A meta-analysis of randomized double-blind clinical trials in CMT1A to assess the change from baseline in CMTNS and ONLS scales after one year of treatment

International audienceCMT1A is the most common inherited peripheral neuropathy. There is currently no approved treatment. We performed a meta-analysis including four randomized, double-blind, Placebo-controlled clinical trials to assess the disease progression after one year under Placebo, Ascorbic Acid (AA) or PXT3003, a combination of three repurposed drugs. We observed a weak deterioration in patients under Placebo, well below the reported natural disease progression. Patients treated with AA were stable after one year but not significantly different from Placebo. Patients undergoing PXT3003 treatment showed an improvement in CMTNS and ONLS, statistically significant versus Placebo and potentially precursory of a meaningful change in the disease course

L'électron libre du gallicanisme : Jean de Launoy (1601-1678)

Longtemps considéré comme un gallican extrême, le docteur de Navarre J. de Launoy était surtout un érudit original et indépendant. L'étude de ses écrits, en particulier un recueil thématique de lettres, met en évidence une vision plus classique ; elle établit la spécificité de sa contribution aux débats ecclésiologiques et canoniques du temps. En démontrant de manière scientifique la vérité historique et théologique de la doctrine de France, il affaiblissait les perspectives tridentines et établissait un modèle d'Église apte à satisfaire les aspirations de nombreux chrétiens.Long perceived as an extreme Gallican, the Navarre Doctor J. de Launoy was above all an independent and original scholar. A study of his writings, in particular a thematic collection of letters, exposes a more classical vision of him; it establishes the singularity of his contribution to the ecclesiastical and canonical debates of his time. In systematically proving the historical and theological truths of the Doctrine of France, he weakened Tridentine perspectives and established a model of the Church capable of responding to the yearnings of many Christians

Incorporating physiologically relevant mobile phases in micellar liquid chromatography for the prediction of human intestinal absorption

Micellar liquid chromatography (MLC) is a popular method used in the determination of a compounds lipophilicity. This study describes the use of the obtained micelle/water partition coefficient (log Pmw) by such a method in the prediction of human intestinal absorption (HIA). As a result of the close resemblance of the novel composition of the micellar mobile phase to that of physiological intestinal fluid, prediction was deemed to be highly successful. The unique micellar mobile phase consisted of a mixed micellar mixture of lecithin and six bile salts, i.e. a composition matching that found in the human intestinal environment, prepared in ratios resembling those in the intestine. This is considered to be the first method to use a physiological mixture of biosurfactants in the prediction of HIA. As a result, a mathematical model with high predictive ability (R2PRED= 81 %) was obtained using multiple linear regression. The micelle/water partition coefficient (log Pmw) obtained from MLC was found to be a successful tool for prediction where the final optimum model included (log Pmw) and polar surface area (PSA) as key descriptors with high statistical significance for the prediction of HIA. This can be attributed to the nature of the mobile phase used in this study which contains the lecithin-bile salt complex, thus forming a bilayer system therefore mimicking absorption across the intestinal membrane

Diagnosis of chylous abdominal effusions: what is the triglyceride threshold value?

IntroductionChylous abdominal effusions are serious complications that can be triggered by various aetiologies. The biochemical diagnosis of chyle leakage in ascites or in peritoneal fluid capsules relies on the detection of chylomicrons. Assaying the fluid’s concentration of triglycerides is still the first-line tool. Given that only one comparative study has sought to quantify the value of the triglyceride assay for diagnosing chylous ascites in humans, our objective was to provide practical triglyceride thresholds. Materials and methodsWe conducted a 9-year, retrospective, single-centre study of adult patients and compared a triglyceride assay with lipoprotein gel electrophoresis for the analysis of 90 non-recurring abdominal effusions (ascites and abdominal collections) of which 65 were chylous. ResultsA triglyceride threshold of 0.4 mmol/L was associated with a sensitivity > 95%, and a threshold of 2.4 mmol/L was associated with a specificity > 95%. According to Youden index, the best threshold was 0.65 mmol/L with a sensitivity of 88 (77-95)%, a specificity of 72 (51-88)%, and, in our series, a positive predictive value of 89 (79-95)% and a negative predictive value of 69 (48-86)%. ConclusionsIn our series, cut-off of 0.4 mmol/L could be used for ruling-out diagnosis of chylous effusions, while cut-off of 2.4 mmol/L could be used for reasonably confirming diagnosis

Cancer Cell Expression of Autotaxin Controls Bone Metastasis Formation in Mouse through Lysophosphatidic Acid-Dependent Activation of Osteoclasts

