Use of bispectral electroencephalogram monitoring to assess neurologic status in unsedated, critically ill patients

OBJECTIVE: To test whether spectral indices derived from the electroencephalogram (EEG), and especially the bispectral index (BIS), can be used as measures of neurologic status in unsedated, critically ill patients. DESIGN: Prospective, observational study. SETTING: Medical intensive care unit (ICU) of a university-affiliated teaching hospital. PATIENTS: Thirty-one awake, unsedated critically ill adults were assessed in 108 separate sessions. MEASUREMENTS AND MAIN RESULTS: In each session, severity of illness was assessed by the Acute Physiology and Chronic Health Evaluation (APACHE III). The APACHE III Acute Physiology Score was used to quantify the degree of physiologic derangement. Neurologic function was assessed using the APACHE III Neurologic Score, the Glasgow Coma Scale, the Reaction Level Scale, and the Modified Ramsay Sedation Scale. All indices were plotted against various spectral parameters of the EEG, including BIS, an empirical index of EEG activity that is scaled from 0 to 100. BIS was significantly (p <.05) correlated with neurologic score regardless of scoring system used and was more strongly correlated than any other EEG spectral parameter. Better neurologic function was associated with higher values of BIS. In multivariate analysis, the combination of BIS and relative power in the theta band of the EEG accounted for 38% of the variability in the Glasgow Coma Scale. CONCLUSIONS: BIS provides a reliable index of neurologic status in awake, unsedated, critically ill patients. Further research is needed to determine whether the effects of neurologic status and pharmacologic sedation upon EEG are additive, whether BIS can be used to assess pharmacologic sedation in the critically ill patient population, and whether such objective measures of neurologic status have prognostic value.     

Pharmacokinetic and pharmacodynamic interaction between mexiletine and propafenone in human beings

BACKGROUND AND OBJECTIVE: Mexiletine and propafenone are often used concomitantly and are metabolized by the same cytochrome P450 isozymes, namely CYP2D6, CYP1A2, and probably CYP3A4. Our objective was to study the potential pharmacokinetic and electrophysiological interactions between mexiletine and propafenone. METHODS: Fifteen healthy volunteers, 8 extensive metabolizers and 7 poor metabolizers of CYP2D6, received oral doses of mexiletine 100 mg two times daily from day 1 to day 8 and oral doses of propafenone 150 mg two times daily from day 5 to day 12. Interdose studies were performed at steady-state on mexiletine alone (day 4), mexiletine plus propafenone (day 8), and propafenone alone (day 12). RESULTS: In subjects in the extensive metabolizer group, coadministration of propafenone decreased oral clearances of R-(-)-mexiletine (from 41+/-11 L/h to 28+/-7 L/h) and S-(+)-mexiletine (from 43+/-15 L/h to 29+/-11 L/h) to an extent such that these values were no longer different between the extensive and the poor metabolizer groups. Propafenone coadministration also decreased partial metabolic clearances of mexiletine to hydroxymethylmexiletine, p-hydroxymexiletine, and m-hydroxymexiletine in extensive metabolizers by 71%, 67%, and 73%, respectively. In contrast, propafenone did not alter the kinetics of mexiletine enantiomers in subjects in the poor metabolizer group except for a slight decrease in the formation of hydroxymethylmexiletine. Pharmacokinetic parameters of propafenone were not changed during concomitant administration of mexiletine in subjects of either phenotype. Finally, electrocardiographic parameters (QRS duration, QTc, RR, and PR intervals) were not modified during the combined administration of the drugs. CONCLUSION: Propafenone is a potent CYP2D6 inhibitor that may cause an increase in plasma concentrations of coadministered CYP2D6 substrates.     

