Mental disorders and drug/alcohol use in patients commencing extensively drug-resistant tuberculosis treatment.

Mental disorders and alcohol/drug use worsen treatment outcomes for multidrug-resistant tuberculosis (TB), but data are lacking for extensively drug-resistant (XDR) TB. We investigated the association of baseline mental disorders and alcohol/drug use on XDR-TB treatment outcomes in a retrospective study of 53 XDR-TB Peruvian patients during 2010-2012. Logistic regression estimated the odds ratios for unfavourable XDR-TB treatment outcomes. Overall treatment success was 25%. Mental disorders and drug/alcohol use were found in respectively 22.4% and 20.4% of patients; neither were associated with unfavourable treatment outcomes. Future research should explore the relationship between mental health and drug/alcohol use in XDR-TB treatment outcomes

Multidisciplinary study of biological parameters and fatigue evolution in quay crane operators

In intermodal terminals the handling of containers and the number of accidents still depends on a wide range of human errors due to fatigue despite the automation level reached nowadays. For this reason it is very important to increase knowledge about the factors affecting the propensity of operators to make errors, increasing the chance of accidents happening. The aim of this work is to propose a novel approach to assess fatigue and performance lev els in quay crane operators as a function of physiological parameters and of the many varying boundary conditions encountered in daily work. During their work, quay crane operators have to deal with variable environmental conditions, such as task type, wind speed and direction, lighting conditions that redu ce visibility that can require an exacting level of attention. In the trial eight operators have been examined in a session lastin g four hours. All actual conditions are reproduced through a fully imme rsive quay crane simulator. The operator completes the assigned task (the same for each one) and can see through four wide monito rs a high quality virtual reality view of the simulation. Most biological parameters are acquired using different devices including a Holter ECG monitor, electromyographic monitoring the four trunk muscles most involved in the test, eye tracker and seat - body pressure interface for both seat pan and backrest. Changes in physiological parameters have been monitored during the trial and interesting correlations with performance levels and boundary conditions ha ve been f ound for each operator, in accord ance with their age and skills. The present study can form the basis for further investigations aimed at developing a cost effective, reliable and robust system for monitoring increasing fat igue and for predicting the critical conditions that may result in an acciden

Programmable models of growth and mutation of cancer-cell populations

In this paper we propose a systematic approach to construct mathematical models describing populations of cancer-cells at different stages of disease development. The methodology we propose is based on stochastic Concurrent Constraint Programming, a flexible stochastic modelling language. The methodology is tested on (and partially motivated by) the study of prostate cancer. In particular, we prove how our method is suitable to systematically reconstruct different mathematical models of prostate cancer growth - together with interactions with different kinds of hormone therapy - at different levels of refinement.Comment: In Proceedings CompMod 2011, arXiv:1109.104

Inferring biochemical reaction pathways: the case of the gemcitabine pharmacokinetics.

Background The representation of a biochemical system as a network is the precursor of any mathematical model of the processes driving the dynamics of that system. Pharmacokinetics uses mathematical models to describe the interactions between drug, and drug metabolites and targets and through the simulation of these models predicts drug levels and/or dynamic behaviors of drug entities in the body. Therefore, the development of computational techniques for inferring the interaction network of the drug entities and its kinetic parameters from observational data is raising great interest in the scientic community of pharmacologists. In fact, the network inference is a set of mathematical procedures deducing the structure of a model from the experimental data associated to the nodes of the network of interactions. In this paper, we deal with the inference of a pharmacokinetic network from the concentrations of the drug and its metabolites observed at discrete time points. Results The method of network inference presented in this paper is inspired by the theory of time-lagged correlation inference with regard to the deduction of the interaction network, and on a maximum likelihood approach with regard to the estimation of the kinetic parameters of the network. Both network inference and parameter estimation have been designed specically to identify systems of biotransformations, at the biochemical level, from noisy time-resolved experimental data. We use our inference method to deduce the metabolic pathway of the gemcitabine. The inputs to our inference algorithm are the experimental time series of the concentration of gemcitabine and its metabolites. The output is the set of reactions of the metabolic network of the gemcitabine. Conclusions Time-lagged correlation based inference pairs up to a probabilistic model of parameter inference from metabolites time series allows the identication of the microscopic pharmacokinetics and pharmacodynamics of a drug with a minimal a priori knowledge. In fact, the inference model presented in this paper is completely unsupervised. It takes as input the time series of the concetrations of the parent drug and its metabolites. The method, applied to the case study of the gemcitabine pharmacokinetics, shows good accuracy and sensitivit

