Control of muscle relaxation during anesthesia: a novel approach for clinical routine

During general anesthesia drugs are administered to provide hypnosis, ensure analgesia, and skeletal muscle relaxation. In this paper, the main components of a newly developed controller for skeletal muscle relaxation are described. Muscle relaxation is controlled by administration of neuromuscular blocking agents. The degree of relaxation is assessed by supramaximal train-of-four stimulation of the ulnar nerve and measuring the electromyogram response of the adductor pollicis muscle. For closed-loop control purposes, a physiologically based pharmacokinetic and pharmacodynamic model of the neuromuscular blocking agent mivacurium is derived. The model is used to design an observer-based state feedback controller. Contrary to similar automatic systems described in the literature this controller makes use of two different measures obtained in the train-of-four measurement to maintain the desired level of relaxation. The controller is validated in a clinical study comparing the performance of the controller to the performance of the anesthesiologist. As presented, the controller was able to maintain a preselected degree of muscle relaxation with excellent precision while minimizing drug administration. The controller performed at least equally well as the anesthesiologist.

Ezrin/radixin/moesin: Versatile controllers of signaling molecules and of the cortical cytoskeleton

Ezrin, radixin and moesin (ERM) proteins are widely distributed proteins located in the cellular cortex, in microvilli and adherens junctions. They feature an N-terminal membrane binding domain linked by an alpha-helical domain to the C-terminal actin-binding domain. In the dormant state, binding sites in the N-terminal domain are masked by interactions with the C-terminal region. The alpha-helical domain also contributes to masking of binding sites. A specific sequence of signaling events results in dissociation of these intramolecular interactions resulting in ERM activation. ERM molecules have been implicated in mediating actin-membrane linkage and in regulating signaling molecules. They are involved in cell membrane organization, cell migration, phagocytosis and apoptosis, and may also play cell-specific roles in tumor progression. Their precise involvement in these processes has yet to be elucidated.

Present state of global wetland extent and wetland methane modelling: conclusions from a model inter-comparison project (WETCHIMP)

Global wetlands are believed to be climate sensitive, and are the largest natural emitters of methane (CH4). Increased wetland CH4 emissions could act as a positive feedback to future warming. The Wetland and Wetland CH4 Inter-comparison of Models Project (WETCHIMP) investigated our present ability to simulate large-scale wetland characteristics and corresponding CH4 emissions. To ensure inter-comparability, we used a common experimental protocol driving all models with the same climate and carbon dioxide (CO2) forcing datasets. The WETCHIMP experiments were conducted for model equilibrium states as well as transient simulations covering the last century. Sensitivity experiments investigated model response to changes in selected forcing inputs (precipitation, temperature, and atmospheric CO2 concentration). Ten models participated, covering the spectrum from simple to relatively complex, including models tailored either for regional or global simulations. The models also varied in methods to calculate wetland size and location, with some models simulating wetland area prognostically, while other models relied on remotely sensed inundation datasets, or an approach intermediate between the two. Four major conclusions emerged from the project. First, the suite of models demonstrate extensive disagreement in their simulations of wetland areal extent and CH4 emissions, in both space and time. Simple metrics of wetland area, such as the latitudinal gradient, show large variability, principally between models that use inundation dataset information and those that independently determine wetland area. Agreement between the models improves for zonally summed CH4 emissions, but large variation between the models remains. For annual global CH4 emissions, the models vary by ±40% of the all-model mean (190 Tg CH4 yr−1). Second, all models show a strong positive response to increased atmospheric CO2 concentrations (857 ppm) in both CH4 emissions and wetland area. In response to increasing global temperatures (+3.4 °C globally spatially uniform), on average, the models decreased wetland area and CH4 fluxes, primarily in the tropics, but the magnitude and sign of the response varied greatly. Models were least sensitive to increased global precipitation (+3.9 % globally spatially uniform) with a consistent small positive response in CH4 fluxes and wetland area. Results from the 20th century transient simulation show that interactions between climate forcings could have strong non-linear effects. Third, we presently do not have sufficient wetland methane observation datasets adequate to evaluate model fluxes at a spatial scale comparable to model grid cells (commonly 0.5°). This limitation severely restricts our ability to model global wetland CH4 emissions with confidence. Our simulated wetland extents are also difficult to evaluate due to extensive disagreements between wetland mapping and remotely sensed inundation datasets. Fourth, the large range in predicted CH4 emission rates leads to the conclusion that there is both substantial parameter and structural uncertainty in large-scale CH4 emission models, even after uncertainties in wetland areas are accounted for.

