Adiabatic dynamic causal modelling

This technical note introduces adiabatic dynamic causal modelling, a method for inferring slow changes in biophysical parameters that control fluctuations of fast neuronal states. The application domain we have in mind is inferring slow changes in variables (e.g., extracellular ion concentrations or synaptic efficacy) that underlie phase transitions in brain activity (e.g., paroxysmal seizure activity). The scheme is efficient and yet retains a biophysical interpretation, in virtue of being based on established neural mass models that are equipped with a slow dynamic on the parameters (such as synaptic rate constants or effective connectivity). In brief, we use an adiabatic approximation to summarise fast fluctuations in hidden neuronal states (and their expression in sensors) in terms of their second order statistics; namely, their complex cross spectra. This allows one to specify and compare models of slowly changing parameters (using Bayesian model reduction) that generate a sequence of empirical cross spectra of electrophysiological recordings. Crucially, we use the slow fluctuations in the spectral power of neuronal activity as empirical priors on changes in synaptic parameters. This introduces a circular causality, in which synaptic parameters underwrite fast neuronal activity that, in turn, induces activity-dependent plasticity in synaptic parameters. In this foundational paper, we describe the underlying model, establish its face validity using simulations and provide an illustrative application to a chemoconvulsant animal model of seizure activity

Phosphoinositide 3-kinase: a critical signalling event in pulmonary cells.

Phosphoinositide 3-kinases (PI-3Ks) are enzymes that generate lipid second messenger molecules, resulting in the activation of multiple intracellular signalling cascades. These events regulate a broad array of cellular responses including survival, activation, differentiation and proliferation and are now recognised to have a key role in a number of physiological and pathophysiological processes in the lung. PI-3Ks contribute to the pathogenesis of asthma by influencing the proliferation of airways smooth muscle and the recruitment of eosinophils, and affect the balance between the harmful and protective responses in pulmonary inflammation and infection by the modulation of granulocyte recruitment, activation and apoptosis. In addition they also seem to exert a critical influence on the malignant phenotype of small cell lung cancer. PI-3K isoforms and their downstream targets thus provide novel therapeutic targets for intervention in a broad spectrum of respiratory diseases.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

A cross sectional study of water quality from dental unit water lines in dental practices in the West of Scotland

OBJECTIVE: To determine the microbiological quality of water from dental units in a general practice setting and current practice for disinfection of units. DESIGN: A cross-sectional study of the water quality from 40 dental units in 39 general practices and a questionnaire of the disinfection protocols used in those practices. SETTING: NHS practices in primarydental care. SUBJECTS: Thirty-nine general practices from the West of Scotland. METHODS: Water samples were collected on two separate occasions from dental units and analysed for microbiological quality by the total viable count (TVC) method. Water specimens were collected from the triple syringe, high speed outlet, cup filler and surgery tap. Each participating practitioner was asked to complete a questionnaire. Results Microbial contamination was highest from the high speed outlet followed by the triple syringe and cup filler. On average, the TVC counts from the high speed water lines at 37 degrees C and for the high speed lines, triple syringe and cup filler at 22 degrees C were significantly higher than that from the control tap water specimens. The study included units from 11 different manufacturers with ages ranging from under one year to over eight years. The age of the dental unit analysed did not appear to influence the level of microbial contamination. Five of the practices surveyed used disinfectants to clean the dental units but these had no significant effect on the microbiological quality of the water. The majority of dental units (25 out of 40) were never flushed with water between patients. A number of different non-sterile irrigants were used for surgical procedures. CONCLUSION: The microbiological quality of water from dental units in general dental practice is poor compared with that from drinking water sources. Suitable sterile irrigants should be used for surgical procedures in dental practice. Further work is required for pragmatic decontamination regimens of dental unit water lines in a general dental practice setting

Comparison of limb kinematics between collected and lengthened (medium/extended) trot in two groups of dressage horses on two different surfaces

Background: Dressage horses are often asked to work in lengthened paces during training and competition, but to date there is limited information about the biomechanics of dressage-specific paces. Preliminary work has shown increased fetlock extension in extended compared with collected paces, but further investigation of the kinematic differences between collected, medium and extended trot in dressage horses is warranted. Objectives: Investigation of the effect of collected versus medium/extended trot on limb kinematics of dressage horses. Study design: Prospective kinematic evaluation. Methods: Twenty clinically sound horses in active dressage training were used: Group 1) ten young horses (≤ 6 years) were assessed at collected and medium trot; Group 2) ten mature horses (≥9 years) were assessed at collected and extended trot. All horses were evaluated on two different surfaces. High-speed motion-capture (240Hz) was used to determine kinematic variables. Forelimb and hindlimb angles were measured at midstance. Descriptive statistics and mixed-effect multilevel-regression analyses were performed. Results: Speed and stride length were reduced and stride duration increased at collected compared with medium/extended trot. Lengthened trot (medium/extended trot) was associated with increased fetlock extension in both the forelimbs and hindlimbs in both groups of horses. Changes were greater in Group 2 compared with Group 1. Shoulder and carpus angles were associated with forelimb fetlock angle. Hock angle was not significantly influenced by pace. Surface had no effect on fetlock or hock angles. Main limitations: Only 2D motion analysis was carried out. Results may have been different in horses with more extreme gait characteristics. Conclusions: Medium/extended trot increases extension of the forelimb and the hindlimb fetlock joints compared with collected trot in both young and mature dressage horses, respectively

