Isometric agonist and antagonist muscle activation interacts differently with 140-Hz transcranial alternating current stimulation aftereffects at different intensities.

During transcranial electric stimulation, increasing intracellular Ca2+ levels beyond those needed for inducing long term potentiation (LTP) may collapse aftereffects. State-dependent plastic aftereffects are reduced when applied during muscle activation as compared with rest. Cortical surround inhibition by antagonistic muscle activation inhibits the center-innervated agonist. The objective of this study is to determine the interaction of state dependency of transcranial alternating current stimulation (tACS) aftereffects at rest and under activation of agonist and antagonist muscles during stimulation with different intensities. In 13 healthy participants, we measured motor-evoked potential (MEP) amplitudes before and after applying tACS at 140 Hz over the motor cortex in nine single-blinded sessions using sham, 1 mA, and 2 mA stimulation intensities during rest and activation of agonist and antagonist muscles. During rest, only 1 mA tACS produced a significant MEP increase, whereas the 2 mA stimulation produced no significant MEP size shift. During agonist activation 1 mA did not induce MEP changes; after 2 mA, first a decrease and later an increase of MEPs were observed. Antagonist activation under sham tACS led to an inhibition, which was restored to baseline by 1 and 2 mA tACS. Increasing stimulation intensity beyond 1 mA does not increase excitability, compatible with too strong intracellular Ca2+ increase. Antagonist innervation leads to MEP inhibition, supporting the concept of surround inhibition, which can be overcome by tACS at both intensities. During agonist innervation, a tACS dose-dependent relationship exists. Our results integrate concepts of "leaky membranes" under activation, surround inhibition, intracellular Ca2+ increase, and their role in the aftereffects of tACS.NEW & NOTEWORTHY Stimulation intensity and activation of center versus surround muscles affect cortical excitability alterations generated by 140-Hz tACS. At rest, excitatory aftereffects were induced by tACS with 1 mA, but not 2 mA stimulation intensity. With agonistic muscle activation, excitability first decreases, and then increases with 2 mA. For antagonist activation, the MEP amplitude reduction observed in the sham condition is counteracted upon by 1 and 2 mA tACS. This reflects the relation of LTP-like aftereffects to Ca2+ concentration alterations.

Patient-reported experiences of mealtime care and food access in acute and rehabilitation hospital settings: a cross-sectional survey.

BACKGROUND: Nutrition and mealtime interventions can improve nutritional intake amongst hospital inpatients; however, patient-reported experience is rarely considered in their development and evaluation. The present study aimed to measure patient-reported food and mealtime experience to evaluate and inform continuous quality improvement of hospital nutrition care. METHODS: A cross-sectional survey with inpatients in seven acute care and rehabilitation wards was conducted. A 27-item validated questionnaire measured five domains of patient experience: food choices, organisational barriers, feeling hungry, physical barriers to eating and food quality. Responses were summarised descriptively and compared between settings (acute versus rehabilitation), patient demographics (age, gender) and time in hospital. RESULTS: Responses from 143 participants (mean age 67 years, 57% male, 28% rehabilitation, median 6 days into hospitalisation) showed that 10% or fewer respondents reported difficulties with food choices, feeling hungry or food quality. The most common difficulties were opening packets (36%), insufficient menu information provided (29%), being interrupted by staff when eating (28%), being disturbed when eating (27%), being in an uncomfortable position when eating (24%) and difficulty reaching food (21%). There were no significant differences in domain patterns by sex, age group or time in hospital. Organisational barriers were reported less frequently amongst rehabilitation participants compared to acute care (P = 0.01). CONCLUSIONS: This survey highlights areas of positive patient-reported experience with nutrition care and suggests that local improvement efforts should focus on physical assistance needs and organisational barriers, especially in acute care wards. The questionnaire may be useful for informing and evaluating systematic nutrition care improvements.

Parasite community similarity in Athabasca River trout-perch (Percopsis omiscomaycus) varies with local-scale land use and sediment hydrocarbons, but not distance or linear gradients.

