First identification of ITM2B interactome in the human retina.

Integral Membrane Protein 2 B (ITM2B) is a type II ubiquitous transmembrane protein which role remains unclear. ITM2B mutations have been associated with different disorders: mutations leading to longer mutant proteins have been reported in two distinct Alzheimer-like autosomal dominant disorders with early-onset progressive dementia and cerebellar ataxia. Both disorders share neurological features including severe cerebral amyloid angiopathy, non-neuritic plaques, and fibrillary tangles as in Alzheimer disease. Our group reported a missense mutation in ITM2B, in an unusual retinal dystrophy with no dementia. This finding suggests a specific role of ITM2B in the retina. As the identification of retinal-specific ITM2B partners could bring new insights into the cellular functions of ITM2B, we performed quantitative proteomics of ITM2B interactome of the human retina. Overall, 457 ITM2B partners were identified with 8 of them involved in visual transduction. In addition, bulk Gene Ontology analyses showed that many ITM2B partners are involved in several other biological functions, such as microtubule organization, protein translation and interestingly, mitochondrial homeostasis. These data represent the first report of the ITM2B interactome in the human retina and may serve as a valuable inventory of new potential ITM2B partners for future investigations of ITM2B physiological functions and dysfunctions.

Development of a rapid risk evaluation tool for herbs/drugs interactions in cancer patients: a multicentric experience in south of France.

Cancer patients use herbs in spite of severe interactions risks with major anticancer drugs. In daily practice, it is very difficult for oncologists to detect and define the risk of a herb-anticancer drug interaction (HDI). In this work, we realised a state of play in one of the most populated region of France by evaluating, through a specific questionnaire, the position of a representative panel of oncologists. About 80% of them thought that herbs interact with anticancer treatments whereas only 15.4% of them actually knew the real HDI. About 89.1% of them thought that a practical detection tool would be relevant and useful for their daily practice. Then, we constructed a tool in order to rapidly evaluate a HDI risk level. Based on experts' reviews and using a criticality matrix, we determined the HDI risk level between 11 herbs and 126 anticancer drugs. Then, we measured satisfactory of oncologists. All of them considered the tool as useful in their daily practice and then used it. This work highlighted that even if HDI has been integrated as a theoretical risk, its practical detection and risk evaluation is difficult to implement for oncologists in their daily practice. Thus, the tool we developed should answer to an unmet medical need.

What can be learned from a chaotic cancer model?

A simple model of three competing cell populations (host, immune and tumor cells) is revisited by using a topological analysis and computing observability coefficients. Our aim is to show that a non-conventional analysis might suggest new trends in understanding the interactions of some tumor cells and their environment. The action of some parameter values on the resulting dynamics is investigated. Our results are related to some clinical features, suggesting that this model thus captures relevant phenomena to cell interactions.

Leakage estimation using Kalman filtering in noninvasive mechanical ventilation.

Noninvasive mechanical ventilation is today often used to assist patient with chronic respiratory failure. One of the main reasons evoked to explain asynchrony events, discomfort, unwillingness to be treated, etc., is the occurrence of nonintentional leaks in the ventilation circuit, which are difficult to account for because they are not measured. This paper describes a solution to the problem of variable leakage estimation based on a Kalman filter driven by airflow and the pressure signals, both of which are available in the ventilation circuit. The filter was validated by showing that based on the attained leakage estimates, practically all the untriggered cycles can be explained.

Nonstationarity signatures in the dynamics of global nonlinear models.

The aim of this paper is to learn how to recognize a posteriori signatures that nonstationarity leaves on global models obtained from data. To this end the effects of nonstationarity on the dynamics of such models are reported for two benchmarks. Parameters of the Rössler and Lorenz models are varied to produce nonstationary data. It is shown that not only the rate of change of the varying parameter but also which recorded variable is used to estimate global models may have visible effects on the results, which are system-dependent and therefore difficult to generalize. Although the effects of nonstationarity are not necessarily obvious from the phase portraits, the first-return map to a Poincaré section is a much more adequate tool to recognize such effects. Three examples of models previously obtained from experimental data are analyzed in the light of the concepts discussed in this paper.

[Radiotherapy and chaos theory: the tit bird and the butterfly...]. / Théorie du chaos en radiothérapie : la mésange et le papillon

Although the same simple laws govern cancer outcome (cell division repeated again and again), each tumour has a different outcome before as well as after irradiation therapy. The linear-quadratic radiosensitivity model allows an assessment of tumor sensitivity to radiotherapy. This model presents some limitations in clinical practice because it does not take into account the interactions between tumour cells and non-tumoral bystander cells (such as endothelial cells, fibroblasts, immune cells...) that modulate radiosensitivity and tumor growth dynamics. These interactions can lead to non-linear and complex tumor growth which appears to be random but that is not since there is not so many tumors spontaneously regressing. In this paper we propose to develop a deterministic approach for tumour growth dynamics using chaos theory. Various characteristics of cancer dynamics and tumor radiosensitivity can be explained using mathematical models of competing cell species.

Finger tapping movements of Parkinson's disease patients automatically rated using nonlinear delay differential equations.