Gradient attenuation as an emergent property of reset-based Retinex models

The Retinex image filtering algorithms have been inspired by experimental findings on the behavior of the Human Vision System. They are known to locally adjust image color and contrast by preserving edges and attenuating gradients. In a reference formulation of the algorithm by Land and McCann, edge preservation and gradient attenuation are granted by two ad-hoc mechanisms: called respectively reset (the distinctive feature of all the Retinex algorithms) and thresholding. A somehow unanticipated finding is that gradient attenuation is also observed with algorithm variants that do not include the latter mechanism, which was explicitly devised to implement gradient attenuation. In this work, we provide an analytic demonstration of the capability of Retinex models to attenuate gradients using only the "reset" mechanism, combined with the local character of the mutual pixel influences. We show that this capability is an emergent property of all the reset-based Retinex models

Cardiac output monitoring during abdominal aortic cross clamping: a comparison between Vigileo/FloTrac system and transoesophageal Doppler

Cardiac output (CO) monitoring is one of the key points in the hemodynamic evaluation of critically ill patients, and can be useful in various settings of high-risk surgery. There is a lack of evidence that the extensive use of invasive devices in the hemodynamic monitoring has a good impact in terms of outcome [1], and less invasive systems have been proposed. Our aim was to compare the CO estimated by Vigileo/FloTrac with the blood flow in thoracic aorta as measured by transoesophageal Doppler in patients undergoing open abdominal aortic aneurysm repair, during the aortic cross-clamping (AoX) phase. We have measured the Augmentation Index (AI), a parameter related to vascular stiffness, using the applanation tonometry method, in order to have a better understanding of the effect of AoX on blood pressure waves. Methods We enrolled 10 consecutive patients (10 men; age 66 \ub1 6 years) undergoing elective open AAA repair (ASA II to III) under general anesthesia. Radial arterial access was used for semi-invasive determination of blood pressures and CO (APCO) with the Vigileo. An esophageal Doppler was positioned after clinical stabilization. Applanation tonometry was measured just before and after the aortic clamping. Results We found a significant (P < 0.05) increase in CO reported by Vigileo/FloTrac system in the post-clamping phase, when compared with the pre-clamping and basal phases, while the blood flow in thoracic aorta resulted decreased, according with the theory of redistribution of fluids in the splanchnic venous vasculature [2]. There was an important contribution of the wave reflection to the aortic pulse pressure wave after the AoX, as expressed by a significant increase in the AI. Conclusions The Vigileo/FloTrac system appears to overestimate CO after AoX when compared with the measure of blood flow in thoracic aorta, and this result could be influenced by the pulse pressure wave reflection occurring after clamping. In high-risk surgical settings, other situations of rapid change of systemic resistance vessels could be similarly misread, thus suggesting the necessity of a more tailored Vigileo algorithm

Chronic Red Bull Consumption during Adolescence: Effect on Mesocortical and Mesolimbic Dopamine Transmission and Cardiovascular System in Adult Rats

Energy drinks are very popular nonalcoholic beverages among adolescents and young adults for their stimulant effects. Our study aimed to investigate the effect of repeated intraoral Red Bull (RB) infusion on dopamine transmission in the nucleus accumbens shell and core and in the medial prefrontal cortex and on cardiac contractility in adult rats exposed to chronic RB consumption. Rats were subjected to 4 weeks of RB voluntary consumption from adolescence to adulthood. Monitoring of in vivo dopamine was carried out by brain microdialysis. In vitro cardiac contractility was studied on biomechanical properties of isolated left-ventricular papillary muscle. The main finding of the study was that, in treated animals, RB increased shell dopamine via a nonadaptive mechanism, a pattern similar to that of drugs of abuse. No changes in isometric and isotonic mechanical parameters were associated with chronic RB consumption. However, a prolonged time to peak tension and half-time of relaxation and a slower peak rate of tension fall were observed in RB-treated rats. It is likely that RB treatment affects left-ventricular papillary muscle contraction. The neurochemical results here obtained can explain the addictive properties of RB, while the cardiovascular investigation findings suggest a hidden papillary contractility impairment

Expression of osterix Is Regulated by FGF and Wnt/β-Catenin Signalling during Osteoblast Differentiation

