The effectiveness of lamotrigine in the treatment of photosensitive epilepsy

Photosensitive epilepsy and associated pattern sensitivity are more prevalent in females and are usually treated with sodium valproate. Sodium valproate has an adverse effect profile, which particularly affects females, including teratogenicity, association with the polycystic ovary syndrome and weight gain. It would be useful therefore if an alternative treatment for photosensitive epilepsy could be found. The principle aim of this study was to investigate the effectiveness of lamotrigine in the treatment of photosensitive epilepsy in adults and children. Patients were either drug-naive, commencing lamotrigine therapy or were transferring from other antiepileptic drugs to lamotrigine (primarily sodium valproate) due to lack of response, adverse effects or desired pregnancy. The photoparoxsymal response in the electroencephalograph was used as the primary measure of photo and pattern sensitivity. In addition the effects of lamotrigine on occipital spikes and normal responses in the EEG to visual stimuli were investigated. Secondary measures also included the resting EEG, seizures, body mass index, menstrual function, mood and cognitive function. The results suggest that in adult patients lamotrigine is efficacious in the treatment of photosensitive epilepsy, although it appears inferior to sodium valproate. Lamotrigine does however have a more favourable adverse effect profile than valproate. The results indicate that lamotrigine therapy is suitable for photosensitive epilepsy in women of childbearing age or in patients experiencing unacceptable adverse effects with valproate therapy. Patients are more likely to respond to lamotrigine treatment if they present with sensitivity to a limited number of frequencies. Lamotrigine does not seem to be as efficacious in the treatment of children, although against it may be considered a second line drug if the child does not respond to or will not tolerate sodium valproate.

Incorporating curvature information into on-line learning

We analyse the dynamics of a number of second order on-line learning algorithms training multi-layer neural networks, using the methods of statistical mechanics. We first consider on-line Newton's method, which is known to provide optimal asymptotic performance. We determine the asymptotic generalization error decay for a soft committee machine, which is shown to compare favourably with the result for standard gradient descent. Matrix momentum provides a practical approximation to this method by allowing an efficient inversion of the Hessian. We consider an idealized matrix momentum algorithm which requires access to the Hessian and find close correspondence with the dynamics of on-line Newton's method. In practice, the Hessian will not be known on-line and we therefore consider matrix momentum using a single example approximation to the Hessian. In this case good asymptotic performance may still be achieved, but the algorithm is now sensitive to parameter choice because of noise in the Hessian estimate. On-line Newton's method is not appropriate during the transient learning phase, since a suboptimal unstable fixed point of the gradient descent dynamics becomes stable for this algorithm. A principled alternative is to use Amari's natural gradient learning algorithm and we show how this method provides a significant reduction in learning time when compared to gradient descent, while retaining the asymptotic performance of on-line Newton's method.

The theory of on-line learning: a statistical physics approach

In this paper we review recent theoretical approaches for analysing the dynamics of on-line learning in multilayer neural networks using methods adopted from statistical physics. The analysis is based on monitoring a set of macroscopic variables from which the generalisation error can be calculated. A closed set of dynamical equations for the macroscopic variables is derived analytically and solved numerically. The theoretical framework is then employed for defining optimal learning parameters and for analysing the incorporation of second order information into the learning process using natural gradient descent and matrix-momentum based methods. We will also briefly explain an extension of the original framework for analysing the case where training examples are sampled with repetition.