Parasite communities have been shown to be structured by processes at scales ranging from continental to microhabitat, but few studies have simultaneously considered spatial and environmental variables, measured at different scales, to assess their relative influences on parasite abundance, species richness, and community similarity. Parasite abundance, diversity, and community similarity in Athabasca River trout-perch (Percopsis omiscomaycus) were examined in relation to water quality, substrate profile, metal and organic compound levels in water and sediment, and landscape use patterns at different scales, as well as distance among sites and upstream-downstream position along the river. Although species richness did not differ among sites, there were significant differences in abundance of individual taxa and community structure. We observed a shift from communities dominated by larval trematodes Diplostomum spp. to domination by gill monogeneans Urocleidus baldwini, followed by a reversion further downstream. Variations in the abundance of these taxa and of overall community similarity were strongly correlated with sediment hydrocarbons (alkanes and polycyclic aromatic hydrocarbons (PAHs)) as well as landscape use within 5 km of study sites. No correlations were noted with any other predictors, indicating that parasite populations and communities in this system were likely primarily influenced by habitat level and landscape-scale filters, rather than larger-scale processes such as distance decay or river continuum effects.

Mechanism-Based QSAR Modeling of Skin Sensitization.

Many chemicals can induce skin sensitization, and there is a pressing need for non-animal methods to give a quantitative indication of potency. Using two large published data sets of skin sensitizers, we have allocated each sensitizing chemical to one of 10 mechanistic categories and then developed good QSAR models for the seven categories that have a sufficient number of chemicals to allow modeling. Both internal and external validation checks showed that each model had good predictivity.

Endoscopic ultrasound guided fine needle aspiration for the diagnosis of pancreatic cystic neoplasms: a meta-analysis.

BACKGROUND AND OBJECTIVES: Mucinous cystic neoplasms and intraductal papillary mucinous tumours have greater malignant potential than serous cystic neoplasms. EUS alone is inadequate for characterising these lesions but the addition of FNA may significantly improve diagnostic accuracy. The performance of EUS-FNA is highly variable in published studies. AIM: To determine the diagnostic accuracy of EUS-FNA to differentiate mucinous versus non-mucinous cystic lesions with cyst fluid analysis for cytology and carcinoembryonic antigen (CEA) by performing a meta-analysis of published studies. METHODS: Relevant studies were identified via structured database search and included if they used a reference standard of definitive surgical histology or clinical follow-up of at least 6 months. Data from selected studies were pooled to give summary sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio and Receiver Operating Characteristic (ROC) curve. Pre-defined subgroup analysis was performed. RESULTS: Eighteen studies (published 2002-2011) were included, with a total of 1438 patients. For cytology, pooled sensitivity was 54(95%CI 49-59)% and specificity 93(90-95)%. The diagnostic odds ratio (DOR) was 13.3 (4.37-49.43), with I(2) of 77.1%. For CEA sensitivity was 63(59-67)% and specificity 88(83-91)%. The DOR was 10.76(6.29-18.41) with an I(2) of 25.4%. The diagnostic accuracy of EUS-FNA was enhanced in prospective studies and studies of <36 months duration. No impact of publication bias on our results was demonstrated. CONCLUSIONS: Fine-needle aspiration has moderate sensitivity but high specificity for mucinous lesions. EUS-FNA, when used in conjunction with cross sectional imaging, is a useful diagnostic tool for the correct identification of mucinous cysts.

Hepatotoxicity: a scheme for generating chemical categories for read-across, structural alerts and insights into mechanism(s) of action.

The ability of a compound to cause adverse effects to the liver is one of the most common reasons for drug development failures and the withdrawal of drugs from the market. Such adverse effects can vary tremendously in severity, leading to an array of possible drug-induced liver injuries (DILIs). As a result, it is not surprising that drug development has evolved into a complex and multifaceted process including methods aiming to identify potential liver toxicities. Unfortunately, hepatotoxicity remains one of the most complex and poorly understood areas of human toxicity; thus it is a significant challenge to identify potential hepatotoxins. The performance of existing methods to identify hepatotoxicity requires improvement. The current study details a scheme for generating chemical categories and the development of structural alerts able to identify potential hepatotoxins. The study utilized a diverse 951-compound dataset and used structural similarity methods to produce a number of structurally restricted categories. From these categories, 16 structural alerts associated with observed human hepatotoxicity were developed. Furthermore, the mechanism(s) by which these compounds cause hepatotoxicity were investigated and a mechanistic rationale was proposed, where possible, to yield mechanistically supported structural alerts. Alerts of this nature have the potential to be used in the screening of compounds to highlight potential hepatotoxicity, whilst the chemical categories themselves are important in applying read-across approaches. The scheme presented in this study also has the potential to act as a knowledge generator serving as an excellent starting platform from which to conduct additional toxicological studies.

A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse.

