Effect of three anaesthetic techniques on isometric skeletal muscle strength

Background. Our aim was to quantify human involuntary isometric skeletal muscle strength during anaesthesia with propofol, sevoflurane, or spinal anaesthesia using bupivacaine. Methods. Thirty‐three healthy patients undergoing anaesthesia for elective lower limb surgery were investigated. Twenty‐two patients received a general anaesthetic with either propofol (n=12) or sevoflurane (n=10); for the remaining 11 patients spinal anaesthesia with bupivacaine was used. We used a non‐invasive muscle force assessment system before and during anaesthesia to determine the contractile properties of the ankle dorsiflexor muscles after peroneal nerve stimulation (single, double, triple, and quadruple stimulation). We measured peak torques; contraction times; peak rates of torque development and decay; times to peak torque development and decay; half‐relaxation times; torque latencies. Results. Males elicited greater peak torques than females, medians 6.3 vs 4.4 Nm, respectively (P=0.0002, Mann‐Whitney rank‐sum test). During sevoflurane and propofol anaesthesia, muscle strength did not differ from pre‐anaesthetic values. During spinal anaesthesia, torques were diminished for single‐pulse stimulation from 3.5 to 2.0 Nm (P=0.002, Wilcoxon signed rank test), and for double‐pulse from 7.6 to 5.6 Nm (P=0.02). Peak rates of torque development decreased for single‐pulse stimulation from 113 to 53 Nm s-1 and for double pulse from 195 to 105 Nm s-1. Torque latencies were increased during spinal anaesthesia. Conclusions. At clinically relevant concentrations, propofol and sevoflurane did not influence involuntary isometric skeletal muscle strength in adults, whereas spinal anaesthesia reduced strength by about 20%. Muscle strength assessment using a device such as described here provided reliable results and should be considered for use in other scientific investigations to identify potential effects of anaesthetic agents. Br J Anaesth 2004; 92: 367-7

Fulminant neuroleptic malignant syndrome after perioperative withdrawal of antiParkinsonian medication

Neuroleptic malignant syndrome is a rare complication when using neuroleptic drugs. We report the case of a patient with severe Parkinson's disease who developed neuroleptic malignant syndrome after withdrawal of his antiParkinsonian medication for elective coronary artery bypass grafting. Sodium dantrolene may be a therapeutic option in severe case

Reproducibility of in vitro contracture test results in patients tested for malignant hyperthermia susceptibility.

BACKGROUND: The in vitro contracture test (IVCT) is the golden standard to diagnose malignant hyperthermia susceptibility (MHS). A high reproducibility is important for a high validity of a test. METHODS: We have therefore analyzed IVCT in 838 patients, investigated in two laboratories. Each halothane and caffeine test was performed in two muscle strips. The test results were analyzed with respect to reproducibility of abnormal outcomes within pairs of tested muscle strips and size of contractures, thresholds and quality criteria. The patients were tested according to the European Malignant Hyperthermia Group protocol (EMHG). To fulfill quality criteria in the EMHG protocol the twitch height should be 10 mN (1 g) or more. For the caffeine test a minimum contracture of 50 mN (5 g) or more at 32 mmol l-1 caffeine could be used as an alternative quality criterion RESULTS: There was better reproducibility with larger contractures. The correlation between size of contractures and fraction of muscle strips with abnormal contractures was 0.77 or larger. Contractures < 5 mN (0.5 g) were reproducible in less than half of the tests. There was no difference in reproducibility or size of contractures between tests fulfillling all quality criteria and those not fulfillling these criteria. CONCLUSIONS: IVCT responses close to cut off limits, i.e. <5 mN (0.5 g) in the EMHG protocol, are less reproducible and must scientifically be considered as less reliable. The clinical cut off limits must remain unchanged for reasons of clinical safety. The outcome of quality measurements does not influence the test results

<i>Trypanosoma brucei rhodesiense</i> transmitted by a single tsetse fly bite in vervet monkeys as a model of human African trypanosomiasis