Assessing the state of Sustainable Land Management research in Kyrgyzstan and Tajikistan

This article synthesizes findings from a review of the state of research on sustainable land management in Kyrgyzstan and Tajikistan and from an analysis of the interface between research and action. Using the Global Land Project (GLP 2005) analytical framework, we analyzed the distribution of 131 selected publications (including a clearly defined set of local and international academic and gray literature) across the framework's components and links in a social–ecological system. There is a strong emphasis in the literature on the impact of changes in land use and management on ecosystems; however, there is little research on the implications for ecosystem services. This finding is opposed to that of a similar analysis of publications at the global scale (Björnsen Gurung et al 2012). Another major gap was the lack of research on Kyrgyzstan and Tajikistan regarding the influence of global factors on social and ecological systems, despite social, economic, and political integration into global structures since the collapse of the Soviet Union and the increasing influence of climate change. Our analysis disaggregated academic literature published in the region and international academic literature, revealing stark differences. These differences are partly attributable to the legacy of the late Soviet era principle of “rational use of land resources,” which fit the planned economy but lacks approaches for decentralized resource governance. Finally, the emphasis of research on systems knowledge, the lack of transdisciplinary research, and the critical feedback of stakeholders at a regional sustainable land management forum suggest that actionable sustainable land management research on Kyrgyzstan and Tajikistan is rare. Recommendations are made for targeted, application-focused, multistakeholder research and knowledge sharing, including local and international researchers as well as practitioners, policy-makers, and land users.

Feasibility of resting-state microstates neurofeedback

Despite major progress, currently available treatment options for patients suffering from schizophrenia remain suboptimal. Antipsychotic medication is one such option, and is helpful in acute phases of the disease. However, antipsychotics cause significant side-effects that often require additional medication, and can even trigger the discontinuation of treatment. Taken together, along with the fact that 20-30% of patients are medication-resistant, it is clear that new medical care options should be developed for patients with schizophrenia. Besides medication, an emerging option to treat psychiatric symptoms is through the use of neurofeedback. This technique has proven efficacy for other disorders and, more importantly, has also proven to be feasible in patients with schizophrenia. One of the major advantages of this approach is that it allows for the influence of brain states that otherwise would be inaccessible; i.e. the physiological markers underlying psychotic symptoms. EEG resting-state microstates are a very interesting electrophysiological marker of schizophrenia symptoms. Precisely, a specific class of resting-state microstates, namely microstate class D, has consistently been found to show a temporal shortening in patients with schizophrenia compared to controls, and this shortening is correlated with the presence positive psychotic symptoms. Under the scope of biological psychiatry, appropriate treatment of psychotic symptoms can be expected to modify the underlying physiological markers accompanying behavioral manifestations of a disease. We reason that if abnormal temporal parameters of resting-state microstates seem to be related to positive symptoms in schizophrenia, regulating this EEG feature might be helpful as a treatment for patients. The goal of this thesis was to prove the feasibility of microstate class D contribution self-regulation via neurofeedback. Given that no other study has attempted to regulate microstates via neurofeedback, we first tested its feasibility in a population of healthy subjects. In the first paper we describe the methodological characteristics of the neurofeedback protocol and its implementation. Neurofeedback performance was assessed by means of linear mixed effects modeling, which provided a complete profile of the neurofeedback’s training response within and between-subjects. The protocol included 20 training sessions, and each session contained three conditions: baseline (resting-state) and two active conditions: training (auditory feedback upon self-regulation performance) and transfer (self-regulation with no feedback). With linear modeling we obtained performance indices for each of them as follows: baseline carryover (baseline increments time-dependent) and learning and aptitude for each of the active conditions. Learning refers to the increase/decrease of the microstate class D contribution, time-dependent during each active condition, and aptitude refers to the constant difference of the microstate class D contribution between each active condition and baseline independent of time. The indices provided are discussed in terms of tailoring neurofeedback treatment to individual profiles so that it can be applied in future studies or clinical practice. In our sample of participants, neurofeedback proved feasible, as all participants at least showed positive results in one of the aforementioned learning indices. Furthermore, between-subjects we observed that the contribution of microstate class D across-sessions increased by 0.42% during baseline, 1.93% during training trials, and 1.83% during transfer. This range is expected to be effective in treating psychotic symptoms in patients. In the second paper presented in this thesis, we explored the possible predictors of neurofeedback success among psychological variables measured with questionnaires. An interesting finding was the negative correlation between “motivational incongruence” and some of the neurofeedback performance indices. Even though this finding requires replication, we discuss it in terms of the interfering effects of incompatible psychological processes with neurofeedback training requirements. In the third paper, we present a meta-analysis on all available studies that have related resting-state microstate abnormalities and schizophrenia. We obtained medium effect sizes for two microstate classes, namely C and D. Combining the meta-analysis results with the fact that microstate class D abnormalities are correlated with the presence of positive symptoms in patients with schizophrenia, these results add further support for the training of this precise microstate. Overall, the results obtained in this study encourage the implementation of this protocol in a population of patients with schizophrenia. However, future studies will have to show whether patients will be able to successfully self-regulate the contribution of microstate class D and, if so, whether this regulation will have an impact on symptomatology.