Inflammatory Multiple-Sclerosis Plaques Generate Characteristic Metabolic Profiles in Cerebrospinal Fluid

International audienceBackgroundMultiple sclerosis (MS), an inflammatory disease of the central nervous system, manifests itself in numerous forms and stages. A number of brain metabolic alterations have been reported for MS patients vs. control subjects. However, metabolite profiles of cerebrospinal fluid (CSF) are not consistent among the published MS studies, most probably due to variations in the patient cohorts studied. We undertook the first investigation of highly homogeneous MS patient cohorts to determine characteristic effects of inflammatory MS plaques on the CSF metabolome, including only patients with clinically isolated syndrome (CIS) with or without inflammatory brain plaques, and controls.Methodology/Principal FindingsCSF obtained by lumbar puncture was analyzed by proton magnetic resonance spectroscopy. 27 metabolites were quantified. Differences between groups of control subjects (n = 10), CIS patients with (n = 21) and without (n = 12) inflammatory plaques were evaluated by univariate statistics and principal component analysis (PCA). Seven metabolites showed statistically significant inter-group differences (p<0.05). Interestingly, a significant increase in β-hydroxyisobutyrate (BHIB) was detected in CIS with vs. without active plaques, but not when comparing either CIS group with control subjects. Moreover, a significant correlation was found, for the first time, between CSF lactate concentration and the number of inflammatory MS brain plaques. In contrast, fructose concentrations were equally enhanced in CIS with or without active plaques. PCA based on all 27 metabolites yielded group-specific clusters.Conclusions/SignificanceCSF metabolic profiles suggest a close link between MS plaque activity in CIS patients on the one hand and organic-acid metabolism on the other. Our detection of increased BHIB levels points to a hitherto unsuspected role for this compound in MS with active plaques, and serves as a basis for further investigation. The metabolic effects described in our study are crucial elements in the explanation of biochemical mechanisms involved in specific MS manifestations

БЕРЕЖЛИВОЕ УПРАВЛЕНИЕ ПРОИЗВОДСТВОМ: УЧЕТ И КОНТРОЛЬ ЗАТРАТ В ПЕРАРБАТЫВАЮЩИХ ПРЕДПРИЯТИЯХ СИСТЕМЫ ПОТРЕБИТЕЛЬСКОЙ КООПЕРАЦИИ

Lean production and management in the system of consumer cooperation remains one of the most difficult problems both in general in all areas of production and in milk processing. A modern solution to this problem, increasing the efficiency of production, improving its quality and reducing cost is the basis of principles and tools that are reflected in the lean manufacturing system. Lean management is possible on the basis of optimal cost accounting and management of dairy production, by reducing losses on waiting, overproduction, transportation, unnecessary processing steps, unnecessary movements, production with broken technology, defective packaging, unnecessary stocks - by regulating business processes and mobilizing internal reserves in the activities of processing enterprises of the consumer cooperation system. The subject of the study is managerial activity in the lean production and processing of milk in enterprises of the consumer cooperation system. The aim of the study is the introduction of advanced and necessary methods of accounting and management of milk production in the enterprises of the consumer cooperation system. In accordance with this goal, the main task was determined: to develop recommendations for improving the accounting and management methods to reduce all kinds of costs and increase the productivity of dairy production. Performance management is an important financial and economic indicator of production in the system of consumer cooperation. This paper analyzes various aspects of lean manufacturing, accounting, control and management, taking into account the technological features and business processes of the consumer cooperation system. It is concluded that for the efficiency of the accounting process in the lean management system of a milk processing enterprise, it is necessary to build a system of accounting and control support, which will allow for detailed accounting of production costs for all objects of accounting and control.Бережливое производство и управление в системе потребительской кооперации, остается одной из самых сложных проблем, как в целом по всем направлениям производства, так и по переработке молока. Современное решение данной проблемы, повышение эффективности производства продукции, улучшение ее качества и снижения себестоимости лежит в основе принципов и инструментов, которые нашли отражение в системе бережливого производства. Бережливое управление становится возможным на основе оптимального учета затрат и управления производством молочной продукции, путем снижения потерь на ожидание, перепроизводство, транспортировки, лишних стадий обработки, ненужных перемещений, выпуска с нарушенной технологией, дефектной упаковки, лишних запасов -&nbsp; путем регулирования хозяйственных процессов и мобилизации внутренних резервов в деятельности перерабатывающих предприятий системы потребительской кооперации. Предметом исследования является управленческая деятельность при бережливом производстве и переработке молока в предприятиях системы потребкооперации. &nbsp;Целью исследования является внедрение прогрессивных и необходимых методов учета и управления деятельностью по производству молока в предприятиях системе потребительской кооперации. В соответствии с указанной целью была определена основная задача: выработать рекомендации по совершенствованию учетно-управленческой методики на уменьшение всевозможных издержек и увеличение производительности производства молочной продукции. Эффективность управления деятельности является важным финансово-экономическим показателем производства продукции в системе потребительской кооперации. В настоящей работе проанализированы различные аспекты бережливого производства, учета, контроля и управления с учетом технологических особенностей и бизнес процессов системы потребительской кооперации. Сделан вывод о том, что для эффективности учетного процесса в системе бережливого управления молокоперерабатывающим предприятием, необходимо построение системы учетно-контрольного обеспечения, которая позволит вести детальный учет затрат на производство по всем объектам учета и контроля