As the human genome project approaches completion, the challenge for mammalian geneticists is to develop approaches for the systematic determination of mammalian gene function. Mouse mutagenesis will be a key element of studies of gene function. Phenotype-driven approaches using the chemical mutagen ethylnitrosourea (ENU) represent a potentially efficient route for the generation of large numbers of mutant mice that can be screened for novel phenotypes. The advantage of this approach is that, in assessing gene function, no a priori assumptions are made about the genes involved in any pathway. Phenotype-driven mutagenesis is thus an effective method for the identification of novel genes and pathways. We have undertaken a genome-wide, phenotype-driven screen for dominant mutations in the mouse. We generated and screened over 26,000 mice, and recovered some 500 new mouse mutants. Our work, along with the programme reported in the accompanying paper, has led to a substantial increase in the mouse mutant resource and represents a first step towards systematic studies of gene function in mammalian genetics.

An examination of the toxic properties of water extracts in the vicinity of an oil sand extraction site.

The industrial extraction of oil sands (OS) in northern Alberta, Canada, has raised concerns about the quality of the Athabasca River. The purpose of this study was to examine the toxic properties of various water extracts on Oncorhynchus mykiss trout hepatocytes. The water samples were fractionated on a reverse-phase C(18) cartridge and the levels of light-, medium- and heavy-weight polycyclic aromatic hydrocarbons (PAHs) were determined by fluorescence spectroscopy. Primary cultures of trout hepatocytes were exposed for 48 h at 15 °C to increasing concentrations of the C(18) extract corresponding to 0.02, 0.1, 0.5 and 2.5X concentrations from upstream/downstream sites in the Athabasca River, lake and groundwater samples, OS tailings and interceptor well-water samples. Changes in cell viability, phase I and phase II biotransformation enzymes (cytochrome P4501A and glutathione S-transferase activities), oxidative damage (lipid peroxidation LPO) and genotoxicity (single and double DNA strand breaks) were monitored in post-exposure cells. The water samples decreased cell viability and increased all the above endpoints at thresholds of between 0.02 and 0.1X the water concentration. The most responsive biomarker was DNA damage but it also offered the least discrimination among sites. LPO was higher at sites downstream of the industrial operations compared to upstream sites. A decision tree analysis was performed to formulate a set of rules by which to identify the distinctive properties of each type of water samples. The analysis revealed that OS tailings and interceptor waters were characterized by an increased concentration in light PAHs (>42 µg L(-1)) and this fraction represented more than 85% of the total PAHs. These samples also inhibited GST activity, which could compromise the elimination of genotoxic PAHs present in the system. An analysis of groundwater samples revealed a contamination pattern similar to that for OS tailings. There is a need for more research into specific biomarkers of toxicity from OS tailings compounds such as naphthenic acids, light PAHs among others, which are a characteristic fingerprint of OS extraction activities.

Parental involvement in paediatric cancer treatment decisions.

This study investigated parents' information needs and involvement in decision-making processes affecting the care of children diagnosed with cancer. Interviews and questionnaires were used to assess parental satisfaction in 50 mothers and 16 fathers responsible for 58 children in an English Paediatric Oncology Unit. Parents reported that doctors contributed almost twice as much to the decision-making process as they did, but parental satisfaction was positively correlated with the amount of information provided when giving informed consent. Satisfaction about their involvement in this process relied heavily upon the level of support received from others. Parents consenting to their child's involvement in non-randomised trials perceived themselves to be under greater pressure from others during the decision-making process while those whose children were further along the treatment trajectory were more uncertain about decisions previously made. Findings indicate that the accessibility, support, information and degree of control afforded to parents by healthcare professionals impacts upon their satisfaction with both the decision-making process and their confidence in the decisions thus made. Information and support tailored to parents' specific needs may therefore enhance satisfaction with clinical decision making and reassure parents about decisions made in the long-term interest of their child's health.

In silico prediction of aqueous solubility: the solubility challenge.

The dissolution of a chemical into water is a process fundamental to both chemistry and biology. The persistence of a chemical within the environment and the effects of a chemical within the body are dependent primarily upon aqueous solubility. With the well-documented limitations hindering the accurate experimental determination of aqueous solubility, the utilization of predictive methods have been widely investigated and employed. The setting of a solubility challenge by this journal proved an excellent opportunity to explore several different modeling methods, utilizing a supplied dataset of high-quality aqueous solubility measurements. Four contrasting approaches (simple linear regression, artificial neural networks, category formation, and available in silico models) were utilized within our laboratory and the quality of these predictions was assessed. These were chosen to span the multitude of modeling methods now in use, while also allowing for the evaluation of existing commercial solubility models. The conclusions of this study were surprising, in that a simple linear regression approach proved to be superior over more complex modeling methods. Possible explanations for this observation are discussed and also recommendations are made for future solubility prediction.