Back from the future:the second chance in the past of aller + infinitive

Typological studies (Bybee et al. 1994, Dahl 2000, Bourdin 2008 among many others) have shown a tendency for spatial elements (such as movement verbs) to grammaticalise into temporal expressions. The periphrasis made of aller + infinitive has been very productive in Romance languages. If in French, Spanish or Portuguese, it refers to future, it refers to a simple past in Catalan. fr.: je vais aller au cinéma esp.: voy a ir al cine pt. Vou ira o cine cat.: vaig anar al cine Barceló & Bres (2005:168) indicate that, In French, «vers le XVIème siècle, […] la périphrase a brièvement fonctionné comme un temps du passé (alors même que l’emploi comme temps du futur émergeait)»: (1) Sur ces propos, firent leur accord et, en regardant le lieu le plus propre pour faire cette belle œuvre, elle va dire qu’elle n’en savait point de meilleure ni plus loin de tout soupçon, qu’une petite maison qui était dedans le parc, où il y avait chambre et lit tout à propos. (Marguerite de Navarre, L’Heptaméron) The future value took over so much so that Damourette & Pichon (1911-1936 :117) claimed the past value had disappeared»: Un second tour, encore plus aberrant, n’a plus, que nous sachions, aucune position en pays d’Oui. Nous voulons parler de l’expression d’un passé au moyen de l’auxiliaire aller, suivi de l’infinitif. Ce tour a eu une grande fortune dans le provençal ancien et le catalan […] En français, on n’en trouve que des traces, notamment du XIVe au XVIe siècles . Ex.:[…] Adoncques s’arrêtèrent le conte et Raimondin soubz un grand arbre ; lors va dire le conte à Raimondin: […]. Et Raimondin va lui dire : Sire, ce qu’il vous plaira. That allegedly extinct use is nonetheless alive and kicking in Contemporary French. Larreya (2005:349)notes that it is « très courant dans les récits – en particulier dans les récits oraux» and it is also found in newspaper language as shown by this except from an obituary for Loulou Gasté (Le Monde 1995): (2) Celle-ci se déroule aux Editions Micro, où il a un bureau. Séduit par la jeune interprète, il commence à lui écrire des chansons sur mesure et leur complicité va mettre cinq ans à se transformer en amour. Au début de leur rencontre, Loulou est neurasthénique parce qu’il vient de divorcer et la future Line, exclusivement préoccupée par son métier, ne songe à rien d’autre. Line et Loulou vont rattraper le temps perdu et créer ensemble un millier de petites chansons dont la plupart sont devenues immortelles. Jusqu’à ces derniers mois, il ne va pas se passer une journée sans que Loulou s’empare de sa guitare pour créer un refrain. Would we be witnessing a linguistic resurrection? The same structure seems therefore to have grammaticalised in diverging and even diametrically opposite ways in different Romance languages. In this talk, we shall try to explain how the phrase aller + infinitive is able to function both as a future and a past. We will especially concentrate on the case of contemporary French where, while the future interpretation has obtained the status of tense as futur proche or périphrastique, a past interpretation is now commonplace. Our reflection will be supported by a personal corpus of authentic examples.

Statnote 17: using a regression line for prediction and calibration

Two types of prediction problem can be solved using a regression line viz., prediction of the ‘population’ regression line at the point ‘x’ and prediction of an ‘individual’ new member of the population ‘y1’ for which ‘x1’ has been measured. The second problem is probably the most commonly encountered and the most relevant to calibration studies. A regression line is likely to be most useful for calibration if the range of values of the X variable is large, if there is a good representation of the ‘x,y’ values across the range of X, and if several estimates of ‘y’ are made at each ‘x’. It is poor statistical practice to use a regression line for calibration or prediction beyond the limits of the data.

Second messenger pathways in the action of cachectic factors

Cachexia in cancer is characterised by progressive depletion of both adipose tissue stores and skeletal muscle mass. Two catabolic factors produced by cachexia-inducing tumours have the potential for inducing these changes in body composition: (i) proteolysis-inducing factor (PIF) which acts on skeletal muscle to induce both protein degradation and inhibit protein synthesis, (ii) lipid-mobilising factor (LMF), which has been shown to directly induce lipolysis in isolated epididymal murine white adipocytes. Administration of lipid-mobilising factor (LMF) to mice produced a specific reduction in carcass lipid with a tendency to increase non-fat carcass mass. Treatment of murine myoblasts, myotubes and tumour cells with tumour-produced LMF, caused concentration dependent stimulation of protein synthesis, within a 24hr period. It produced an increase in intracellular cyclic AMP levels, which was linearly related to the increase in protein synthesis. The observed effect was attenuated by pretreating cells with the adenylate cyclase inhibitor, MDL12330A and was additive with stimulation produced by forskolin. Both propranolol and a specific 3 adrenergic antagonist SR59230A, significantly reduced the stimulation of protein synthesis induced by LMF. LMF also affected protein degradation in vitro, as demonstrated by a reduction in proteasome activity, a key component of the ubiquitin-dependent proteolytic pathway. These effects were opposite to those produced by PIF which caused both a decrease in the rate of protein synthesis and an elevation on protein breakdown when incubated in vitro.Incubation of LMF with a fat cell line produced alterations in the levels of guanine-nucleotide binding proteins (G proteins). This was also evident in adipocyte plasma membranes isolated from mice bearing the tumour model of cachexia, MAC16 adenocarcinoma and from patients with cancer cachexia. Progression through the cachectic state induced an upregulation of stimulatory G proteins paralleled with a downregulation of inhibitory G proteins. These changes would contribute to the increased lipid mobilisation seen in cancer cachexia.

The geometric correction and registration of airborne line-scanned imagery for temporal thermal studies

This thesis begins by providing a review of techniques for interpreting the thermal response at the earth's surface acquired using remote sensing technology. Historic limitations in the precision with which imagery acquired from airborne platforms can be geometrically corrected and co-registered has meant that relatively little work has been carried out examining the diurnal variation of surface temperature over wide regions. Although emerging remote sensing systems provide the potential to register temporal image data within satisfactory levels of accuracy, this technology is still not widely available and does not address the issue of historic data sets which cannot be rectified using conventional parametric approaches. In overcoming these problems, the second part of this thesis describes the development of an alternative approach for rectifying airborne line-scanned imagery. The underlying assumption that scan lines within the imagery are straight greatly reduces the number of ground control points required to describe the image geometry. Furthermore, the use of pattern matching procedures to identify geometric disparities between raw line-scanned imagery and corresponding aerial photography enables the correction procedure to be almost fully automated. By reconstructing the raw image data on a truly line-by-line basis, it is possible to register the airborne line-scanned imagery to the aerial photography with an average accuracy of better than one pixel. Providing corresponding aerial photography is available, this approach can be applied in the absence of platform altitude information allowing multi-temporal data sets to be corrected and registered.