Parkinson's disease is a degenerative condition whose severity is assessed by clinical observations of motor behaviors. These are performed by a neurological specialist through subjective ratings of a variety of movements including 10-s bouts of repetitive finger-tapping movements. We present here an algorithmic rating of these movements which may be beneficial for uniformly assessing the progression of the disease. Finger-tapping movements were digitally recorded from Parkinson's patients and controls, obtaining one time series for every 10 s bout. A nonlinear delay differential equation, whose structure was selected using a genetic algorithm, was fitted to each time series and its coefficients were used as a six-dimensional numerical descriptor. The algorithm was applied to time-series from two different groups of Parkinson's patients and controls. The algorithmic scores compared favorably with the unified Parkinson's disease rating scale scores, at least when the latter adequately matched with ratings from the Hoehn and Yahr scale. Moreover, when the two sets of mean scores for all patients are compared, there is a strong (r = 0.785) and significant (p<0.0015) correlation between them.

[Chaos theory: a fascinating concept for oncologists]. / Théorie du chaos : un concept fascinant pour l'oncologue.

The oncologist is confronted daily by questions related to the fact that any patient presents a specific evolution for his cancer: he is challenged by very different, unexpected and often unpredictable outcomes, in some of his patients. The mathematical approach used today to describe this evolution has recourse to statistics and probability laws: such an approach does not ultimately apply to one particular patient, but to a given more or less heterogeneous population. This approach therefore poorly characterizes the dynamics of this disease and does not allow to state whether a patient is cured, to predict if he will relapse and when this could occur, and in what form, nor to predict the response to treatment and, in particular, to radiation therapy. Chaos theory, not well known by oncologists, could allow a better understanding of these issues. Developed to investigate complex systems producing behaviours that cannot be predicted due to a great sensitivity to initial conditions, chaos theory is rich of suitable concepts for a new approach of cancer dynamics. This article is three-fold: to provide a brief introduction to chaos theory, to clarify the main connecting points between chaos and carcinogenesis and to point out few promising research perspectives, especially in radiotherapy.

Global models for patient-ventilator interactions in noninvasive ventilation with asynchronies.

Noninvasive ventilation is a clinical procedure that enables patients with chronic respiratory failure to reduce the work of breathing and to improve blood oxygenation. In order to attain such goals, the ventilation support is expected to be phase synchronized with the patient spontaneous breathing. Unfortunately, asynchrony events are not rare. In order to provide more effective ventilation schemes, the patient-ventilator interactions should be better understood both during normal rhythm and asynchronism. This paper investigates this problem using data-driven modeling. Hence the estimation of input-output and autonomous models from pressure and airflow time series is discussed and illustrated. Issues concerning the nonlinearity of the interactions and modeling assumptions are dealt with. The results presented include models obtained from airflow and pressure measurements of a set of patients.

Protecting effect of vitamin E supplementation on submaximal exercise-induced oxidative stress in sedentary dogs as assessed by erythrocyte membrane fluidity and paraoxonase-1 activity.

The aim of this placebo-controlled study was to investigate the effects of oral vitamin E supplementation for 10 weeks on exercise-induced oxidative damage in untrained dogs. Eight dogs were randomly assigned to a supplementation (n=4) or control (n=4) group and underwent two isolated submaximal exercise sessions, 10 weeks apart. Blood was collected during each session to measure erythrocyte membrane fluidity (EMF), paraoxonase-1 (PON1) activity, plasma malondialdehyde (MDA) and vitamin E concentrations. These biomarkers were measured in venous blood samples collected before (t(0)), just after (t, EMF only) and 1d (t+1d) and 7d (t+7d) after the dogs ran on a treadmill. Prior to vitamin E supplementation, exercise induced a significant decrease in PON1 activity, EMF, vitamin E concentration and a significant increase in MDA concentration at t+1d. After a 10 week vitamin E supplementation period, these exercise-induced changes in PON1 activity, EMF and MDA concentration were still significant in the control group, but not in the supplemented group. These results suggested that vitamin E supplementation had a protective effect on submaximal exercise-induced oxidative damage in sedentary dogs.

Comparison of tests for embeddings.

It is possible to compare results for the classical tests for embeddings of chaotic data with the results of a recently proposed test. The classical tests, which depend on real numbers (fractal dimensions, Lyapunov exponents) averaged over an attractor, are compared with a topological test that depends on integers. The comparison can only be done for mappings into three dimensions. We find that the classical tests fail to predict when a mapping is an embedding and when it is not. We point out the reasons for this failure, which are not restricted to three dimensions.

Recurrence plots for dynamical analysis of non-invasive mechanical ventilation.

Quantifiers were introduced to convert recurrence plots into a statistical analysis of dynamical properties. It is shown that the Shannon entropy, if properly computed, increases as the chaotic regime is developed as expected. Recurrence plots and a new estimator for the Shannon entropy are then used to identify asynchronisms in non-invasive mechanical ventilation. It is thus shown that the phase coherence-easily identified using a Shannon entropy-is relevant in the quality of the mechanical ventilation. In particular, some patients with chronic respiratory diseases or healthy subjects can have a high rate of asynchronisms but a regular breathing rhythm.