Association of Multiple Sclerosis Susceptibility Variants and Early Attack Location in the CNS

Objective: The anatomic location of subsequent relapses in early multiple sclerosis (MS) appears to be predicted by the first attack location. We sought to determine if genetic polymorphisms associated with MS susceptibility are associated with attack location. Methods: 17 genome-wide association study-identified MS susceptibility polymorphisms were genotyped in 503 white, non-Hispanic patients seen within a year of MS onset. Their association with the CNS location of the first two MS attacks was assessed in multivariate repeated measures analyses (generalized estimating equations with robust standard errors). Results: The IL12A polymorphism was independently associated with increased odds of attacks involving the spinal cord (OR = 1.52, 95% CI 1.11, 2.07, p = 0.009), as was the IRF8 polymorphism (OR = 2.40, 95% CI [1.04, 5.50], p = 0.040). The IL7R polymorphism was associated with reduced odds of attacks involving the brainstem/cerebellum (OR = 0.46, 95% CI 0.22, 0.97, p = 0.041), as were the TNFRSF1A and IL12A polymorphisms. The CD6 polymorphism conferred reduced odds of optic neuritis as an attack location (OR = 0.69, 95% CI [0.49, 0.97], p = 0.034). Several other genes showed trends for association with attack location. Conclusions: Some of the MS susceptibility genes may be associated with MS attack location. The IL12A polymorphism is of particular interest given that interferon beta therapy appears to influence IL12 levels. These findings may lead to improved understanding of MS pathogenesis and treatment

Prevalence of Grey Matter Pathology in Early Multiple Sclerosis Assessed by Magnetization Transfer Ratio Imaging

The aim of the study was to assess the prevalence, the distribution and the impact on disability of grey matter (GM) pathology in early multiple sclerosis. Eighty-eight patients with a clinically isolated syndrome with a high risk developing multiple sclerosis were included in the study. Forty-four healthy controls constituted the normative population. An optimized statistical mapping analysis was performed to compare each subject's GM Magnetization Transfer Ratio (MTR) imaging maps with those of the whole group of controls. The statistical threshold of significant GM MTR decrease was determined as the maximum p value (p<0.05 FDR) for which no significant cluster survived when comparing each control to the whole control population. Using this threshold, 51% of patients showed GM abnormalities compared to controls. Locally, 37% of patients presented abnormalities inside the limbic cortex, 34% in the temporal cortex, 32% in the deep grey matter, 30% in the cerebellum, 30% in the frontal cortex, 26% in the occipital cortex and 19% in the parietal cortex. Stepwise regression analysis evidenced significant association (p = 0.002) between EDSS and both GM pathology (p = 0.028) and T2 white matter lesions load (p = 0.019). In the present study, we evidenced that individual analysis of GM MTR map allowed demonstrating that GM pathology is highly heterogeneous across patients at the early stage of MS and partly underlies irreversible disability

Atrophy mainly affects the limbic system and the deep grey matter at the first stage of multiple sclerosis

International audienceThe existence of grey matter (GM) atrophy right after the first clinical event suggestive of multiple sclerosis (MS) remains controversial. The aim of this study was therefore to establish whether regional GM atrophy is already present in the earliest stage of MS assessing regional GM atrophy in a large group of patients. Sixty two patients with a clinically isolated syndrome (CIS) were examined on a 1.5T MR imager within six months after their first clinical events. A group of thirty seven matched healthy control subjects were also included in the study. An optimized Voxel Based Morphometric (VBM) method customised for MS was applied on volumetric T1-weighted images. The functional status of patients was assessed using the Expanded Disability Status Scale (EDSS) and the Brief Repeatable Battery. VBM analysis (p<0.005, FWE corrected) on patients versus control subjects showed the presence of significant focal GM atrophy in patients involving the bilateral insula, the bilateral orbitofrontal cortices, the bilateral internal and inferior temporal regions, the posterior cingulate cortex, the bilateral thalami, the bilateral caudate nuclei, the bilateral lenticular nuclei, and the bilateral cerebellum. EDSS was slightly correlated (rho=-0.37 p=0.0027) with the atrophy of the right cerebellum. No correlations have been evidenced between the cognitive status of patients and the regional GM atrophy. The present study performed on a large group of CIS patients demonstrated that regional GM atrophy is present right after the first clinical event of multiple sclerosis and mainly affects the deep GM and the limbic system

Cerebral plasticity and multiple sclerosis: data from functional imaging

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Functional magnetic resonance imaging and cognition at the very early stage of MS

Dysfunction of high controlled information processing is present in patients with multiple sclerosis (MS) right at the beginning of the disease. One hypothesis is that disruption of communication inside large-scale cortical networks, occurring as a consequence of white matter damage, may constitute the anatomical substrate of cognitive impairment at the very early stage of MS. Disturbance of interregional synchronization might be the main pathogenic factor in controlled information processing deficiency in early MS. Preliminary functional MRI studies (fMRI) have provided important clues to corroborate the connectivity hypotheses. First, brain connectivity assessed by fMRI has brought new data about the influence of diffuse white matter damage on connectivity efficiency inside large-scale networks. These studies have suggested that connectivity disturbances occur inside the working memory network in patients at the very early stage of MS and appear related to the extent of structural white matter damage. Also, fMRI studies have suggested that patients may partially compensate for connectivity impairment by a greater cognitive control. Such a compensatory mechanism could limit the determinant functional impact of diffuse white matter damage on high controlled information processing