, optokinetic tracking, optical coherence tomography and histology) were performed at 3, 7, 14 and 28 days post-trauma. Olfactory epithelium and optic nerves were also examined. Anterior pathologies were more common in the DBA/2J than in the C57Bl/6 and could be prevented with non-medicated viscous eye drops. Visual acuity decreased over time in both strains, but was more rapid and severe in the DBA/2J. Retinal cell death was present in approximately 10% of the retina at 7 and 28 days post-blast in both strains. Approximately 60% of the cell death occurred in photoreceptors. Increased oxidative stress and microglial reactivity was detected in both strains, beginning at 3 days post-injury. However, there was no sign of injury to the olfactory epithelium or optic nerve in either strain. Although our model directs an overpressure air-wave at the left eye in a restrained and otherwise protected mouse, retinal damage was detected in the contralateral eye. The lack of damage to the olfactory epithelium and optic nerve, as well as the different timing of cell death as compared to the blast-exposed eye, suggests that the injuries were due to physical contact between the contralateral eye and the housing chamber of the blast device and not propagation of the blast wave through the head. Thus we describe a model of mild blunt eye trauma.
Poor adherence to guidelines aimed at reducing the incidence of postoperative nausea and vomiting (PONV) is well known. In a before-and-after study, we tested the effectiveness of a simplified ...algorithm for PONV prophylaxis on the incidence of PONV.
In the first audit, we examined the adherence to our institutional guidelines for PONV prevention. In response to the results of this audit, we introduced a simplified algorithm for PONV prevention female patients receiving triple prophylaxis (dexamethasone and ondansetron plus either a target-controlled infusion with propofol or droperidol) and male patients receiving double prophylaxis, dexamethasone, and ondansetron. The impact of the simplification of the PONV algorithm was evaluated in a second audit. In both audits, we reviewed the medical records of all adult patients undergoing elective non-cardiac non-day-case surgery under general anaesthesia and being admitted to our post-anaesthesia care unit during two arbitrarily chosen weeks. We assessed the incidence of nausea, vomiting, and PONV after 1 and 24 h, and the compliance with the departmental algorithm for PONV prophylaxis.
After simplification of the PONV algorithm, the overall incidence of PONV within 24 h after surgery was significantly lower than before the implementation of the simplified PONV algorithm (22% vs 33%, P=0.02). The PONV incidence within 1 h was comparable between the audits (11% vs 14%, P=0.45). The adherence to departmental guidelines for PONV prophylaxis was significantly higher after the implementation of the simplified PONV algorithm (46% vs 18%, P=0.0001).
A simplified algorithm for PONV prophylaxis resulted in a significant reduction in the PONV incidence and better compliance with the PONV algorithm.
Chronic stress impairs learning and memory in humans and rodents and disrupts long-term potentiation (LTP) in animal models. These effects are associated with structural changes in hippocampal ...neurons, including reduced dendritic arborization. Unlike the generally reversible effects of chronic stress on adult rat hippocampus, we have previously found that the effects of early-life stress endure and worsen during adulthood, yet the mechanisms for these clinically important sequelae are poorly understood. Stress promotes secretion of the neuropeptide corticotropin-releasing hormone (CRH) from hippocampal interneurons, activating receptors (CRF(1)) located on pyramidal cell dendrites. Additionally, chronic CRF(1) occupancy negatively affects dendritic arborization in mouse organotypic slice cultures, similar to the pattern observed in middle-aged, early-stressed (CES) rats. Here we found that CRH expression is augmented in hippocampus of middle-aged CES rats, and then tested whether the morphological defects and poor memory performance in these animals involve excessive activation of CRF(1) receptors. Central or peripheral administration of a CRF(1) blocker following the stress period improved memory performance of CES rats in novel-object recognition tests and in the Morris water maze. Consonant with these effects, the antagonist also prevented dendritic atrophy and LTP attenuation in CA1 Schaffer collateral synapses. Together, these data suggest that persistently elevated hippocampal CRH-CRF(1) interaction contributes importantly to the structural and cognitive impairments associated with early-life stress. Reducing CRF(1) occupancy post hoc normalized hippocampal function during middle age, thus offering potential mechanism-based therapeutic interventions for children affected by chronic stress.
Neuroinflammation is a normal and healthy response to neuronal damage. However, excessive or chronic neuroinflammation exacerbates neurodegeneration after trauma and in progressive diseases such as ...Alzheimer's, Parkinson's, age-related macular degeneration, and glaucoma. Therefore, molecules that modulate neuroinflammation are candidates as neuroprotective agents. Erythropoietin (EPO) is a known neuroprotective agent that indirectly attenuates neuroinflammation, in part, by inhibiting neuronal apoptosis. In this review, we provide evidence that EPO also modulates neuroinflammation upstream of apoptosis by acting directly on glia. Further, the signaling induced by EPO may differ depending on cell type and context possibly as a result of activation of different receptors. While significant progress has been made in our understanding of EPO signaling, this review also identifies areas for future study in terms of the role of EPO in modulating neuroinflammation.
Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To ...elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.
Acyclic Boryl Complexes of Copper(I) Charman, Rex S. C.; Hobson, Josie A.; Jackson, Ross A. ...
Chemistry : a European journal,
January 2, 2024, Letnik:
30, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Reaction of (6‐Dipp)CuOtBu (6‐Dipp=C{NDippCH2}2CH2, Dipp=2,6‐iPr2C6H3) with B2(OMe)4 provided access to (6‐Dipp)CuB(OMe)2 via σ‐bond metathesis. (6‐Dipp)CuB(OMe)2 was characterised by NMR ...spectroscopy and X‐ray crystallography and shown to be a monomeric acyclic boryl of copper. (6‐Dipp)CuB(OMe)2 reacted with ethylene and diphenylacetylene to provide insertion compounds into the Cu‐B bond which were characterised by NMR spectroscopy in both cases and X‐ray crystallography in the latter. It was also competent in the rapid catalytic deoxygenation of CO2 in the presence of excess B2(OMe)4. Alongside π‐insertion, (6‐Dipp)CuB(OMe)2 reacted with LiNMe2 to provide a salt metathesis reaction at boron, giving (6‐Dipp)CuB(OMe)NMe2, a second monomeric acyclic boryl, which also cuproborated diphenylacetylene. Computational interrogation validated these acyclic boryl species to be electronically similar to (6‐Dipp)CuBpin.
A ring‐expanded NHC, 6‐Dipp ((6‐Dipp=C{NDippCH2}2CH2, Dipp=2,6‐iPr2C6H3)), has been shown to support two acyclic boryls. Reaction of (6‐Dipp)CuOtBu with B2(OMe)4 provided access to (6‐Dipp)CuB(OMe)2, the first acyclic boryl of copper, which was shown to react similarly to its cyclic cousins. Remarkably, however, it could also be subjected to salt metathesis to access (6‐Dipp)CuB(OMe)NMe2, the second acyclic boryl of copper.
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