Osteoblast differentiation from mesenchymal cells is regulated by multiple signalling pathways. Here we have analysed the roles of Fibroblast Growth Factor (FGF) and canonical Wingless-type MMTV integration site (Wnt/β-Catenin) signalling pathways on zebrafish osteogenesis. We have used transgenic and chemical interference approaches to manipulate these pathways and have found that both pathways are required for osteoblast differentiation in vivo. Our analysis of bone markers suggests that these pathways act at the same stage of differentiation to initiate expression of the osteoblast master regulatory gene osterix (osx). We use two independent approaches that suggest that osx is a direct target of these pathways. Firstly, we manipulate signalling and show that osx gene expression responds with similar kinetics to that of known transcriptional targets of the FGF and Wnt pathways. Secondly, we have performed ChIP with transcription factors for both pathways and our data suggest that a genomic region in the first intron of osx mediates transcriptional activation. Based upon these data, we propose that FGF and Wnt/β-Catenin pathways act in part by directing transcription of osx to promote osteoblast differentiation at sites of bone formation

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

Rationale Most habitual smokers find it difficult to quit smoking because they are dependent upon the nicotine present in tobacco smoke. Tobacco dependence is commonly treated pharmacologically using nicotine replacement therapy or drugs, such as varenicline, that target the nicotinic receptor. Relapse rates, however, remain high and there remains a need to develop novel non-nicotinic pharmacotherapies for the dependence that are more effective than existing treatments. Objective The purpose of this paper is to review the evidence from preclinical and clinical studies that drugs that antagonise the metabotropic glutamate receptor 5 (mGluR5) in the brain are likely to be efficacious as treatments for tobacco dependence. Results Imaging studies reveal that chronic exposure to tobacco smoke reduces the density of mGluR5s in human brain. Preclinical results demonstrate that negative allosteric modulators (NAMs) at mGluR5 attenuate both nicotine self-administration and the reinstatement of responding evoked by exposure to conditioned cues paired with nicotine delivery. They also attenuate the effects of nicotine on brain dopamine pathways implicated in addiction. Conclusions Although mGluR5 NAMs attenuate most of the key facets of nicotine dependence they potentiate the symptoms of nicotine withdrawal. This may limit their value as smoking cessation aids. The NAMs that have been employed most widely in preclinical studies of nicotine dependence have too many \u201coff target\u201d effects to be used clinically. However newer mGluR5 NAMs have been developed for clinical use in other indications. Future studies will determine if these agents can also be used effectively and safely to treat tobacco dependence

Mir-125a-3p negatively regulates oligodendrocyte precursor cells maturation and is altered in human multiple sclerosis

In the central nervous system, oligodendrocytes provide support to axons thanks to the production of a myelin sheath. During their maturation oligodendroglial precursors (OPCs) follow a very precise differentiation program, finely orchestrated by transcription factors, epigenetic factors and microRNAs, a class of small non-coding RNAs involved in post-transcriptional regulation. Any alterations in this program can potentially contribute to dysregulated myelination, impaired remyelination and neurodegenerative conditions, as it happens in multiple sclerosis. Recently, we identified miR-125a-3p as a new actor of oligodendroglial maturation, that could also be involved in the pathological consequences of multiple sclerosis, showing that its over-expression impairs, whereas its silencing promotes, oligodendrocyte maturation (Lecca et al., Sci Rep, 2016). To shed light on the mechanism underlying this effect, we performed a microarray analysis on OPCs after miR-125a-3p over-expression. This analysis suggested that miR-125a-3p is indeed involved in the regulation of biological processes important for OPC maturation, such as cell-cell interaction and morphological differentiation. To evaluate whether miR-125a-3p modulation may influence the progression of remyelination in vivo, we overexpressed the miR-125a-3p by lentiviral approach in a focal lysolecithin-mediated demyelinating lesion in the subcortical white matter of adult mice. Interestingly, also in this case, we found that miRNA-overexpressing OPCs persisted in an immature (i.e. PDGR\u3b1+/NG2+) state. Moreover, we found that miR-125a-3p levels are altered in both brain active lesions and cerebrospinal fluid of multiple sclerosis patients, suggesting that it could be a potential biomarker of disease. The identification of a new miRNA modulating oligodendrocyte differentiation provides new findings about the complex regulation of myelination processes and we postulate that an antago-miRNA for miR-125a-3p may help promoting oligodendrocyte maturation in diseases characterized by impaired myelin repair. Sponsored by Fondazione Italiana Sclerosi Multipla 2013/R-1 project to MPA and by Fondazione Cariplo, grant n\ub0 2014-1207 to DL