IGF1R signalling in testicular germ cell tumour cells impacts on cell survival and acquired cisplatin resistance

Testicular germ cell tumours (TGCTs) are the most frequent malignancy and cause of death from solid tumours in the 20‐ to 40‐year age group. Although most cases show sensitivity to cis‐platinum‐based chemotherapy, this is associated with long‐term toxicities and chemo‐resistance. Roles for receptor tyrosine kinases other than KIT are largely unknown in TGCT. We therefore conducted a phosphoproteomic screen and identified the insulin growth factor receptor‐1 (IGF1R) as both highly expressed and activated in TGCT cell lines representing the nonseminomatous subtype. IGF1R was also frequently expressed in tumour samples from patients with nonseminomas. Functional analysis of cell line models showed that long‐term shRNA‐mediated IGF1R silencing leads to apoptosis and complete ablation of nonseminoma cells with active IGF1R signalling. Cell lines with high levels of IGF1R activity also showed reduced AKT signalling in response to decreased IGF1R expression as well as sensitivity to the small‐molecule IGF1R inhibitor NVP‐AEW541. These results were in contrast to those in the seminoma cell line TCAM2 that lacked IGF1R signalling via AKT and was one of the two cell lines least sensitive to the IGF1R inhibitor. The dependence on IGF1R activity in the majority of nonseminomas parallels the known role of IGF signalling in the proliferation, migration, and survival of primordial germ cells, the putative cell of origin for TGCT. Upregulation of IGF1R expression and signalling was also found to contribute to acquired cisplatin resistance in an in vitro nonseminoma model, providing a rationale for targeting IGF1R in cisplatin‐resistant disease. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Dystrophin expression in muscle following gene transfer with a fully deleted ("gutted") adenovirus is markedly improved by trans-acting adenoviral gene products

Helper-dependent adenoviruses (HDAd) are Ad vectors lacking all or most viral genes. They hold great promise for gene therapy of diseases such as Duchenne muscular dystrophy (DMD), because they are less immunogenic than E1/E3-deleted Ad (first-generation Ad or FGAd) and can carry the full-length (Fl) dystrophin (dys) cDNA (12 kb). We have compared the transgene expression of a HDAd (HDAdCMVDysFl) and a FGAd (FGAdCMV-dys) in cell culture (HeLa, C2C12 myotubes) and in the muscle of mdx mice (the mouse model for DMD). Both vectors encoded dystrophin regulated by the same cytomegalovirus (CMV) promoter. We demonstrate that the amount of dystrophin expressed was significantly higher after gene transfer with FGAdCMV-dys compared to HDAdCMVDysFl both in vitro and in vivo. However, gene transfer with HDAdCMVDysFl in the presence of a FGAd resulted in a significant increase of dystrophin expression indicating that gene products synthesized by the FGAd increase, in trans, the amount of dystrophin produced. This enhancement occurred in cell culture and after gene transfer in the muscle of mdx mice and dystrophic golden retriever (GRMD) dogs, another animal model for DMD. The E4 region of Ad is required for the enhancement, because no increase of dystrophin expression from HDAdCMVDysFl was observed in the presence of an E1/E4-deleted Ad in vitro and in vivo. The characterization of these enhancing gene products followed by their inclusion into an HDAd may be required to produce sufficient dystrophin to mitigate the pathology of DMD by HDAd-mediated gene transfer.     

Potential clinical use of butyric acid derivatives to induce antigen-specific T cell inactivation

Compounds with the capacity to induce antigen-specific unresponsiveness in CD4(+) T cells can in some clinical situations be more beneficial than general immune suppressants. Newly synthesized ester, ester/amide, and amide derivatives of butyrate with the capacity to induce antigen-specific T cell unresponsiveness in vivo and in vitro were tested here. The ester and ester/amide derivatives of butyrate were shown to block proliferation by interleukin-2-stimulated murine Th1 cells in vitro. A 3-day treatment with these same two derivatives also suppressed a primary antibody response to a thymus-dependent antigen in mice. In addition, even a single injection of the ester derivative of n-butyrate 2-(4-morpholinyl)ethyl butyrate hydrochloride (MEB) on day 2 or 3 after immunization suppressed the generation of memory T cells capable of proliferating to antigen or of promoting a secondary antigen-specific antibody response. MEB also induced antigen-specific unresponsiveness in antigen-activated, but not resting or interleukin-2-activated, T cells in vitro. DNA analysis showed that regardless of when MEB was added to the cultures, it induced the eventual G(1) sequestration of essentially all activated Th1 cells. Because G(1) blockade is associated with Th1 cell anergy, this finding suggests that MEB has the potential to induce anergy in already-activated CD4(+) T cells. Taken together, the results presented here establish MEB as a novel means of inducing anergy in CD4(+) T cells both in vitro and in vivo and underscore the likelihood that MEB and/or other butyrate derivatives can be used as immunotherapeutic reagents.     