Optical regeneration at 40 Gb/s in dispersion-managed transmission lines with in-line synchronous modulators

Numerical optimization is performed of the 40-Gb/s dispersion-managed (DM) soliton transmission system with in-line synchronous intensity modulation. Stability of DM soliton transmission results from a combined action of dispersion, nonlinearity, in-line filtering, and modulation through effective periodic bandwidth management of carrier pulses. Therefore, analysis of the multiparametric problem is typically required. A two-stage time-saving numerical optimization procedure is applied. At the first step, the regions of the stable carrier propagation are determined using theoretical models available for DM solitons, and system parameters are optimized. At the second stage, full numerical simulations are undertaken in order to verify the tolerance of optimal transmission regimes. An approach developed demonstrates feasibility of error-free transmission over 20 000 km in a transmission line composed of standard fiber and dispersion compensation fiber at 40 Gb/s.

Laser-induced breakdown spectroscopy quantitative analysis method via adaptive analytical line selection and relevance vector machine regression model

Abstract A new LIBS quantitative analysis method based on analytical line adaptive selection and Relevance Vector Machine (RVM) regression model is proposed. First, a scheme of adaptively selecting analytical line is put forward in order to overcome the drawback of high dependency on a priori knowledge. The candidate analytical lines are automatically selected based on the built-in characteristics of spectral lines, such as spectral intensity, wavelength and width at half height. The analytical lines which will be used as input variables of regression model are determined adaptively according to the samples for both training and testing. Second, an LIBS quantitative analysis method based on RVM is presented. The intensities of analytical lines and the elemental concentrations of certified standard samples are used to train the RVM regression model. The predicted elemental concentration analysis results will be given with a form of confidence interval of probabilistic distribution, which is helpful for evaluating the uncertainness contained in the measured spectra. Chromium concentration analysis experiments of 23 certified standard high-alloy steel samples have been carried out. The multiple correlation coefficient of the prediction was up to 98.85%, and the average relative error of the prediction was 4.01%. The experiment results showed that the proposed LIBS quantitative analysis method achieved better prediction accuracy and better modeling robustness compared with the methods based on partial least squares regression, artificial neural network and standard support vector machine.

The redoxomics of PTEN: walking a fine line between damage and signaling:mass spectrometry-based approaches to study the effect of oxidation on PTEN function, structure, and protein-protein interactions

The research described in this PhD thesis focuses on proteomics approaches to study the effect of oxidation on the modification status and protein-protein interactions of PTEN, a redox-sensitive phosphatase involved in a number of cellular processes including metabolism, apoptosis, cell proliferation, and survival. While direct evidence of a redox regulation of PTEN and its downstream signaling has been reported, the effect of cellular oxidative stress or direct PTEN oxidation on PTEN structure and interactome is still poorly defined. In a first study, GST-tagged PTEN was directly oxidized over a range of hypochlorous acid (HOCl) concentration, assayed for phosphatase activity, and oxidative post-translational modifications (oxPTMs) were quantified using LC-MS/MS-based label-free methods. In a second study, GSTtagged PTEN was prepared in a reduced and reversibly H2O2-oxidized form, immobilized on a resin support and incubated with HCT116 cell lysate to capture PTEN interacting proteins, which were analyzed by LC-MS/MS and comparatively quantified using label-free methods. In parallel experiments, HCT116 cells transfected with a GFP-tagged PTEN were treated with H2O2 and PTENinteracting proteins immunoprecipitated using standard methods. Several high abundance HOCl-induced oxPTMs were mapped, including those taking place at amino acids known to be important for PTEN phosphatase activity and protein-protein interactions, such as Met35, Tyr155, Tyr240 and Tyr315. A PTEN redox interactome was also characterized, which identified a number of PTEN-interacting proteins that vary with the reversible inactivation of PTEN caused by H2O2 oxidation. These included new PTEN interactors as well as the redox proteins peroxiredoxin-1 (Prdx1) and thioredoxin (Trx), which are known to be involved in the recycling of PTEN active site following H2O2-induced reversible inactivation. The results suggest that the oxidative modification of PTEN causes functional alterations in PTEN structure and interactome, with fundamental implications for the PTEN signaling role in many cellular processes, such as those involved in the pathophysiology of disease and ageing.