Bone metastases are highly frequent complications of breast cancers. Current bone metastasis treatments using powerful anti-resorptive agents are only palliative indicating that factors independent of bone resorption control bone metastasis progression. Autotaxin (ATX/NPP2) is a secreted protein with both oncogenic and pro-metastatic properties. Through its lysosphospholipase D (lysoPLD) activity, ATX controls the level of lysophosphatidic acid (LPA) in the blood. Platelet-derived LPA promotes the progression of osteolytic bone metastases of breast cancer cells. We asked whether ATX was involved in the bone metastasis process. We characterized the role of ATX in osteolytic bone metastasis formation by using genetically modified breast cancer cells exploited on different osteolytic bone metastasis mouse models.Intravenous injection of human breast cancer MDA-B02 cells with forced expression of ATX (MDA-B02/ATX) to immunodeficiency BALB/C nude mice enhanced osteolytic bone metastasis formation, as judged by increased bone loss, tumor burden, and a higher number of active osteoclasts at the metastatic site. Mouse breast cancer 4T1 cells induced the formation of osteolytic bone metastases after intracardiac injection in immunocompetent BALB/C mice. These cells expressed active ATX and silencing ATX expression inhibited the extent of osteolytic bone lesions and decreased the number of active osteoclasts at the bone metastatic site. In vitro, osteoclast differentiation was enhanced in presence of MDA-B02/ATX cell conditioned media or recombinant autotaxin that was blocked by the autotaxin inhibitor vpc8a202. In vitro, addition of LPA to active charcoal-treated serum restored the capacity of the serum to support RANK-L/MCSF-induced osteoclastogenesis.Expression of autotaxin by cancer cells controls osteolytic bone metastasis formation. This work demonstrates a new role for LPA as a factor that stimulates directly cancer growth and metastasis, and osteoclast differentiation. Therefore, targeting the autotaxin/LPA track emerges as a potential new therapeutic approach to improve the outcome of patients with bone metastases

Computational approaches for modeling human intestinal absorption and permeability

Human intestinal absorption (HIA) is an important roadblock in the formulation of new drug substances. Computational models are needed for the rapid estimation of this property. The measurements are determined via in vivo experiments or in vitro permeability studies. We present several computational models that are able to predict the absorption of drugs by the human intestine and the permeability through human Caco-2 cells. The training and prediction sets were derived from literature sources and carefully examined to eliminate compounds that are actively transported. We compare our results to models derived by other methods and find that the statistical quality is similar. We believe that models derived from both sources of experimental data would provide greater consistency in predictions. The performance of several QSPR models that we investigated to predict outside the training set for either experimental property clearly indicates that caution should be exercised while applying any of the models for quantitative predictions. However, we are able to show that the qualitative predictions can be obtained with close to a 70% success rate

Further Aspects for the Foundation of A Conceptual Framework for Systems Life Science Under Space Conditions

A strong impetus for the elaboration of a conceptual framework for integrative research under space conditions is clearly noticeable. A group of space-experienced investigators forwarded explicitly a request to the scientific community for such a conceptual framework [Goswami et al., 2012]. The EU funded THESEUS project (Towards Human Exploration of Space: a EUropean Strategy, http://www.theseus-eu.org/home.html) favors integrated physiology. A central method for setting up a conceptual framework is basically the elaboration of an integrated set of terms (concepts) and developing tools (like a markup language-based system) to implement the term set. The approach of Andrew McCulloch et al. [Hunter et al, 2006] for human physiology with six levels for multi-level integration (from the gene to the whole human body level) is extended here by two additional levels. For human physiology research in the context of space exploitation, first at all, a further level beyond the whole human body level is required, namely a human - environment level. Furthermore, arguments for a division of the molecular level into a molecular and an atomic level are put forward, e.g. for discussing electron configurations of free radicals. Essential terms of system theory (subsystem, structure, function, process, system environment, etc.) are introduced, complementing the main terms LEVEL and SCALE to comprise core elements of the framework proposal. The advancement reported is centered round a more rigorous definition of the term LEVEL, derived from an understanding of the system of interest (e.g. a bone cell) and setting levels via an embedded hierarchy of systems/subsystems. However, the full-flagged elaboration of a conceptual framework has to be organized as community-led, open project, similar to the way topical ontology groups are organized (compare with the approach of the Environment Ontology group, www.environmentontology.org).So far, the proposed core set of elements for the requested conceptual framework are exemplified with applications cases (e.g. space habitats and algae phenols, the world of picoNewtons in the microenvironment of osteocytes, unpaired electrons and the effects of free radicals for microbe control). The applications cases are interlinked with a recurrent theme: reactive species and antioxidants. A new relationship between hypothesis- (theory- and model-) driven und data-driven research is seen in the way that an iterative evolutionary alignment is needed, especially in the context of the rising importance of high throughput omics, combinatory screening, data-mining and meta-analysis

Towards a new science for autonomous manned space exploration

Abstract Long duration human exploration of the solar system calls for a stable contribution from different communities. of organized expertise and singular emerging know-how. The challenge of such a project appears to be technological, but designing a reliable socio-technical system for international astronaut explorers is a problem of integrating validated heterogeneous knowledge into an open interdisciplinary civilizational repository guided by humanizing value. In our paper, we will show that the human species can develop a form of collective intelligence using a paradigm that reintegrates a phenomenology of the living which is relatively different from the traditional process of scientific objectification. To support this hypothesis we will show the epistemological limits of constituted science and more particularly of modern physics. We will draw the relationship that exists between the evolution of theories in the human sciences and quantum physics while insisting on the role of culture as a catalyst for a always possible evolution of the Human being (conscious and free). Going beyond the previous science and reintegrating the living observer could allow to increase the horizon of human and technological possibilities in response to the new challenges that are emerging present on a global scale. We will focus on the need to activate natural intelligence with a methodological cycle that develops and maintains a continuous process between the subjective and objective poles of the human being in gestation. As a prerequisite, this process requires recognizing the human species qualities as well as its potential. Operationally this path requires mutual listening and shared responsibility of partners with a focused on the delegation process centered on the human being in the making in an extra-planetary perspective.</jats:p