Evidence for variation in the effective population size of animal mitochondrial DNA

Background: It has recently been shown that levels of diversity in mitochondrial DNA are remarkably constant across animals of diverse census population sizes and ecologies, which has led to the suggestion that the effective population of mitochondrial DNA may be relatively constant. Results: Here we present several lines of evidence that suggest, to the contrary, that the effective population size of mtDNA does vary, and that the variation can be substantial. First, we show that levels of mitochondrial and nuclear diversity are correlated within all groups of animals we surveyed. Second, we show that the effectiveness of selection on non-synonymous mutations, as measured by the ratio of the numbers of non-synonymous and synonymous polymorphisms, is negatively correlated to levels of mitochondrial diversity. Finally, we estimate the effective population size of mitochondrial DNA in selected mammalian groups and show that it varies by at least an order of magnitude. Conclusions: We conclude that there is variation in the effective population size of mitochondria. Furthermore we suggest that the relative constancy of DNA diversity may be due to a negative correlation between the effective population size and the mutation rate per generation

Evaluation of the efficacy of Alpron disinfectant for dental unit water lines

AIMS: To assess the efficacy of a disinfectant, Alpron, for controlling microbial contamination within dental unit water lines. METHODS: The microbiological quality of water emerging from the triple syringe, high speed handpiece, cup filler and surgery hand wash basin from six dental units was assessed for microbiological total viable counts at 22 degrees C and 37 degrees C before and after treatment with Alpron solutions. RESULTS: The study found that the use of Alpron disinfectant solutions could reduce microbial counts in dental unit water lines to similar levels for drinking water. This effect was maintained in all units for up to six weeks following one course of treatment. In four out of six units the low microbial counts were maintained for 13 weeks. CONCLUSIONS: Disinfectants may have a short term role to play in controlling microbial contamination of dental unit water lines to drinking water quality. However, in the longer term attention must be paid to redesigning dental units to discourage the build up of microbial biofilms

Premenopausal endogenous oestrogen levels and breast cancer risk: a meta-analysis.

BACKGROUND: Many of the established risk factors for breast cancer implicate circulating hormone levels in the aetiology of the disease. Increased levels of postmenopausal endogenous oestradiol (E2) have been found to increase the risk of breast cancer, but no such association has been confirmed in premenopausal women. We carried out a meta-analysis to summarise the available evidence in women before the menopause. METHODS: We identified seven prospective studies of premenopausal endogenous E2 and breast cancer risk, including 693 breast cancer cases. From each study we extracted odds ratios of breast cancer between quantiles of endogenous E2, or for unit or s.d. increases in (log transformed) E2, or (where odds ratios were unavailable) summary statistics for the distributions of E2 in breast cancer cases and unaffected controls. Estimates for a doubling of endogenous E2 were obtained from these extracted estimates, and random-effect meta-analysis was used to obtain a pooled estimate across the studies. RESULTS: Overall, we found weak evidence of a positive association between circulating E2 levels and the risk of breast cancer, with a doubling of E2 associated with an odds ratio of 1.10 (95% CI: 0.96, 1.27). CONCLUSION: Our findings are consistent with the hypothesis of a positive association between premenopausal endogenous E2 and breast cancer risk

Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy.

Neocortical epilepsy is frequently drug-resistant. Surgery to remove the epileptogenic zone is only feasible in a minority of cases, leaving many patients without an effective treatment. We report the potential efficacy of gene therapy in focal neocortical epilepsy using a rodent model in which epilepsy is induced by tetanus toxin injection in the motor cortex. By applying several complementary methods that use continuous wireless electroencephalographic monitoring to quantify epileptic activity, we observed increases in high frequency activity and in the occurrence of epileptiform events. Pyramidal neurons in the epileptic focus showed enhanced intrinsic excitability consistent with seizure generation. Optogenetic inhibition of a subset of principal neurons transduced with halorhodopsin targeted to the epileptic focus by lentiviral delivery was sufficient to attenuate electroencephalographic seizures. Local lentiviral overexpression of the potassium channel Kv1.1 reduced the intrinsic excitability of transduced pyramidal neurons. Coinjection of this Kv1.1 lentivirus with tetanus toxin fully prevented the occurrence of electroencephalographic seizures. Finally, administration of the Kv1.1 lentivirus to an established epileptic focus progressively suppressed epileptic activity over several weeks without detectable behavioral side effects. Thus, gene therapy in a rodent model can be used to suppress seizures acutely, prevent their occurrence after an epileptogenic stimulus, and successfully treat established focal epilepsy