Sleeping sickness is caused by a species of trypanosome blood parasite that is transmitted by tsetse flies. To understand better how infection with this parasite leads to disease, we provide here the most detailed description yet of the course of infection and disease onset in vervet monkeys. One infected tsetse fly was allowed to feed on each host individual, and in all cases infections were successful. The characteristics of infection and disease were similar in all hosts, but the rate of progression varied considerably. Parasites were first detected in the blood 4-10 days after infection, showing that migration of parasites from the site of fly bite was very rapid. Anaemia was a key feature of disease, with a reduction in the numbers and average size of red blood cells and associated decline in numbers of platelets and white blood cells. One to six weeks after infection, parasites were observed in the cerebrospinal fluid (CSF), indicating that they had moved from the blood into the brain; this was associated with a white cell infiltration. This study shows that fly-transmitted infection in vervets accurately mimics human disease and provides a robust model to understand better how sleeping sickness develops

PSSA-2, a Membrane-Spanning Phosphoprotein of Trypanosoma brucei, Is Required for Efficient Maturation of Infection

The coat of Trypanosoma brucei consists mainly of glycosylphosphatidylinositol-anchored proteins that are present in several million copies and are characteristic of defined stages of the life cycle. While these major components of the coats of bloodstream forms and procyclic (insect midgut) forms are well characterised, very little is known about less abundant stage-regulated surface proteins and their roles in infection and transmission. By creating epitope-tagged versions of procyclic-specific surface antigen 2 (PSSA-2) we demonstrated that it is a membrane-spanning protein that is expressed by several different life cycle stages in tsetse flies, but not by parasites in the mammalian bloodstream. In common with other membrane-spanning proteins in T. brucei, PSSA-2 requires its cytoplasmic domain in order to exit the endoplasmic reticulum. Correct localisation of PSSA-2 requires phosphorylation of a cytoplasmic threonine residue (T305), a modification that depends on the presence of TbMAPK4. Mutation of T305 to alanine (T305A) has no effect on the localisation of the protein in cells that express wild type PSSA-2. In contrast, this protein is largely intracellular when expressed in a null mutant background. A variant with a T305D mutation gives strong surface expression in both the wild type and null mutant, but slows growth of the cells, suggesting that it may function as a dominant negative mutant. The PSSA-2 null mutant exhibits no perceptible phenotype in culture and is fully competent at establishing midgut infections in tsetse, but is defective in colonising the salivary glands and the production of infectious metacyclic forms. Given the protein's structure and the effects of mutation of T305 on proliferation and localisation, we postulate that PSSA-2 might sense and transmit signals that contribute to the parasite's decision to divide, differentiate or migrate

European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility

It is 30 yr since the British Journal of Anaesthesia published the first consensus protocol for the laboratory diagnosis of malignant hyperthermia susceptibility from the European Malignant Hyperthermia Group. This has subsequently been used in more than 10 000 individuals worldwide to inform use of anaesthetic drugs in these patients with increased risk of developing malignant hyperthermia during general anaesthesia, representing an early and successful example of stratified medicine. In 2001, our group also published a guideline for the use of DNA-based screening of malignant hyperthermia susceptibility. We now present an updated and complete guideline for the diagnostic pathway for patients potentially at increased risk of developing malignant hyperthermia. We introduce the new guideline with a narrative commentary that describes its development, the changes to previously published protocols and guidelines, and new sections, including recommendations for patient referral criteria and clinical interpretation of laboratory finding

The Legionella effector WipB is a translocated Ser/Thr phosphatase that targets the host lysosomal nutrient sensing machinery

Legionella pneumophila infects human alveolar macrophages and is responsible for Legionnaire’s disease, a severe form of pneumonia. L. pneumophila encodes more than 300 putative effectors, which are translocated into the host cell via the Dot/Icm type IV secretion system. These effectors highjack the host’s cellular processes to allow bacterial intracellular growth and replication. Here we adopted a multidisciplinary approach to investigate WipB, a Dot/Icm effector of unknown function. The crystal structure of the N-terminal domain at 1.7 Å resolution comprising residues 25 to 344 revealed that WipB harbours a Ser/Thr phosphatase domain related to the eukaryotic phospho-protein phosphatase (PPP) family. The C-terminal domain (residues 365–524) is sufficient to pilot the effector to acidified LAMP1-positive lysosomal compartments, where WipB interacts with the v-ATPase and the associated LAMTOR1 phosphoprotein, key components of the lysosomal nutrient sensing (LYNUS) apparatus that controls the mammalian target of rapamycin (mTORC1) kinase complex at the lysosomal surface. We propose that WipB is a lysosome-targeted phosphatase that modulates cellular nutrient sensing and the control of energy metabolism during Legionella infection