Achieving a sustained reduction in benzodiazepine use through implementation of an area-wide multi-strategic approach

OBJECTIVE: This study aimed to evaluate the impact, in a regional setting, of a multi-strategic partnership approach for reducing benzodiazepine use in the management of insomnia, as recommended in Australia's National Policy on Quality Use of Medicines. METHOD: The setting was a rural region of South Australia, covering approximately 2000 km2, with a population of over 20 000. The study involved participatory action research, with qualitative and quantitative evaluations. The intervention involved a multi-strategic approach, including provision of treatment guidelines, provision of consumer information, a local media campaign and education and training of health professionals. The quantitative evaluation involved a single region before/after study with 2 years of follow-up using pharmacy-based dispensing data for benzodiazepines and antidepressants, gathered for the months of November to April in 1998/99 ('before' period) through to 2000/01 ('after' period). The data were analysed using non-parametric statistics. RESULTS: There was a 19% reduction in benzodiazepine dispensing 2 years after the intervention compared with a 6% reduction nationally. Dispensing of antidepressants increased by 33%, compared with a 28% increase nationally. CONCLUSION: It was concluded that the multi-strategic approach to the management of sleep disorders proved successful in promoting the use of non-drug alternatives, achieving sustained reduction in benzodiazepine consumption in a rural community, without therapeutic substitution of antidepressants. IMPLICATIONS: The study demonstrated that a sustainable reduction in prescribing of benzodiazepines can be achieved through the implementation of a multi-strategic approach involving local consumers, health professionals, a Division of General Practice, a government department, aged-care facilities and the local media.     

Modified system outcome score and outcome index--method of monitoring patient care in a special care area

A scoring system intended both to assess mortality risk and permit surveillance, evaluation, and comparison of medical care was developed in our surgical ICU. Five simple clinical indices of organ system failure were selected and weighted according to their statistically validated relationship to mortality, resulting in a daily System Outcome Score (SOS). Cluster analysis was used to divide the creation data set of 2,777 patients into suitable groupings of scores to predict mortality; the clustering was confirmed for reproducibility with a validation set of an additional 2,860 patients. Based on this validation of the scoring system, two computer-controlled patient care surveillance techniques were developed. The first involved the definition of three unfavorable SOS patterns evolving during the course of a patient's admission. Detection of one or more of these patterns, described by the acronym SDL, permits review of the care administered to the specific patient generating the pattern. A global assessment of care is achieved with the Outcome Index (OI), which relates overall mortality risk in the ICU to the actual mortality rate over a given time period. Effectiveness of care can then be compared between different time periods within the one unit or between different units with similar patient mix. The overall system offers the potential for a surveillance-based quality assurance system with widespread applicability.     

Aminoglycoside-induced increase of intracellular calcium in LLC-PK1 cells due to an artifact caused by trypsin and EDTA.

Dietary calcium supplements attenuate experimental aminoglycoside nephrotoxicity. In cultured renal tubular cells, intracellular calcium levels have been reported to rise with aminoglycoside addition to the culture medium. In experiments designed to verify the in vitro influence of calcium on cultured kidney cells, we detected an unexpected artifact. When we resuspended cultured LLC-PK1 cells with trypsin and EDTA to measure intracellular calcium levels, our results correlated well with previously reported values. However, we saw no increase in intracellular calcium levels when we measured them by digital imaging video microscopy unless trypsin-EDTA exposure preceded aminoglycoside exposure. This apparent artifact should be considered in any study of the effects of various agents on intracellular calcium levels.     

Stopping the active intervention: CARET

The Carotene and Retinol Efficacy Trial (CARET) was a large, multicenter randomized chemoprevention trial designed to test a combined lung cancer prevention agent in heavy smokers and workers exposed to asbestos. In January 1996, the CARET Steering Committee decided to stop the intervention due to an adverse effect. This paper describes the decision process used to apply the stopping rules and the activities engaged in by CARET participants and staff to implement the decision. The most important activity was to draft and mail a letter to the participants informing them of the disappointing CARET results and asking them to stop taking the study vitamins and to return any unused study vitamins. The steering committee, with the support of the National Cancer Institute, planned to follow participants for disease endpoints and smoking behavior for 5 years. These activities led to smooth closure of active intervention and maintained high retention rates during the transition.