Classification of chemicals according to mechanism of aquatic toxicity: an evaluation of the implementation of the Verhaar scheme in Toxtree.

A number of mechanisms have been identified that can lead to (acute) aquatic toxicity. The assignment of compounds to a particular mechanism of action is important in the development and utilisation of (quantitative) structure-activity relationships ((Q)SARs) for ecotoxicity. Assignment to a mechanism can be difficult; however in 1992 Verhaar et al. published a series of structural rules which aimed to classify compounds according to mechanism of action. Recent interest has seen the Verhaar rules coded into freely available software such as Toxtree available from the European Chemicals Bureau. To date, a complete critical evaluation of these rules has been lacking. Therefore, the aim of this study was to evaluate the Toxtree implementation of the Verhaar rules using two well characterised aquatic toxicity datasets (Pimephales promelas and Tetrahymena pyriformis phenol databases) for which mechanisms of toxic action are well established. The present study highlights rule, and possible coding, errors that may lead to misclassifications. Improvements to both the rules and prediction architecture are suggested. In particular further rules to improve predictions for polar narcosis (class 2) are suggested.

Antioxidant properties of carotenoids: QSAR prediction of their redox potentials.

There is a great need to predict the antioxidant properties of molecules such as carotenoids. These compounds are of great interest due to their contribution to various important biological and industrial processes, including toxicity and fate. In our study, redox potentials were compiled from several literature sources. Redox potential values ranged from 537.2 mV for zeaxanthin up to 691.5 mV for beta-carotene; they correspond to the formation of cation radicals, using the standard calomel electrode (SCE). The redox potential values were measured using conventional electrochemical techniques, cyclic voltammetry and Osteryoung square-wave voltammetry. A quantitative structure-activity relationship (QSAR) was developed to model and consequently to predict the values of redox potential. The predicted values of redox potential for four external carotenoids, namely beta-carotene, zeaxanthin, cantaxanthin and astaxanthin, are presented and discussed. They indicate the dependence of redox potential on structure, donor and acceptor groups and polarisability.

Structure-based modelling in reproductive toxicology: (Q)SARs for the placental barrier.

The replacement of animal testing for endpoints such as reproductive toxicity is a long-term goal. This study describes the possibilities of using simple (quantitative) structure-activity relationships ((Q)SARs) to predict whether a molecule may cross the placental membrane. The concept is straightforward, if a molecule is not able to cross the placental barrier, then it will not be a reproductive toxicant. Such a model could be placed at the start of any integrated testing strategy. To develop these models the literature was reviewed to obtain data relating to the transfer of molecules across the placenta. A reasonable number of data were obtained and are suitable for the modelling of the ability of a molecule to cross the placenta. Clearance or transfer indices data were sought due to their ability to eliminate inter-placental variation by standardising drug clearance to the reference compound antipyrine. Modelling of the permeability data indicates that (Q)SARs with reasonable statistical fit can be developed for the ability of molecules to cross the placental barrier membrane. Analysis of the models indicates that molecular size, hydrophobicity and hydrogen-bonding ability are molecular properties that may govern the ability of a molecule to cross the placental barrier.

Improved correlation between animal and human potency of non-steroidal anti-inflammatory drugs using quantitative structure-activity relationships (QSARs).

Animal models are known not to predict human responses well, in general. However, we have been able to demonstrate that, for a series of non-steroidal anti-inflammatory drugs that are or were in clinical use, the incorporation of two simple physicochemical properties results in excellent correlations between human and rodent potencies for anti-inflammatory, analgesic and anti-pyretic activities. This has the potential to allow the use of historical data to improve drug development.

Cancer prevalence and survivorship issues: analyses of the 1992 National Health Interview Survey.