Anomaly detection in elderly daily behavior in ambient sensing environments

Current ubiquitous computing applications for smart homes aim to enhance people’s daily living respecting age span. Among the target groups of people, elderly are a population eager for “choices for living arrangements”, which would allow them to continue living in their homes but at the same time provide the health care they need. Given the growing elderly population, there is a need for statistical models able to capture the recurring patterns of daily activity life and reason based on this information. We present an analysis of real-life sensor data collected from 40 different households of elderly people, using motion, door and pressure sensors. Our objective is to automatically observe and model the daily behavior of the elderly and detect anomalies that could occur in the sensor data. For this purpose, we first introduce an abstraction layer to create a common ground for home sensor configurations. Next, we build a probabilistic spatio-temporal model to summarize daily behavior. Anomalies are then defined as significant changes from the learned behavioral model and detected using a cross-entropy measure. We have compared the detected anomalies with manually collected annotations and the results show that the presented approach is able to detect significant behavioral changes of the elderly

Systematic Functional Analysis of Bicaudal-D Serine Phosphorylation and Intragenic Suppression of a Female Sterile Allele of BicD

Protein phosphorylation is involved in posttranslational control of essentially all biological processes. Using mass spectrometry, recent analyses of whole phosphoproteomes led to the identification of numerous new phosphorylation sites. However, the function of most of these sites remained unknown. We chose the Drosophila Bicaudal-D protein to estimate the importance of individual phosphorylation events. Being involved in different cellular processes, BicD is required for oocyte determination, for RNA transport during oogenesis and embryogenesis, and for photoreceptor nuclei migration in the developing eye. The numerous roles of BicD and the available evidence for functional importance of BicD phosphorylation led us to identify eight phosphorylation sites of BicD, and we tested a total of 14 identified and suspected phosphoserine residues for their functional importance in vivo in flies. Surprisingly, all these serines turned out to be dispensable for providing sufficient basal BicD activity for normal growth and development. However, in a genetically sensitized background where the BicDA40V protein variant provides only partial activity, serine 103 substitutions are not neutral anymore, but show surprising differences. The S103D substitution completely inactivates the protein, whereas S103A behaves neutral, and the S103F substitution, isolated in a genetic screen, restores BicDA40V function. Our results suggest that many BicD phosphorylation events may either be fortuitous or play a modulating function as shown for Ser103. Remarkably, amongst the Drosophila serines we found phosphorylated, Ser103 is the only one that is fully conserved in mammalian BicD

Repeated administration of the GABAB receptor positive modulator BHF177 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine seeking in rats

Abstract: Rationale $\gamma$-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is implicated in the modulation of central reward processes. Acute or chronic administration of GABA$_B$ receptor agonists or positive modulators decreased self-administration of various drugs of abuse. Furthermore, GABA$_B$ receptor agonists inhibited cue-induced reinstatement of nicotine- and cocaine-seeking behavior. Because of their fewer adverse side effects compared with GABA$_B$ receptor agonists, GABA$_B$ receptor positive modulators are potentially improved therapeutic compounds for the treatment of drug dependence compared with agonists. Objectives and methods: We examined whether the acute effects of the GABA$_B$ receptor positive modulator N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine (BHF177) on nicotine self- administration and food-maintained responding under a fixed-ratio 5 schedule of reinforcement were maintained after repeated administration. The effects of acute BHF177 administration on cue-induced nicotine- and food-seeking behavior, a putative animal model of relapse, were also examined. Results: Repeated administration of BHF177 for 14 days decreased nicotine self-administration, with small tolerance observed during the last 7 days of treatment, whereas BHF177 minimally affected food-maintained responding. Acute BHF177 administration dose-dependently blocked cue-induced reinstatement of nicotine-, but not food-, seeking behavior after a 10-day extinction period. Conclusions: These results showed that BHF177 selectively blocked nicotine self-administration and prevented cueinduced reinstatement of nicotine seeking, with minimal effects on responding for food and no effect on cue-induced reinstatement of food seeking. Thus, GABA$_B$ receptor positive modulators could be useful therapeutics for the treatment of different aspects of nicotine dependence by facilitating smoking cessation by decreasing nicotine intake and preventing relapse to smoking in humans