When are projections also embeddings?

We study an autonomous four-dimensional dynamical system used to model certain geophysical processes. This system generates a chaotic attractor that is strongly contracting, with four Lyapunov exponents lambdai that satisfy lambda1+lambda2+lambda3<0 , so the Lyapunov dimension is DL=2+|lambda3|/lambda1<3 in the range of coupling parameter values studied. As a result, it should be possible to find three-dimensional spaces in which the attractors can be embedded so that topological analyses can be carried out to determine which stretching and squeezing mechanisms generate chaotic behavior. We study mappings into R3 to determine which can be used as embeddings to reconstruct the dynamics. We find dramatically different behavior in the two simplest mappings: projections from R4 to R3 . In one case the one-parameter family of attractors studied remains topologically unchanged for all coupling parameter values. In the other case, during an intermediate range of parameter values the projection undergoes self-intersections, while the embedded attractors at the two ends of this range are topologically mirror images of each other.

Recurrence plots and Shannon entropy for a dynamical analysis of asynchronisms in noninvasive mechanical ventilation.

Recurrence plots were introduced to quantify the recurrence properties of chaotic dynamics. Hereafter, the recurrence quantification analysis was introduced to transform graphical interpretations into statistical analysis. In this spirit, a new definition for the Shannon entropy was recently introduced in order to have a measure correlated with the largest Lyapunov exponent. Recurrence plots and this Shannon entropy are thus used for the analysis of the dynamics underlying patient assisted with a mechanical noninvasive ventilation. The quality of the assistance strongly depends on the quality of the interactions between the patient and his ventilator which are crucial for tolerance and acceptability. Recurrence plots provide a global view of these interactions and the Shannon entropy is shown to be a measure of the rate of asynchronisms as well as the breathing rhythm.

Global models from the Canadian lynx cycles as a direct evidence for chaos in real ecosystems.

Real food chains are very rarely investigated since long data sequences are required. Typically, if we consider that an ecosystem evolves with a period corresponding to the time for maturation, possessing few dozen of cycles would require to count species over few centuries. One well known example of a long data set is the number of Canadian lynx furs caught by the Hudson Bay company between 1821 and 1935 as reported by Elton and Nicholson in 1942. In spite of the relative quality of the data set (10 undersampled cycles), two low-dimensional global models that settle to chaotic attractors were obtained. They are compared with an ad hoc 3D model which was proposed as a possible model for this data set. The two global models, which were estimated with no prior knowledge about the dynamics, can be considered as direct evidences of chaos in real ecosystems.

Delivery of DNA vaccines by agarose hydrogel implants facilitates genetic immunization in cattle.

The present study demonstrates the interest of two slow-release systems as vaccination tools in cattle. Two experiments show that a first intradermal administration of one DNA vaccine dose combined with the slow-release of a second dose conduct to a priming of the bovine herpesvirus 1-specific immune response similar to the one generated by two discrete administrations 4 weeks apart. The first experiment demonstrates the efficacy of the slow-release system with well-characterized Alzet osmotic pumps, whereas the second experiment extends the same concept with innovative agarose hydrogel implants. These latter implants are cheaper and more convenient than the osmotic pumps or repeated intradermal administrations since they contribute to an efficient priming of the immune response in a single manipulation of the animals.

Effects of exercise and oral antioxidant supplementation enriched in (n-3) fatty acids on blood oxidant markers and erythrocyte membrane fluidity in horses.

The aim of this study was to investigate in a placebo-controlled field study the effect of a (n-3)-vitamin supplementation on erythrocyte membrane fluidity (EMF), oxidant/antioxidant markers and plasmatic omega3/omega6 fatty acid ratio (FAR) in 12 eventing horses. Venous blood was sampled at rest before (PRE) and after (POST) a three week treatment period with either the supplement (group S, n=6) or a placebo (group P, n=6) as well as after 15min (POST E15') and 24h (POST E24h) after a standardised exercise test. The following markers were analysed: EMF, plasma antioxidant capacity of water and lipid soluble components, ascorbic acid, uric acid (UA), glutathione (reduced: GSH, oxidised: GSSG), vitamin E (Vit E), beta-carotene, glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity, selenium, copper (Cu), zinc (Zn), oxidised proteins (Protox), lipid peroxides (Pool) and FAR. EMF did not differ between group S and P after treatment, but GPx remained unchanged in group S whereas it decreased in group P and plasma Cu/Zn ratio remained unchanged whereas it increased in group P. FAR were significantly increased in group S. Exercise induced a significant decrease of EMF (POST vs. E24h) in both groups, but which was significantly lower at E15' in group S than in group P. Exercise induced a significant increase of UA and ACW (POST vs. E15') and Protox (POST vs. E24h) in both groups. An exercise-related decrease in GSH and Pool (POST vs. E15') was found in group P, whereas Vit E and FAR (POST vs. E24h) significantly decreased in both groups. The study showed that exercise induced a decrease in EMF in horses associated with changes of blood oxidative balance. The (omega-3)-vitamin supplementation tested improved the oxidative balance poorly but delayed the exercise-induced decrease of EMF and increased the FAR.