BACKGROUND/METHODS: Relatively little is known about the size and makeup of the growing population of cancer survivors or about the social implications of a diagnosis of cancer. To explore these issues, we analyzed cancer survivorship information from the 1992 National Health Interview Survey (NHIS), and resulting cancer prevalence estimates were compared with those derived from cancer registry data. RESULTS: According to the NHIS, there were an estimated 7.2 million adult survivors of cancer-excluding nonmelanoma skin cancer-in 1992, representing 3.9% of the U.S. adult population. Comparisons with prevalence estimates from cancer registry data suggest that cancer is underreported in the NHIS. Nearly three fifths (58.0%) of cancer survivors self-identified on the NHIS reported that their cancer was first detected when they noticed something wrong and went to a doctor. The majority (55.7%) of cancer survivors had obtained a second opinion or multiple opinions regarding their treatment. Most (58.0%) had received patient educational materials from a health care provider. However, relatively few had received counseling or participated in support groups (14.2%), contacted cancer organizations after their diagnosis (10.9%), or participated in a research study or clinical trial as part of their cancer treatment (4.7%). One ninth (10.7%) of the survivors had been denied health or life insurance coverage because of their cancer. Nearly one fifth (18.2%) of the cancer survivors who worked before or after their cancer was diagnosed experienced employment problems because of their cancer. CONCLUSIONS: While cancer appears to be underreported on the 1992 NHIS, the survey provides valuable information about the medical, insurance, and employment experience of cancer survivors selected from a nationally representative sample of U.S. households.

Da Vinci robot emergency undocking protocol.

The role of robot-assisted surgery across gynaecology is evolving with increasing numbers of procedures being undertaken with varying degrees of complexity. While the risk of conversion is low at approximately 1 %, the reasons for conversion are variable. These range from technical issues with the robot, surgical complications such as haemorrhage and anaesthetics issues such as an inability to ventilate the patient adequately. While many conversions to open or laparoscopic approach are not due to life-threatening indications, it is important that the theatre staff are aware of the indication and can perform an emergency undocking as effectively, efficiently and safely as possible when the need arises. Unfortunately, there is a paucity of the literature available outlining such protocols. For this reason, we developed an emergency undocking protocol clearly outlining the role of each theatre staff member and the need for clear concise communication.

Steer by ear: Myoelectric auricular control of powered wheelchairs for individuals with spinal cord injury.

PURPOSE: Providing mobility solutions for individuals with tetraplegia remains challenging. Existing control devices have shortcomings such as varying or poor signal quality or interference with communication. To overcome these limitations, we present a novel myoelectric auricular control system (ACS) based on bilateral activation of the posterior auricular muscles (PAMs). METHODS: Ten able-bodied subjects and two individuals with tetraplegia practiced PAM activation over 4 days using visual feedback and software-based training for 1 h/day. Initially, half of these subjects were not able to voluntarily activate their PAMs. This ability was tested with regard to 8 parameters such as contraction rate, lateralized activation, wheelchair speed and path length in a virtual obstacle course. In session 5, all subjects steered an electric wheelchair with the ACS. RESULTS: Performance of all subjects in controlling their PAMs improved steadily over the training period. By day 5, all subjects successfully generated basic steering commands using the ACS in a powered wheelchair, and subjects with tetraplegia completed a complex real-world obstacle course. This study demonstrates that the ability to activate PAM on both sides together or unilaterally can be learned and used intuitively to steer a wheelchair. CONCLUSIONS: With the ACS we can exploit the untapped potential of the PAMs by assigning them a new, complex function. The inherent advantages of the ACS, such as not interfering with oral communication, robustness, stability over time and proportional and continuous signal generation, meet the specific needs of wheelchair users and render it a realistic alternative to currently available assistive technologies.

Laparoscopic Adjustable Gastric Band Slippage Rates Following Laparoscopic Gastric Band Insertion: a Single Centre Experience.

INTRODUCTION: Laparoscopic adjustable gastric bands (LAGB) are placed around the superior aspect of the stomach to aid weight loss and co-morbidity resolution in morbidly obese patients. Slippage of the LAGB from its original position to lower in the fundus of the stomach leads to gastric obstruction, and sometimes ischaemia or perforation, necessitating LAGB repositioning or removal. This study aimed to identify the incidence of LAGB slippage, as well as predisposing factors that may influence its development. METHODS: All LAGBs inserted at one centre, via a pars flaccida technique, by four Bariatric specialist consultants, were reviewed utilising a prospectively maintained Bariatric database, computer records and case notes review. RESULTS: Seven hundred nineteen LAGBs were inserted and 33 slips treated; however, only 22 slips had their LAGB inserted at our centre (local slip rate 3.1 %). Multivariate analysis demonstrated a significant association between LAGB slip and younger median age at LAGB insertion (41 years slip vs. 45 years non-slip; p = 0.027), higher median total excess weight loss (64 % slip vs. 36 % non-slip; p < 0.001) and higher mean excess weight loss per month (2.41 % slip vs. 1.00 % non-slip; p < 0.001). There was no significant effect by sex, BMI at insertion or band type. CONCLUSIONS: Band slips are associated with greater excess weight loss and younger age. Larger studies may be necessary to further elucidate the risk factors contributing to, and mechanisms of, band slippage.